CN1224365A - Inhaler apparatus with modified surfaces for enhanced release of dry powders - Google Patents

Abstract

The invention is an inhaler providing surface topology (202, 204) for minimizing the area of contact between the medicament (107) and the surfaces of the inhaler. The surfaces are preferably made of a material having a low surface energy, and more preferably, also having, when uncharged, no substantial van der Waals or electrostatic interaction with the medicament. Furthermore, the material is preferably substantially chemically unreactive with the medicament.

Description

Inhaler device with the improvement surface of disengaging with the raising dry powder

Relevant common unsettled U.S. Patent application comprises: No. 08/630049 application (" sound type dispenser ", 1996.4.9 application and its part continuity application of applying for simultaneously with the application), No. 08/630050 application (" electrostatic chuck " 1996,4.9 application and its part continuity application of applying for simultaneously with the application), 08/630012 (" being used for multiple material is positioned at on-chip sucker and method ", 1996.4.9 application), 08/471889 (" being used for method and apparatus " 1995.6.6 application and its part continuity application (1996.6.6) at on-chip presumptive area electrostatic precipitation drug powder, 08/467647 (" being used for electrostatic precipitation and the device that keeps material on substrate ", 1995.6.6 apply for) and 08/506703 (" utilizing the inhaler device of frictional electrification technology " 1995,7.25 the application), they especially introduced material for example powder particle in for example on-chip electrostatic precipitation of inhaler of a substrate.Therefore incorporated can be for reference here in above-mentioned patent application.

According to one aspect of the present invention, a kind of inhaler device is provided, it comprises and the contacted inner surface of the medicine of inhaling clothes, and this internal table bread contains the inner surface of ozzle and deposits the substrate of medicine on it.According to the present invention, one of them is planted inner surface and wherein has some recessed road or rising zones, has the paddy district between rising zone.The structure that the improvement on these surfaces forms make between the interior surface of medicine and inhaler to touch area as far as possible little, therefore, help medicine disengaging from inhaler.

Oneself has a lot of schemes at the design of dryness powder inhalator and manufacture view.For example WO93/09832 discloses a kind of inhaler device with elongate carrier of drug powder, and drug powder disengages after being subjected to hammering, and this inhaler device has the tortuous passageway of a depolymerization drug powder.

The shortcoming of the inhaler of prior art for example comprises: the patient who suffers from respiratory disease such as asthma is difficult to have sufficient power to suck whole drug doses.For example patient only may reach the about 15 liters throughput of per minute.In most of dryness powder inhalators, patient's suction clothes will provide the energy that is enough to obtain required medicine from inhaler.The throughput that is provided by patient pulmonary obviously influence is come out and is arrived the medication amount of pulmonary from inhaler.

Other shortcomings of the inhaler of prior art comprise: the throughput that for example depends on patient may be taken too much or too small medication amount from inhaler, and this just can not accurately determine the medication amount of taking.

Another shortcoming of the inhaler of prior art is the coalescent problem of drug powder.Coalescent granule falls into mouth and throat usually, rather than remains in the air-flow so that be deposited on pulmonary.One of method of remedying this problem is in the inhaler of prior art tortuous passageway to be set, so that help depolymerization.Yet there is shortcoming in this method, and for example therefore medicine causes and can not accurately according to dosage take medicine along this passage deposition.

Another shortcoming that runs in the inhaler of prior art is for example when inhaler falls, and medicine is scattered and causes unexpected the discharge.

For above-mentioned reasons, need a kind of like this dryness powder inhalator, it can for example accurately carry drug dose under the situation of 15 liters of per minutes in the low-flow amount, can be maintained medicine basically when for example inhaler falls being subjected to impacting.

Summary of the invention

The present invention partly relates to a kind of inhaler device, it comprises and the contacted inner surface of the medicine of inhaling clothes, this internal table bread contains the surface, inside of ozzle and deposits the substrate surface of medicine on it, these inner surfaces one of them comprises some recessed road or bulge area at least, the paddy district is arranged between rising zone.In some preferred embodiment, this surface, inside is the surface that deposits the substrate of medicine on it, and in other preferred embodiments, this surface, inside is the inner surface of the ozzle in the inhaler.The best size of this recessed road or bulge area and at interval through selecting, so that reduce the quantity of the drug particles that may contact with the flat surface of substrate.Best, the surface of substrate and ozzle and other surface of contacting with medicine all have some recessed roads or bulge area or other surface texture, be used to be reduced in selected medicine and should the surface between contact area.

The summary of figure

Fig. 1 is that 3 kinds of expressions are attached to the curve chart of the on-chip active force in the inhaler, i.e. power (" Fim ") and Robert Van de Walle power (" Fv ") that electrostatic force (" Fe ") electric charge imaging distributes and produces with granule.

Fig. 2 A-E is the micro-figure of taking pictures that disengages powder from the polypropylene substrate with the recessed road of flute profile structure.Shown in Fig. 2 A-E by 42 times of amplifications.Powder before Fig. 2 A represents to disengage; Fig. 2 B be illustrated in after the throughput effect that is subjected to 15 liters of per minutes surplus powder; Fig. 2 C be illustrated in after the throughput effect that is subjected to 30 liters of per minutes surplus powder; Fig. 2 D be illustrated in after the throughput effect that is subjected to 4.5 liters of per minutes surplus powder; Fig. 2 E be illustrated in after the throughput effect that is subjected to 57 liters of per minutes surplus powder.

Fig. 2 F is illustrated under the situation that improves flow the curve chart that disengages the data that powder obtains from the substrate shown in Fig. 2 A-E.

