US20190009019A1

Movatterモバイル変換

Info

Publication number: US20190009019A1
Application number: US16/027,804
Authority: US
Inventors: Eran Shor; Tsabar Mor; Tamir Ben David; Nir Lilach; Rami Grossfeld; Shai Alfandari; Ram Nadler; Dmitry Golom; Daniel Shaki; Yoav Tikochinsky; Serdar Ozsumer
Original assignee: Neuroderm Ltd
Current assignee: Neuroderm Ltd
Priority date: 2017-07-07
Filing date: 2018-07-05
Publication date: 2019-01-10
Also published as: JP7141474B2; PT3714922T; US20200093984A1; IL289611B2; AU2018295533A1; CN111093735A; JP2020526306A; KR20200080336A; RS63324B1; BR112020000066B1; RU2020105401A3; US20190209773A1; CN113274578A; US10463787B2; KR102510743B1; EP4389173A2; IL271672B; CN111467608B; RU2021139906A; BR122020018051A2

Abstract

An improved device delivers a fluid medicament to the subcutaneous tissue of a user. The device is better suited for patients with Parkinson's Disease and other central nervous system disorders, than conventional infusion devices. The device can include a reusable part including a drive component (e.g., motor) and control electronics and a disposable part including a medicament reservoir. Medicament can be evacuated from the medicament reservoir by a plunger assembly that includes a plunger attached to a lead screw that is rotated by a nut, all within the disposable part. The device can be fluidically coupled with the tissue via a flexible cannula. Various embodiments relate to an improved cannula insertion mechanism that delivers the cannula under a force applied by a spring. Various embodiments relate to improved filling of the device, for example, using a vial adapter and an automated filling station.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority to U.S. Provisional Patent Application No. 62/576,362 entitled “Device for Subcutaneous Delivery of Fluid Medicament,” filed on Oct. 24, 2017 and to U.S. Provisional Patent Application No. 62/529,784 entitled “Delivery Device for a Fluid Medicament,” filed on Jul. 7, 2017, the contents of both of which are incorporated herein by reference in their entireties.

TECHNICAL FIELD

The invention relates generally to systems and methods for medicament delivery and, more particularly, to a fluid medicament delivery device, and methods of using the same.

BACKGROUND

Delivery of medicaments, nutrients, or other liquid substances into the subcutaneous tissue of a patient is known to be an effective treatment technique for various medical conditions. Subcutaneous liquid administration may result in a more effective delivery of a substance into the circulatory system than other administration techniques (e.g., digestive tract, respiratory tract, etc.).

Subcutaneous delivery is often performed with an infusion pump. An infusion pump is typically a portable device carried by the patient that contains a medicament reservoir and drive components for delivering the medicament into the patient. Infusion pumps can deliver medicament in a more precise and controlled manner than can be accomplished with manual delivery by a patient or medical personnel. Infusion pumps are generally one of two types. The first type includes a standalone pump unit worn by a patient at a location remote from the delivery site (e.g., on a belt). The standalone pump unit pumps medicament from the reservoir through tubing to an infusion set attached to the patient's skin and accessing the subcutaneous tissue (e.g., via a flexible cannula). The second type is generally referred to as a “patch pump” and incorporates the medicament reservoir, drive components, and cannula all in a single unit adhered to the patient's skin. In some situations, infusion pumps deliver a continuous flow of medicament into a patient (sometimes called a basal dose). Infusion pumps can also deliver intermittent doses, in some cases controlled by the patient (sometimes called a bolus dose).

Given that subcutaneous medicament administration is typically performed with liquid substances, most infusion pump development has been for the treatment of medical conditions for which a liquid formulation medicament is therapeutically viable. The most prominent example is the use of infusion pumps for the subcutaneous delivery of insulin to patients with diabetes.

The most common medicament for the treatment of Parkinson's Disease is the drug levodopa, which is often administered in combination with the drug carbidopa. To date, therapeutic formulations of levodopa/carbidopa have only been available in solid or powder form and are typically administered with an oral pill or an inhaler product.

Recently, the Applicant has developed the first ever liquid formulation of levodopa/carbidopa having a therapeutic concentration appropriate for delivery to the subcutaneous tissue (described in greater detail in U.S. Patent Application Publication Nos. 2013/0253056 and 2014/0051755, which are incorporated by reference herein in their entireties). This discovery makes it practical, for the first time, to develop an infusion pump device for use by patients with Parkinson's Disease and other CNS disorders.

Individuals with Parkinson's Disease and other CNS disorders exhibit different symptoms than individuals with diabetes. In addition, the drug dosage volumes are different for different conditions. Thus, currently available infusion pumps designed for the treatment of diabetes or other conditions are often inappropriate and ineffective for the treatment of Parkinson's Disease. Accordingly, a need exists for a new drug delivery device appropriate for use by individuals with Parkinson's Disease or other CNS disorders.

SUMMARY

Accordingly, the present disclosure describes an improved medicament delivery devices, appropriate for delivering liquid medicaments to patients with Parkinson's Disease and other CNS disorders, and methods of using the same. Although this disclosure will sometimes refer to the delivery devices as delivering liquid formulations of levodopa/carbidopa to patients with Parkinson's Disease, it will be understood that the devices can be used to deliver other fluids, as well (liquid and gas). In general, the devices can be used for the delivery of any fluid medicament for the treatment of any medical condition, as well as for the delivery of non-drug fluids, e.g., nutrients, vitamins, imaging agents, etc. In addition, although this disclosure will often describe the delivery devices as performing subcutaneous injections, in some embodiments the devices can perform other types of injections, e.g., intravenous, intra-arterial, intra-articular, intramuscular, etc.

More than 10 million people are living with Parkinson's Disease worldwide. Common symptoms of Parkinson's Disease include tremor, slowness of movement, muscle stiffness, balance problems, dizziness, and problems sleeping (fatigue). In some embodiments, the drug delivery devices described herein are designed to be easier to use than conventional devices for patients exhibiting some or all of these symptoms. As one example, many conventional devices require the patient to navigate a syringe needle into a relatively small septum opening and manually force medicament out of the syringe in order to fill the pump. In some embodiments, the device described herein uses a filling station and a vial adapter operable to receive a vial for filling the device, which requires less strength and/or dexterity than conventional approaches.

As another example, a conventional technique for inserting a cannula into the tissue (e.g., subcutaneous tissue) requires the patient to manually apply the insertion force. In some embodiments, the delivery device described herein uses at least one cannula insertion mechanism that drives one or more cannulas into the tissue with force exerted thereby. Such cannula insertion mechanism may include, for example, a mechanical displacement mechanism (e.g., a mechanical energy storage device such as, for example, a torsion spring), an electro-mechanical mechanism, a pneumatic mechanism, and/or an electromagnetic mechanism.

The cannula insertion mechanism may be adapted or configured to require significantly less force to be applied by the patient in order to ensure puncturing of the skin for allowing, for example, subcutaneous delivery of the drug. The amount of force to be required by the patient may, for example, range from about 3 Newton to about 50 Newton. While the discussion herein may refer to subcutaneous delivery of a fluid medicament, it is noted that this should by no means be construed in a limiting manner. In some cases, the fluid medicament may for example be delivered to other layers of the user's skin tissue and/or directly into the user's blood vessels.

In some examples, the device may comprise a plurality of cannulas (e.g., two cannulas, three cannulas or more) for delivering fluid medicament into the tissue. Optionally, the plurality of cannulas, when in an extended position, can engage the tissue simultaneously. The tip of the cannulas may be spaced at a given minimum distance apart from each other to reduce the likelihood of generating or alleviating skin-related conditions such as nodules, abscesses, hematomas and/or the like.

In some embodiments, the device may be operable to allow selectively delivering, via the plurality of cannulas, fluid medicament to the patient. For example, the cannulas may be employed in succession for delivering, via a selected cannula, a desired quantity of the fluid medicament within a certain time period. In cases where the device comprises only two cannulas, they may be used alternatingly.

In another example, the plurality of cannulas may be grouped into two or more sets of selectable cannulas, allowing employment of the two or more cannula sets in succession or in parallel for delivering a desired quantity of the fluid medicament to the patient within a given time period. If the plurality of cannulas comprises only two sets, then these two sets may be employed alternatingly. In case the plurality of cannulas are operably grouped into three or more sets of cannulas, the sets may be employed successively or in parallel, each set for a given time period. The time period for employing one set of cannulas may be the same as or differ from the employment time period of another set of cannulas.

In some embodiments, the device may have bolus and basal fluid medicament delivery capabilities. The device may be operable to allow for manual, semi-automatic and fully-automated control of bolus and basal delivery of the fluid medicament such as, for example, carbidopa and/or levodopa and/or levodopa prodrugs (e.g., levodopa-amide, levodopa phosphate, carbidopa phosphate) and/or apomorphine.

As yet another example, in some embodiments the delivery device includes a reusable part including a motor and control electronics and a disposable part including a medicament reservoir. While the general concept of having a reusable part and a disposable part is known, in conventional devices the attachment between the two parts can involve complicated mechanical schemes that can require significant strength and/or dexterity to engage and disengage. In some embodiments, the reusable part and disposable part of the device described herein are attached with attachment schemes that are comparatively simple to engage and disengage, for example, in a single-step procedure by employing, for example, magnetic and/or snap connections. In addition, in some embodiments, the disposable part includes a linear actuator such as, for example, a rotation-to-linear displacement mechanism. The linear actuator may comprise, for example, a nut for rotating a lead screw to drive a plunger through the medicament reservoir. In some instances, the nut can engage directly with a structure in the disposable part (e.g., a gear) to enable the attachment of the two parts. These example features and other features for improved medicament delivery devices are described in detail below.

It is noted that merely to simplify the discussion that follows, embodiments and examples may refer to driving “a plunger”. However, this should by no means be construed in a limiting manner. Accordingly, the device may in some embodiments be operable to drive a seal member through the medicament reservoir. In some examples, a seal member may be operably coupled with a plunger. Optionally, a seal member may be integrally formed with a plunger. Optionally, a distal end of a plunger may terminate in a seal member.

In some embodiments, the device is operable to selectively drive a plunger in a first direction to force fluid out of the reservoir for, e.g., subcutaneous delivery of the fluid medicament, and in an opposite direction to generate a suction force that draws fluid medicament back into the reservoir.

In some embodiments, a reservoir that is operable to contain fluid may be a selectively compressible (e.g., squeezable) and expandable reservoir. Compressing such reservoir may force fluid out of the reservoir for delivery to the user, and expanding such reservoir may generate a suction force drawing fluid back into the reservoir. Accordingly, the device may be adapted or configured to be “plunger-less.” In other words, the device may free of a translating plunger and/or seal member.

In some embodiments, control of the device to selectively force fluid out of a reservoir or to generate a suction force to draw fluid back into the reservoir may, for example, depend on measured physiological or other parameter values. For example, the device may force fluid out of the reservoir for delivery to the user as long as one or more physiological parameter values meet a certain “delivery criterion”. On the other hand, if the one or more physiological parameter values later meet a certain “suction criterion”, the device may stop forcing fluid out of the reservoir and generate a suction force instead.

In one aspect, the invention relates to a device for delivering a fluid medicament to subcutaneous tissue of a user. The device can include (i) a reusable part that includes a drive component, and a control unit for controlling the drive component; and (ii) a disposable part attachable to the reusable part, the disposable part including a reservoir for containing the fluid medicament, a plunger for driving the fluid medicament out of the reservoir, a lead screw attached to the plunger, and a nut operable to displace the lead screw, such that when the reusable part and the disposable part are attached, the nut operably engages with the drive component, e.g., via a drive train that is coupled with the drive component.

In some embodiments of the above aspect, the reservoir can contain a fluid medicament including a liquid formulation of levodopa and/or carbidopa. The reusable part can further include a battery for powering the drive component (e.g., a motor assembly, which can include a motor and a planetary gear, a chain transmission, a belt transmission, a pneumatic transmission, a magnet-based transmission, and/or the like). In some cases, the drive train includes at least one gear (e.g., a drive gear, an idler gear, and a load gear in series). The nut can have a profile operable to engage with a mating profile of the load gear.

In some embodiments, the disposable part can further include an exterior surface operable to be adhered to a skin surface of the user. Micro dermal anchors can be attached to the exterior surface for adhering the device to the skin surface. In some cases, the exterior surface is adhered to the skin surface by a sub-pressure generated therebetween. The device can also include an adhesive layer adhered to the exterior surface, where a skin surface side of the adhesive layer includes continuous adhesive and an opposing device side of the adhesive layer includes discontinuous adhesive.

In some embodiments, the disposable part further includes a cannula fluidically coupled with the reservoir, such that, when the cannula operably engages with the patient's tissue, the cannula delivers the fluid medicament to the subcutaneous tissue of the user. The reusable part and the disposable part can be attached using a magnetic force and/or a snap connection. In some instances, when the reusable part and the disposable part are attached, the drive component and the reservoir are co-planar. In some cases, when the reusable part and the disposable part are attached, a longitudinal axis of the drive component is substantially parallel with a longitudinal axis of the reservoir. In some cases, when the reusable part and the disposable part are attached, the drive component and the reservoir overlap in a longitudinal direction by at least 50 percent.

In some embodiments, the disposable part can further include a second reservoir for containing additional fluid medicament, a second plunger for driving the additional fluid medicament out of the second reservoir, a second lead screw attached to the second plunger, and a second nut operable to displace the second lead screw, such that when the reusable part and the disposable part are attached, the second nut is coupled with the drive component. In some instances, the drive component simultaneously drives both of the first and second plungers. In other instances, the drive component separately drives each of the first and second plungers. The plunger can include a fluid-contacting surface made from an elastic material. In certain configurations, the reusable part forms a void for receiving the lead screw when the lead screw is retracted from the reservoir.

In some embodiments, the reusable part can further include a computing unit that monitors operation of the device. The reusable part can also include a control button to allow a user to select a mode of operation of the device (e.g., a priming mode, a delivery mode, and/or a pause mode). In some embodiments, the device can include a fluid sensor for sensing fluid medicament (e.g., for the detection of fluid and/or for measuring quantity and/or volume thereof) in the reservoir and/or a contact sensor for sensing contact between an exterior surface of the disposable part and a skin surface of the user. In some cases, the fluid sensor and/or contact sensor can for example include a capacitance sensor. The contact sensor can measure an electrical resistivity between at least two locations on the device. In some configurations, the fluid sensor is disposed along the reservoir and substantially parallel to the skin surface of the user. The fluid sensor and the contact sensor can be the same component.

In some embodiments, the device further includes a connection sensor (e.g., a hall effect sensor) for determining a connection between the reusable part and the disposable part. In some instances, the device further includes a physiological sensor for sensing at least one physiological characteristic of the user. Examples of the physiological sensor include (i) a temperature sensor for measuring a skin temperature of the user, (ii) a conductivity sensor for measuring a sweat level of the user, (iii) a movement sensor for measuring body motion of the user, (iv) a neural activity sensor, (v) an oxygen saturation level sensor, (vi) a blood analyte sensor (e.g., haemoglobin, cholesterol, glucose, etc.); (vii) a sound sensor for measuring bowel activity, (viii) an ECG sensor for detecting a heart rate of the user, and/or (ix) an EMG sensor for detecting a muscle spasm of the user. In some instances, the device further includes a functionality sensor for sensing at least one functional parameter of the device. Examples of the functionality sensor include a flow rate sensor, a pressure sensor, a DC current sensor, and/or a temperature sensor. In some embodiments, the fluid medicament can include levodopa.

In another aspect, the invention relates to a method for delivering a fluid medicament to subcutaneous tissue of a user. The method can include the steps of (a) providing a device including (i) a reusable part having a drive component, and a control unit for controlling the drive component; and (ii) a disposable part attachable to the reusable part, the disposable part including a reservoir for containing the fluid medicament, a plunger for driving the fluid medicament out of the reservoir, a lead screw attached to the plunger, and a nut operable to displace the lead screw, such that when the reusable part and the disposable part are attached, the nut is operably coupled with the drive component, e.g., via a drive train; (b) fluidically coupling the device to the subcutaneous tissue of the user; and (c) controlling the device such that the fluid medicament is delivered from the device to the subcutaneous tissue of the user.

In some embodiments of this aspect, the reservoir contains the fluid medicament that includes a liquid formulation of levodopa and/or carbidopa. The reusable part can include a battery and the method can further include powering the reusable part with the battery. The drive component can include a motor assembly (e.g., a motor and a planetary gear). The drive train can include at least one gear (e.g., a drive gear, an idler gear, and a load gear in series). In some instances, the nut has a profile operable to engage with a mating profile of the load gear.

In some embodiments, the fluidically coupling step includes adhering an exterior surface of the disposable part to a skin surface of the user. The adhering step can further include adhering micro dermal anchors attached to the exterior surface to the skin surface. The adhering step can also include generating a sub-pressure between the exterior surface and the skin surface. In some cases, the adhering step can include adhering an adhesive layer adhered to the exterior surface to the skin surface, where the skin surface side of the adhesive layer includes continuous adhesive and an opposing side of the adhesive layer include discontinuous adhesive.

In some embodiments, the fluidically coupling step includes inserting a cannula fluidically coupled with the reservoir into the subcutaneous tissue. In some cases, the method can include, before fluidically coupling the device to the subcutaneous tissue, attaching the reusable part and disposable part using, for example, a magnetic connection and/or a snap connection. The attaching step can include attaching the reusable part and disposable part such that the drive component and the reservoir are co-planar. In some instances, the reusable part and disposable part can be attached such that a longitudinal axis of the drive component is substantially parallel with a longitudinal axis of the reservoir and/or such that the drive component and the reservoir overlap in a longitudinal direction by at least 50 percent.

In some embodiments, the disposable part can further include a second reservoir for containing additional fluid medicament, a second plunger for driving additional fluid medicament out of the second reservoir, a second lead screw attached to the second plunger, and a second nut operable to displace the second lead screw, such that when the reusable part and the disposable part are attached, the second nut is coupled with the drive component. In some instances, the step of controlling the device such that the fluid medicament is delivered includes simultaneously driving both of the first and second plungers. In other instances, the step of controlling the device such that the fluid medicament is delivered includes separately driving both of the first and second plungers. In some cases, the plunger includes a fluid-contacting surface made from an elastic material. In some cases, the reusable part forms a void for receiving the lead screw when the lead screw is retracted from the reservoir.

In some embodiments, the reusable part further includes a computing unit operable to monitor operation of the device. The reusable part can include a control button to allow the user to select a mode of operation of the device (e.g., a priming mode, a delivery mode, and a pause mode). In some instances, the method can further include sensing fluid medicament in the reservoir using a fluid sensor and sensing contact between an exterior surface of the disposable part and a skin surface of the user using a contact sensor. The fluid sensor and the contact sensor can include a capacitance sensor. The method can include measuring an electrical resistivity between at least two locations on the device using the contact sensor. The fluid sensor can be disposed along the reservoir and substantially parallel to the skin surface of the user. In some cases, the fluid sensor and the contact sensor are the same component.

In some embodiments, the method can further include sensing a connection between the reusable part and the disposable part using a connection sensor (e.g., a hall effect sensor). In some instances, the method can further include sensing at least one physiological characteristic of the user using a physiological sensor. Examples of the physiological sensor include (i) a temperature sensor for measuring a skin temperature of the user, (ii) a conductivity sensor for measuring a sweat level of the user, (iii) a movement sensor for measuring body motion of the user, (iv) a neural activity sensor, (v) an oxygen saturation level sensor, (vi) a blood analyte sensor (e.g., hemoglobin, cholesterol, glucose, etc.); (vii) a sound sensor for measuring bowel activity, (viii) an ECG sensor for detecting a heart rate of the user, and/or (ix) an EMG sensor for detecting a muscle spasm of the user. In some instances, the method can further include sensing at least one functional parameter of the device using a functionality sensor. Examples of the functionality sensor include a flow rate sensor, a pressure sensor, a DC current sensor, and/or a temperature sensor. In some embodiments, the fluid medicament can include levodopa.

In another aspect, the invention relates to another device for delivering a fluid medicament to subcutaneous tissue of a user. The device can include a pump module having at least one reservoir for containing the fluid medicament; and a cannula insertion mechanism attachable to the pump module, the cannula insertion mechanism including an insertion needle, a cannula assembly including a flexible cannula connected to a rigid fluidic link and detachably coupled with the insertion needle such that, when the flexible cannula is located in the subcutaneous tissue, the cannula assembly fluidically couples the reservoir to the subcutaneous tissue via the rigid fluidic link.

In some embodiments, the device further includes a skin property control unit. In some cases, the skin property control unit can apply ultrasonic vibration to an injection site. In certain instances, the cannula can form a delivery aperture in a side wall of the cannula. In some embodiments, the cannula can form a plurality of delivery apertures, each delivery aperture being formed at a different height along a side wall of the cannula. The cannula can be formed from stainless steel, silicon, carbon fiber, PTFE, and/or combinations thereof. The cannula can include a surface coating (e.g., an oily substrate, a pain killer medicament, etc.) that reduces a trauma associated with insertion of the cannula. In some embodiments, the device further includes a penetration depth control unit that controls a depth that the cannula is inserted into the subcutaneous tissue. In some embodiments, the device further includes a tissue detection unit that detects a type of subcutaneous tissue proximate the cannula (e.g., dermis, muscle, fat, blood vessel, air, water, and/or combinations thereof, etc.). In some embodiments, the fluid medicament can include levodopa.

In another aspect, the invention relates to another method for delivering a fluid medicament to subcutaneous tissue of a user. The method can include the steps of (a) providing a pump module including at least one reservoir for containing the fluid medicament; (b) attaching a cannula insertion mechanism to the pump module, the cannula insertion mechanism including an insertion needle, a cannula assembly including a flexible cannula connected to a rigid fluidic link and detachably coupled with the insertion needle; and (c) fluidically coupling the pump module to the subcutaneous tissue of the user such that, the cannula assembly fluidically couples the reservoir with the subcutaneous tissue via the rigid fluidic link.