Fig. 3 A-C is the photomicrography figure of an inhaler substrate.Fig. 3 A is the photomicrography figure with the polypropylene substrate in the recessed road of flute profile.Fig. 3 B is the photomicrography figure of the same substrate of deposited powder on it.Fig. 3 C is the photomicrography figure of the same substrate after disengaging powder.

Fig. 4 A-C has the photomicrography figure of the inhaler substrate of being made by silicon in the recessed road of flute profile at substrate surface.Fig. 4 A is the photomicrography figure of substrate; Fig. 4 B is the photomicrography figure that deposits the same substrate of powder on the base; Fig. 4 C is the photomicrography figure of the same substrate after disengaging powder.

Fig. 5 A-C represents the photomicrography figure shown in Fig. 4 A-C of high-amplification-factor more.

Fig. 6 A-C represents the photomicrography figure shown in Fig. 5 A-C of high-amplification-factor more.

Fig. 7 is the graph of an embodiment of the ozzle of inhaler of the present invention, the air intake of this ozzle of arrow points.

Fig. 8 A and 8B are the cutaway views of an embodiment of inhaler device of the present invention.Fig. 8 A represents not have the inhaler of electronics auxiliary device, and Fig. 8 B represents to have the inhaler of electronics auxiliary device.

Fig. 9 is the graph that is used for the device that disengages on the substrate of test powders by inhaler.

Figure 10 is that expression is compared with the substrate with the recessed road of flute profile, by the curve chart of the drug powder quantity of disengaging on the smooth substrate.

Figure 11 A and 11B are the schematic cross-sectional views of an embodiment that deposits the substrate of medicine on it, and the configuration of substrate is suitable for discharging so that electronics is auxiliary of medicine.

Figure 12 A and 12B are the schematic cross-sectional views of another embodiment that deposits the substrate of medicine on it.

Figure 13 is in the schematic cross-sectional view that is used for having on the conductive layer in the electric charge imaging electrostatic chuck of floating electrode.

Figure 14 is the top view of the floating electrode shown in Figure 13.

Detailed Description Of The Invention

With after powder deposition is to the substrate of inhalator, preferably powder can accurately disengage when patient sucks. That powder particle is for the absorption of substrate for disengaging one of the obstacle that must overcome. Making particle remain on on-chip a kind of active force is Robert Van de Walle power. Another kind of confining force is electrostatic force. The third confining force is the active force that charge image forms, it be by be attached in the substrate regional area powder particle with charge generation. It is believed that the variation that has the order of magnitude according to these active forces of electric conductivity of substrate. Robert Van de Walle gravitation increases in time in addition, the speed of increase with because the particle deformation speed when long-pending than large contact surface is relevant. Moreover when granular size increased, these active forces increased. For example as seen from Figure 1, this figure is that the curve of the mathematical operation of above-mentioned active force represents.

In a lot of embodiments of the present invention, utilize the electric field apply with charged drug particles adventitious deposit on substrate.After deposition, preferably electric field is stopped, dropping to minimum with Robert Van de Walle power with adsorption particle, therefore make non-imaging adhesive force drop to minimum.Minimizing of captivation

Above-mentioned variety of issue is that the present invention is particularly related to.One aspect of the present invention provides some to have the inhaler of the improvement substrate that can change captivation.Best, when inhaling clothes,, particularly disengage greater than 80% medicine greater than 70%.Disengage for the medicine that makes dosage unit reaches about 80～100%, required throughput is preferably approximately less than 60 liters of per minutes, preferably approximately less than 30 liters of per minutes, more preferably no more than 15 liters of about per minutes.For example referring to Fig. 2 A-E, when these figure are illustrated in the throughput of per minute 15 liters (B), perminute 30 liters (C), per minute 45 liters (D) and per minute 57 liters (E), the situation of disengaging medicine by reticulate pattern substrate with the recessed road of flute profile.Also can consult Fig. 2 F, this figure is the curve chart of gained data, when the expression throughput increases, is increased by the medicine that disengages on the substrate.The data that example 1 provides produce the curve shown in Fig. 2 F.To relate to according to sequence number be the ion printing that proposes in 08/471889 application to the deposition technique of Shi Yonging in this example.In a preferred embodiment of the invention, use electrostatic chuck with the charged drug particles of electrostatic precipitation to the inhaler substrate, as being introduced in by 08/030050 application in sequence number.It is believed that using electrostatic chuck is a kind of preferred deposition technique, can cause by the medicine that disengages higher percentage ratio on the inhaler substrate.Also can adopt other deposition technique in conjunction with improved inhaler substrate of the present invention.

Preferably the inhaler substrate is improved, drop to for a short time, make these granules have selected size so that the contact surface between powder particle and the substrate surface is long-pending.Granule with required size contacts seldom with substrate.Therefore be easier to disengage from substrate.Except making required granule is easier to disengage, the configuration of improved substrate can make the granule with non-required size be kept here.For example, long-pending when big as the contact surface between granule and substrate, for the granule of size less than selected size, bigger contact can cause staying these granules on substrate rather than being disengaged.

Preferably realize minimizing of contact area according to following mode.As by forming some recessed roads on the flat surface or on flat surface, forming rising zone, surperficial contact area can be reduced as far as possible.In a preferred embodiment of the invention, having recessed road on the inner surface in inhaler at least, perhaps is the rising zone of paddy therebetween; Perhaps other surface improvements, so as to be reduced in selected drug particles and the inner surface of the inhaler that contacts with medicine between contact area.For example before inhaling clothes or inhale clothes process Chinese medicine and may take place to contact, for example contact with this surface in the deposition process before absorbing, perhaps in inhaling the clothes process, contact with the inner surface of ozzle with this surface.Best, deposit the substrate surface and the ozzle of medicine, and all have some recessed road or bulge area with contacted other surface of medicine, perhaps any be used to reduce selected medicine and should the surface between other surface texture of contact area.

This recessed road or bulge area be linear for example.Circuitous shape, shaped form, annular or other required form.Be the recessed road of straight line flute profile in some preferred embodiment, it is easy to make.By Fig. 3 A-C as can be seen, have the situation that the polypropylene substrate in the recessed road of flute profile disengages medicine.

Specifically, Fig. 3 A is the photomicrography figure that wherein has the substrate in the recessed road of flute profile.Fig. 3 B is the photomicrography figure behind Fig. 3 A substrate deposition of medicament powder.Fig. 3 C is at the photomicrography figure of medicine after Fig. 3 B substrate disengages.Fig. 4 A-4C represents to have the corresponding series photomicrography figure of the silicon chip of flute profile.Fig. 5 A-5C and 6A-6C are expressed as same train photomicrography figure, have just improved amplification.The lines that provide 100 microns in Fig. 4 A-4C and 5A-5C are as the reference size, and the lines that provide 10 microns in Fig. 6 A-6C are as the reference size.

Best, the degree of depth in recessed road or the height of rising zone are slightly smaller than the size of the smallest particles that hope disengages by inhaler, and for example approximately little 5%-50% cans be compared to the little 5%-20% of selected smallest particles most.

The width of paddy between recessed road or two rising zones preferably is slightly smaller than the diameter of the selected smallest particles that need disengage, for example approximately little 5%-20%, preferably approximately little 10%-20%.For example, if the selected size of granule of being disengaged by inhaler is about 2 to 6 microns, preferably about 1.8 microns of the width of then recessed road or paddy.Best, recessed road or paddy radially less than the diameter of respirable minimum drug particles.For example the paddy center preferably is about 1 to 2.5 micron to the on-chip spacing of the center metering of rising zone, so that scatter the granule of 2-6 micron.The for example available scanning electron microscope of particulate size is measured.

Except recessed road and rising zone, for example by utilizing porous substrates also can swell surperficial contact area between low medicine and the substrate.In addition, can carry out more than one improvement to single substrate.Preferably the whole surface area with the contacted surface of powder particle is improved, minimize so that make with contacting of drug powder.

Another aspect of the present invention is to select the material of formation and the contacted substrate surface of powder particle.Best, this material is that part is selected according to the principle of low-surface-energy.For example consult " adherent physicochemical properties " 149-164 page or leaf (John Wiley ﹠amp of Kaelble; Sons1971), quoting its full text here can be for reference.Preferably the surface energy on the surface that contacts with powder particle is about the 10-25 dynes per centimeter.Be more preferably when not charged, the surface does not have Robert Van de Walle power basically or does not have electrostatic interaction with medicine.In addition, this material does not preferably carry out chemical reaction with medicine basically.The example that can be used for the material on this class surface comprises perfluorinated polymers, for example, and politef (" polytetrafluoroethylene "), silicone, sial pottery, polymeric photoconductor, Merlon, polyimides, polypropylene and polyethylene.In certain embodiments, this surface and silane for example are that the reaction of silicon fluoride or amino silane forms the thin film with low-surface-energy.In addition, can handle this surface, divided by fluoridized thin polymer film.For example consult United States Patent (USP) 4252848, incorporated can be for reference here.For example also can with reference to the 4th about plasma chemical international discussion collected works 152-163 page or leaf on by the paper of being entitled as of works such as S.Peprek and J.Hertz " by characteristic " to the fluorocarbon thin film of the plasma polymerization preparation of 1.3 perfluorodimethylcyclohexanes, the full text of quoting it here can be for reference.

Constitute with the material on the contacted surface of powder particle and preferably also select according to having low chemical reactivity with powder particle.For example, if to wait to be deposited on on-chip powder be charged or be polar granule, then the surface of substrate is preferably uncharged or non-polar.Be used to constitute selection with the material on the contacted surface of medicine and preferably can reduce Robert Van de Walle power and electrostatic adsorption as far as possible, and minimum chemical reactivity is arranged medicine.

In addition, be used to form material with the contacted surface of medicine preferably hard with stiff, this is because flexibility can cause increasing contact area.For example consult " mechanical property of polymer and compositions " (Marcel Dekker Inc.YN 1974) 367-369 page or leaf of Nielsen, quoting it here in full can be for reference.Best, the dimension formula hardness that this material has for example is polystyrene, poly-methyl isobutene. ester, Merlon, polyacetals, polyethylene terephthaldehyde base ester and phenolic resins approximately greater than 10 kip/square millimeters.

Being preferably used in the material that constitutes with the contacted surface of medicine is a kind of polymer, is used for these surperficial preferred materials and comprises: organic photoconductor, polyvinylcarbazole, Merlon, polyimides and the polyethylene of politef, sial pottery, aluminising.In certain embodiments, recessed road is the groove in the aluminum ceramic substrate printed board.As consult Fig. 4-6.This printed board can utilize conventional photoetching technique to make.In one embodiment, use the making ide of groove to take the mold pressing substrate,, make substrate, for example consult shown in Figure 3 with required recessed road with this with 2 microns intervals.

In certain embodiments, for example silicon fluoride or amino silane come treatment surface to utilize silane.In certain embodiments, polyimides is not preferred, because in some cases, because its possibility absorption powder of chemistry or electrostatic interaction.Best, employed material and be satisfied from the property of medicine to the processing on surface can not cause toxicity.

Can select the size and dimension of substrate according to operating position.In some cases, substrate is that dish type or elongated shape are as band.Best, deposition multiple dose unit on substrate, each dosage unit is in other zone of branch, is separated by the substrate region that does not have deposited powder on it.In some preferred embodiments, with substrate sealing, not to be subjected to for example humidity effect and realize aseptic of environment.