In some embodiments, the method can further include controlling a temperature of the fluid medicament using a control unit (e.g., a heating element and/or a cooling element). For example, the temperature of the fluid medicament can be controlled to be within a temperature range of about 8 to about 15 degrees Celsius, from about 22 to about 37 degrees Celsius, and/or from about 32 to about 42 degrees Celsius (among many other examples). The temperature controlling step can include heating and/or cooling the fluid medicament contained within the reservoir. The temperature controlling step can also include heating and/or cooling the fluid medicament, when the fluid medicament is within the cannula. The temperature controlling step can also include thermally isolating the fluid medicament from at least one of a body temperature of the user and an ambient temperature. In some cases, the method includes sensing the temperature of the fluid medicament (e.g., at a tip of the cannula) using the temperature control unit. In some cases, the controlling the temperature step includes using thermoelectric techniques.

In some embodiments, the method further includes controlling a skin property of the user using a skin property control unit. The controlling the skin property step can include applying ultrasonic vibration to an injection site. In some instances, the cannula can form a delivery aperture in a side wall of the cannula. In some cases, the cannula forms a plurality of delivery apertures, each delivery aperture being formed at a different height along a side wall of the cannula. The cannula can be formed from stainless steel, silicon, carbon fiber, PTFE, and/or combinations thereof. The cannula can include a surface coating (e.g., an oily substrate, a pain killer medicament, etc.) that reduces a trauma associated with insertion of the cannula. In some instances, the method can further include controlling a depth that the cannula is inserted into the subcutaneous tissue using a penetration depth control unit. In some instances, the method can further include detecting a type of subcutaneous tissue proximate the cannula using a tissue detection unit (e.g., dermis, muscle, fat, blood vessel, air, water, and/or combinations thereof, etc.). In some embodiments, the fluid medicament can include levodopa.

In another aspect, the invention relates to a control unit for a device delivering a fluid medicament to a subcutaneous tissue of a user. The device can include a fluid medicament drive component, at least one patient sensor for detecting a medical condition status of the user, and a clock. The control unit can include a drive component module operable to control the drive component and deliver the fluid medicament based on signals received from both the patient sensor(s) and/or the clock.

In some embodiments of this aspect, the drive component includes a motor. The signals received from the patient sensor can include a sleep condition of the user, a food consumption measure for the user, and/or an exercise measure for the user. In some cases, the sleep condition of the user includes a sleep stage of the user, and the drive component module is operable to control the drive component and deliver the fluid medicament based on the sleep stage. The patient sensor for detecting the exercise measure for the user can include an ECG sensor and/or an accelerometer. The patient sensor for detecting the food consumption measure for the user can include a sound sensor. The signals received from the clock can include the time of day. In some instances, the drive component module is further operable to control a volume of fluid medicament delivered to an injection site during a particular time period. In some instances, the drive component module is further operable to deliver fluid medicament intermittently including at least one on period and at least one off period. The device can further include a pressure sensor operable to sense a pressure of the fluid medicament, and the drive component module can be further operable to control the drive component based on a signal received from the pressure sensor. In some embodiments, the fluid medicament can include levodopa.

In another aspect, the invention relates to a method of controlling a device delivering a fluid medicament to a subcutaneous tissue of a user. The device can include a fluid medicament drive component, at least one patient sensor for detecting a medical condition status of the user, and a clock. The method can include the steps of receiving a signal from the patient sensor(s), receiving a signal from the clock, and controlling the drive component to deliver the fluid medicament based the signals received from both the patient sensor(s) and the clock.

In some embodiments of this aspect, the drive component can include a motor. The signal received from the patient sensor can include a sleep condition of the user, a food consumption measure for the user, an exercise measure for the user, and/or a weight of the user. In some cases, the sleep condition of the user includes a sleep stage of the user, and the drive component module is operable to control the drive component and deliver the fluid medicament based on the sleep stage. The patient sensor for detecting the exercise measure for the user can include an ECG sensor and/or an accelerometer. The patient sensor for detecting the food consumption measure for the user can include a sound sensor. The signal received from the clock can include a time of day. In some instances, the method further includes controlling a volume of fluid medicament delivered to an injection site during a particular time period. The method can also include controlling the drive component to deliver fluid medicament intermittently including at least one on period and at least one off period. The method can also include sensing a pressure of the fluid medicament using a pressure sensor, where the controlling step can further include controlling the drive component based on a signal received from the pressure sensor. In some embodiments, the fluid medicament can include levodopa.

In another aspect, the invention relates to a charging/filling station for a device operable to deliver a fluid medicament to a subcutaneous tissue of a user. The charging/filling station can include a cradle for receiving the device, a charging unit operable to charge a rechargeable battery of the device, a display, and a communication module operable to instruct at least one of a control unit and a drive component of the device to initiate a filling operation of the device.

In some embodiments of this aspect, the device includes a medicament reservoir and the cradle is operable to hold the device within the reservoir, e.g., in a substantially vertical orientation. Optionally, the cradle may comprise a connection or proximity sensor configured to detect the operable positioning of the device in the cradle. Responsive to detecting the presence of the device in the cradle, the filling station may provide an output prompting the user to authorize starting a battery charging sequence. Alternatively, responsive to detecting the presence of the device in the cradle, the filling station may automatically initiate a battery charging sequence.

In some embodiments, vial adapters(s) (described below) may comprise a connection or proximity sensor which is configured to detect operable coupling of a vial to a vial adapter. Responsive to detecting operable coupling of a vial to the vial holder, and provided that the device is operably positioned in the cradle, the filling station may provide an output prompting the user to initiate a vial charging sequence. Alternatively, responsive to detecting the operable coupling of a vial to the vial adapter, the filling station may automatically initiate a vial filling charging sequence, provided that the device is operably positioned in the cradle.

The term “the device is operably positioned in the cradle” may, for instance, refer to an orientation of the device in the cradle as well as to the orientation of the device relative to world coordinates. For example, the device may be considered to be in “operable position” when in certain orientation relative to the earth's field of gravity, e.g., such that fluid medicament could flow, merely through gravity, from a vial into the device's reservoir(s).

In some cases, the charging unit charges the battery wirelessly. The display can include an LED display. The display can include a graphical user interface, which can enable a user to input an instruction to initiate the filling operation. In some cases, the display further includes a touchscreen. In some cases, the communication module can communicate with a computing device via a wired and/or a wireless communication network (not shown).

A used herein, a computing device may include, for example, a multifunction mobile communication device also known as a “smartphone”, a personal computer, a laptop computer, a tablet computer, a server (which may relate to one or more servers or storage systems and/or services associated with a business or corporate entity, including for example, a file hosting service, cloud storage service, online file storage provider, peer-to-peer file storage or hosting service and/or a cyberlocker), personal digital assistant, a workstation, a wearable device, a handheld computer, a notebook computer, a vehicular device, a stationary device and/or a home appliances control system.

The communication module may, for example, include I/O device drivers (not shown) and network interface drivers (not shown) for enabling the transmission and/or reception of data over a communication network for enabling external communication with the communication device. A device driver may for example, interface with a keypad or to a Universal Serial Bus (USB) port. A network interface driver may for example execute protocols for the Internet, or an Intranet, Wide Area Network (WAN), Local Area Network (LAN) employing, e.g., Wireless Local Area Network (WLAN), Metropolitan Area Network (MAN), Personal Area Network (PAN), extranet, 2G, 3G, 3.5G, 4G including for example Mobile WIMAX or Long Term Evolution (LTE) advanced, 5G, Bluetooth® (e.g., Bluetooth smart), ZigBee™, near-field communication (NFC) and/or any other current or future communication network, standard, and/or system.

The communication module can receive a medical condition status of the user, e.g., from the device and/or the cloud. In some instances, the display can display the medical condition status. The filling operation can include movement of a plunger through a medicament reservoir to generate a suction force to draw the fluid medicament from a vial into the medicament reservoir via a vial adapter. The communication module can be operable to instruct the device to initiate the filling operation when the device is within the cradle of the charging/filling station. In some embodiments, the fluid medicament can include levodopa.

In some embodiments, the device may be operable to allow a user to initiate drawing fluid from vial(s) into a medicament reservoir of the disposable part without necessarily requiring the employment of a filling station. For example, the device may include a user interface provided on the reusable and/or the disposable part, which allows the user to provide a command input causing the pump to rotate the drive component, which in turn may cause the displacement of the plunger and, therefore, the filling of the medicament reservoir.

In another aspect, the invention relates to a method of charging/filling a device operable to deliver a fluid medicament to a subcutaneous tissue of a user. The method can include the steps of receiving the device within a cradle, charging a rechargeable battery of the device with a charging unit, and instructing at least one of a control unit and a drive component of the device to initiate a filling operation of the device. The device's rechargeable battery and charging coil may be arranged within the housing of the reusable part at a desirable distance. For example, as far apart as practicably possible, e.g., to avoid damage to the battery by electromagnetic radiation that may be present in the coil's vicinity.

In some embodiments of this aspect, the method can further include holding the device within the cradle such that, when a fluid is contained in the medicament reservoir of the device, the fluid is subjected to the earth's gravity field to flow towards an outlet of the reservoir. In some instances, the charging step can include wirelessly charging the rechargeable battery. The device can include a display, which can include a graphical user interface and/or a touch screen. In some cases, the method can further include receiving an instruction to initiate the filling operation from a user interacting with the graphical user interface. The method can further include communicating information with a computing device via a wired and/or wireless network. In some cases, the method can include receiving a medical condition status of a user, e.g., from the device and/or the cloud. In some cases, the method can include displaying the medical condition status. The filling operation can include movement of a plunger through a medicament reservoir to generate a suction force to draw the fluid medicament from a vial into the medicament reservoir via a vial adapter. In some cases, the step of instructing the device to initiate the filling operation occurs when the device is within the cradle. In some embodiments, the fluid medicament can include levodopa.

In another aspect, the invention relates to a medicament vial adapter for use with a device for delivering a fluid medicament to subcutaneous tissue of a user. The device can include a reservoir for containing the fluid medicament. The medicament vial adapter can include a first port operable to connect to the reservoir, a second port operable to connect to a medicament vial containing the fluid medicament, and a needle disposed in the first and second ports, such that when the vial adapter is connected to the reservoir and the medicament vial, the needle fluidically couples the medicament vial to the reservoir.

In some embodiments of this aspect, the needle is operable to pierce (i) a septum disposed in the device to access the reservoir and (ii) a vial plug to access contents of the medicament vial. In some cases, the needle can include a metal material and can be operable to pierce the vial plug under an insertion force of no greater than about10N. The needle can be shielded from inadvertent user contact. In some embodiments, the fluid medicament can include levodopa.

In another aspect, the invention relates to a method for filling a device for delivering a fluid medicament to subcutaneous tissue of a user. The device can include a reservoir for containing the fluid medicament. The method can include the steps of connecting a first port of a medicament vial adapter to the reservoir, connecting a second port of the medicament vial adapter to a medicament vial containing the fluid medicament, and disposing a needle in the first and second port to fluidically couple the medicament vial to the reservoir.

In some embodiments of this aspect, the needle is operable to pierce (i) a septum disposed in the device to access the reservoir and (ii) a vial plug to access contents of the drug vial. The needle can include a metal material and can be operable to pierce the vial plug under an insertion force of no greater than about10N. In some cases, the method can further include shielding the needle from inadvertent user contact. In some embodiments, the fluid medicament can include levodopa.

In another aspect, the invention relates to a filling system that can include (i) a device for delivering a fluid medicament to subcutaneous tissue of a user, the device including a reservoir for receiving and containing the fluid medicament, and (ii) a vial adapter including a first port operable to connect to the reservoir, a second port operable to connect to a medicament vial containing the fluid medicament, and a needle disposed in the first and second ports, wherein when the vial adapter is connected to the reservoir and the medicament vial, the needle fluidically couples the medicament vial to the reservoir.

In another aspect, the invention relates to a holder for securing a pump device to a user. The holder can include a receiving portion operable to receive the pump device and detachably retain the pump device, an attachment component for attaching the holder to the user and/or an article of apparel (e.g., clothing) worn by the user, and a position altering component inter disposed between the receiving portion and the attachment component to alter a position and/or orientation of the pump relative to the attachment component.

In some embodiments of this aspect, the position altering component is operable to change the orientation of the pump device to multiple angular positions, and/or the position of the pump device. In some cases, the pump device includes external tubing and the position altering component is operable to rotate the pump device to advantageously position the tubing. In some cases, the attachment component can include a clip operable to clip onto a belt worn by the user. The receiving portion can include a quick release coupling.

In another aspect, the invention relates to a method for securing a pump device to a user. The method can include the steps of receiving and detachably retaining the pump device on a holder, attaching the holder to at least one of the user and an article of clothing worn by the user, and altering a relative position of the pump device using a position altering component on the holder.

In some embodiments of this aspect, the altering the relative position step includes rotating the pump device to multiple angular positions. In some cases, the pump device includes external tubing and the rotating the pump device step includes rotating the pump device to advantageously position the tubing. In some cases, the attaching the holder step includes attaching a clip of the holder onto a belt worn by the user. In some cases, the receiving and detachably retaining step includes using a quick release coupling.

In some aspects, the device may include a cannula part, a reservoir part, and a control and drive part, all, some, or none of which can be the same as or have common features with the disposable and/or reusable parts described above. The cannula part includes the cannula which is operable to engage with the patient's skin to subcutaneously deliver a fluid medicament. The reservoir part includes the medicament reservoir operable to receive the fluid medicament from a vial. The control and drive part includes the motor and control electronics for controlling the delivery of the fluid medicament from the reservoir via the cannula to a subcutaneous tissue site.

The cannula part may be detachably and operably coupleable with the reservoir part such that the cannula of the cannula part is in fluid communication with the reservoir of the reservoir part. The control and drive part may be detachably and operably coupleable with the reservoir part such that the control electronics and the drive can control the operation of delivery of fluid from the medicament reservoir.

The cannula part, the reservoir part and/or the control and drive part may be reusable or disposable or both reusable and disposable.

This Summary introduces a selection of concepts in a simplified form that are further described below in the Description of the Figures and the Detailed Description. This Summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used to limit the scope of the claimed subject matter.

BRIEF DESCRIPTION OF THE FIGURES

In the drawings, like reference characters generally refer to the same parts throughout the different views. Also, the drawings are not necessarily to scale, emphasis instead generally being placed upon illustrating the principles of the invention. In some cases, references to previously presented elements are implied without necessarily further citing the drawing or description in which they appear. The number of elements shown in the drawings should by no means be construed as limiting and is for illustrative purposes only. In the following description, various embodiments of the present invention are described with reference to the following drawings, in which:

FIG. 1 is a schematic, transparent 3D view of a medicament delivery device, according to some embodiments;

FIG. 2 is a schematic, transparent 3D view of a disposable part, according to some embodiments;

FIG. 3 is a transparent schematic 3D view of a reusable part, according to some embodiments;

FIG. 4A is a schematic, side view illustrating how the disposable part and the reusable part fit together, according to some embodiments;

FIG. 4B is a schematic, side view illustrating a sealing arrangement of the disposable and the reusable part, according to some embodiments;

FIG. 5 is a schematic, cross-sectional 3D view of a plunger assembly within a medicament reservoir, according to some embodiments;

FIG. 6 is a schematic, 3D view of a plunger head with a cover, according to some embodiments;

FIGS. 7A-7C are schematic, 3D views illustrating a magnetic connection between the disposable part and the reusable part, according to some embodiments;

FIGS. 8A-8B are schematic, 3D views illustrating a snap connection between the disposable part and the reusable part, according to some embodiments;

FIGS. 9A-9F are schematic, 3D views illustrating a swing latch connection between the disposable part and the reusable part, according to some embodiments;

FIGS. 10A-10C are schematic, 3D views showing the medicament delivery device with multiple reservoirs, according to some embodiments;

FIG. 10D is a schematic side view illustration of a plunger head and a lead screw attached to the plunger head of the delivery device, according to some embodiments;

FIG. 10E is a schematic cross-sectional side view illustration of the plunger head and the lead screw ofFIG. 10D, according to some embodiments;

FIG. 11 is a schematic, 3D view of vial adapters attached to a disposable part within a blister, according to some embodiments;

FIGS. 12A-12C are various views of the filling station and the filling station containing the delivery device, according to some embodiments;

FIG. 13A is a schematic, transparent 3D view of the medicament delivery device within the filling station, according to some embodiments;

FIG. 13B is an enlarged close-up view of the vial adapter shown inFIG. 13A, according to some embodiments;

FIG. 14 is a schematic, 3D view of the delivery device including an access aperture and a control button, according to some embodiments;

FIGS. 15A-15G are schematic illustrations of various configurations and techniques for charging the delivery device, according to some embodiments;

FIG. 16 is a schematic, 3D view of a standalone pump unit and an infusion set, according to some embodiments;

FIGS. 17A-17G are schematic, 3D views of a pump holder, according to some embodiments;

FIGS. 18A-18D illustrate adhesive patterns for an adhesive portion, according to some embodiments;

FIG. 19 is a schematic illustration of adhesive on a skin surface side of the adhesive portion, according to some embodiments;

FIG. 20 is a schematic illustration of adhesive on a device surface side of the adhesive portion, according to some embodiments;

FIGS. 21A-21C are schematic illustrations of a cannula insertion mechanism, according to some embodiments;

FIGS. 22A-22B are schematic illustrations of a cannula having side wall apertures, according to some embodiments;

FIGS. 23A-23D are schematic illustrations of a technique for fluidically coupling the reservoir to a cannula, according to some embodiments;

FIGS. 24A-24E are schematic illustrations of another cannula insertion mechanism, according to some embodiments;

FIGS. 25A-25E are schematic illustrations of various delivery device configurations having multiple reservoirs and/or multiple cannulas, according to some embodiments;

FIG. 26 is a schematic, 3D view showing an antenna sensor of the medicament delivery device, according to some embodiments;

FIGS. 27A-27F are schematic depictions of various sensors that can be included on the delivery device, according to some embodiments;

FIG. 28 is a schematic, 3D view of a temperature control unit of the delivery device, according to some embodiments;

FIGS. 29A-29C are schematic, 3D views of a skin/tissue property control unit and a skin/tissue detection unit of the delivery device, according to some embodiments;

FIG. 30 is a schematic, 3D view of a cannula opening unit of the delivery device, according to some embodiments;

FIG. 31 is a schematic, 3D view of a depth penetration control unit of the delivery device, according to some embodiments;

FIG. 32 is a flowchart showing example steps performed by a patient using the medicament delivery device, according to some embodiments;

FIG. 33 is a chart listing example values for parameters related to the configuration and operation of the medicament delivery device, according to some embodiments;

FIG. 34A is a schematic block diagram illustration of a liquid quantity sensor device, according to some embodiments;

FIGS. 34B-34J schematically show various embodiments of liquid quantity sensor devices operably coupled with reservoirs;

FIG. 35 is a schematic block diagram illustration of a liquid quantity sensor device, according to alternative embodiments;

FIG. 36 is a schematic side view illustration of a disposable/reusable part operably coupled with a position encoder, according to some embodiments;

FIG. 37A schematically shows a liquid quantity sensor device that is operably coupled with a reservoir, according to some embodiments;

FIG. 37B schematically shows a side view of a reusable part of the device comprising a liquid quantity sensor device, according to some embodiments;

FIG. 37C schematically shows a partial sectional top view of the reusable part, according to some embodiments;

FIG. 37D schematically shows an enlarged view of the partial sectional top view ofFIG. 37C with the liquid quantity sensor device;

FIG. 37E schematically shows a 3D view of the positional relationship between and a reservoir and a capacitor-based liquid quantity sensor configured to measure a liquid quantity in the reservoir, according to some embodiments;

FIG. 37F schematically shows the disposable part when operably coupled with the reusable part and the resulting positional relationship between the capacitance-based liquid quantity sensor of the reusable part and the reservoir of the disposable part;

FIG. 37G schematically shows front and back views of a capacitor-based liquid quantity sensor, according to some embodiments;

FIG. 37H is a schematic block diagram illustration of a capacitor-based liquid quantity measurement system, according to some embodiments;

FIG. 38 schematically shows sensors that are arranged at or near the outlet of a cannula for measuring a characteristic of fluid contained in cannula, according to some embodiments;

FIG. 39 schematically shows various stirring elements that are coupled with a reservoir, according to some embodiments; and

FIG. 40 is a flow chart of an example method for setting operating parameter values of the pump device.

DETAILED DESCRIPTION

Embodiments of the present invention relate to an improved device for the subcutaneous delivery of medicament to a patient. In some embodiments, the device can take the form of either a patch pump or a standalone pump used with an infusion set.FIG. 1 shows anexample patch pump100 that includes adisposable part102 and areusable part104. A transparent view of the exampledisposable part102 is shown inFIG. 2. As shown, thedisposable part102 includes amedicament reservoir106, aplunger assembly108, and anadhesive portion110 for attachment to a patient's skin. A transparent view of the examplereusable part104 is shown inFIG. 3. As shown, thereusable part104 can include a drive component112 (e.g. a motor (DC or AC)), a drive train114 (e.g., a gear train), amemory unit115, acontrol unit116, and a power supply118 (e.g., a battery). In some embodiments, thedisposable part102 may comprise apower supply119.

In some cases, thememory unit115 andcontrol unit116 can be part of asingle computing unit117.

It will be appreciated that separate controllers and/or memory units can be allocated for each processing function and/or element (such as thedevice100 and/or the filling station154 (described below)). For simplicity, the following description will refer tocomputing unit117 as a generic controller and memory unit that conduct all the necessary controlling and/or processing functions. In some cases, only thedevice100 includescomputing unit117.

Each of thedisposable part102 and thereusable part104 and how they engage and interact with each other are described in more detail below.

FIG. 4A is a schematic diagram illustrating how thedisposable part102 andreusable part104 interact. As shown, in some embodiments, theplunger assembly108 of thedisposable part102 includes aplunger head120, alead screw122 attached to theplunger head120 with substantially no rotational ability therebetween, and anut124 having an inner threaded profile that engages with threads on thelead screw122. Rotation of thenut124 can cause linear translation of thelead screw122 such that theplunger head120 is displaced in either direction through thereservoir106, depending on the direction thenut124 is rotated. In some instances,nut124 has an opening125 (seeFIG. 5) to allow displacement of thelead screw122 in aproximal direction172 towards thereusable part104.