The advantage of inhaler device of the present invention is included in when disengaging the smoking of powder, and need not to utilize mechanical force, as with hammer.Require mechanical force to disengage the powder meaning powder accident is disengaged, for example when inhaler falls.

Though the structural design of inhaler of the present invention is to disengage drug powder when inhaling clothes, is preferably in to inhale to obey and does not disengage medicine before.For example be preferably in inhaler device and carry out after the drop test, medicine still maintains on the substrate, and this test case is as being undertaken by in about 48 inches high pipes inhaler being fallen under the relative humidity of 65 ℃ temperature and about 65%.

Of the present invention preferred aspect, this inhaler device also comprises its configuration can prevent the adherent ozzle of drug powder.For example, this ozzle preferably has through selecting the adherent inner surface of the anti-powder particle of energy.For example preferably have recessed road or rising zone on this inner surface, as the various improvement of introducing above, to help disengaging of powder.Best, by the parallel recessed road of the airflow direction that utilizes flute profile,, preferably form laminar flow basically so that increase the surface area of the inner surface of ozzle with in the ozzle.

Of the present invention other preferred aspect in, this ozzle has a plurality of air intakes, passage is communicated with each inlet, in order to strengthen disengaging of drug powder.For example referring to Fig. 7, each enters the mouth arrow points wherein.The opening of this passage through being called " air intake hole " makes the inside of ozzle be communicated with the ambient atmosphere environment facies.Best, by with about 20 °～70 ° angle, particularly with about 45 angle boring and form this air intake hole.Best, each passage is extended by about 20～70 ° angle by the air intake of correspondence.Particularly this passage and level are 45.In some preferred embodiments, passage is columniform, and diameter is approximately less than 5 millimeters, for example 0.1 to 5 millimeter, and in certain embodiments approximately less than 0.1 millimeter.Best, the configuration of ozzle makes the throughput between powder and the substrate big as far as possible, and powder is easy to by disengaging on the substrate when inhaling clothes with box lunch.In some preferred embodiment, air intake and corresponding passage are about 2 to 20.In other preferred embodiments, 4 to 8 air intakes of having an appointment.

Best, air intake can fall so that what throughput can both keep constant compression force regardless of by patient's wish or via the gate mechanism automatic shutter.

In Fig. 8 A and 8B the illustrative embodiment of some inhaler device of the present invention of expression it have a plurality of air intakes, each channel connection is to each inlet.Fig. 8 A represents anozzle 94, and dress has eachair intake 82 ofcommunication passage 83 on it.For several air intakes are equipped with gate mechanism.Ozzle 94 with its on deposit medicine 87 (not shown)ssubstrate 86 communicate by air-flow.Substrate 86 is elongated band shape.Send band byspool 92, byspool 90 take-ups.Substrate has the sealant (not shown) byspool 88 take-ups.The inhaler of Fig. 8 B inpresentation graphs 8A, also comprise electronic type and separate the releasing mechanism (not shown), it is bybattery 96 power supplies.

In certain embodiments, each air intake all arrives medicament part separately through channel connection.For example, just can make it to obey medicament into 100 milligrams of dosage by with each aligns in each and 4 air intakes in 4 each medicaments of 25 milligrams.

Best, only the granule of described size for example can respirable grade deposit on the substrate of inhaler.Because this device is best with the sedimentary drug use of required granulometric range, and because in each preferred embodiment, the granule of non-required magnitude range all is trapped on the substrate basically, so do not need other device to encourage depolymerization.Therefore, the present invention is more superior than the inhaler that needs depolymerizer, and the latter has the circuitous shape passage that can be detained medicine.Take under the occasion of medicine at some, preferably the particulate size of being scattered by inhaler is not more than about 15 microns, particularly is not more than 10 microns.

In some preferred embodiments, substrate band in the inhaler is useful on the auxiliary conductive layer that disengages of powder electronics, as what introduce at the common pending application that " has the inhaler device that is used for strengthening the electronic installation that the dryness powder disengages " with the present invention being entitled as of applying for simultaneously.

Inhaler can also be provided with and be used to strengthen other mechanism of disengaging, and comprises for example diamond tip emitter of electronic emitter, so that neutralization makes powder remain on on-chip electric charge.In addition, for example substrate of deposition of medicament can be photoconductive build substrate on it, can disengage medicine when illumination.Utilizing electric field to strengthen disengages

The present invention also partly relates to a kind of like this inhaler device, and it comprises the substrate that deposits medicine, comprises conductive layer and insulating barrier on this substrate.In certain embodiments, this conductive layer comprises at least one lead of inserting in the substrate, and in other embodiments, the conductive layer in substrate has some perforates, for example net.Best, conductive layer is connected on the voltage source.In addition, in some preferred embodiment, conductive layer comprises at least one floating electrode, and preferably according to the figure of determining by floating electrode with drug deposition to substrate.

In some preferred embodiments, this inhaler also comprises the 2nd conductive layer that is positioned at the substrate top that one deck does not contact with substrate.Have some perforates in best second conductive layer, be more preferably the diameter of the perforate in second conductive layer about 1.5 times to the average diameter of drug particles.In some preferred embodiment, with voltage source be connected in substrate conductive layer and on second conductive layer above the substrate.When in on-chip conductive layer if any perforate, preferably the diameter of this perforate is near the diameter of perforate in second conductive layer above substrate.The diameter of the perforate in second conductive layer best 1.5 times to the average diameter of drug particles.

In other preferred embodiments, inhaler device also comprises the 3rd conductive layer that one deck is positioned at the substrate below, preferably voltage source is connected at second conductive layer above the substrate with on the 3rd conductive layer below the substrate.