In some embodiments, the proximal side of thereusable part104 has a screw-receivingtube cavity127 formed in a sealing arrangement with thereusable part104. When thedisposable part102 and thereusable part104 are operably coupled with each other, the screw-receivingtube cavity127 can be located opposite and oriented relative to theopening125 such that their axes are substantially coinciding, and further such that the portion of the translatedlead screw122 protruding out of theopening125 is received within the screw-receivingtube cavity127. Optionally, the screw-receivingtube cavity127 may be a rotation axis for aload gear136, whose functionality is outlined herein in more detail. This configuration allows housing at least some or all electronic parts of thereusable part104 in a sealed manner, thus protecting them from the environment external to thereusable part104 while, at the same time, allowing proper functionality of the device during operation and control of the moving parts of thedisposable part102 through the electronic components of thereusable part104. As shown inFIG. 4B, the sealing arrangement may be obtained by employing one or more O-rings. For example, a first O-ring129A may be coupled with (e.g., disposed over) a proximal end of the screw-receivingtube cavity127, and a second O-ring129B may be coupled with (e.g., disposed over) a distal end of the screw-receivingtube cavity127.

In some embodiments, screw-receivingtube cavity127 can be open to the reservoir at both ends, thus enabling drainage of liquids when disassembled. In other embodiments, screw-receivingtube cavity127 can also be closed at one or both ends, to prevent ingress of materials, for example, when thedisposable part102 and thereusable part104 are assembled. In some embodiments, components of the device may be made or consist of inert material or materials having comparatively high elasticity such that after a force that caused deformation of the component is removed, the component attains its original form. For example, the component may exhibit comparatively non-plasticity characteristics and, for example, non-rigid characteristics. Optionally,plunger head120 may be made of a single part which is compressibly confined within the reservoir to create liquid-sealing properties. Hence, in some embodiments, theplunger head120 may be liquid sealing, but not include an O-ring. Additional or alternative components of the device may also not include an O-ring.

Thenut124 can be rotated within a bushing126 (seeFIG. 5). Displacement of theplunger head120 in one direction can force medicament contained in the reservoir out of the reservoir into the patient (as described below). Displacement of theplunger head120 in the other direction can create space in the reservoir (and, in some cases, generate a vacuum) to enable filling of the reservoir106 (as described below). In some embodiments, linear translation to generate forces within the reservoir106 (e.g., compressive forces to deliver fluid or suction forces to enable filling) are only performed by components within the disposable part102 (e.g., thelead screw122 and the plunger head120). In such embodiments, the drive components within thereusable part104 do not translate linearly within thereservoir106.

As shown inFIG. 6, in some embodiments, thefluid contacting surface139 of theplunger head120 can be made from an elastic material that is safe to contact the fluids contained in thereservoir106. Thefluid contacting surface139 can be defined as a surface that makes fluidic contact with the fluid contained in thereservoir106, during either delivery or filling operations. Thefluid contacting surface139 can reduce or eliminate contact with the medicament by other materials (e.g., of other components of the device100). In some instances, thefluid contacting surface139 is formed from acover141 placed over the plunger head. In such instances, thecover141 can serve as a seal that prevents fluid in thereservoir106 from flowing past theplunger head120. In some cases, in addition to or as an alternative from thecover141 seal, an O-ring143 (seeFIG. 4A) (or gasket or other sealing mechanism) can be included on theplunger head120.

Returning toFIG. 4A, in some embodiments, thenut124 can be rotated via engagement with structure in thereusable part104. As mentioned above, thereusable part104 can include adrive component112 for generating a force for driving the plunger assembly108 (e.g., rotating the nut124). In general thedrive component112 can be any component capable of generating this force; for example, a motor. Thereusable part104 can also include adrive train114 for transferring the drive force from thedrive component112 to theplunger assembly108. For example, thedrive train114 can be a gear train. As shown, the gear train can include a planetary gear130 (e.g., for reducing the speed and increasing the moment of the motor), adrive gear132 coupled with theplanetary gear130, anidler gear134 coupled with thedrive gear132, and aload gear136 coupled with theidler gear134. Many different gear configurations are possible. Alternative drive train systems are also contemplated, e.g., belt and pulley systems, rack and pinion systems, etc.

In the configuration shown inFIG. 4A, thenut124 can be detachably coupled with theload gear136 to enable transfer of the drive force from thedrive component112 to thenut124. In some embodiments, thenut124 can include an outer profile that engages with a mating profile of theload gear136. As depicted inFIG. 4A, the mating profile can be formed within aboss128 protruding from theload gear136. As mentioned above, theload gear136 can transmit a force tonut124 which can cause linear translation oflead screw122 within thereservoir106. In some instances, only components within thedisposable part102 translate linearly within thereservoir106. Thus, in some embodiments, theload gear136 does not translate linearly within thereservoir106. Other techniques for detachably coupling thenut124 to theload gear136 are contemplated.

In some embodiments, when thedisposable part102 and thereusable part104 are engaged, thedrive component112 and thereservoir106 are co-planar. For example, as shown inFIG. 4A, thelongitudinal axis135 of thedrive component112 and thelongitudinal axis137 of thereservoir106 are both within the same plane. In some instances, when thedisposable part102 and thereusable part104 are engaged, thelongitudinal axis135 of thedrive component112 and thelongitudinal axis137 of thereservoir106 are substantially parallel. In some instances, when thedisposable part102 and thereusable part104 are engaged, thedrive component112 and thereservoir106 can overlap in the longitudinal direction. The amount of overlap can be at least 30%, at least 40%, at least 50%, at least 60%, and/or at least 70% of the length of thedrive component112, or in some cases at least 30%, at least 40%, at least 50%, at least 60%, and/or at least 70% of the length of thereservoir106. Each of the configurations described earlier in this paragraph can reduce the profile of thedevice100, which can make thedevice100 more wearable and discrete for the user. As one example, if thedrive component112 and thereservoir106 were not co-planar and, for example, thelongitudinal axis135 were in the z axis, then the device would be much thicker and bulkier.

In addition to, or as an alternative from, the engagement between thenut124 and theload gear136, several techniques can be used for attaching thedisposable part102 and thereusable part104. In some embodiments, the parts are attached using a magnetic force. As shown inFIGS. 7A-7C (depicting an embodiment including two medicament reservoirs, described below), afirst magnet138 of thedisposable part102 and asecond magnet140 of thereusable part104 can be arranged to attract one another when the two parts are positioned together (e.g., such that thenut124 engages the load gear136). In some embodiments, the parts can be attached using a snap connection that uses alocking feature142 to hold the parts together, as shown for example inFIGS. 8A-8B. In some embodiments, the parts are attached using a swing latch. As shown inFIG. 9A, the swing latch can include anarm144 on thedisposable part102 that engages acorresponding groove146 on thereusable part104 to hold the parts together. Thearm144 can have aflexible hinge148 that, when pressed, releases thearm144 from thegroove146. In some instances, thearm144 is on thereusable part104 and thegroove146 is on thedisposable part102. Various alternate configuration and locations of the swing latch are shown inFIGS. 9B-9F.

Regardless of the connection technique employed, in general, thedisposable part102 and thereusable part104 can be attached and detached at any time, regardless of the position of theplunger head120 within thereservoir106 or the amount of fluid in thereservoir106. In some instances, the parts are detached when thereservoir106 is empty and it is time to replace thedisposable part102, but the parts are not required to only be detached at that time.

In general, thereusable part104 can be operably coupled with thedisposable part102 in any orientation relative to each other. With reference toFIGS. 10A-10C, in some embodiments, thereusable part104 and thedisposable part102 can be attached such thatnut124aengagesload gear136aandnut124bengagesload gear136b, and thereusable part104 and thedisposable part102 can also be attached when rotated180 degrees with respect to this orientation, e.g., such thatnut124aengagesload gear136bandnut124bengagesload gear136a. In some instances, this feature can improve the usability of thedevice100 because the patient need not ensure that thereusable part104 anddisposable part102 are in the correct orientation before attaching the parts. In other embodiments, thereusable part104 and thedisposable part102 must be in a particular orientation in order to attach to each other (e.g.,nut124aonly engagesload gear136aandnut124bonly engagesload gear136b). This can be accomplished using many techniques, e.g., having unique mating profiles fornut124a/load gear136aandnut124b/load gear136b.

In some embodiments, thedevice100 can include multiple reservoirs.FIGS. 10A-10C show an example embodiment in which thedisposable part102 includes two

reservoirs

106a,106bthat contain

separate plunger assemblies

108a,108b, each of which are driven by

separate drive trains

114a,114b. As shown inFIG. 10C, in some instances, both

plunger assemblies

108a,108bcan be driven by asingle drive component112. With reference toFIG. 10C, thedrive component112 can cause rotation of a single drive gear132 (e.g., via planetary gear130), which can cause rotation of both load gears136a,136b(via idler gears134a,134b), which can cause translation of both

plungers

120a,120bto drive fluid out of both

reservoirs

106a,106b(or to generate a suction force to fill the reservoirs, as described below). In some embodiments, the gears, nuts, and/or lead screws can be modified such that

plunger assemblies

108a,108btranslate in the same or opposite directions from each other. In other embodiments, thedevice100 can be modified such that thedrive component112 controls the plunger apparatuses completely separately from each other. In other embodiments, thedevice100 can be modified such that aseparate drive component112 controls each of the

plunger assemblies

108a,108b. In some embodiments with multiple reservoirs, all of the reservoirs (or a subset of two or more) can deliver fluid through a common outlet. In other instances, each reservoir can deliver fluid through its own dedicated outlet.

In some embodiments with multiple reservoirs, each of the reservoirs can include the same fluid or different fluids. In instances in which the reservoirs are filled with the same fluid, the multiple reservoirs can increase the dosage capacity of the device, or increase the amount of time the device can be used without replacing thedisposable part102. In some instances in which the reservoirs are filled with different fluids, each reservoir can contain a different medicament (e.g., medicaments that are prescribed together). For example, one reservoir can include levodopa and the other reservoir can include carbidopa. In some instances, one of the reservoirs can be empty (in such instances, the device can be configured or adapted such that a plunger assembly does or does not translate through the empty reservoir. In certain embodiments, thedevice100 can be further operable to include more than two reservoirs (e.g., 3, 4, 6, 8, etc.). The same concepts described above regarding control of the plunger assemblies by either a single or multiple drive components can be applied to embodiments with more than two reservoirs.

Further referring toFIGS. 10D and 10E, thelead screw122 may have a threadedportion121 that extends along thelead screw122 and anon-threaded portion123, e.g., at a terminal end of thelead screw122. Thenon-threaded portion123 can extend from a distal end of thelead screw122 in proximal direction thereof towards theplunger head120. In other words, a tip portion at the distal end of thelead screw122 may be non-threaded. The diameter of thenon-threaded portion123 can be smaller than, larger than, or the same as the outer diameter of the threadedportion121. Optionally, the other tip portion at the proximal end of thelead screw122, just below theplunger head120, may also be non-threaded.

By configuring thelead screw122 to have a non-threadeddistal tip portion123, limited mechanical positional tolerance can be afforded. For example, in cases where a plurality of lead screws are employed for concurrently forcing fluid medicament out of a respective plurality of reservoirs. For example, rotation of the

corresponding nuts

124aand124bby thedrive gear132 can cause the first and the second lead screws122aand122b(along with their corresponding plunger heads120aand120b) to concurrently translate in

reservoirs

106aand106b, as for example in embodiments of the double-piston arrangement schematically shown inFIG. 10C.

The first and second lead screws122aand122bmay not, for example, translate in perfect temporal and/or spatial synchronization. As a result thereof, thefirst plunger head120afor instance may arrive at the distal end of thereservoir106aprior to thesecond plunger head120b. Thus, thefirst plunger head120amay abut against the distal end of thereservoir106aand be brought to a stop thereby, while thefirst nut124ais still forced to rotate and further while thenut124bimparts a rotational force on thesecond plunger head120bcausing it to translate in distal direction. By having a non-threaded portion tip portion on either one of the two lead screws, the blockedlead screw122auncouples from the nut's124ainner thread. As a result thereof, both

nuts

124aand124bcan continue to rotate, only withnut124bcontinuously imparting a translational force on the corresponding lead screw. In such embodiments, the drive gear131 can continuously impart a rotational force onto

nuts

124aand124b, while avoiding damage to the mechanical components of the device's motor or plunger assemblies in case of abutment of the plunger heads120aand120bagainst the reservoirs' distal ends.

In some embodiments, thedisposable part102 is delivered to the patient with themedicament reservoir106 not yet filled. To facilitate filling, in some cases thedisposable part102 is delivered to the patient with an attached vial adapter150 (e.g., pre-packaged in sterilized packaging). Optionally, the vial adapter may be pre-assembled with thedisposable part102 in a packaging. Once unpackaged, the vial adapter is removable from thedisposable part102 to allow the fluid coupling thereof with a (e.g., standard) infusion or tubing of the patch pump for delivery of the fluid medicament that was delivered from the vials to the reservoir(s) of thedisposable part102.

Anexample blister152 containing thedisposable part102 attached tovial adapters150 is shown inFIG. 11 (depicting an embodiment including twovial adapters150 for two

medicament reservoirs

106a,106b). In other embodiments, thedevice100 can be provided to the patient with thedisposable part102 andvial adapter150 detached from each other (e.g., in separate sterilized packages). As shown inFIG. 11, for a multiple reservoir embodiment, aseparate vial adapter150 can be used for each reservoir. In other instances, asingle vial adapter150 can be used to fill all of the reservoirs106 (or in some cases a subset of two or more). In yet other embodiments, thedisposable part102 can be delivered pre-filled with medicament and avial adapter150 is not used.

In some embodiments, thedevice100 is operable to use a filling station to fill themedicament reservoir106 with medicament. Anexample filling station154 is shown inFIG. 12A.

The fillingstation154 can include acradle155 that receives thedevice100 such that the fillingstation154 and thedevice100 are communicatively connected. Any type of connection can be used, e.g., a wired connection and/or a wireless connection (e.g., via a WiFi network, Bluetooth, etc.). In some instances, thecradle155 holds thedevice100 such that thereservoir106 is held in a substantially vertical orientation (e.g., with reference toFIG. 4A,longitudinal axis137 substantially along the y-axis) to reduce the flow of air into thereservoir106 during the filling process.

As shown inFIG. 12A, in some embodiments, the fillingstation154 can be controlled by a computing device (e.g., a smartphone)156 in communication with the filling station154 (wired or wirelessly). In such embodiments, thecomputing device156 can provide a display having a graphical user interface (“GUI”) for a user to interact with to input control instructions. The GUI can be provided when thecomputing device156 executes a mobile application stored thereon and/or accessed from the cloud. Thecomputing device156 can transmit (wired or wirelessly) the instructions to afilling station controller157 of the fillingstation154, which can instructcontrol unit116 within thedevice100, to control the components of thedevice100 in accordance with the user's instructions. In other instances, the fillingstation controller157 can control the components of thedevice100 directly (e.g., via a wired or wireless connection). In still other instances, thecomputing device156 can control the components of thedevice100 directly. In instances in which thecomputing device156 controls thedevice100 directly, the fillingstation154 may not be used. In other embodiments, thecomputing device156 may not be used and the fillingstation154 may include its own user interface. In general, the filling station user interface can be any interface capable of receiving user instructions, e.g., a display presenting a GUI, buttons, etc. In operation, after a user removes thedisposable part102 andvial adapter150 from theblister152, these components can be attached to the reusable part104 (which the user may already have from a prior dose administration) and the attached parts can be inserted into the fillingstation154. Avial158 can then be inserted into thevial adapter150. Thevial158 can include the fluid to be delivered by thedevice100, e.g., a medicament to be delivered to a patient.FIG. 13A shows a transparent side view of an example of this configuration.

FIG. 13B is an enlarged view of theexample vial adapter150 shown inFIG. 13A. As shown, thevial adapter150 can attach to thedisposable part102 via afirst port160. Thefirst port160 can be attached using known connection techniques, e.g., a threaded connection (as shown), interference fit, notch and groove connection, etc. Thevial adapter150 can include ahollow fill needle162 that pierces afill septum164 on thedisposable part102 to fluidically access thereservoir106. In order to avoid the potential for lateral/shear forces imparted by thevial adapter150 to cause the septum to crawl (e.g., during shipment and/or shelf life), in some instances, thefill needle162 is not rigidly connected to thevial adapter150 and is instead held in place by a floatingpart166 that enables relative movement between thefill needle162 and thevial adapter150. The relative movement can be in any direction, e.g., up and down (along the axis of the fill needle162), side to side (perpendicular to the axis of the fill needle162), etc. The end of thefill needle162 opposite the end that pierces thefill septum164 extends into asecond port168 of thevial adapter150. A user can insert thevial158 into thesecond port168 such that thefill needle162 fluidically accesses the contents of the vial158 (e.g., by piercing a vial septum170 (or other vial plug) located on the vial158). Thevial adapter150 can shield thefill needle162 to prevent inadvertent user contact.

Thefill needle162 can be adapted or configured such that the insertion force required to pierce the vial septum is relatively low, e.g., about 4N or less, about 5N, about 6N, about 7N, about 8N, about 9N, about 10N, etc., compared to the higher insertion forces typically required to pierce a vial septum, which is often done with a plastic spike. The reduced insertion force can be advantageous for patients with reduced strength, e.g., those suffering from Parkinson's Disease or other CNS disorders. For example, theneedle162 can be formed from a rigid metal material to enable a lower insertion force. By piercing both thefill septum164 and thevial septum170, the hollow interior of thefill needle162 creates a fluidic pathway between thevial158 and themedicament reservoir106. In other cases, thefill needle162 can be formed from plastic, in which case the insertion force can be , for example, in a range from about 30N to about 40N.

In some embodiments, once thevial158 and thereservoir106 are fluidically connected, the contents of thevial158 can be transferred to thereservoir106 to fill thereservoir106. In some embodiments, the fill process requires translation of theplunger head120, e.g., because theplunger head120 is blocking the reservoir and/or because a suction force needs to be generated to draw fluid from thevial158 through thefill needle162 into thereservoir106. In such embodiments, theplunger head120 can be translated in response to control signals sent from control unit116 (or in some cases from the fillingstation controller157 of the fillingstation154 or from the computing device156. For example, the control signals can cause thedrive component112 to drive thedrive train114 such that thenut124 rotates and causes thelead screw122 and attachedplunger head120 to translate away from thevial158, e.g., in a direction towards the reusable part104 (schematically illustrated by arrow172) generating a suction force (e.g., a vacuum) within thereservoir106 that draws fluid from thevial158 into thereservoir106. Theplunger head120 can be translated in the direction ofarrow172 until it abuts bushing126 and/or until a predetermined amount of fluid is contained within themedicament reservoir106.

In some instances, thereusable part104 forms a void orcavity176 for receiving alead screw122, when the plunger translates in the direction ofarrow172, for example, from a proximal to a distal end of thereusable part104. Including thevoid176 within thereusable part104 of thedevice100 ensures that thelead screw122 remains enclosed and protected at all times, which can reduce obstructions that may otherwise block or interfere with the travel of thelead screw122. In addition, enclosing thelead screw122 can increase safety and wearability for the patient by shielding the patient from moving component(s). In some embodiments, thedevice100 can include an access aperture184 (seeFIG. 14) such that thelead screw122 can be accessed, e.g., for lubrication, repair, and/or to remove an obstruction or interference.

In some embodiments, thereusable part104 comprises one or more openings at a distal end thereof. Example purposes of such opening(s) can include preventing the accumulation of dirt or other debris within thevoid176, removing debris from the void via the opening(s), and/or gaining access to the void via the opening(s). An opening is for example shown inFIG. 4A (opening177) and inFIG. 12B (

openings

177A and177B).

In general, thereservoir106 can be filled at any appropriate filling rate. For example, the fill rate can be in a range from about 0.1 ml/min to about 5 ml/min. As further examples, the fill rate can be in a range from about 0.5 ml/min to about 2 ml/min, 0.7 ml/min to about 1.5 ml/min, and/or 1 ml/min to about 1.2 ml/min.

Thevial adapter150 can be either vented or not vented. Thevial adapter150 may not be vented in order to prevent fluid from exiting the vent ports when thevial adapter150 is disconnected from thedevice100. In embodiments with a non-vented vial adapter, the pressure within thevial158 may be reduced as fluid is drawn out of thevial158 during the filling process. In some cases, the pressure within thevial158 at the end of the filling process is between about 0.3 bar and about 0.5 bar.

In some cases, the control signals can cause more complex motions of theplunger head120. For example, in some instances, upon receipt of a fill instruction, thecontrol unit116 can cause the drive component to translate theplunger head120 until it contacts thedelivery end174 of the medicament reservoir106 (e.g., in instances in which theplunger head120 does not contact thedelivery end174 when thedisposable part102 is provided to the patient). This action can serve multiple functions. For example, it can remove air from thereservoir106 to ensure that a vacuum is created upon retraction of theplunger head120. As another example, it can provide thecontrol unit116 with a known location of theplunger head120 before filling (retraction) begins to ensure a repeatable amount of fluid is drawn into the reservoir. This may be advantageous in instances in which the position of theplunger head120 within thereservoir106 may vary when thedisposable part102 is provided to the patient.

In some instances, thecontrol unit116 can receive information from a sensor that informs it of the starting location of theplunger head120, to determine how far theplunger head120 needs to be translated to contact thedelivery end174 of thereservoir106. In other instances, thecontrol unit116 can cause theplunger head120 to be translated until a sensor informs it that theplunger head120 is at thedelivery end174 of thereservoir106. The device sensors are described in more detail below. In still further instances, thecontrol unit116 can operate open loop and cause theplunger head120 to be translated a pre-determined amount that is known to bring theplunger head120 into contact with thedelivery end174. Once theplunger head120 is located at thedelivery end174, it can be retracted in the direction ofarrow172 to cause filling of thereservoir106, as described above. Many other techniques and control algorithms for filling thereservoir106 are contemplated. In some embodiments, thecontrol unit116 can operate in a closed loop, e.g., based on a force-feedback signal provided by a sensor (not shown).

In some instances, the control unit116 (or in some cases the fillingstation controller157 on the fillingstation154 or the computing device156) can initiate a filling operation upon receipt of instructions from a user to initiate filling. For example, the user can select an “initiate filling” icon on a GUI, e.g., on thecomputing device156 or the fillingstation154. In other instances, the control unit116 (or in some cases the fillingstation controller157 on the fillingstation154 or the computing device156) can automatically initiate the filling operation upon receipt of thedevice100 within thecradle155, without receipt of a user input fill instruction. In still other instances, the filling operation can be initiated based on the time of day (e.g., determined by a signal received from a clock of theprocessing unit182 of the filling station154).

In some embodiments, the fillingstation154 can perform other functions, in addition to or as an alternative from the filling function described above. For example, the fillingstation154 can include a charging module178 (seeFIG. 12A) for charging the power supply118 (seeFIG. 3). Thecharging module178 can use any known charging technologies, e.g., electrical contract leads, inductive coils for wireless charging, etc. Thecharging module178 can charge thepower supply118 to have at least enough power for a fully delivery cycle (e.g., 12 hours, 18 hours, 24 hours, 36 hours, 48 hours, 72 hours, etc.)

Some example charging configurations and techniques are described with reference toFIGS. 15A-15G.FIG. 15A shows an example wireless charging technique that uses inductive energy transfer from acharging module178 to the device100 (e.g., to power supply118). Thecharging module178 inFIG. 15A is a schematic depiction. As mentioned above, in some embodiments, it can be included in the filling station154 (seeFIG. 12A).FIG. 15B shows an example charging technique that uses acharging wire175. The wire can connect to any power supply (e.g., a charging station, a wall outlet, a computing device, etc.). In some instances, thecharging wire175 can also have data communication capabilities. In some embodiments, as shown for example inFIG. 15C, thedevice100 can be charged while it is attached to the patient's body. For example, as shown, thecharging module178 may emit a wireless charging field that charges thedevice100 while the patient is wearing it. In some instances, thedevice100 can be actively delivering medicament while being charged. In some embodiments, as shown for example inFIG. 15D, thecharging module178 can be a pad (or other structure) that can be placed on, under, and/or within any surface on which the user may be laying, sitting, and/or standing. For example, as shown, thecharging module178 can be placed on a mattress and/or charging pad and wirelessly charge thedevice100 while the patient is sleeping. In some embodiments, as shown for example inFIG. 15E, the charging module can be worn by the user (e.g., clipped to the patient's clothing (e.g., belt), wristband, necklace, etc.). Thewearable charging module178 can charge thedevice100 wirelessly (as shown) and/or with a wire. In some embodiments, thedevice100 can be charged by an adhesive paper battery adhered to the device (seeFIG. 15F). In some embodiments, the medicament contained by thedevice100 can serve as the electrolyte of a battery that powers the device100 (seeFIG. 15G). In general, thedevice100 can be powered by anysuitable power supply118. In some embodiments, thepower supply118 is a particular battery having voltage and/or current parameters that fits the performance requirements of the device100 (e.g., 3.7V).

In some embodiments, the fillingstation154 can include a feature to detect the presence of thedevice100 in thecradle155, which in some cases can cause the fillingstation154 to initiate the filling process, the charging process (e.g., wireless charging), and/or another process. For example, the filling station can include a magnetic relay171 (e.g., a reed switch) that can detect amagnet173 within the device100 (e.g., the reusable part104).FIG. 12B is a bottom perspective view of the filling station154 (in phantom) containing thedevice100, showing an examplemagnetic relay171.FIG. 12C is a cross-sectional view of the fillingstation154 containing thedevice100, showing an example configuration of themagnetic relay171 and themagnet173.

As another example, the fillingstation154 can include acommunication module180. In some cases, thecommunication module180 and the fillingstation controller157 are part of asingle processing unit182. Thecommunication module180 can receive and transmit information between thedevice100 and the fillingstation154, thecomputing device156, and/or the cloud. For example, the transmitted information can include information regarding the user's status and/or medical condition that can affect the configuration and operation of thedevice100. As one example, a user may input their medical condition (e.g., stage two Parkinson's Disease) into the fillingstation154 and/or thecomputing device156, which can be transmitted to thedevice100 via thecommunication module180. In such instances, the electronics on the device100 (e.g., via computing unit117) can configure and operate the device appropriately for a patient having that condition. A medical condition is one of many examples of information that can be transmitted to thedevice100 for configuration and operation of the device. A few other examples include particular dosing schedules, user sleeping schedule, user eating schedule, user weight/height, user age, status of user's medical condition, time of day, etc. In some cases, a user's dosing schedule is time based, e.g., the amount of medicament to be delivered is set on an hourly basis. In such cases, a clock of theprocessing unit182 of the filling station154 (or in some cases the computing device156) can synchronize with a clock of thecomputing unit117 of thedevice100, to ensure that the proper dosage is delivered on the correct schedule.

Thecommunication module180 can also communicate information from thedevice100 back to the fillingstation154 and/orcomputing device156. For example, as described in more detail below, thedevice100 can track data collected by its sensors while thedevice100 is worn by the patient. The collected data can include medical data, e.g., amount of medicament delivered, amount of time medicament was delivered, delivery schedule, etc. The collected data can also include user data, e.g., number of steps taken, hours asleep/awake, etc. The collected data can also include operational data for thedevice100, e.g., if any malfunctions occurred, amount of charge in thepower supply118, if thereusable part104 is scheduled for maintenance or replacement, etc. The information communicated from thedevice100 to the fillingstation154, thecomputing device156, and/or the cloud via thecommunication module180, can be presented to the user on the display of the fillingstation154 and/orcomputing device156.

In some embodiments, thecommunication module180 is not used and/or not included and communication occurs directly between thedevice100 and acomputing device156 and/or the cloud and vice versa. In such embodiments, information transmitted to and from thedevice100 can occur with devices remote from the device100 (e.g., computers, laptops, smartphones, tablets, smart watches, and/or any device that can communicate via wireless networks and/or access the cloud). In such instances, the information transmitted from thedevice100 can be accessed remotely by the user, a caregiver, medical personnel, or other individuals. In some cases, the user (or other parties) can also transmit information to thedevice100 from remote locations.

In some embodiments, once the filling process is complete, thevial158 andvial adapter150 can be removed from thedevice100. More particularly, thefirst port160 of thevial adapter150 can be removed (e.g., unthreaded) from the device. Thedevice100 can then be removed from the fillingstation154, in some instances following any data exchange or charging processes taking place. In some instances, the user can be alerted if thepower supply118 has not received a sufficient charge to complete a full dosing regimen. In some such cases, a user may not be able to activate the delivery mode (e.g., by pressingbutton230, described below) unless thepower supply118 has a sufficient charge (e.g., to complete a full dosing regimen). Thedevice100 can then be coupled with the patient.

As shown inFIG. 16, in embodiments in which thedevice100 is a standalone pump unit,tubing186 can be attached to the outlet(s)188 of the reservoir(s)106 of thedevice100. In some cases, thetubing186 can be attached to the outlet(s)188 with aLuer connector190. The other end of the tubing can include an infusion set192 that can include an infusion setneedle194 that accesses the subcutaneous tissue. The infusion set192 (or in some cases multiple infusion sets) can be adhered to desired infusion site(s) on the body of the patient, e.g., abdomen, thigh, arm, etc. Thedevice100 can be carried by the patient, e.g., clipped to an article of clothing worn by the patient (e.g., a belt), adhered to the patient's skin, carried in the patient's pocket or in a fanny pack, etc.

In some embodiments, thedevice100 can be held by apump holder196 that allows the pump to be held in multiple different orientations. Anexample pump holder196 can be seen inFIGS. 17A-17B. As shown, thepump holder196 can include aclip portion197 for attaching to a user or an article of clothing worn by the user (e.g., a belt) and alatch portion198 for attaching to thedevice100.FIG. 17C shows thepump holder196 with thelatch portion198 attached to thereusable part104 of the device100 (though in other embodiments thelatch portion198 can attach to the disposable part102).FIGS. 17D-17E illustrate an example attachment scheme between thelatch portion198 and thereusable part104, which can generally employ any quick connect/disconnect scheme that allow thedevice100 to be quickly and easily connected and disconnected from theholder196.FIG. 17D is a side view of theholder196 attached to thereusable part104 andFIG. 17E is a close-up cross sectional view of the circled portion inFIG. 17D. As shown, thereusable part104 can include agroove193 and anotch195 that are operable to engage

corresponding clips

193a,195a on thelatch portion198. In some embodiments, either thegroove193 and/or notch195 can be omitted. Many other attachment schemes are possible (e.g., alternative groove/notch configurations, magnets, etc.). In some instances, thedevice100 can be connected or disconnected with a single hand.

In some situations, it can be advantageous to have thetubing186 connected to thedevice100 directed in a particular orientation that is advantageous for reaching a particular infusion site, e.g., to avoid tugging/discomfort or to keep the tubing out of the patient's way. Theholder196 can offer a solution by including arotation mechanism199 that rotates the device100 (and, as a result, the tubing186) to a desired orientation. In general, theholder196 can include any structure capable of rotating and holding the tubing in various orientations (e.g., angular positions). Anexample rotation mechanism199 can be seen inFIGS. 17F-17G (with reference toFIG. 17A). As shown therotation mechanism199 can include adisc189. In some instances, thedisc189 is rotationally fixed to theclip portion197 and abore191 of thelatch portion198 can rotate about thedisc189 to position thedevice100 at various angular positions. In other instances, thedisc189 is rotationally fixed to a latch portion of thedisc189 and can rotate with respect to theclip portion197 to rotate thedevice100 to various angular positions. In general, thedevice100 can be positioned at any desirable angular position. In some instances, therotation mechanism199 can include structure to position thedevice100 at certain predetermined locations. As one example, therotation mechanism199 can includedetents187 operable to hold thedisc189 at4 predetermined positions (as shown inFIGS. 17F-17G).

In operation, fluid can be evacuated from the reservoir(s)106 through thetubing186, through the infusion set192 and into the subcutaneous tissue. In some instances, eachreservoir106 can deliver fluid to separate infusions sets192. In other instances, two ormore reservoirs106 can deliver fluid to the same infusion set192.

In embodiments in which thedevice100 is a patch pump, thedevice100 can be adhered to a skin surface of the patient (e.g., abdomen, thigh, arm, etc.) In general, any adhesion technique that results in thedevice100 being firmly secured to the skin surface can be used. For example, an exterior surface of thedisposable part102 can be adapted or configured to be adhered to the skin surface. In some instances, microdermal anchors can be used to attach the exterior surface to the skin surface. In other instances, a sub-pressure can be generated between the skin surface and the exterior surface (e.g., using a suction cup). In other instances, theadhesive portion110 can be used (seeFIG. 2). Theadhesive portion110 can include a layer of adhesive having a device surface side that adheres to thedevice100 and a skin surface side that adheres to the skin surface. Theadhesive portion110 and/or the adhesive layer can have elastic properties that enable theadhesive portion110 and/or layer to be stretched to conform to a particular surface. Theskin surface side110aand thedevice surface side110bcan each include either a continuous or a discontinuous adhesive. In some cases, one side contains a continuous adhesive (e.g., theskin surface side110a) and the other side contains a discontinuous adhesive (e.g, thedevice surface side110b).

In general, adhesive can be applied to theadhesive portion110 in any pattern that will reliably adhere thedevice100. A few examples are shown inFIGS. 18A-18D.FIG. 18A shows a pattern of three adhesive183 spots, which in some instances is the minimum number of spots that will fix the device in a given plane and prevent undesirable rotations.FIG. 18B shows a pattern with more adhesive183 spots in a linear array pattern.FIG. 18C shows a pattern having a concentric ring of adhesive183 located around anaperture185 in theadhesive portion110 through which a cannula is inserted (described below). In some cases the concentric ring of adhesive183 is discontinuous and/or spaced radially away from theaperture185.FIG. 18D shows a pattern having, relative to the device's longitudinal axis, diagonally oriented adhesive183 strips (in other embodiments, the strips can be linear, curved, etc.). Many other examples of adhesive patterns are possible.

The adhesive patterns described above can be applied on either theskin surface side110aor thedevice surface side110bof theadhesive portion110. For example,FIG. 19 shows the linear array adhesive spot pattern ofFIG. 18B on theskin surface side110aof theadhesive portion110. As another example,FIG. 20 shows the three adhesive spot pattern ofFIG. 18A on thedevice surface side110bof theadhesive portion110.

In embodiments in which thedevice100 is a patch pump, once thedevice100 is adhered to the skin surface of the patient, a fluidic connection can be established between the reservoir(s)106 of thedevice100 and the subcutaneous tissue. In general any prior known technique for inserting a cannula into the subcutaneous tissue can be used to fluidically couple theabove device100 to subcutaneous tissue. In addition, a new inventive technique for establishing the fluidic connection is described herein.

Various embodiments of this description relate to acannula insertion mechanism200. In some instances, thecannula insertion mechanism200 can be a standalone component attachable to thepump100, when thepump100 is adhered to the skin surface of the patient. In some instances, like thedisposable part102 andvial adapter150, thecannula insertion mechanism200 can be distributed to the patient in sterilized packaging.FIGS. 21A-21C illustrate an example configuration and operation of themechanism200, according to certain embodiments. Themechanism200 may include, for example, atorsion spring202 that rotates acam204. Thecam204 has aneccentric link206 attached to acannula plunger208. Thecannula plunger208 includes anupper portion210 fixedly attached to aneedle214 and alower portion212 that holds a cannula216 (e.g., a flexible cannula), such that thecannula216 is mounted on theneedle214. Before thecannula216 is delivered, thetorsion spring202 is prevented from rotating by apin218. In operation, when a user presses abutton220, thepin218 is displaced allowing thetorsion spring202 to rotate thecam204. As shown inFIG. 21B, in the example embodiment, during a first stage of delivery, rotation of thetorsion spring202 initially causes thecannula plunger208 to displace downwards, causing insertion of both theneedle214 and thecannula216 into the subcutaneous tissue of the patient. At the bottom of stroke, thelower portion212 of thecannula plunger208 is held in place (e.g., via a notch and groove assembly,222 and224). As shown inFIG. 21C, in the example embodiment, during the second stage of delivery, as thetorsion spring202 continues to rotate thecam204, theupper portion210 of thecannula plunger208 is displaced upward removing theneedle214 from the subcutaneous tissue, while leaving thecannula216 in place. Once thecannula216 is in place, the cannula insertion mechanism200 (e.g., including thetorsion spring202, thecam204, theeccentric link206, theupper portion210, and the needle214) can be removed from thedevice100, while leaving thelower portion212 andcannula216 in place to deliver fluid from thereservoir106 to the subcutaneous tissue.

In some instances, thecannula216 is hollow and fluid flows through a central hollow void out of thetip215 of thecannula216. In other instances, thecannula216 forms at least onedelivery aperture217 in aside wall219 of thecannula216, as shown for example inFIGS. 22A and 22B. In some cases, thecannula216 can form a plurality ofdelivery apertures217 formed at different heights along theside wall219 of thecannula216. Thedelivery apertures217 can be formed at the same or different circumferential positions about thecannula side wall219. In some cases, theapertures217 are formed equidistant from each other and/or the top or bottom of thecannula216. In other cases, theapertures217 are formed non-equidistant from each other and/or the top or bottom of thecannula216. Thecannula216 can be made of any appropriate material, e.g., stainless steel, silicon, carbon fiber, PTFE, and/or combinations thereof. In some cases, asingle cannula216 can be split into multiple injection tubes. In some embodiments, a cannula comprises a plurality of apertures, and at least two of the plurality of apertures are formed at a different height or the same height along a side wall of the cannula.

In some embodiments, many modifications to themechanism200 shown inFIGS. 21A-21C are contemplated. For example, thetorsion spring202 can be released using structures other than thebutton220 and pin218 assembly. In general any structure that reliably holds, for example, the torsion spring in a compressed position until a user moves the structure and releases the torsion spring can be used. One example can include a pivoting latch. Many other structures are possible. As another example, the insertion force can be provided by structures other than a torsion spring, e.g., a linear spring, a user-applied force, etc. As another example, thelower portion212 of thecannula plunger208 can be held in place using structures other than the notch and

groove assembly

222 and224. In general, any structure that reliably holds thelower portion212 in place once theneedle214 is delivered to the subcutaneous tissue can be used. For example, in some embodiments the holding structure can include an interference fit, flexible fingers, etc.

In some embodiments, thecannula insertion mechanism200 also performs the function of fluidically coupling thereservoir106 to thecannula216, such that fluid evacuated from thereservoir106 is delivered through thecannula216 to the subcutaneous tissue of the patient.FIGS. 23A-23C illustrate the fluidic coupling functionality, according to example embodiments, with reference to the same delivery stages as the cannula placement shown inFIGS. 21A-21C.FIGS. 23A-23C do not show thetorsion spring202 andcam204 portion of thecannula insertion mechanism200, so as to not block certain structures that illustrate the fluidic coupling function. In operation, however, thetorsion spring202 andcam204 portion of thecannula insertion mechanism200 can be attached to thecannula plunger208 shown inFIGS. 23A-23C, to translate theupper portion210 and thelower portion212 into the various depicted positions. The same reference numerals refer to generally the same structures inFIGS. 21A-21C andFIGS. 23A-23C, although the structures have slightly different geometries between the two sets of figures, according to some embodiments.

As described above, in some embodiments, before thecannula216 is inserted into the subcutaneous tissue, thereservoir106 andcannula216 are not fluidically coupled. Thefluid reservoir106 can be sealed by adelivery septum226. Thedelivery septum226 can be different than the fill septum164 (seeFIGS. 23A-23C) or the same as thefill septum164. In addition to holding thecannula216, thelower portion212 of thecannula plunger208 can also include a rigid fluidic link228 (e.g., a needle) in fluidic communication with thecannula216. In such embodiments, during the first delivery stage (seeFIG. 23B), when thecannula216 is placed in the subcutaneous tissue, thelink228 can pierce thedelivery septum226, fluidically coupling thereservoir106 with the cannula216 (i.e., fluid evacuated from thefluid reservoir106 travels through thelink228 into thecannula216, from where it is delivered to the subcutaneous tissue of the patient). As described above, in some instances, during the second delivery stage (seeFIG. 23C), theupper portion210 of thecannula plunger208 is withdrawn with theneedle214, while thelower portion212, thecannula216, and thelink228 remain in place.FIG. 23D is an enlarged view of thelower portion212, thecannula216, and thelink228 in place after the cannula insertion mechanism200 (including thetorsion spring202, thecam204, theeccentric link206, theupper portion210, and the needle214) are removed from thedevice100.

FIGS. 24A-24E illustrate a differentcannula insertion mechanism400 that, in some embodiments, can be used to insert thecannula216 into the subcutaneous tissue and/or fluidically couple thereservoir106 to thecannula216. Similar to thecannula insertion mechanism200 shown inFIGS. 21A-21C, thecannula insertion mechanism400 can be used to deliver acannula plunger208 having anupper portion210 and alower portion212. Parts that are interchangeable (or nearly interchangeable with minor structural changes) between the two

cannula insertion mechanisms

200,400 are referred to with the same reference numerals inFIGS. 21A-21C andFIGS. 24A-25E, although these structures may be depicted with slight geometric differences in the different figures.

In some embodiments, thecannula insertion mechanism400 also uses the rotational force of atorsion spring202. However, instead of being attached to aneccentric link206, thetorsion spring202 can be attached to ahub404. Thetorsion spring202 can attach to thehub404 using any known technique, e.g., a portion of thetorsion spring202 can fit into aslot405 in the hub404 (seeFIG. 24B). Thehub404 can attach to aninner gear406 such that rotation of thehub404 rotates theinner gear406 within anouter gear407. In general, thehub404 andinner gear406 can be attached using any technique, e.g., a slot and pin connection, a notch and groove connection, a shaft connection, etc. Theinner gear406 can also be attached to theupper portion210 of thecannula plunger208. In general, theinner gear406 andupper portion210 can be attached using any known technique, e.g., theinner gear406 can include apin409 that fits into acorresponding slot411 in theupper portion210.

FIGS. 24C-24E illustrate an example operation of thecannula insertion mechanism400, according to certain embodiments.FIG. 24C shows themechanism400 before the cannula is inserted into the tissue. Thetorsion spring202 can be restrained (e.g., prevented from being released) using any technique. For example, thehub404 can be held with a pin that can be released by pressing a button, similar to the configuration shown inFIGS. 21A-21B withpin218 andbutton220. In this approach, thetorsion spring202 can be the only component in tension, which can allow the remainder of theinsertion mechanism400 to be non-stressed. As another example, theinner gear406 can be held with a pin that can be released by pressing a button, similar to the configuration shown inFIGS. 21A-21B withpin218 andbutton220. As another example, theupper portion210 of thecannula plunger208 can be held with a pin that can be released by pressing a button, similar to the configuration shown inFIGS. 21A-21B withpin218 andbutton220. In this approach, freedom of motion between the components of theinsertion mechanism400 can be minimized.

When thetorsion spring202 is released, rotation of thetorsion spring202 rotates thehub404, which causes theinner gear406 to rotate counter clockwise, forcing theupper portion210,lower portion212,cannula216, andneedle214 towards the patient's skin/tissue. Themechanism400 can be adapted or configured such that when theinner gear406 reaches the position within theouter gear407 that is closest to the patient's skin, thecannula216 and theneedle214 are delivered to a desired depth within the patient (seeFIG. 24D). After thecannula216 and theneedle214 are delivered to the desired depth, theinner gear406 can continue rotating withinouter gear407. As in the embodiment described above, theupper portion210 can be fixedly connected to theneedle214 and detachably connected to thelower portion212, such that as theinner gear406 continues to rotate, theupper portion210 is separated from thelower portion212 and theneedle214 is withdrawn from the patient and thecannula216, while thelower portion212 and thecannula216 remain in their delivered position (seeFIG. 24E). In some instances, thecannula insertion mechanism400 can be adapted or configured such that the insertion force (e.g., the force applied to thecannula216/needle214 for insertion into the tissue) remains constant during various portions of the delivery process (e.g., during insertion of thecannula216 and theneedle214 into the tissue and/or during retraction of the needle214).

Thecannula insertion mechanism400 can also fluidically couple thereservoir106 with thecannula216, e.g., by piercing a septum with arigid fluidic link228, in a similar manner to that described with respect to thecannula insertion mechanism200 above. Once thecannula216 is delivered, theinsertion mechanism400, thetorsion spring202, thehub404, theinner gear406, theouter gear407, theupper portion210, and the needle414 can be removed from the device.