On the other hand, the invention provides a kind of method that is used for being inhaled by inhaler the thing of taking medicine, it comprises: (a) provide to have the inhaler that deposits the medicine substrate, described substrate comprises conductive layer and insulating barrier, and voltage source is connected on the described conductive layer; And (b) starting voltage source.

Best, voltage source and air-flow start simultaneously, and start preferably that the persistent period is about 300 milliseconds to 1 millisecond pulse.The voltage that adopts is preferably approximately by 500 to 2000 volts.

Therefore, the invention provides a kind of inhaler that is used to strengthen the electronic installation that dry powder disengages that has on the other hand.As the preferred embodiments of the invention, the substrate that is used to strengthen the electronic installation that disengages and is by the inhaler that includes conductive layer and insulating barrier provides, and insulating barrier contacts with sedimentary powder on the substrate.The electric charge that conductive layer is used on the one hand according to deposition of medicament is provided as the picture distributed charge, forms a kind of medicine that helps with this and is adsorbed onto active force on the insulating barrier.Preferably this insulating barrier is enough thick, be enough to shield the active force that this imaging distributes, prevent the surface adsorb powder too tight, but also will be thinned to is enough to be formed with the active force that enough imagings distribute, prevent that powder from disengaging prematurely, for example when inhaler falls owing to the impulsive force that causes is disengaged.

For example, be that d, dielectric constant are e in order to make at thickness_rInsulating barrier on charge-mass ratio be that the powder particle of q/m can bear 500 times gravity, when the dielectric constant of free space is e.And ignore under the gravitational condition of Robert Van de Walle, need satisfy following equation:$500\&times;g\&le;\frac{{(q/m)}^{2}m}{4p{e}_o{\mathrm{<figure-callout\; label="e\; r\; d"\; filenames="A9719538000231.png,A9719538000252.png"\; state="\{\{state\}\}">e</figure-callout>}}_r{d}^{}{}^2}$

Suppose q/m=30 millicoulomb/gram, m=7 microgamma, and e_r=2, then d can be at least greatly to 76 millimeters.In fact, it is believed that under many circumstances that because the gravitational existence of Robert Van de Walle, retentivity will be above 500 * g.When determining the insulating barrier preferred thickness of substrate, above-mentioned equation can be used as general guide.

Deposit powder on the substrate in the inhaler, when inhaling clothes, disengage.A kind of mode of powder deposition is the ion printing, is for example introduced in sequence number is 08/471889 application.Yet preferably so that before being adsorbed on powder on the substrate, substrate is pre-not charged to this substrate in deposition of medicament.So preferably use electrostatic chuck, utilize the Electrostatic Absorption charged powder to deposit.For example in some preferred embodiment, substrate itself constitutes electrostatic chuck.Specifically, conductive layer in the substrate has the configuration of the electrostatic chuck of the floating electrode that is used for the electric charge imaging, this has done in sequence number is 08/630050 common pending application application and has introduced (being entitled as " electrostatic chuck " 1996.4.9 application), and incorporated can be for reference here.In sequence number is 08/630049 common pending application application, (be entitled as: " sound type dispenser ", 1996.4.9 application) introduced a kind of utilization sound type dispenser can be on substrate deposited powder, quote it here and also can be used as reference in full.

In brief, be used to make the electrostatic chuck of electric charge imaging to comprise three layers, preferably also can have the 4th layer.Bottom is a lower conductiving layer, and it also is called as the backing electrode.The second layer on this lower conductiving layer end face is an insulating barrier, the 3rd layer of conductive layer on the insulating barrier end face, and conductive layer has two types electrode on this, floating electrode and bucking electrode.In some preferred embodiments, floating electrode is isolated with other conductor electricity, and a gap is arranged between floating electrode and bucking electrode.The 4th layer on last conductive layer end face is insulating barrier, its preferably with the contacted layer of drug powder, the thickness of this layer is the key element in the above-mentioned mathematical formulae.Preferably this one deck is that material by polyimides or other high dielectric strength constitutes.Be not limited to specific principle, it is believed that electric charge redistributes when applying voltage between bucking electrode and backing electrode on floating electrode.The redistribution of this electric charge is adsorbed onto and the corresponding sucker of floating electrode zone the granule of static electrification, and causes being deposited on these zones.Being preferably in has a strong scattering field in the gap between floating electrode and the bucking electrode, but this scattered field had better not be even as big as causing discharge.

For example consult Figure 13, this figure one has the schematic cross-sectional view of the electrostatic chuck of the floating electrode that is used for the electric charge imaging on last conductive layer.Figure 14 is the top view of the floating electrode among Figure 13.The sequence number that also can consult the 1996.4.9 application is 08/630050 common unsettled U.S. Patent application, and name is called: electrostatic chuck ", its wherein part continuity is filed an application simultaneously with the application.For example consult Figure 13, sucker 1110 has lower conductiving layer 1120, and insulating barrier 1130 is arranged on its end face.Last conductive layer 1140 is arranged on the insulating barrier end face.Last conductive layer 1140 is electrically connected, but between buckingelectrode 1160 and floatingelectrode 1170gap 1150 is arranged.What represent among Figure 14 is the top view of going up conductive layer 1140, and floatingelectrode 1170 has agap 1150 at the center between floating electrode and bucking electrode on everyside 1160.

The floating electrode of electric charge imaging sucker has been determined drug powder sedimentary figure on substrate, and powder is remained on the substrate.In the process of deposited powder, electric charge imaging sucker is electrically connected on the power supply, then disconnects after deposition.Floating electrode can constitute figure, so that determine each drug dose by the gap on the inhaler substrate.For example, the conductive layer in the substrate shown in Figure 11 A and the11B 101 100 can be used as electric charge imaging sucker.The conductive layer of this sucker can be used as also that powder electronics of the present invention is auxiliary to be disengaged.