Many adaptations to thecannula insertion mechanism400 shown inFIGS. 24C-24E are possible. As one example, althoughFIGS. 24C-24E show theinner gear406 as rotating counter clockwise withinouter gear407, in other embodiments theinner gear406 can rotate clockwise withinouter gear407. As another example, in some embodiments, thehub404 can be attached to theouter gear407, which can be attached to thecannula plunger208 and rotate (e.g., with respect to a fixed inner gear) to deliver thecannula216 into the tissue. As another example, in some embodiments, theinner gear406 and theouter gear407 can be replaced with structures that engage without threads, e.g., a cam and follower connection, a slot and groove connection, etc.

In some embodiments, many other techniques can be used to fluidically couple thereservoir106 and thecannula216. As one example, thetorsion spring202 can be replaced with a linear spring that expands and retracts in a linear fashion to deliver and retract theinsertion needle214. As another example, thelower portion212 can include an aperture (as opposed to the rigid fluidic link228) that fluidically couples thereservoir106 and thecannula216 upon placement of thelower portion212. In other instances, a flexible tubing can couple thereservoir106 to thecannula216. In some cases, the tubing is attached to thelower portion212 and/orcannula216 after placement of thelower portion212.

In some embodiments, multiplecannula insertion mechanisms200 can be used to delivermultiple cannulas216 into the subcutaneous tissue. An example embodiment of thedevice100 havingmultiple cannulas216 is shown inFIG. 25A. In some embodiments, themultiple cannulas216 can be connected to a single reservoir106 (e.g., seeFIG. 25B). In some embodiments including more than onereservoir106, a separatecannula insertion mechanism200 can be used to deliver acannula216 into the subcutaneous tissue corresponding to each reservoir106 (e.g., seeFIG. 25C). In other embodiments including more than one reservoir106 (e.g., when more than onereservoir106 delivers fluid through a single outlet), a singlecannula insertion mechanism200 can be used to deliver asingle cannula216 coupled with more than one reservoir106 (e.g., seeFIG. 25D). In such embodiments, various schemes can be used to control which fluid from which reservoir is delivered through thesingle cannula216 at any given time. An example scheme is shown inFIG. 25E that includes adelivery valve221afor afirst reservoir106aand adelivery valve221bfor asecond reservoir106b. The valves can be independently controllable such that thedelivery valve221acan be open while thedelivery valve221bis closed and vice versa, which can enable delivery of the contents of either

reservoir

106aor106bat a given time. In some cases, both

delivery valves

221aand221bare open which can result in a combination of the contents of

reservoirs

106aand106bbeing delivered at a given time. In some cases, both

delivery valves

221aand221bare closed and none of the contents are delivered. The

delivery valves

221aand221bcan be opened and closed using any technique, e.g., electronically (e.g., with control unit116), with pressure and/or hydrodynamic forces generated within thedevice100, operated as one-way flapper valves, etc. Although the above embodiments were generally described and depicted including two cannulas and/or tworeservoirs106, in various other embodiments any number ofcannulas216 and/orreservoirs106 can be included. For example, 2, 3, 4, 5, 6, 10, or more cannulas can be included and 2, 3, 4, 5, 6, 10, ormore reservoirs106 can be included.

The use ofmultiple cannulas216 and/ormultiple reservoirs106 can have various beneficial advantages For example, the dosage rate can be increased. As another example, thedevice100 can be kept in operation if one of thecannulas216 becomes occluded or otherwise malfunctions. As another example, delivery from themultiple cannulas216 and/orreservoirs106 can be performed in an alternating manner, which can have various advantages (e.g., non-constant use of various components can prolong and/or improve their functionality). Embodiments that includemultiple reservoirs106 can enable the delivery of different drugs either intermittently or simultaneously. For example, as described above, one reservoir can contain levodopa and another reservoir can contain carbidopa. In some cases, the different drugs can be delivered through separate cannulas (e.g., seeFIG. 25C). In other cases, the different drugs can be delivered through the same cannula (seeFIGS. 25D-25E).

In some embodiments, once thedevice100 is coupled with the subcutaneous tissue (e.g., viatubing186 and infusion set192 or via cannula216), thedevice100 can deliver the contents of thereservoir106 to the subcutaneous tissue, in some cases at a particular predetermined rate. In some instances, thedrive component112 can be operative to translate theplunger head120 a predetermined distance over a predetermined time so as to deliver a predetermined amount of fluid over the predetermined time. For example, the drive component112 (e.g., a DC motor) can be operable to rotate a certain amount (e.g., number of rotations) that will causeload gear136 to rotatenut124 a certain number of rotations (e.g., viaplanetary gear130,drive gear132, and idler gear134) that will cause thelead screw122 and theplunger head120 to translate a predetermined distance through thereservoir106 to evacuate a predetermined amount of fluid to the subcutaneous tissue. In some cases, fluid is delivered to the patient in discrete micro step volumes (e.g., one micro step volume can be delivered based on a certain number or fraction of rotations of the lead screw122). The micro step volume and delivery rate can combine to determine how often a micro step volume is delivered to the patient. For example, if the micro step is 5 μl and the delivery rate is 40 μl/hour, then a micro step would be delivered to the patient every 7.5 minutes. In other cases, thedrive component112 operates such that fluid is delivered continuously to the subcutaneous tissue. In other cases, thedrive component112 operates such that fluid is delivered in intermittent cycles (e.g., on cycles (when fluid is being delivered) and off cycles (when fluid is not being delivered)). In embodiments in which thedrive component112 is a motor, the motor shaft can include an optical encoder (e.g., encoder disk) to monitor the rotational movement of the motor. As mentioned, thedrive component112 can be controlled by thecontrol unit116, which in some instances can receive instructions from the fillingstation154 and/or thecomputing device156.

In some embodiments, thedevice100 can include a user interface that the user engages with before thedevice100 begins delivery. For example, the user interface can be a mechanical control button230 (seeFIG. 14). In some cases, the user interface can enable the user to toggle the device through various modes, e.g., a priming mode, a delivery mode, and a pause mode. The priming mode can occur at the start of a dosing cycle with a newdisposable part102 and can include priming the system such that the fluidic pathway from thereservoir106 to the subcutaneous tissue is filled with fluid (e.g., therigid fluidic link228, thelower portion212, and the cannula216). The delivery mode can include delivery of the fluid into the subcutaneous tissue at a desired rate on a desired schedule. The pause mode can include stopping the delivery of fluid (temporarily or permanently), e.g., if thedevice100 needs to be readjusted or removed or for any other reason. In other embodiments, thedevice100 can automatically begin delivering fluid once thecannula216 is delivered into the subcutaneous tissue.

In some embodiments, thedevice100 can include sensors to sense various conditions of thedevice100, the patient, and/or the environment. For example, as shown inFIG. 26, thedevice100 can include anantenna232 that senses adjacent material. Theantenna232 can have asurface234 adjacent to thereservoir106 that senses the fluid level in thereservoir106 and/or the position of theplunger head120 in thereservoir106, which can be used to determine the amount of fluid in the device100 (e.g., by computing unit117). Theantenna232 can also have asurface236 that is substantially parallel with the skin surface of the patient so that theantenna232 can sense a degree of contact between thedevice100 and the skin surface. In some instances, the degree of contact can be measured by measuring an electrical resistivity between at least two locations on thedevice100. In some embodiments, theantenna232 can be a capacitance sensor (e.g., a CapSense® sensor). In some cases, if the degree of contact between thedevice100 and skin surface is insufficient, an indicator unit can communicate an alert to the patient (the indicator unit and alerts are described in greater detail below), or, in some cases halt operation of thedevice100, at least temporarily. Conversely, the patient can also be alerted if the degree of contact is sufficient.

Thedevice100 can include various other types of sensors. For example, the device can include a connection sensor for determining connection between thedisposable part102 and thereusable part104. The connection sensor can include a hall effect sensor that can include a hollow magnet. The sensor can measure an unsymmetrical shape of a metal plate in thedisposable part102 and/or thereusable part104. In some cases, the connection sensor can measure a level of proximity of thedisposable part102 and the reusable part104 (e.g., far apart, closer together, attached, etc.). Thedevice100 can also include physiological sensors for sensing at least one physiological characteristic of the user. The physiological sensors can include; for example (i) a temperature sensor for measuring a skin temperature of the user, (ii) a conductivity sensor for measuring a sweat level of the user, (iii) a movement sensor for measuring body motion of the user, (iv) a neural activity sensor, (v) an oxygen saturation level sensor, (vi) a sound sensor for measuring digestion or bowel activity, (vii) an ECG sensor for detecting a heart rate of the user, and/or (viii) an EMG sensor for detecting a muscle spasm of the user, among many other examples. In some embodiments, some of the above-described sensors can be located remote from thedevice100 and communicate with thedevice100 via a wired and/or wireless connection. As one non-limiting example, the movement sensor can be worn around the patient's neck or wrist and communicate wirelessly with thedevice100.

Thedevice100 can also include functionality sensors for sensing at least one functional parameter of thedevice100. The functional sensors can include, for example, (i) a flow rate sensor for measuring the flow rate of fluid through thedevice100, (ii) a pressure sensor for measuring the pressure of the fluid within the device100 (or the pressure of other locations/components within the device100), (iii) a DC current sensor for measuring the current delivered to thedrive component112, and/or (iv) a temperature sensor for measuring the temperature of the fluid within the device100 (or the temperature of other locations/components within the device100).

FIG. 27A shows an exampleflow rate sensor229. Theflow rate sensor229 can use any flow rate sensing technology, e.g., it can perform echo Doppler measurements to measure the speed of the medicament as it flows through therigid link228 and/or thecannula216. In some instances, measurements from theflow rate sensor229 or another sensor can be used to determine the actual amount of medicament delivered to patient. In some cases, the actual delivery amount and/or rate can be compared to a programmed amount and/or rate to assess the performance of thedevice100 and/or physiological parameters of the patient that may affect delivery (e.g., high and/or low resistivity to injection). The comparison can be performed by thecomputing unit117 of thedevice100, theprocessing unit182 of the fillingstation154, and/or another device (e.g., a smartphone). Delivery parameters can then be changed based on the comparison, if necessary. For example, if the actual delivery amount and/or rate is lower than the programmed amount and/or rate, then thecontrol unit116 can increase the delivery amount and/or rate. Conversely, if the actual delivery amount and/or rate is higher than the programmed amount and/or rate, then thecontrol unit116 can decrease the delivery amount and/or rate.

FIG. 27B shows anexample pressure sensor231. Thepressure sensor231 can use any pressure sensing technology, e.g., it can be a piezo-electric sensor. As shown inFIG. 27B, in some cases, thepressure sensor231 can be placed inside the reservoir106 (e.g., on the plunger head120). In some instances, the pressure measurements can indicate an issue with the functionality of thedevice100. For example, a low pressure measurement can indicate a leak. As another example, a high pressure measurement can indicate an occlusion of thecannula216. In some instances, thepressure sensor231 can provide an indication of the resistivity to injection of a particular injection site. For example, if the pressure of the fluid within the cannula216 (or elsewhere in the device100) is high it can indicate that the injection site into which fluid is being delivered is resistive to the injection. In some instances, if a particular pressure threshold is exceeded, an alert can be generated to change the injection site (or, in some cases, operation of thedevice100 can be halted).

As an alternative or additional technique for determining injection resistivity, the skin impedance can be measured to determine how well the medicament is being absorbed into the body (e.g., by measuring a level of body hydration). For example, if the medicament is not being well absorbed, the skin and/or underlying tissue may have different properties than if the medicament is being well absorbed.FIGS. 27C-27D depict

example electrodes

223a,223bcan be used to measure the skin's impedance (in other embodiments, more or less electrodes can be used).

As shown inFIG. 27C, in some instances, the

electrodes

223a,223bare located directly beneath thedevice100. For example, the

electrodes

223a,223bcan extend through

apertures

225a,225b in theadhesive portion110. In such instances, the

electrodes

223a,223bcan have a spring-like base in order to maintain contact with the patient's skin. As shown inFIG. 27D, in other instances, the

electrodes

223a,223bcan be located outside the area directly under thedevice100. For example, the

electrodes

223a,223bcan extend from thedevice100 via

tab portions

227a,227b. In some embodiments, the

electrodes

223a,223bcan be located on thereusable part104 and/or thedisposable part102. In some instances, the

electrodes

223a,223bcan communicate with thecontrol unit116 to generate a closed feedback system in order to improve (or optimize) fluid delivery rates. For example, if the medicament is not being well absorbed, thecontrol unit116 can decrease (or in some cases increase) the delivery rate and vice versa.

FIG. 27E shows

example temperature sensors

233a,233b. In general, a temperature sensor can be located anywhere on the device. For example, as shown inFIG. 27E, onetemperature sensor233acan be proximate thereservoir106 to measure a temperature of the contents of the reservoir and anothertemperature sensor233bcan be proximate the skin surface to measure the temperature of the patient. The

temperature sensors

233a,233bcan use any temperature sensing technology, e.g., they can be thermocouples, resistance temperature detectors, thermistors, infrared based devices, silicon-based devices, etc.

FIG. 27F shows an example DCcurrent sensor235. The DCcurrent sensor235 can be located at any location on thedevice100, e.g., embedded proximate thedrive component112. The DCcurrent sensor235 can operate using any current sensing technology, e.g., it can be an ampere meter.

Thedevice100 can also include and/or communicate with medicament level sensors. The medicament level sensors can determine an amount and/or concentration of a particular medicament or other analyte within the blood, tissue, muscle, fat, and/or other biological structures of the patient. In general, the medicament level sensor can sense the amount and/or concentration of any detectable medicament, e.g., levodopa, carbidopa, levodopa/carbidopa combinations, insulin, etc. In some instances, the medicament level sensor is a component within thedevice100. In other instances, the medicament level sensor is remote from thedevice100, e.g., an external wearable device, a device implanted within the patient, etc. Remote medicament level sensors can communicate with the device via wired and/or wireless connections.

In some embodiments, thecontrol unit116 can receive signals from the various device sensors (e.g., those mentioned above, among many other examples) and can control thedrive component112 in response to the received signals. In some instances, thecontrol unit116 can also receive input from the clock of the computing unit117 (e.g., the time of day) and can control thedrive component112 to deliver fluid based on input from the clock and/or signals received from the sensors. Examples of information that can be communicated to thecontrol unit116 in signals from the sensors include, e.g., a sleep condition of the user, a food consumption measure for the user, an exercise measure for the user, an amount of movement of the user, a medicament level of the user, a temperature of the user, other physical parameters of the user (e.g., age, height, weight), etc.

As one of many examples, solely for the purpose of illustrating the functionality of thecontrol unit116, thecontrol unit116 can receive a signal from a movement sensor (e.g., accelerometer, gyroscope, etc.) on thedevice100 indicating that the user experienced above average physical activity for the day. In addition, thecontrol unit116 can receive an input from the clock indicating that it is 2 PM and, based on information stored in thememory unit115, thecontrol unit116 can know that according to the patient's normal eating schedule, he will not eat another meal until 5 PM. Under these conditions, thecontrol unit116 can be programmed to know that the user should receive an increased dosage of medicament until 5 PM to maintain a stable health condition. Thecontrol unit116 can then control thedrive component112 based on this determination, e.g., thecontrol unit116 can cause the motor to rotate an additional amount more, to cause theload gear136 to rotatenut124 an additional amount (e.g., viaplanetary gear130,drive gear132, and idler gear134) that will cause thelead screw122 and theplunger head120 to translate an additional distance through thereservoir106 to evacuate an additional amount of fluid to the subcutaneous tissue. In some instances, a drive component module of thecontrol unit116 is used to control thedrive component112. In some embodiments, the control of thedrive component112 can be performed in an adaptive or a dynamic manner. In this context, the term “adaptive” relates to controlling in response to changes in sensed or measured characteristics (e.g., one or more physiological characteristics of the patient). In this context, the term “dynamic” relates to control through forcefully changing operational parameters of thedrive component112.

As another example, thecontrol unit116 can receive a signal from a movement sensor (e.g., accelerometer, gyroscope, etc.) on the device100 (or sometimes remote from the device100) that provides an indication of a medical condition status of the patient. For example, patients with Parkinson's Disease or other CNS disorders (e.g., essential tremor) sometimes exhibit a more pronounced tremor when they are not properly medicated. Based on the signal from the movement sensor, thecontrol unit116 can determine whether the amount of medicament being delivered to the patient should be altered (e.g., increased or decreased). For example, if the signal from the movement sensor indicates that the patient is displaying an abnormally pronounced tremor, thecontrol unit116 can control thedrive component112 to deliver more medicament to the patient. Alternatively, as another example, if the signal from the movement sensor indicates that a patient is moving slowly or sluggishly (a possible side effect of over medication), thecontrol unit116 can control thedrive component112 to deliver less medicament. In some embodiments, the movement sensor and thecontrol unit116 can operate in a closed loop feedback system in order to effect desired movement characteristics of the patient (e.g., reduce a tremor).

As another example, thecontrol unit116 can receive a signal from an ECG sensor measuring the patient's heart rate and/or another movement sensor (e.g., accelerometer) indicating that the patient is exercising or performing another physically strenuous activity. Based on the signal, thecontrol unit116 can alter the dosage of medicament being delivered to the patient (e.g., increase or decrease the dosage). In some cases, the dosage can be altered to varying degrees, corresponding to a variance between the measured heart rate and a resting heart rate.

As another example, thecontrol unit116 can receive a signal from a sound sensor or another sensor indicating that the patient is digesting food (e.g., the sound sensor can detect sounds from the digestive system (e.g., stomach, intestines, bowels) characteristic of food being digested).

In some cases, the sensors can determine a relative amount of food consumed. Based on the signal, thecontrol unit116 can alter the dosage of medicament being delivered to the patient (e.g., increase or decrease the dosage).

As another example, thecontrol unit116 can receive a signal from the medicament level sensor and control thedrive component112 to deliver medicament in response to that signal. For example, if the signal from the medicament level sensor indicates that the medicament level is low, thecontrol unit116 can control thedrive component112 to deliver more medicament. Conversely, if the signal from the medicament level sensor indicates that the medicament level is high, thecontrol unit116 can control thedrive component112 to deliver less medicament (or, in some cases, halt delivery of medicament, at least temporarily). In this way, the medicament level sensor and thecontrol unit116 can form a closed loop feedback system to maintain a desired medicament level.

As another example, thecontrol unit116 can receive a signal from a sensor indicating a sleep condition and/or sleep stage of the user. The sensor can be any type of sensor capable of determining a sleep condition and/or stage, e.g., an accelerometer, a clock, polysomnography devices (e.g., electroencephalogram (EEG) sensors, electrocochleogram (EOG) sensors, electrocardiogram (ECG) sensors, electromyogram (EMG) sensors, oxygen level sensors, breathing/air flow sensors, microphone), etc. Based on the signal, thecontrol unit116 can alter the dosage of medicament being delivered to the patient (e.g., increase or decrease the dosage). In some cases, medicament is only delivered when the patient is in a particular sleep condition or stage. For example, medicament is only delivered if the patient is in REM sleep or deep sleep. In other cases, no medicament is delivered when the patient is in particular sleep conditions or stages. In other cases, medicament is continually delivered, but the dosage is varied depending on the sleep condition and/or stage.

In some embodiments, the dosage can be delivered to control the patient's medical condition/status in accordance with the patient's sleep schedule. As one of many examples, the dosage to a patient with Parkinson's Disease can be controlled such that the patient wakes up in “ON state” (the concepts of “ON state” and “OFF state” relate to stages experiences by a patient with Parkinson's Disease, in which a patient generally feels better during the “ON state” in which a medicament is controlling symptoms and generally feels worse during the “OFF state” in which the medicament is not controlling symptoms; these concepts are well understood by those skilled in the art and should not be confused with the “on period” and “off period” of medicament delivery described elsewhere in this application). In some instances, a user can instruct thecontrol unit116 regarding the patient's sleep schedule, e.g., by inputting a wake-up time and fall-asleep time into a GUI presented by the fillingstation154, thecomputing device156, and/or thedevice100 itself. The sleep schedule may be stored in thememory unit115. For example, if the user inputs a wake up time of 6 AM, thecontrol unit116 can alter the dosage delivery schedule such that the patient will be in “ON state” at 6 AM. The exact delivery schedule will depend on the individual patient, e.g., thedevice100 may switch to delivering more medicament at 2 AM, 4 AM, etc. As another example, if the user inputs a fall asleep time of 10 PM, thecontrol unit116 can alter the dosage delivery schedule such that the patient will not enter “OFF state” until they are already asleep (e.g., not until 11 PM). Many additional examples of altering dosage rates based on the patient's sleep schedule are possible.

In general, thedevice100 can be adapted or configured to alter the dosage amount from an “ON state” amount (e.g., day schedule) to an “OFF state” amount (e.g., night schedule) at any time of day or night.

Delivering medicament to a patient based on the patient's sleep schedule is an example of a delivery profile. As used herein, delivery profile means a schedule on which medicament is delivered to the patient, which in some cases can be based on the activities and/or environment of the patient. In general, thedevice100 is capable of delivering medicament on any schedule within the physical limitations of the device. A few examples include: (i) a delivery profile for a relaxed day at home, which may include delivery of a lower amount of medicament than for a high activity day; (ii) a delivery profile for a high activity day, which may include delivery of a higher amount of medicament than for a relaxed day at home; (iii) a delivery profile for an evening out, which may include delivery of a higher amount of medicament in the evening (e.g., keeping the patient in “ON state” for longer than normal). Many other delivery profiles are possible. In some instances, a user can select pre-programmed delivery profiles from a GUI presented by the fillingstation154, thecomputing device156, and/or another device. In some instances, a user can program thedevice100 to deliver a custom delivery profile.

In some embodiments, thecomputing unit117 can include a module that monitors the control unit116 (or any other unit) and mitigates processing malfunctions (e.g., hang outs, freeze conditions, etc.) In some cases, the monitoring module can be a watchdog. The monitoring module can be implemented on a separate circuit or even a different board from thecontrol unit116. In some instances, the monitoring module can be programmed to receive an acknowledge signal from thecontrol unit116 during a repeating time period. If the monitoring module does not receive an update during a particular time period it can generate a signal to reset thecontrol unit116. Thecomputing unit117 can also verify the device's connection to the cloud (or in some cases theprocessing unit182 can verify the filling station's connection to the cloud).