Specifically, Figure 11 A and 11B are the schematic cross-sectional view that deposits thesubstrate 101 of medicine on it, and this substrate hasconductive layer 100 and insulating barrier 105.Preferably improve with thesurface 103 ofmedicine 107 contactedsubstrates 101 according to the common pending application that " has the inhaler device that is used to strengthen the improvement surface that dry powder disengages " with the application being entitled as of applying for simultaneously.Disengage in the process auxiliary, the conductive layer of representing withnet 109 is located at the substrate top, and adds voltage between these two conductive layers, as shown in Figure 11 B.

Therefore, according to an aspect of the present invention, when inhaling clothes by patient, utilize auxiliary the disengaging of electronic mechanism to make powder by disengaging in the inhaler.Preferably the conductive material in the substrate is applied electric pulse.

In some preferred embodiment, for example when substrate is entity,, voltage is added on the conductive layer of sucker for the substrate from inhaler disengages medicine.Be preferably in the process of disengaging, with a kind of conductive material for example net place substrate top, do not contact with substrate, voltage is added between substrate and the net.As consult Figure 11 B and can understand.

High-voltage pulse is applied between net and the conductive layer in substrate so that triggering disengages.Best, the air-flow when this pulse is obeyed with suction triggers synchronously and by air-flow.For example, inhaler preferably has a switch, so that start this pulse when inhaling clothes formation air-flow.About 0.3-1 millisecond of persistent period of best start pulse.The preferably about 500-2000 volt of used voltage.

This substrate can also comprise the conductive layer that is not electric charge imaging sucker in addition.For example, this substrate can have the porous, electrically conductive layer, to constitute net.For disengaging, can not contact there being porous second conductive layer to place the above and below of substrate with substrate.To discharge in order to the electronics that carries out powder from substrate is auxiliary in the electrical connection between two conductive layers of substrate above and below.For example consulting Figure 12 A and 12B can understand.The position that preferably places the conductive layer above or below the substrate is apart from the about 1-2 millimeter of substrate.In the process of disengaging, high-voltage pulse is applied between two conductive mesh.Best, the air-flow when this pulse is obeyed with suction triggers synchronously and by air-flow.

Figure 12 A and 12B are the schematic cross-sectional view that deposits thesubstrate 200 ofmedicine 107 on it, and thissubstrate 200 is net.In auxiliary process of disengaging, twoconductive layers 202 wherein representing with porous net and 204 are positioned at the above and below of substrate, and voltage is added between these two conductive layers, shown in Figure 12 B.When substrate has porous, preferably use one disengaging medicine with two conductive layers below substrate from substrate above the substrate.Be not limited to specific principle, it is believed that use alive two conductive layers between it, strengthened powder from porous substrate being arranged upward to disengaging towards ozzle.Best, the about 1-30 of the thickness of substrate Mill.

When having porous in the conductive material of substrate and for example be a net, preferably the structure shape in hole can make the throughput maximization, so that disengage the powder of quite big quantity, in some preferred embodiments, the about 0.6-2 millimeter of the diameter in hole.Best, this net be by metal for example rustless steel make, best, this net scribbles insulant, for example politef (" polytetrafluoroethylene ").This net can be the part of ozzle, preferably aims at the single drug dose before inhaling clothes.

In addition, the substrate that for example deposits on it in inhaler of medicine also can embed in a kind of solid conductive material.For example substrate wherein have one or many leads in.Preferably this conductive material is a kind of metal.

Only schematically illustrate in the exemplary inhaler in Fig. 8 B and be used for the auxiliary power supply of usefulness that disengages of electronics, it has an embodiment that battery-powered electronics separates the inhaler device of releasing mechanism (not shown) as of the present invention.In this embodiment, a plurality ofair intakes 82 have improved powder disengaging byozzle 94 with thepassage 83 that is communicated to each inlet.Several air intakes 82 are provided with gate mechanism 84.Ozzle 94 with its on deposit medicine 87 (not shown)ssubstrate 86 be connected with air-flow.Substrate 86 is elongated band shape.Supply band byspool 92, byspool 90 take-ups.Substrate tool sealant (not shown), it is byspool 88 take-ups.

The auxiliary releasing device of this electronics can be used to promote other mechanism of disengaging to combine, have the substrate in the recessed road of flute profile including but not limited to use, in order to reduce the area that this substrate contacts with the surface of powder particle.

Those skilled in the art will appreciate that inhaler of the present invention can except oral, can also use in conjunction with the nose clothes in conjunction with the drug use of a lot of types.The biological preparation that can be used as medicine normally for example can act on the material of the chemicals of cell, virus, tissue, organ or body, including but not limited to medicine (being medicine), so that the function of cell, virus, organ or body is changed.Best, this body is mammal, particularly people.

As mentioned above, (Attorney Docket DSRC12212) sequence number that the application enjoys 1996.6.10 application is the priority of 08/661212 U. S. application, and is that the sequence number of 1996.6.10 application is the part continuity of 08/661212 U. S. application (Attorney Docket DSRC 11894).These priority applications draw this reference as disclosure file in full.

Utilize following non-limiting example further the present invention to be introduced.

Example 1 disengages powdery medicine from improved substrate

As shown in Figure 3 improved polypropylene substrate is carried out a kind of powder medicaments, and the mometasone furoate disengages test.With the milligram unit to 2 square centimeters substrate weigh (substrate, milligram) at first at microbalance.Utilizing in sequence number then is disclosed ion printing technology deposited powder medicine on substrate in 08/471889 the U. S. application.Utilize several of short duration air-flows to scatter powder cloud, medicine is pressed 4 spot depositions.Then, to the substrate that has medicine on it weigh (substrate+medicine, milligram).By deduct the weight (medicine, milligram) of weight (substrate, milligram) to determine medicine of substrate before deposition by post-depositional substrate weight (substrate+medicine, milligram).Each data point averages (meansigma methods) by two weight measurement and gets.