In some embodiments, thedevice100 can provide information and/or alerts to the patient before, during, and/or after delivery, e.g., based on the data collected by the sensors described above (among many others). Thedevice100 can include any type of indicator unit capable of communication with the patient, e.g., via visual, audible, and/or haptic feedback. The indicator unit can communicate any amount of information collected by the sensors. As one example, the indicator unit can include a single light that communicates the remaining amount of fluid in thereservoir106. For example, the light can be green, yellow, or red depending on the amount of fluid remaining. In some cases the intensity of the signal delivered to the patient can increase as thereservoir106 gets closer to being empty. For example, a warning signal (e.g., a yellow light, a single sound, a single vibration) can be generated when thereservoir106 has a first predetermined amount remaining (e.g., 20%), a replace signal (e.g., a red light, multiple sounds, multiple vibrations) can be generated when thereservoir106 has a second predetermined amount remaining (e.g., 10%), and an emergency replace signal (e.g., flashing red light, repeated sound, repeated vibrations) can be generated when the reservoir is empty (e.g., 5% or less). As another example, the indicator unit can communicate if the patient's medicament level is too high and/or too low (e.g., as determined by the medicament level sensor). As yet another example, the indicator unit can communicate if the device malfunctions and needs to be readjusted or replaced (e.g., if thecontrol unit116 freezes, if pressure in the device is abnormal, if contact with the skin is insufficient, among many other examples). As a further another example, the indicator unit can include a screen display that digitally communicates the data being collected by the sensors (or a subset thereof) to the patient. In some instances, the patient's status can be taken into account when determining the intensity of an alert. For example, if the patient is sleeping, the alert may be more intense (e.g., louder, longer, brighter, etc.) to ensure that the patient is alerted. Alternatively, if the alert is noncritical, the alert may be less intense if the patient is sleeping, so as to not disturb the patient. In some embodiments, the indicator unit can provide many additional feedbacks.

The indicator unit can also provide a feedback when thedisposable part102 andreusable part104 are attached and/or detached. In some instances, if thedisposable part102 andreusable part104 are not properly attached, then operation of the pump cannot occur (e.g., thecontrol unit116 will not initiate the filling and/or delivery operations). In some instances, if thedisposable part102 andreusable part104 become detached during operation of the pump, then the operation can be stopped (e.g., thecontrol unit116 can stop the filling and/or delivery operations). Operations may be initiated (or resumed) once thedisposable part102 andreusable part104 are attached (or reattached).

In some embodiments, all data collected by the sensors described above (among many other examples) can be communicated to the fillingstation154, thecomputing device156, and/or the cloud, as initially described above. In some cases, the data (or a subset thereof) is communicated, processed, and/or displayed in real time as it is being collected (e.g., to alert a caregiver, medical professional, and/or patient to an emergency situation). In other cases, the data (or a subset thereof) is downloaded, processed, and/or displayed solely when thedevice100 is placed in the fillingstation154.

In some embodiments, thedevice100 can include units for additional control over the fluid delivery process. For example, thedevice100 can include atemperature control unit237 that can control the temperature of the fluid and/or other components of thedevice100, as shown for example inFIG. 28. In general, the temperature of the fluid can be controlled to be any advantageous temperature. For example, the temperature of the fluid can be controlled to be within a range from about 4° Celsius to about 40° Celsius. Many other temperature ranges are contemplated. For example, in some embodiments, every integer value within the range of about 4° Celsius to about 40° Celsius (e.g., 5° C., 6° C., 7° C., etc.) can be a minimum or a maximum within a subrange with any other integer value within the range. A few example temperature ranges include about 8° C. to about 15° C., about 22° C. to about 37° C., and about 32° C. to about 42° C.. In some instances, thetemperature control unit237 can control the temperature of the drug to be within an effective range for that particular drug. In embodiments in which thedevice100 contains multiple drugs, each drug can be maintained at a different temperature (or within a different temperature range). In other instances, all drugs can be maintained at the same temperature (or within the same temperature range).

Thetemperature control unit237 can include components that heat, cool, and/or thermally isolate the fluid. In general, thetemperature control unit237 can include any components capable of performing these actions, e.g., a heating element, a cooling element, a thermoelectric module, a thermally isolating jacket, etc. In some instances, thetemperature control unit237 can heat and/or cool the fluid while it is in thereservoir106. In some instances, thetemperature control unit237 can heat and/or cool the fluid while it is in thecannula216. In some embodiments, thetemperature control unit237 can include a temperature sensor (seeFIG. 27E) for sensing fluid temperature at various locations in thedevice100, that can be used as an input to thecontrol unit116 and/or another components. In some instances, thetemperature control unit237 includes a temperature sensor at the delivery site from the cannula216 (e.g.,tip215 and/or sidewall aperture217), as shown for example bysensor233c. Based on the measurements from the temperature sensor the unit can heat and/or cool the fluid using various techniques (e.g., thermoelectric techniques that use the Peltier effect).

In some embodiments, thedevice100 can include a skin/tissueproperty control unit239 used for controlling the properties of the skin surface at a delivery site, as shown for example inFIG. 29A. In general any property of the skin can be controlled. For example, the skin/tissueproperty control unit239 can include a vibration unit that causes ultrasonic vibration of the skin/tissue, which can facilitate easier introduction and/or disbursement of the medicament within the tissue. As another example, the skin/tissueproperty control unit239 can prepare the skin for cannula insertion and/or medicament delivery. For example, thecontrol unit239 can include an agent delivery unit that can delivery lubricating agents, therapeutic agents, etc., that can enhance the receptiveness of the skin/tissue to thecannula216 and/or fluid. Many other examples are possible.

In some embodiments, thedevice100 can include a skin/tissue detection unit241 for detecting the properties of the tissue that surround thecannula216, e.g., once thecannula216 is delivered into the tissue. An example skin/tissue detection unit241 is shown inFIGS. 29B-C. In some cases, thedetection unit241 can determine the type of biological material (e.g., tissue) surrounding the cannula216 (e.g., dermis, skin, fat, blood vessel, bone, muscle, etc.) For example, the type of biological material can be identified by measuring the impedance between two

electrodes

243a,243blocated on thecannula216. The measured impedance can be mapped to known values for various biological materials.

In some embodiments, thedevice100 can include acannula opening unit245 for opening an occluded or partiallyoccluded cannula216, as shown for example inFIG. 30. For example, thecannula216 may be occluded with medicament, skin, tissue, and/or other matter. In general, any technique for opening thecannula216 can be used. For example, theopening unit245 can be a vibrating unit that applies ultrasonic vibrations to thecannula216. As another example, a suction force can be applied to thecannula216. As yet another example, thecannula216 can be heated (e.g., q tip heating) and/or cooled.

In some embodiments, thedevice100 can include a depthpenetration control unit247 for controlling the depth (or altitude) to which thecannula216 and/or theneedle214 is inserted into the skin/tissue, as shown for example inFIG. 31. For example, theunit247 can be used to penetrate the skin/tissue up to a depth dl, e.g., to avoid undesirable contact with the patient's muscle, bone, organs, etc., which may located at additional depth d2. In some instances, the unit can include a sensor that performs subcutaneous inspection, e.g., via an optical system that delivers and receives infrared (or other wavelength) waves into the body at an identified treatment site. If the optical system identifies that there is an undesirable structure located at a depth to which thecannula216 and/or theneedle214 will be delivered, then the delivery system can be deactivated. This can be accomplished in many ways, e.g., blocking an aperture through which thecannula216 and/or theneedle214 is delivered. In other embodiments, the depthpenetration control unit247 can deliver theneedle214 and/or thecannula216 further into the tissue to a desired position and/or retract theneedle214 and/or thecannula216 back to a desired position. In some embodiments, the adjustment of theneedle214 and/or thecannula216 position can be automatically controlled (e.g., bycontrol unit116 or by a controller of the cannula insertion mechanism200). In other embodiments, a manual technique can be used in which the user can manually adjust the position of theneedle214 and/or the cannula216 (e.g., by manipulating thecannula insertion mechanism200 and/or by deliveringneedles214 and/orcannulas216 of varying lengths).

As mentioned above, the patient can receive a signal (e.g., visual, audible, and/or haptic feedback) when thereservoir106 is empty or close to empty. At this point, the patient can remove the device100 (e.g., disconnect a standalone pump from the belt and infusion sets192, remove a patch pump from a skin surface, etc.), detach thedisposable part102 from thereusable part104, dispose of thedisposable part102, attach thereusable part104 to a newdisposable part102, and repeat the filling and delivery process described above.

FIG. 32 is a flowchart showing example daily steps300 that can be taken by patients using thedevice100. Atstep302, the patient can prepare new parts to be used (e.g., the disposable part (including attached vial adapter) and the vial). Atstep304, the patient can remove the previous day's device from the skin (e.g., remove the adhesive layer from the skin). Atstep306, the patient can detach the reusable part from the previous disposable part and dispose of the previous disposable part. Atstep308, the patient can attach the reusable part to the new disposable part (including attached vial adapter) and place the assembled device into the filling station. Atstep310, the patient can insert a new vial into the vial adapter. Atstep312, the patient can initiate the filling process by inputting instructions to the filling station and/or the computing device. Atstep314, once the filling process is complete, the patient can remove the device from the filling station and detach the vial adapter and the vial from the device and dispose of the vial adapter and the vial. Atstep316, the patient can locate a new infusion site and clean it (e.g., with an alcohol wipe). Atstep318, the patient can remove a liner from the adhesive portion and place the device on the cleaned infusion site. Atstep320, the patient can attach the cannula insertion mechanism to the device and activate the cannula insertion mechanism (e.g., by pressing a button). Atstep322, the patient can remove the cannula insertion mechanism from the device and dispose of it. Atstep324, the patient can initiate the delivery process (e.g., by pressing a button on the device). After the reservoir is depleted, the steps300 can be repeated. In some embodiments, some or all of the above steps300 can be performed by someone other than the patient (e.g., caregiver, medical professional, etc.) Further the above steps300 are provided for purposes of example only; in other embodiments, some of the above steps are not performed and other steps are performed.

FIG. 33 is a chart providing minimum, maximum, and nominal values for certain parameters related to the configuration and operation of thedevice100, according to some embodiments. Every value between the minimum value and the maximum value for each parameter shown inFIG. 33 (not just the nominal value), is contemplated and expressly supported herein, subject to the number of significant digits expressed in each particular range.

Fluid Medicaments

Contemplated liquid medicaments may include an o-quinone scavenger selected from the group consisting of: ascorbic acid and/or a salt thereof, L-cysteine, NAC, glutathione, diacetylcystine and/or a salt thereof, and a combination thereof. A formulation may further include about 0.1% to about 10% by weight ascorbic acid or a salt thereof and a component selected from the group consisting of about 0.01% to about 1% by weight of NAC, about 0.01% to about 1% by weight Lcysteine, about 0.001% to about 1% by weight glutathione, about 0.001% to about 1% by weight diacetylcystine or a salt thereof, or any combination thereof.


Components	Exemplary Amount	Exemplary amount

Levodopa	0-16%	5-7%
Carbidopa	0.1-6%	0.6-1.5%
Arginine	0.1-40%	14-16%
Ascorbic acid or Na	0.1-10%	03-0.7%
ascorbate
L-cysteine or NAC or	0.01-1%	03-0.5%
glutathione

In particular embodiments, the formulation includes about 2% to about 8% by weight levodopa, about 0.1% to about 3% by weight carbidopa, about 10% to about 25% by weight arginine, about 0.1% to about 10% (e.g., about 0.3% to about 2%) by weight ascorbic acid or a salt thereof, and about 0.001% to about 5% by weight L-cysteine or a salt thereof. In other embodiments, the formulation includes: about 8% to about 16% by weight levodopa; about 1% to about 4% by weight carbidopa; about 12% to about 40% by weight of a component selected from the group consisting of arginine, or of meglumine, or a combination thereof; about 0.1% to about 10% by weight ascorbic acid or a salt thereof; about 0.001% to about 1% by weight L-cysteine or a salt thereof, or any combination of the aforesaid. In these embodiments, the formulation has less than about 0.5 or 0.1 μg/ml hydrazine (e.g., less than about 0.05 or less than about 0.01 μg/ml hydrazine), as determined by GCMS. The formulation may include the components in the following Tables:


Components	Exemplary Amount	Exemplary amount

Levodopa	4-8%	5-7%
Carbidopa	0.5-2%	0.6-1.5%
Arginine	13-18%	14-16%
Ascorbic acid	0.1-2%	0.3-0.7%
L-cysteine, cysteine HCl,	0.1-2%	0.3-0.5%
and/or N-acetyl cysteine


Components	Exemplary Amount	Exemplary amount

Levodopa	10-15%	12-15%
Carbidopa	1.2-4%	2-4%
Arginine/meglumine or a	25-40%	30-38%
combination thereof
Ascorbic acid or sodium	0.1-2%	0.3-0.7%
ascorbate
L-cysteine or cysteine-HCl	0.1-1%	0.2-0.5%

In other particular embodiments, the formulation includes about 2% to about 8% by weight levodopa, about 0.1% to about 3% by weight carbidopa, about 10% to about 25% by weight arginine, about 0.1% to about 10% by weight ascorbic acid or a salt thereof, and about 0.001% to about 5% by weight NAC. In other embodiments, the formulation includes: about 8% to about 16% by weight levodopa; about 1% to about 4% by weight carbidopa; about 12% to about 40% by weight of a component selected from the group consisting of arginine, or meglumine, or a combination thereof; about 0.1% to about 10% by weight ascorbic acid or a salt thereof; about 0.001% to about 1% by weight NAC, or any combination of the aforesaid. In these embodiments, the formulation has less than about 0.5 μg/ml or less than about 0.1 μg/ml hydrazine (e.g., less than 0.05 μg/ml or less than about 0.01 μg/ml hydrazine), as determined by GCMS. The formulation may include the components in the following Tables:


Components	Exemplary Amount	Exemplary amount

Levodopa	4-8%	5-7%
Carbidopa	0.5-2%	0.6-1.5%
Arginine	13-18%	14-16%
Ascorbic acid	0.1-2%	0.3-0.7%
NAC	0.1-2%	0.3-0.5%


Components	Exemplary Amount	Exemplary amount

Levodopa	10-15%	12-15%
Carbidopa	1.2-4%	2-4%
Arginine/meglumine or a	25-40%	30-38%
combination thereof
Ascorbic acid or sodium	0.1-2%	0.3-0.7%
ascorbate
NAC	0.1-1%	0.2-0.5%

In particular embodiments, the formulation includes about 2% to about 8% by weight levodopa, about 0.1% to about 3% by weight carbidopa, about 10% to about 25% by weight arginine, about 0.1% to about 10% by weight ascorbic acid or a salt thereof, and about 0.001% to about 5% by weight glutathione. In other embodiments, the formulation includes: about 8% to about 16% by weight levodopa; about 1% to about 4% by weight carbidopa; about 12% to about 40% by weight of a component selected from the group consisting of arginine, or meglumine, or a combination thereof; about 0.1% to about 10% by weight ascorbic acid or a salt thereof; about 0.001% to about 1% by weight glutathione, or any combination of the aforesaid. In these embodiments, the formulation has for example less than about 0.5 μg/ml or less than about 0.1 μg/ml hydrazine (e.g., less than about 0.05 μg/ml or less than about 0.01 μg/ml hydrazine), as determined by GCMS. The formulation may include the components in the following Tables:


Components	Exemplary amount	Exemplary amount

Levodopa	4-8%	5-7%
Carbidopa	0.5-2%	0.6-1.5%
Arginine	13-18%	14-16%
Ascorbic acid	0.1-2%	0.3-0.7%
Glutathione	0.1-2%	0.3-0.5%


Components	Exemplary amount	Exemplary amount

Levodopa	10-15%	12-15%
Carbidopa	1.2-4%	2-4%
Arginine/meglumine or a	25-40%	30-38%
combination thereof
Ascorbic acid or	0.1-2%	03-0.7%
sodium ascorbate
Glutathione	0.1-1%	0.2-0.5%

In particular embodiments, the formulation includes about 2% to about 8% by weight levodopa, about 0.1% to about 3% by weight carbidopa, about 10% to about 25% by weight arginine, about 0.1% to about 10% by weight ascorbic acid or a salt thereof, and about 0.001% to about 5% by weight diacetylcystine or a salt thereof. In other embodiments, the formulation includes: about 8% to about 16% by weight levodopa; about 1% to about 4% by weight carbidopa; about 12% to about 40% by weight of a component selected from the group consisting of arginine, or meglumine, or a combination thereof; about 0.1% to about 10% by weight ascorbic acid, and/or a salt thereof; about 0.001% to about 1% by weight diacetylcystine or a salt thereof, or any combination of the aforesaid. In these embodiments, the formulation has for example less than about 0.5 μg/ml or less than about 0.1 μg/ml hydrazine (e.g., less than 0.05 μg/ml or less than 0.01 μg/ml hydrazine), as determined by GCMS. The formulation may include the components in the following Tables:


Components	Exemplary amount	Exemplary amount

Levodopa	4-8%	5-7%
Carbidopa	0.5-2%	0.6-1.5%
Arginine	13-18%	14-16%
Ascorbic acid	0.1-2%	03-0.7%
Diacetylcystine	0.1-2%	03-0.5%


Components	Exemplary amount	Exemplary amount

Levodopa	10-15%	12-15%
Carbidopa	1.2-4%	2-4%
Arginine/meglumine or a	25-40%	30-38%
combination thereof
Ascorbic acid or	0.1-2%	0.3-0.7%
sodium ascorbate
Diacetylcystine	0.1-1%	0.2-0.5%

The formulation of any of the above embodiments may include a surfactant. The surfactant may be any of one of

polysorbate

20, 40, 60, or 80, or any combination thereof. In particular embodiments, the formulation includes about 0.01% to about 5% surfactant (e.g., polysorbate 80) or about 0.1% to 0.5% surfactant (e.g., polysorbate 80). In more particular embodiments, the formulation includes about 0.3% surfactant (e.g., polysorbate 80).

The formulation of any of the above embodiments may include about11% to about 15% by weight levodopa. For example, the formulation may include about 12% to about 14% by weight levodopa (e.g., about 12% or about 13.2% levodopa).

The formulation of any of the above embodiments may include about 0.6% to about 4%, about 0.8% to about 3%, or about 1.2% to about 4% by weight carbidopa. For example, the formulation may include about 2.5% to about 3.5% (e.g., about 3.0% or about 3.3%) by weight carbidopa.

The formulation of any of the above embodiments may include about 25% to about 40% (e.g., about 32% to about 40%, about 32%, or about 36%) by weight of a component selected from the group consisting of arginine, or meglumine, or a combination thereof. For example, the formulation may include about 32% arginine, about 32% meglumine, about 36% arginine, or about 36% meglumine.

The formulation of any of the above embodiments may, after storage for 1, 2, 3, 4, 6, 8, 10, 12, 15, 18, 20, or 24 hours; 1, 2, 3, 5, 7, 10, 14, 21, 28, or 30 days; 1, 2, 3, 4, 6, 9, or 12 months; or 1, 1.5, 2, 2.5, or 3 years, at 25° C., 2-8° C. or at −20° C., have less than about 0.1 μg/ml of hydrazine, as determined by GCMS. The formulation of any of the above embodiments may have less than about 5% (e.g., less than about 4%, 3%, 2%, 1%, 0.5%, 0.3%, 0.2%, 0.1% or 0.05%) byweight 3,4dihydroxyphenyl-2-methylpropionic acid (Degradant RRT 1.4), relative to the amount of carbidopa, as determined by HPLC.

The formulation of any of the above embodiments may be in a form selected from the group consisting of a liquid, a gel, a cream, a solid, a film, an emulsion, a suspension, a solution, an aerosol (e.g., a liquid formulation) or any combination of the aforesaid.

In some embodiments, a contemplated liquid medicament features a pharmaceutically acceptable liquid formulation including about 4% to about 8% (e.g., about 6%) by weight levodopa, about 0.1% to about 1.5% (e.g., about 0.6% to about 1.4%, about 0.75%, or about 1.4%) by weight carbidopa, about 10% to about 20% (e.g., about 15% to about 16%, about 15.2%, or about 15.6%) by weight arginine, and about 0.1% to about 1.5% (e.g., about 0.4% to about 1%, about 0.4% to about 0.6%, or about 0.5%) by weight ascorbic acid or a salt thereof, In such embodiments the formulation, after 1 day at 25° C., after 30 days at 25° C., or after 180 days at 25° C., has less than about 1.0, less than about 0.75 μg/ml, less than about 0.5 μg/ml, less than about 0.2 μg/ml, less than about 0.1 μg/ml, or less than about 0.05 μg/ml hydrazine, as determined by GCMS. The formulation may further include about 0.1% to about 0.7% (e.g., about 0.4% or about 0.5%) by weight of L-cysteine or NAC. In a particular embodiment, the formulation includes (a) about 0.4% to about 0.6%, or about 0.4 to about 1% by weight ascorbic acid or a salt thereof; and (b) about 0.1% to about 0.7% by weight of L-cysteine or NAC. In this aspect, the formulation may further include about 0.1% to about 0.5% (e.g., about 0.3%) by weight Tween-80.