In order to scatter powder, substrate is for example placed by this device shown in Fig. 9, and the inhaler ozzle is received on the cylinder 98.Suck the organ mouth and comprise 8 air intakes, each inlet all has one to be the passage (capillary tube) of 45 with ozzle, to strengthen the lifting of drug powder.By ozzle to be provided to 4 kinds of different throughputs of substrate: 15,30,45 and 57 liters/minute, and powder tested by disengaging of substrate." flow " representative is used to throughput that medicine is disengaged by inhaler.After disengaging medicine to substrate weigh (substrate-medicine, milligram).Utilization disengage the remaining drug weight in back and disengaging before drug weight, the percentage rate (% medicine) of definite medicine that disengages by substrate." humidity/temperature " humidity percentage value when testing of representative and ambient temperature (℃).Its result is illustrated among the following table 1-2.The data of the average percentage value that disengages medicine of each flow in three kinds of flows among the table 3 summary table 1-2 with and standard deviation.Data in table 3 are used curve representation in Fig. 2 F.

Table 1

Sample	Apply/pound/inch2	Substrate+medicine (milligram)	Substrate (milligram)	Medicine (milligram)	Substrate-medicine after scattering	Surplus medicine (milligram)	The medicine that % scatters	Flow (rise/minute)	Humidity/temperature
										????1	?5/7.5	?8.7735	?8.6095		?8.6494			????57	????68/81
		?8.7735	?8.6092		?8.6495
										On average		?8.7735	?8.60935	?0.16415	?8.64945	?0.0401	?75.5711
????2	?5/7.5	?7.2482	?7.1406					????57	????67/81
												?7.2486	?7.1409
On average		?7.2484	?7.14075	?0.10765	?7.16	?0.01925	?82.1179
															?8.2274
????3	?4/7.5	?8.3174	?8.1912		?8.2257			????n/d	????68/81
												?8.3161	?8.1911		?8.2238
On average		?8.31675	?8.19115	?0.1256	?8.225633333	?0.03448	?72.5451
										????4	?4/7.5	?6.8848	?6.7813					????n/d	????68/81
		?6.8844	?6.7816
										On average		?6.8846	?6.78145	?0.10315	?n/d
????5	?5/7.5	?8.7858	?8.681					????45	????68/81
												?8.7862	?8.682
On average		?8.786	?8.6815	?0.1045	?8.7215	?0.04	?61.7224
										????6	?3/7.5	?7.6297	?7.5486		?7.5782			????n/d	????68/90

		?7.63	?7.547		?7.582
										On average		?7.62985	?7.5478	?0.08205	?7.578133333	?0.03033	?83.0306
?7	?4/7.5	?8.1118	?7.9899					????15	????68/90
												?8.1117	?7.9905
On average		?8.11175	?7.9902	?0.12155			?6.3
										?8	?5/7.5	?7.517	?7.4066					????30	????68/90
		?7.5168	?7.4063
										On average		?7.5169	?7.40645	?0.11045	?7.4913	?0.08485	?23.1779

Table 2

Sample	Apply/pound/inch2	Substrate (milligram) (sample+substrate)	Substrate+medicine substrate	Medicine (milligram) (milligram)	Substrate-medicine (scattering the back)	Surplus medicine (milligram)	The medicine that % scatters	Throughput (rise/minute)	Humidity/temperature (F)
										?9	????6/7.5	?7.0404	?6.9084		?6.9337			????60	????67/83
		?7.0408	?6.9086		?6.9344
										On average		?7.0406	?6.9085	?0.1321	?6.93405	?0.02555	?80.658592
	????4/7.5	?7.5945	?7.4758		?7.5067			????45	????66/83
												?7.5938	?7.4765		?7.507
On average		?7.59415	?7.47615	?0.118	?7.50685	?0.0307	?73.983051
										11	????3/7.5	?8.037	?7.9513		?8.037			????15	????66/83

Sample	Apply/pound/inch2	Substrate (milligram) (sample+substrate)	Substrate+medicine substrate	Medicine (milligram) (milligram)	Substrate-medicine (scattering the back)	Surplus medicine (milligram)	The medicine that % scatters	Throughput (rise/minute)	Humidity/temperature (F)
												?8.0371	?7.9514		?8.0366
On average		?8.03705	?7.95135	?0.0857	?8.0368	?0.08545	?0.2917153
										12	????4/7.5	?8.8213	?8.7376		?8.8202			????15	?65/83
		?8.8207	?8.7375		?8.8212
										On average		?8.821	?8.73755	?0.08345	?8.8207	?0.08315	?0.3594967
13	????5/7.5	?7.1802	?7.1081		?7.1794			????15	?65/83
												?7.1796	?7.1081		?7.1795
On average		?7.1799	?7.1081	?0.0718	?7.17945	?0.07135	?0.6267409
										14	????3/7.5	?6.8602	?6.7494		?6.8293			????30	?70/84
		?6.8597	?6.7485		?6.8294
										On average		?6.85995	?6.74895	?0.111	?6.82935	?0.0804	?27.567568
15	????5/7.5	?9.3052	?9.1824		?9.2381			????45	?70/86
												?9.305	?9.1825		?9.238
On average		?9.3051	?9.18245	?0.12265	?9.23805	?0.0556	?54.667754
										16	????5/7.5	?8.983	?8.8723		?8.9582			????30	?71/86
		?8.9845	?8.8727		?8.958
										On average		?8.98375	?8.8725	?0.11125	?8.9581	?0.0856	?23.05618
17	????7/7.5	?9.3624	?9.2077		?9.2326			????60	?70/86
												?9.3623	?9.2081		?9.2324