In some embodiments, a liquid medicament features a pharmaceutically acceptable liquid formulation including: about 8% to about 16% (e.g., about 12% to about 15%, about 12%, or about 13.2%) by weight levodopa; about 1% to about 4% (e.g., about 3.0% or about 3.3%) by weight carbidopa; about 20% to about 42% (e.g., about 32% to about 42%, about 32%, or about 36%) by weight of a component selected from the group consisting of arginine, or meglumine, or a combination thereof; about 0.1% to about 1.5% (e.g., about 1.0% to about 1.4%, about 1.2%, or about 1.3%) by weight ascorbic acid or a salt thereof (e.g., sodium ascorbate), e.g., where the formulation, after 1, 2, 3, 4, 6, 8, 10, 12, 15, 18, 20, or 24 hours; 1, 2, 3, 5, 7, 10, 14, 21, 28, or 30 days; 1, 2, 3, 4, 6, 9, or 12 months; or 1, 1.5, 2, 2.5, or 3 years at 25° C., has less than about 1.0, less than about 0.75 μg/ml, less than about 0.5 μg/ml, less than about 0.2 μg/ml, less than about 0.1 μg/ml, or less than about 0.05 μg/ml hydrazine as determined by GCMS. The formulation may further include about 0.1% to about 1% (e.g., about 0.1% to about 0.5%, about 0.3%, or about 0.5%) of L-cysteine or salt thereof (e.g., cysteine HCl) or NAC. In a particular embodiment, the formulation includes about 0.1% to about 0.5% of L-cysteine or NAC, and about 1.0 to about 1.4% by weight ascorbic acid or a salt thereof, or any combination of the aforesaid.

In certain embodiments, a liquid medicament can include about 0.1% to about 10% carbidopa, e.g., about 0.5% to about 8%, about 0.6% to about 5%, about 0.1% to about 1%, about 1% to about 2%, particularly about 0.75%, about 1.4%, or about 4% carbidopa. For example, a disclosed formulation can include about 1% to about 3% by weight, about 2.5% to about 3.5% by weight, about 0.6% to about 4% by weight, or about 1.2% to about 4% by weight carbidopa. In certain embodiments, disclosed compositions include about 0.01% to about 6% by weight carbidopa, about 0.1% to about 6% by weight carbidopa, or about 1% about to about 4% by weight carbidopa, e.g., about 0.6% to about 4% or about 1.2% to about 3% or about 4% by weight carbidopa.

In certain embodiments, the formulation can include arginine, and/or meglumine, or a salt thereof or any combination thereof. For example, a disclosed formulation can include about 0.1% to about 42%, e.g., about 1% to about 10%, about 12% to about 18%, about 0.1% to about 40%, about 2% to about 7%, about 3.2%, about 3.4%, about 3.6%, about 3.7%, or about 4.6% arginine and/or meglumine, or a salt thereof or any combination thereof. In other embodiments, disclosed formulations include about 10% to about 20%, about 10% to about 25%, about 12% to about 18%, about 12.8%, about 14.8%, about 15.2%, about 15.5%, or about 18.5% arginine and/or meglumine or a salt thereof or any combination thereof. In certain embodiments, arginine, meglumine, a salt thereof, or any combination thereof are present at about 25% to about 40%, about 30% to about 38%, about 32% or about 36%.

The formulations can include levodopa. For example, in certain embodiments the formulation includes about 1% to about 20% levodopa, e.g., about 2% to about 8%, about 4% to about 7%, about 5%, or about 6% levodopa. In other embodiments, the formulations include about 8% to about 20%, about 8% to about 16%, about 10% to about 14%, about 11% to about 14%, about 12%, or about 13.2% levodopa. A disclosed formulation can have a molar ratio of carbidopa to arginine (or meglumine) of about 1:1 to about 1:25 or of about 1:1 to about 1:35.

The formulations can include one, two, or more anti-oxidants or o-quinone scavenger agents. For example, a disclosed formulation can include one, two, or more of an agent each independently selected from the group consisting of ascorbic acid, a salt thereof (e.g., sodium ascorbate, calcium ascorbate, potassium ascorbate, ascorbyl palmitate, or ascorbyl stearate, particularly sodium ascorbate), cysteine or a cysteine derivative (e.g., L-cysteine, Nacetylcysteine (NAC), glutathione, diacetylcystine, S-methyl-N-acetylcysteine amide, an acetyl derivative of S-methyl-N-acetylcysteine methylhydrazide, S-methylcysteine morpholineamide, Smethyl-N-acetylcysteine morpholineamide, or a salt thereof), or any suitable combination thereof. For example, a disclosed formulation can include ascorbic acid or a salt thereof, and a cysteine derivative, such as NAC.

The formulations can include other antioxidants, such as di-tert-butyl methyl phenols, tert-butyl-methoxyphenols, polyphenols, tocopherols, and ubiquinones (e.g., caffeic acid).

The formulations can also include a tyrosinase inhibitor. Exemplary tyrosinase inhibitors include captopril, methimazole, quercetin, arbutin, aloesin, N-acetylglucoseamine, retinoic acid, atocopheryl ferulate, MAP (Mg ascorbyl phosphate), substrate analogues (e.g., sodium benzoate, Lphenylalanine), and Cu⁺⁺ chelators (for example, Na₂-EDTA, Na₂-EDTA-Ca, DMSA (succimer), DPA (D-penicillamine), trientine-HCl, dimercaprol, clioquinol, sodium thiosulfate, TETA, TEPA, curcumin, neocuproine, tannin, and cuprizone).

The formulations can include ascorbic acid or a salt thereof (e.g., sodium ascorbate). For example, disclosed formulations can include 0.1% to about 10% or more ascorbic acid (or a salt thereof), or about 0.1% to about 2%, e.g., about 0.2% to about 1.5%, about 0.2% to about 2.0%, about 0.2% to about 2.5%, about 0.3% to about 1.2%, e.g., about 0.4%, about 0.5%, about 0.75%, about 0.85%, or about 1.0% by weight ascorbic acid. For example, a disclosed formulation can include about 0.8% to about 1.3% or about 1% to about 2.5% by weight ascorbic acid or a salt thereof. In a particular embodiment, a disclosed formulation can include about 0.5% to about 0.85%, or, e.g., about 0.5%, about 0.75%, about 0.85%, about 1.0%, about 1.2%, or about 1.3% by weight sodium ascorbate or ascorbic acid.

In particular embodiments, the formulations can include a bisulfite, e.g., sodium bisulfite or one or more other sulfite salts, e.g., sodium hydrogen sulfite or sodium metabisulfite. In some embodiments, the formulations can include for example, NAC, L-cysteine, diacetylcystine, and/or glutathione. In particular embodiments, the formulations include about 0.001% to about 5%, about 0.01% to about 5%, about 0.1% to about 5%, about 0.001% to about 1%, about 0.01% to about 1%, or about 0.1% to about 1% by weight of each of NAC, L-cysteine, diacetylcystine, and/or glutathione. For example, a disclosed formulation can include about 0.01% to about 5%, e.g., about 0.05% to about 1%, about 0.1% to about 0.6%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, or about 0.5% of NAC and/or L-cysteine. In a particular embodiment, a disclosed formulation includes about 0.4% or about 0.5% NAC. In another particular embodiment, a disclosed formulation includes about 0.3%, about 0.4%, or about 0.5% L-cysteine.

For example, a formulation can include ascorbic acid (or a salt thereof) and a cysteine derivative, e.g., L-cysteine and/or NAC. In an exemplary embodiment, a disclosed formulation includes about 0.1% to about 10% ascorbic acid (or a salt thereof) and about 0.001% to about 5% or about 0.001% to about 1% by weight of each of L-cysteine and/or NAC and/or diacetylcystine and/or glutathione. In particular embodiments, the composition includes ascorbic acid and Lcysteine, sodium ascorbate and NAC, ascorbic acid and NAC, sodium ascorbate and L-cysteine, ascorbic acid and diacetylcystine, sodium ascorbate and diacetylcystine, ascorbic acid and glutathione, or sodium ascorbate and glutathione.

Contemplated formulations are liquid, and can include a surfactant. For example,

polysorbate

20, 40, 60, or 80 may be present in a disclosed formulation at, e.g., about 0.01% to about 5%, about 0.1% to about 0.5%, e.g., about 0.3

% polysorbate

20, 40, 60, and/or 80. In particular embodiments, polysorbate 80 is present at about 0.3%.

Such formulations or solutions can have a pH that is pharmaceutically acceptable for subcutaneous administration, e.g., a pH of about 8 to about 10, for example, about 9.1 to about 9.8, e.g., 9.2 to 9.6, at 25° C.

In particular embodiments, a liquid medicament is one of those in Tables 1 and 2.

TABLE 1

				Ascorbic
DS (%)	LD	CD	Arginine	Acid	L-Cysteine	NAC	Tween-80	pH

1	6	1.4	15.5	0.5	0.4	—	0.3	9.4-9.6
2	6	1.4	15.5	0.5	—	0.5	0.3	9.4-9.6
3	6	0.75	15.2	0.5	0.4	—	0.3	9.4-9.6
4	6	0.75	15.2	0.5	—	0.5	0.3	9.4-9.6
Margins	6	0.6-1.4	15-16	0.5	0.4	0.5	0.3	9.4-9.6

TABLE 2

DS					Sodium	L-		Cysteine-	Tween-
(%)	LD	CD	Arginine	Meglumine	Ascorbate	Cysteine	NAC	HCl	80	pH

1	12	3	32	—	1.2	0.3	—	—	—	9.6-9.8
2	13.2	3.3	36	—	1.3	0.3	—	—	—	9.6-9.8
3	13.2	3.3	—	36	1.3	0.3	—	—	—	9.6-9.8
4	12	3	—	32	1.2	—	0.3	—	—	9.6-9.8
5	12	3	32	—	1.2	—	0.3	—	—	9.6-9.8

	*	**

*Can replace L-cysteine.
**Optionally added to stabilize the formulation

In other embodiments, the fluid medicament may include apomorphine and an organic acid or an amino acid. As used herein, the term “organic acid” refers to an organic compound with acidic properties such as carboxylic acids, dicarboxylic acids, sulfonic acids, alcohols, hydroxy acids, thiols, and thio-acids. For example, the organic acids for use in the formulation may contain at least two, at least three, or at least four carbon atoms, e.g., tartaric acid. Examples of organic acids include, but are not limited to, amino acids such as aspartic acid, glutamic acid, and arginine, and dicarboxylic acids such as fumaric acid, oxalic acid, malonic acid, succinic acid, glutaric acid, maleic acid, and the like. Further examples of organic acids include lactic acid, malic acid, aconitic acid, citric acid, alycolic acid, ascorbic acid, formic acid, acetic acid, tartaric acid, and glucuronic acid. Exemplary organic acids include, but are not limited to, amino acids, carboxylic acids, and dicarboxylic acids. For example, contemplated carboxylic acids and/or dicarboxylic acids for use in the composition may contain at least two, at least three, or at least four carbon atoms, e.g., tartaric acid. Contemplated dicarboxylic acids for use in the claimed formulations may be hydrophilic or substituted with hydrophilic groups, e.g., hydroxyl groups. Contemplated amino acids for use in the claimed formulations may be, without limiting, acidic natural amino acids such as aspartic acid or glutamic acid, or acidic unnatural amino acids such as cysteic acid. The term “natural amino acid” refers to any of the amino acids found in proteins. Examples of natural amino acids include, but are not limited to, alanine, arginine, aspartic acid, glutamic acid, histidine, lysine, and the like. The term “non-natural amino acid” refers to non-proteinogenic amino acids that either occur naturally or are chemically synthesized. Examples of non-natural amino acids include, but are not limited to, ornithine, β-alanine, 2-aminoadipic acid, 3-aminoadipic acid, y-carboxyglutamic acid, hydroxylysine, 4-guanidinobutyric acid, 3-guanidinopropionic acid, 4-azidobutanoic acid, 5azidopentanoic acid, and the like. Both D- and L- amino acids are contemplated herein.

In certain embodiments, the liquid medicament further comprises a local anaesthetic, i.e., a drug which causes a reversible loss of sensation for a limited region of the body while maintaining consciousness, and/or an anti-inflammatory agent. Examples of local anaesthetics include, without limitation, amide based local anaesthetics such as lidocaine, prilocaine, bupivicaine, levobupivacaine, ropivacaine, mepivacaine, dibucaine, and etidocine, and ester based local anaesthetics such as procaine, amethocaine, cocaine, benzocaine, and tetracaine. Examples of anti-inflammatory agents include, without limitation, non-steroidal anti-inflammatory agents such as diclofenac, ketorolac, salicylates ibuprofen, piroxicam, and benzydamine, and steroidal anti-inflammatory agents such as prednisone, dexmethasone, betamethasone, prednisone hydrocortisone, and salts thereof.

The pharmaceutical composition may be a liquid solution, i.e., a substantially homogeneous liquid mixture at room temperature, e.g., at 25° C., or a semisolid solution formulated, e.g., as a gel, a gum, or a candy. Such liquid or semi-solid mixtures may comprise water and/or other pharmaceutically acceptable carriers and/or excipients. In a particular embodiment, the disclosed composition is substantially aqueous.

Each numerical value presented herein is contemplated to represent a minimum value or a maximum value in a range for a corresponding parameter. Accordingly, when added to the claims, the numerical value provides express support for claiming the range, which may lie above or below the numerical value, in accordance with the teachings herein. Every value between the minimum value and the maximum value within each numerical range presented herein (including in the chart shown inFIG. 33), is contemplated and expressly supported herein, subject to the number of significant digits expressed in each particular range.

As already briefly mentioned herein, the device may include a first fluid sensor for sensing one or more characteristics of the fluid medicament. The one or more characteristics may be monitored continuously. Such characteristics can include, for example, a chemical characteristic, an optical characteristic, a biological characteristic, and/or a physical characteristic.

Non-limiting examples of chemical characteristics may include an analyte concentration (e.g., concentration of an active pharmaceutical ingredient (API) such as carbidopa, levodopa and/or apomorphine), a distribution of the API in the fluid medicament, an aggregate condition of the API and/or the fluid medicament, a map of aggregate conditions of the API and/or the fluid medicament, and/or pH value.

Non-limiting examples of physical characteristics may include mass, volume, electrical conductivity, temperature, density, color, reflectance, transmissivity, viscosity, type of fluid, and/or thermal conductivity. Physical characteristics may optionally be measured to determine if the fluid medicament received in the reservoir contains bubbles.

In some embodiments, the fluid sensor may comprise an optical sensor operable to measure a characteristic of and/or related to the fluid. Characteristics pertaining to fluid contained in the reservoir may be measured using methods that are based on continuous, discrete, transmissive and/or reflective measuring techniques.

The optical sensor may measure or determine a characteristic of the fluid based on one or more characteristics of light detected by one or more light detectors of the fluid sensor. Such characteristic of light can pertain, for example, to the light's wavelength, amplitude, polarization, a phase difference, or any combination of the aforesaid. Detection of light may comprise transmission- and/or reflection-based methods.

Optionally, a liquid quantity in thereservoir106 may be determined based on a liquid level and/or volume in thereservoir106. The fluid sensor may be operable to continuously or discretely measure the quantity of a fluid in the reservoir.

Referring toFIG. 34A, a fluid sensor may for example include a liquidquantity sensor device3100. Liquidquantity sensor device3100 may include a radiation source3102 (e.g., an emitter) operable to emit light, adetector3104 operable to sense light, amemory3106, aprocessor3108 and a power module3110 (e.g., a power source such as a battery) for powering the various components of liquidquantity sensor device3100.

In some embodiments, liquidquantity sensor device3100 may be operable to continuously or discretely measure the quantity of a fluid in the reservoir. Optionally, liquid quantity measurement may be transmission-based, reflection-based, or both. Optionally, liquid quantity in the reservoir may be determined based on a liquid level and/or volume in the reservoir. In some embodiments the measurement of the drug volume inside the reservoir may be measured by determining the time-of-flight (TOF) of emitted light inside the drug reservoir and/or by measuring attenuation of light that propagated through thereservoir106.

The arrangements referred to herein below with respect toFIGS. 34B to 34G may be considered to enable a method of continuous measurement of liquid quantity in thereservoir106, based on one or more characteristics of light detected by the one or more detectors of the a rra ngement(s).

Referring toFIG. 34B, theradiation source3102 may in some embodiment be arranged on the underside of or embedded in theplunger head120, and thedetector3104 may be arranged opposite theradiation source3102 such thatlight500A emitted by theradiation source3102 propagates from theplunger head120 towards a distal end of thereservoir106 comprisingdetector3104 arranged to detect light500A. The example shown inFIG. 34B schematically illustrates a method for measuring liquid quantity that is light transmissive-based. Displacement direction of theplunger120 from a proximal to a distal end of the reservoir106 (or vice versa) is herein schematically illustrated by double-headed arrow P.

Referring now toFIG. 34C, theradiation source3102 may be in some embodiments arranged on the distal end of thereservoir106 and thedetector3104 may be arranged on the underside of or embedded in theplunger head120 such thatlight500A emitted by theradiation source3102 propagates from the distal end of thereservoir106 towards theplunger head120 comprisingdetector3104 arranged to detect reflected light500B. The example shown inFIG. 34C schematically illustrates, in analogy toFIG. 34B, a method for measuring liquid quantity that is light transmissive-based.

Referring toFIG. 34D, both theradiation source3102 and thedetector3104 may in some embodiments be arranged on the underside of or embedded inplunger head120, such that reflected light500B which is generated in response to radiating light500A from theplunger head120 into the distal end of thereservoir106 are detectable by thedetector3104. The arrangement shown inFIG. 34D shows an example reflection-based method for measuring liquid quantity.

Further referring toFIG. 34E, thereservoir106 may additionally include asecond detector3105 arranged on the distal end of thereservoir106 and which is operable to detect light500A emitted by theradiation source3102 towards the distal end of thereservoir106. The arrangement shown inFIG. 34E shows an example reflection- and transmissive-based method for measuring a quantity of liquid contained in thereservoir106.

Referring now toFIGS. 34F and 34G, the arrangement shown inFIGS. 34D and 34E may be reversed. As schematically illustrated inFIG. 34F, theradiation source3102 and thefirst detector3104 may in some embodiments be arranged at the distal end of thereservoir106 such thatreflections500B produced in response to radiating light500A from the distal end towardsplunger head120 are detectable by thedetector3104. The arrangement shown inFIG. 34F thus shows a reflection-based method for measuring a quantity of liquid contained in thereservoir106.

The arrangement shown inFIG. 34G may additionally include thesecond detector3105 arranged on the underside of or embedded in theplunger head120 such thatlight500A radiated from the distal end ofreservoir106 towards theplunger head120 is detectable by thesecond detector3105.

The arrangement shown inFIG. 34G thus show examples of both a reflection- and transmissive-based method for measuring a quantity of liquid contained in thereservoir106.

In some embodiments the radiation source and the detector presented inFIGS. 34D-34F are arranged to be at identical positions. In some embodiments, a plurality of radiation sources may be arranged circumferential to a detector, or vice versa.

As already indicated herein, the arrangements schematically shown inFIGS. 34B to 34G may be considered to enable a method of continuous measurement of liquid quantity in thereservoir106, based on one or more characteristics of light detected by the one or more detectors of the a rra ngement(s).

The arrangements referred to herein below with respect toFIGS. 34H to 34I may be considered to implement methods for discretely measuring a quantity of liquid contained in thereservoir106. For example, a plurality ofradiation sources3112 may be arranged on a cylindrical shell or curved body of thereservoir106 in a row extending from the reservoir's bottom to top at different heights h_iof thereservoir106. Thereservoir106 may further include a plurality ofdetectors3114 that are arranged on the cylindrical shell body of thereservoir106 such to be able to detect light emitted by each one of the plurality ofradiation sources3112. For instance, the plurality ofdetectors3114 may be arranged opposite the plurality ofradiation sources3112 in a row extending from the reservoir's bottom to top, facing thelight sources3112.

Each one oflight sources3112 may emit a plurality oflight rays500C from different positions h_ialong thereservoir106. A light ray500Ci propagates acrossreservoir106 in a direction that may be substantially perpendicular to thelongitudinal axis137 of theplunger head120 and is incident onto the corresponding detector3114i. In response to detecting light500C that is incident onto thedetectors3114, thedetectors3114 may generate an output which relates to a characteristic of the detected light ray. Such characteristic can pertain to a change in intensity of the light ray500Ci propagating through thereservoir106 and/or to a time-of-flight. The arrangement shown inFIG. 34H may for example allow generating a height-dependent function of a characteristic of fluid contained in thereservoir106. For example, density, color, transmissivity, and/or the like, may be measured as a function of the height relative to a level of fluid contained in thereservoir106. In some embodiments, a plurality oflight sources3112 and/or a plurality ofdetectors3114 may be employed at a corresponding height h1 above the bottom of thereservoir106.

As shown inFIG. 34H, the arrangement shown inFIG. 34I may additionally include thelight source3102 and thesecond detector3105 arranged, for example, on the underside of theplunger120, and thefirst detector3104 arranged on the distal end of thereservoir106. The light sources and detectors shown inFIG. 34I may thus allow radiating light lengthwise and/or radial into thereservoir106. Additional or alternative arrangements may be employed for radiating light lengthwise and/or radially intoreservoir106. Optionally, light may be selectively (e.g., alternatingly) radiated in lengthwise and radial direction intoreservoir106.. For example, during time-period t1, light500A may be radiated lengthwise intoreservoir106, and during a consecutive time-period t2, light500C may be radiated transversely into thereservoir106, and so forth.

Further reference is made toFIG. 34J. In some embodiments, a matrix oflight sources3102 may be arranged on one side of thereservoir106 and a matrix ofdetectors3104 may be arranged opposite the matrix oflight sources3102. In this manner, light and, correspondingly, liquid characteristics may be mapped radially, across thereservoir106, as schematically illustrated by arrow R, for example, to determine a value relating to homogeneity and/or inhomogoneity of fluid contained in thereservoir106.

According to some embodiments, a liquidquantity sensor device4100 may be operable to determine a quantity of liquid in thereservoir106 based on the measurement characteristics of pressure waves propagating through the liquid.FIG. 35 is a block diagram illustrating a liquid quantity sensor device. The liquidquantity sensor device4100 may, for example, include a mechanical wave generator (e.g., a transducer)4102 and amechanical wave sensor4104 that is operable to measure characteristics of mechanical waves produced bytransducer4102. For example, thetransducer4102 may include an ultrasound transducer, and themechanical wave sensor4104 may include an ultrasound sensor. In some embodiments, the same sensing element may be employed by thetransducer4102 and themechanical wave sensor4104. Optionally, micro-electromechanical and/or piezoelectric transducers may be employed to generate pressure waves in liquid contained in thereservoir106, e.g., for determining a value relating to a characteristic of the liquid such as temperature, transparency, cloudiness, viscosity, and/or the like. For example, a less transparent liquid may be indicative of an increased level of crystallization. In the event a measured characteristic indicates that the fluid's level of transparency is below a low threshold level, delivery of the fluid medicament may be stopped. Optionally, the fluid may be stirred for a predetermined time period. Optionally, the fluid may be stirred until the level of fluid transparency exceeds a high transparency threshold level.

In some embodiments the reservoir may include an automatic steering element that will operate according to a pre-programed timing and/or according to the level of liquid transparency.

In some embodiments, thedevice100 may include a position tracker (e.g., a position encoder600), e.g., for determining the position (e.g., penetration length), of theplunger120 relative to the distal end and/or proximal end ofreservoir106 to derive, for example, the amount of fluid that is contained in thereservoir106. The number of revolutions can be counted by theencoder600 in either rotation direction. The most proximal or distal position of theplunger120 in thereservoir106 may be a reference starting or endpoint for counting the number of revolutions of, e.g., theload gear136, to determine a penetration distance of theplunger head120.

In some embodiments, theplunger head120 may comprise a contact sensor (not shown) on its under and/or upper surface to allow determining when theplunger head120 engages or makes contact with the bottom or the upper surface of thereservoir106.

With reference toFIG. 36, a position tracker is schematically designated by reference numeral “600” and schematically illustrated as being operably coupled, for example, with theload gear136, e.g., for providing a load gear position output that is indicative of a rotational position of theload gear136. Theload gear136 can be operably engaged with thenut124. A rotational position of thenut124 can be determined based on the rotational position ofload gear136. The rotational position of thenut124 can be associated with a translational position of theplunger head120 within thereservoir106. As a result, the load gear position output provided by theposition tracker600 can be used for determining a translational position of theplunger head120. Based on the translational position ofplunger head120, the quantity of fluid contained inreservoir134 can be determined, e.g., by thecomputing unit117.

In some embodiments, thedevice100 may employ a sensor (not shown) for sensing an angular orientation of theplunger head120 relative to thereservoir106.

With reference toFIG. 37A, asensor3700 may be employed for determining a liquid quantity in thereservoir106 by measuring a change in an electrical characteristic of thesensor3700. Thesensor3700 may be arranged internal to and extend longitudinally along thereservoir106, parallel to the longitudinal axis thereof, so that thesensor3700 can make direct contact with a fluid contained in thereservoir106. A measurable electrical characteristic of thesensor3700 may change depending on the amount overlap between the sensor and the fluid and, optionally, based on a characteristic of the fluid. Such electrical characteristic can pertain, for example, to the capacitance and/or electrical impedance. For example, a measured capacitance of thesensor3700 may increase as a function of an increase of a level of fluid in thereservoir106. In another example, the capacitance of thesensor3700 may decrease as a function of an increase in the level of fluid of thereservoir106. In some embodiments, a portion of thesensor3700 may protrude or extend beyond thereservoir106 or be otherwise arranged such that said portion does not come into operational sensing engagement with the fluid. Accordingly, a sensing output of said fluid portion may not be influenced by the amount of fluid contained in reservoir. The output provided by the protruding portion may thus serve as a reference for determining an amount of fluid contained in thefluid reservoir106.

Referring now toFIGS. 37B to 37F, acapacitor sensor3800 may be coupled with (e.g., glued and/or otherwise fastened) aleg portion145 of thereusable part104 such that when thedisposable part102 and thereusable part104 are operably coupled with each other, the

sensors

3800aand3800bare positioned opposite and/or facing

reservoirs

106aand106bsuch to provide an output related to the quantity of fluid stored in the

reservoirs

106aand106b. Although the discussion concerning the capacitance-based fluid quantity measurement is exemplified with respect to the device employing a double-piston arrangement, this should by no means be construed in a limiting manner.

Considering the double-piston arrangement, the reusable part may have a generally T-shaped configuration, of whichleg portion145 may comprise magnet140 (seeFIGS. 7B-C) and the

sensors

3800aand3800b, as schematically shown inFIG. 37C. Thereusable part104 of the single-piston arrangement may be considered to have a generally L-shaped configuration, of which theleg portion145 may comprise thesensor3800.

As shown inFIGS. 37C and 37D, thesensor3800 may be bendable. A sensor such assensor3800 shown herein may be implemented by a flexible printed circuit board (FPCB). Optionally, theleg portion145 may be curved inwardly or have a concave shape, in order to conformably abut against the rounded surface of areservoir106. Accordingly, thesensor3800 may attain a bent shape when fastened onto theleg portion145 of for example thereusable part104 of a single- or double-piston arrangement.

Further reference is made toFIG. 37E, which schematically shows a 3D view illustration of the positional relationship between areservoir106 and a capacitor-basedliquid quantity sensor3800 configured to measure a liquid quantity in thereservoir106, according to some embodiments; and further toFIG. 37F which schematically shows adisposable part102 of thedevice100 when operably coupled with areusable part104 of the device, and the resulting positional relationship between the capacitance-basedliquid quantity sensor3800 of the reusable part and the reservoir of the disposable part. As exemplified inFIG. 37F, the capacitance-basedliquid quantity sensor3800 is external to thereservoir106 and part of thereusable part104.

Additional reference is made toFIG. 37G, which schematically shows front and back view illustrations of a capacitance-basedliquid quantity sensor3800, according to some embodiments. A capacitance-basedfluid measurement sensor3800 may be configured to provide sensing outputs without requiring the sensor to directly engage with the fluid. In other words,sensor3800 may be a non-contact fluid quantity sensor.

Thesensor3800 may comprise asubstrate3802 having arranged thereon afront inlet electrode3812, afront outlet electrode3814 and afront reference electrode3816. Thefront outlet electrode3814 can be arranged between thefront inlet electrode3812 and thefront reference electrode3816. Analogously, thesensor3800 can further comprise aback inlet electrode3822, aback outlet electrode3824 and aback reference electrode3826. Theback outlet electrode3824 is arranged between theback inlet electrode3812 and theback reference electrode3816. The front and

back inlet electrodes

3812 and3822 may be arranged opposite each other to form a reference liquid capacitor (C_RL)3832; the front and

back level electrodes

3814 and3824 may be arranged to form an level capacitor (C_level)3834. Moreover, the front and back

reference electrode

3816 and3826 may be arranged to form an environmental capacitor sensor, which may provide a reference environmental capacitance output (C_RE) of anenvironmental sensor3836.

In some other embodiments, as schematically illustrated inFIG. 37H, two electrodes forming a capacitor may be arranged side-by-side or juxtaposed on the same surface ofsubstrate material3802 and shielded from one another by ashielding material3830. The positional terms “front” and “back” designating the different electrodes may in some cases be replaced by the terms “left” and “right”, respectively. The electrodes may be electronically coupled with each other in a variety of configurations.

Positional terms such as “upper”, “lower” “right”, “left”, “bottom”, “below”, “lowered”, “low”, “top”, “above”, “elevated”, “high”, “vertical” and “horizontal” as well as grammatical variations thereof as may be used herein do not necessarily indicate that, for example, a “bottom” component is below a “top” component, or that a component that is “below” is indeed “below” another component or that a component that is “above” is indeed “above” another component as such directions, components or both may be flipped, rotated, moved in space, placed in a diagonal orientation or position, placed horizontally or vertically, or similarly modified. Accordingly, it will be appreciated that the terms “bottom”, “below”, “top” and “above” may be used herein for exemplary purposes only, to illustrate the relative positioning or placement of certain components, to indicate a first and a second component or to do both.

As already shown inFIG. 37F, for example, the device may be configured such that when thedisposable part102 and thereusable part104 are operably coupled with each other, the inlet and

outlet capacitors

3832 and3834 are facing the reservoir(s)106, while thereference capacitor3836 never faces any fluid that may be contained in thereservoir106. Accordingly, the output of thereference capacitor3836 may be substantially constant, irrespective of the type and/or amount of fluid contained in thereservoir106. Hence, thesensor3800 can be calibrated to measure a large variety of liquids without necessarily requiring knowledge of the liquids' characteristics. The relationship between the values output by the inlet and

outlet capacitors

3832 and3836, along with the reading obtained from thereference capacitor3836, enables determining an amount of fluid in thereservoir106. Theprocessor3108 of thedevice100 may be operable to independently process signals provided by a plurality ofsensors3800 for providing separate fluid quantity outputs for each one of the plurality of reservoirs that may be employed by the same device.

Reverting toFIG. 37H, the output of the capacitance-basedliquid quantity sensor3800 may be fed into a capacitance todigital converter148, the output of which may be provided to thecontrol unit116, e.g., for further processing.

A level of liquid may for example be determined based on the following equation:

\begin{matrix} Level = h_{RL} \frac{C_{level} - C_{level} (0)}{C_{RL} - C_{RE}} & (1) \end{matrix}

where:

h_RL=the unit height of the reference liquid sensor (often, but not always, 1);
C_level=capacitance of the level capacitor;
C_level(0)=capacitance of the level capacitor when no liquid is present (empty);
C_RL=capacitance of the reference liquid sensor; and
C_RE=capacitance o the reference environmental sensor.

In some embodiments, an electrical property of thesensor3700 may change as a result of a change of the position of theplunger head120.

According to some embodiments, fluid sensor(s) and/or pump-related functional outputs may be utilized for determining a functional state of thepump device100. For example, a power output required to drive fluid out of thereservoir106; the number of, e.g., nut rotations required for expelling a certain amount of liquid from cannula216 (e.g., indicated by a rotary encoder output); a flow rate (e.g., measured by a fluid sensor); a pressure (e.g., measured by a fluid sensor); and/or the like, may be input to, for example, theprocessor3108 for monitoring a functional state ofpump device100 and to detect, for example, clogging of a fluid path of thepump device100 and/or to detect leakage of fluid from thepump device100.

For example, if theprocessor3108 determines that a sensor and/or pump-related functional output meets the conditions of a “clogging criterion,” the processor may provide a corresponding output. Optionally, such clogging criterion may relate to a measured flow rate that drops, during a certain time period, below a low flow-rate threshold value. Optionally, such clogging criterion may relate to a pressure output that raises, for a certain time period, above a certain high-pressure threshold value. For example, if an output corresponds to a pressure of 4 bars or more during a certain time period, the clogging criterion conditions may be met. An output that is provided in case the conditions of a clogging condition is met may include, for example, an alert (e.g., visual, audible, and/or haptic); a command to stop operation of thedrive component112; and/or the like.

In some embodiments, a sensor and/or pump-related functional output may be analyzed to determine a viscosity of the fluid contained in the pump's reservoir and/or pathway. For example, the pressure required to force fluid out of thereservoir106 for delivery to the patient may be indicative of the fluid's viscosity.

In some embodiments, theplunger assembly108 may comprise a rotatable element (not shown) for implementing a rotational viscometer. Alternative techniques for measuring viscosity of fluid in thepump device100 include, for example, vibrational techniques for measuring the damping of an oscillating electromechanical resonator immersed in the fluid. The fluid's temperature and/or other fluid characteristics may be taken into account for determining the fluid's viscosity.

In another example, theprocessor3108 may determine that a sensor and/or a pump-related functional output meets the conditions of a “leakage criterion,” so that the processor may provide a corresponding output.

Optionally, such leakage criterion may relate to a measured flow rate that raises, during a certain time-period, above a high flow-rate threshold value. Optionally, such leakage criterion may relate to a pressure drop, for a certain time period, below a low-pressure threshold value. For example, if an output corresponds to a pressure of1 bar or less during a certain time-period, the leakage criterion condition may be met. An output that is provided in case the conditions of a leakage condition is met, may include, for example, an alert (e.g., visual, audible, and/or haptic); a command to stop operation of thedrive component112; and/or the like.

According to some embodiments, measurements of a plurality of fluid sensors may be compared with each other, for example, to determine if a characteristic of the fluid medicament undergoes changes and, if so, to what extent, from the moment the fluid medicament leaves thereservoir106 until it arrives at thecannula216 for delivery into the patient. The measurements may be employed, for example, to determine a change in an analyte concentration in the fluid medicament, flow rate and/or pressure within thecannula216, and/or the like.

A measured and/or determined characteristic of the fluid medicament may be input to controlunit116 for controlling pumping operation. For example, operation of thedrive component112 may be based on such input.

With reference toFIG. 38, thedevice100 may include one or more additional fluid sensors (e.g.,

fluid sensors

3810A and3910B) that are arranged at or near the outlet of thecannula216 for measuring a characteristic of fluid contained in thecannula216. The additional

fluid sensors

3810A and3810B may for example be employed to determine the flow rate at which the fluid medicament is delivered to the patient.

Although

sensors

3810A and3810B are shown as being arranged in successive order with respect to a flow direction, which is schematically designated by arrow F, this should by no means be construed in a limiting manner. For instance, the

sensors

3810A and3810B may be positioned within thecannula216 to face each other. Additional or alternative configurations may be applicable as well.

In some embodiments, data provided by the fluid sensor(s) may be descriptive of the drug volume that was delivered to the patient within a certain time period, expected remainder time for delivering a certain amount of fluid medicament to the patient (e.g., required amount, and/or remainder amount in the reservoir), and/or the like.

According to some embodiments, thedevice100 may comprise stirring elements arranged and operable to stir, actively and/or passively, the fluid medicament while stored and/or being urged to flow through a fluid path of thedevice100. Stirring elements may for example comprise fins (not shown) that protrude inwardly into a cavity formed by the fluid path to change a local fluid direction of the fluid medicament. Optionally, the fins are alternatingly arranged opposite each other along the longitudinal axis of the fluid path's cavity. Optionally, the fins are arranged in a screw-like progression along the fluid path. As described above, stirring elements may be actuated if a measured characteristic indicates that the fluid's level of transparency is at or below a low-threshold level. The stirring element can have a physical element inside the reservoir or alternatively comprise a mechanism that operates on thereservoir106 from the outside thereof, for example by using vibration and/or acoustic waves. As is shown, for example, inFIG. 39, a stirring element may comprise a vibration-inducingelement133 that is coupled with thereservoir106.

In some embodiments,plunger assembly108 and the drive components may be configured such that theplunger head120 rotates during the axial translation thereof in thereservoir106. Rotation of theplunger head120 may be utilized to stir fluid contained in thereservoir106. For example, the stirring element may be implemented byfins4200 that are arranged on the distal surface portion of theplunger head120 to extend into the part of thereservoir106 that can contain fluid for delivery to a patient, and thefins4200 can be arranged to stir the fluid during axial displacement of theplunger head120. As is for example shown inFIG. 39, theplunger head120 and thefins4200 arranged thereon may rotate in a direction R1 during axial displacement of theplunger head120 in a distal direction P1, and rotate in a direction R2 during axial displacement of theplunger head120 in a proximal direction P2. Thefins4200 may optionally be integrally formed with theplunger head120. Optionally, thefins4200 may be coupled to theplunger head120.

According to some embodiments, one or more physiological sensors may be operably coupled with and/or employed by thedevice100 for measuring one or more physiological characteristics of the patient using thepump device100, prior, during and/or after delivery of the fluid medicament. With reference toFIG. 38,pump device100 may include one or more

physiological sensors

3910A and3910B. A firstphysiological sensor3910A may be, for example, coupled to thecannula216 for percutaneously sensing a subcutaneous environment of a patient, and a secondphysiological sensor3910B may be, for example, coupled to the underside ofpatch110. The firstphysiological sensor3910A may be configured to subcutaneously measure a physiological characteristic of the patient, and the secondphysiological sensor3910B may be configured to non-invasively engage a skin surface portion of the patient for measuring a physiological characteristic related to the patient. In some embodiments, a physiological sensor may be embodied by a non-inertial sensor and/or by an inertial sensor (not shown). Inertial sensors can include accelerometers and/or gyroscopes for measuring parameters related to, e.g., tremor, stiffness of a patient's gait, and/or the like. Such non-inertial sensors may thus be coupled to the patient's limb and/or torso, for measuring the patient's tremor, stiffness and/or gait. Output of the non-inertial and/or inertial sensors may be used for controlling the pump operation.

In some embodiments, imaging sensors may be employed in conjunction with thepump device100 for imaging the patient's facial expressions, and/or other motions. Imaging sensor outputs may be used for controlling the pump operation.

In some embodiments, thepump device100 may employ sensors (not shown) which are configured to determine a type of fluid that is contained in thereservoir106 and/or delivered through the pump device's fluid pathway. For example, based on one or more markers contained in the fluid medicament, an output of such sensors may be used for determining whether the fluid medicament comprises carbidopa, levodopa, and/or dopamine.

Referring now toFIG. 40, a method for setting operating parameter values of the pump device may include, as indicated byblock3902, receiving, e.g., at the filling station, user-defined pump operating parameter values. In some embodiments, user-defined pump operating parameter values may be given preference over default pump operating parameter values.

The user-defined pump operating parameter values may be provided, for example, by a user via a touch screen of the fillingstation154. As indicated byblock3904, the method may further include determining whether the received user-defined pump operating values are within allowed operating parameter limits. If the received user-defined pump operating parameter values are within the allowed operating parameter limits, the method may include controlling operation of thepump device100 according to the received user-defined pump operating parameter values (block3906). For example, the user-defined pump operating parameter values may be sent (e.g., wirelessly) from the fillingstation154 to thepump device100.

If the received user-defined pump operating parameter values are not within the allowed limits (block3904), the method may include operating thepump device100 according to default pump operating values (block3908). In that case, the method may include, for example, sending default pump operating parameter values (e.g., from the filling station154) to thepump device100, and controlling thepump device100 accordingly.

Optionally, the default pump operating parameter values and/or the pump operating parameter limits may be stored in thepump device100 and/or in the fillingstation154. Optionally, the default pump operating parameter values may be sent from thepump device100, along with the pump operating parameter limits, to the fillingstation154. Optionally, the default pump operating parameter values may be stored (or pre-stored) in the fillingstation154 along with the pump operating parameter limits.

Optionally, the (for example received or for example pre-stored) default pump operating parameter values can be output (e.g., displayed) by the fillingstation154 to the user. Optionally, if the provided user-defined pump operating parameter values are not within the allowed operating limits, the default pump operating parameter values may be sent to thepump device100 to perform control thereof accordingly. Optionally, if the provided user-defined pump operating parameter values are not within the allowed operating limits, a command may be sent to thepump device100 to initiate control thereof according to the default pump operating parameter values stored in thepump device100.

The term “controller” as used herein, may also refer to a processor. A controller may, for example, include a circuit programmed to cause the device to implement the methods, processes and/or operations as disclosed herein. For example, a controller may be implemented as a hardware circuit comprising, e.g., custom VLSI circuits or gate arrays, application-specific integrated circuit (ASIC), off-the-shelf semiconductors such as logic chips, transistors, and/or other discrete components. A controller may also be implemented in programmable hardware devices such as field programmable gate arrays, programmable array logic, programmable logic devices and/or the like.

Program instructions for implementing the methods and/or processes disclosed herein may be implemented as a computer program product that may be tangibly embodied in an information carrier including, for example, in a non-transitory tangible computer-readable and/or non-transitory tangible machine-readable storage device. The computer program product may directly loadable into an internal memory of a digital computer, comprising software code portions for performing the methods and/or processes as disclosed herein.

Additionally or alternatively, the methods and/or processes disclosed herein may be implemented as a computer program that may be intangibly embodied by a computer readable signal medium. A computer readable signal medium may include a propagating data signal (e.g., a communication signal) with computer readable program code embodied therein, for example, in baseband or as part of a carrier wave. Such a propagating signal may take any of a variety of forms, including, but not limited to, electro-magnetic, optical, or any suitable combination thereof. A computer readable signal medium may be any computer readable medium that is not a non-transitory computer or machine-readable storage device and that can communicate, propagate, or transport a program for use by or in connection with apparatuses, systems, platforms, methods, operations and/or processes discussed herein.

The terms “non-transitory computer-readable storage device” and “non-transitory machine-readable storage device” encompasses distribution media, intermediate storage media, execution memory of a computer, and any other medium or device capable of storing for later reading by a computer program implementing embodiments of a method disclosed herein, and these terms do not encompass a propagating data signal.

The computer readable and executable instructions may also be loaded onto a computer, other programmable data processing apparatus, or other device to cause a series of operational steps to be performed on the computer, other programmable apparatus or other device to produce a computer implemented process, such that the instructions which execute on the computer, other programmable apparatus, or other device implement the functions/acts specified in the flowchart and/or block diagram block or blocks.

In the description, unless otherwise stated, adjectives such as “substantially” and “about” that modify a condition or relationship characteristic of a feature or features of an embodiment of the invention, are to be understood to mean that the condition or characteristic is defined to within tolerances that are acceptable for operation of the embodiment for an application for which it is intended. For example, the terms “about,” “substantially,” and/or “close” with respect to a magnitude or a numerical value may imply to be within an inclusive range of −10% to +10% of the respective magnitude or value.

“Coupled with” means indirectly or directly “coupled with”.

It is noted that the terms “operable to” and “operative to” can encompass the meaning of the term “adapted or configured to”. In other words, a machine “operable to” perform a task can, in some embodiments, embrace a mere capability and, in some other embodiments, a machine that is actually made to perform the function.

As used herein, the phrase “A,B,C, or any suitable combination of the aforesaid” should be interpreted as meaning all of the following: (i) A or B or C or any combination of A, B, and C, (ii) at least one of A, B, and C, and (iii) A, and/or B and/or C. This concept is illustrated for three elements (i.e., A,B,C), but extends to fewer and greater numbers of elements (e.g., A, B, C, D, etc.).

The terms and expressions employed herein are used as terms and expressions of description and not of limitation and there is no intention, in the use of such terms and expressions, of excluding any equivalents of the features shown and described or portions thereof. In addition, having described certain embodiments of the invention, it will be apparent to those of ordinary skill in the art that other embodiments incorporating the concepts disclosed herein may be used without departing from the spirit and scope of the invention. The structural features and functions of the some embodiments may be arranged in various combinations and permutations, and all are considered to be within the scope of the disclosed invention. Unless otherwise necessitated, recited steps in the various methods may be performed in any order and certain steps may be performed substantially simultaneously. Accordingly, the described embodiments are to be considered in all respects as only illustrative and not restrictive. Furthermore, the configurations described herein are intended as illustrative and in no way limiting. Similarly, although physical explanations have been provided for explanatory purposes, there is no intent to be bound by any particular theory or mechanism, or to limit the claims in accordance therewith.