Sample	Apply/pound/inch2	Substrate (milligram) (sample+substrate)	Substrate+medicine substrate	Medicine (milligram) (milligram)	Substrate-medicine (scattering the back)	Surplus medicine (milligram)	The medicine that % scatters	Throughput (rise/minute)	Humidity/temperature
										On average		9.36235	?9.2079	?0.15445	?9.2325	?0.0246	?84.072515

Table 3

Flow	????57	????45	????30	????15
						80.658592	?54.6677538	?27.5675676	?0.29171529
	84.0725154	?73.9830508	?23.0561798	?0.3594967
						82.1179749	?61.722488	?23.1779086	?0.62674095
					On average	82.28302743	?63.4577642	?242.600552	?0.425984313
Standard deviation	1.712936076	?9.773871401	?2.570231634	?0.177132719
	80.658592	?54.6677538	?27.5675676	?0.29171529
					A data point of W/ (falling)	84.0725154		?23.0561798	?0.3594967
	82.1179749	?61.722488	?23.1779086	?0.62674095
On average	82.28302743	?58.1951209	?24.600552	?0.425984313
					Standard deviation	1.712936076	?4.988450392	?2.570231634	?0.177132719

Example 2 improved substrates compare with not improved substrate

Utilization in the application of sequence number 08/471889 (" utilizing the method and apparatus of electrostatic precipitation drug powder on the substrate predetermined zone " is in the 1995.6.6 application) disclosed ion print process at 2cm²The suction thing of taking medicine of the about 50 milligrams of dosage of deposition on the polypropylene substrate.Utilize microbalance to confirm the weight of medicine.

Utilizing the device shown in Fig. 9 that the medicine by the inhaler substrate that deposits medicine on it is disengaged tests.Consult Fig. 9, produce air-flow by the vacuum pump (not shown) that is connected on thepipeline 97,pipeline 97 is received again on the cylinder 98, to link to each other with inhaler ozzle (not shown).Ozzle comprises 8 air intakes, and each all has the passage (capillary tube) that is 45 withozzle.Effusion meter 99 is used to measure throughput.Each 3 sample to two kinds of substrates of different are tested, and first substrate has the flute profile surface, and as shown in Figure 3, second substrate has not improved flat surface.Two kinds of substrates are all made by polypropylene.Test result is illustrated in the following table 4.

Table 4

The sample number	The medicine that % is disengaged by the substrate of trough of belt	The medicine that % is disengaged by smooth substrate
			????1	????80.5	????62
????2	????84	????64.5
			????3	????82	????67
Meansigma methods	????82.16	????64.5
			Standard deviation	????1.84	????2.5

Above shown in data in Figure 10, use curve representation, it shows, the medicine that is disengaged by the substrate with the recessed road of flute profile is far more than the medicine that is disengaged by non-improved substrate.

Claims (15)

1. inhaler device with inner surface, it comprises the surface that the inner surface of (1) ozzle and (2) deposit the substrate of drug particles on it, at least a portion in this ozzle inner surface or the substrate has recessed road and the rising zone of clearly demarcated paddy is arranged, their size and at interval through selecting, so that reduce the quantity of the drug particles that may contact with the evener branch on surface.

2. inhaler device as claimed in claim 1, the surface that wherein comprises recessed road or rising zone are the substrates that deposits medicine on it.

3. inhaler device as claimed in claim 2, wherein at least a portion drug particles utilizes electrostatic means charged, and wherein this substrate comprises or fully approaching a kind of material, this material can produce the electric charge that enough imagings distribute by the appearance of charged particle, so that charged particle is remained on the substrate.

4. inhaler device as claimed in claim 3, substrate wherein comprises (a) insulating barrier, and its first go up to form recessed road or bulge area and deposition of medicament granule thereon, and (b) conductive layer, second of its contiguous insulating barrier, this second face is first a reverse side.

5. inhaler device as claimed in claim 2 wherein for making the arbitrary part of substrate by the predetermined medicine that disengages a dosage, make at least about the power of the attached work of the granule of a dosage on described substrate sections and be not more than 5000 grams.

6. one kind is used for carrying the drug particles inhaler device to treatment target, it comprises ozzle, this ozzle has outer surface and inner surface, this ozzle also comprises the air intake that a plurality of ecto-entads extend, each inlet is connected with a passage, each passage is extended to the outside by the inside of ozzle, and each passage and ozzle wall are 20 °～70 ° angle orientation.

7. inhaler device as claimed in claim 6, wherein passage and ozzle wall are 45 ° angle orientation.

8. inhaler device as claimed in claim 6, passage wherein is cylindrical basically.

9. inhaler device as claimed in claim 6, wherein channel diameter is approximately less than 5 millimeters.

10. inhaler device as claimed in claim 6, the inner surface of ozzle wherein also comprises recessed road or rising zone, their size is through selecting, so as to reduce may with the quantity of the contacted drug particles of flat surface of substrate.

11. inhaler device as claimed in claim 6, it also comprises gate mechanism, is used for optionally closing one of them air intake at least.

12. a method of making inhaler device comprises:

(a) provide substrate with the surface that is used for deposition of medicament, have recessed road or rising zone on this substrate, the paddy district is arranged, the size of recessed road and rising zone and between each bulge area at interval through selecting, so that reduce the quantity of the drug particles that may contact with the smooth part on this surface;

(b) deposition of medicament on substrate, and

(c) this substrate is assembled in the housing.

13. method as claimed in claim 12, wherein, deposition realizes with electrostatic means.

14. method as claimed in claim 12 also comprises the substrate that will deposit medicine on it and seals.

15. method as claimed in claim 12, wherein the granular size of sedimentary medicine is about the 1-15 micron on substrate.

Images