DRUG DELIVERY SYSTEM
Background of the Invention Field of the Invention The present invention relates to drug delivery systems. More specifically, the invention relates to drug delivery systems comprising a drug in liquid form in combination with a flow-altering agent which allows controlled delivery of the drug.
Description of the Related Art Drugs can be administered to patients in a variety of formulations, including solids, liquids, aerosols, creams and ointments. In most formulations, drugs are combined with other substances that act to prolong drug activity, reduce side effects, increase efficacy, facilitate handling, or to simply make them more palatable. One example of combining a drug with another substance in a solid formulation to make a tablet for oral administration is E-mycin, a broad spectrum antibiotic used to treat a variety of bacterial infections (Knoll Laboratories, Mount Olive, l\IJ). E-mycin requires a special coating to protect the drug from the inactivating effects of gastric acidity and to permit efficient absorption of the antibiotic in the small intestine. One example of combining a drug with another substance in a liquid formulation to make an orally administered syrup is Flumaπne, an antiviral agent used to treat strains of influenza (Forest Laboratories, New York, NY). Flumanne is combined with sodium saccharin, sorbitol and flavoring agents to increase its palatabi tγ. In liquid drug formulations, such as syrups and solutions, the properties of both the drug and the substance(s) with which it is combined must be considered. These properties, including density, solubility, pH, thermal and electrical conductivity, and viscosity, affect the manner in which the drug formulation is administered, and ultimately determine the safety and efficacy of the drug formulation in treating the patient. Viscosity of liquid drug formulations is another important parameter. Viscosity-reducing agents have been used in ophthalmic compositions due to the high viscosity of the polymers used to regulate the absorption of drug in the eye (see, for example, U.S. Patent Nos. 5,795,913, 5,710,182, 5,698,219 and 5,679,665). Transdermal drug formulations discussed in, for example, U.S. Patent Nos. 5,780,050 and 5,654,000, utilize viscosity altering agents that change with temperature to provide greater exposure of drug at delivery sites. Roorda et al. (U.S. Patent No. 5,540,912) utilize the viscosity of the liquid or semi-liquid carrier in which large drug particles are mixed to promote the uniform suspension of the drug and to regulate the rate at which the drug will diffuse through the mixture Altering the viscosity of the carrier, typically non aqueous liquids and aqueous media, reduces the rate of diffusion of the drug particles through the suspension. The formulation of the drug will vary depending on the concentration of the drug in the carrier, and lattice or pore structure of the carrier matrix
However, the references discussed above assume the driving force of the drug within the suspension is diffusion, and examines the formulation as two different species, the carrier and the drug. The viscosity of the carrier is altered to affect the movement of the drug within the carrier, not the movement of the drug and carrier as a mixture.
The rate at which a drug is delivered to a patient is often critical to the efficacy of the treatment. If a drug is delivered at a rate which is too low, its pharmaceutical effectiveness may be compromised. In contrast, if a drug is administered too quickly, it may be toxic or have other adverse effects. The rate of drug delivery is often controlled by administering the drug with a driving force to ensure that the proper dosage is supplied to the patient. This driving force may take the form of a pressure source, or any other suitable source of energy for driving a fluid. The rate of drug delivery will be affected by the nature of the driving force, the properties of the drug mixture and the flow path of the mixture.
In many drug therapy regimens, it is important to provide a sustained release of drug over an extended period of time, such as hours, days or weeks. However, the inherent characteristics of some drugs do not make such sustained delivery practical. For example, some drugs are only soluble in aqueous media that have low viscosities such as water or saline. In a drug delivery system, such aqueous drug mixtures could be expelled at a rate which is incompatible with the desired clinical effect of the drug.
Thus, there is a need for a drug delivery system which allows a drug to be delivered by an external energy source at a controlled rate. The present invention addresses this need.
Summary of the Invention
One embodiment of the present invention is a drug delivery system, comprising: a drug in liquid form; an agent which alters the flow characteristics of the drug when combined with the drug; an energy source configured to pressurize the drug and the flow altering agent; and a flow path through which the drug is delivered. In one aspect of this preferred embodiment, the flow-altering agent is a viscosity enhancing agent. Preferably, the viscosity enhancing agent is selected from the group consisting of glycerol, propylene glycol, carboxymethylcellulose and hydroxypropylmethylcellulose. Preferably, the drug is used to treat a bladder disorder selected from the group consisting of urge incontinence, bladder infection, interstitial cystitis, pain, neuralgia and cancer. In one aspect of this preferred embodiment, the drug is selected from the group consisting of oxybutynm, an antibiotic, a diagnostic agent and an anticancer drug. Advantageously, the drug is delivered at a rate of between about 0.05 and about 100 cc/day.
Preferably, the flow path includes an aperture.
The present invention also provides a drug delivery system, comprising: an energy source; a drug in liquid form within a reservoir operatively connected to the energy source; and a flow altering agent in combination with the drug. In one aspect of this preferred embodiment, the flow-altering agent is a viscosity enhancing agent. Preferably, the delivery rate of the drug is between about 0.05 and 100 cc/day. In another aspect of this preferred embodiment, the energy source pressurizes the drug.
The present invention also provides a drug delivery system, comprising: a pressurized drug in liquid form; and a viscosity altering agent in combination with the drug, wherein the viscosity-altering agent effects a rate at which the pressurized drug is delivered Another embodiment of the invention is a drug delivery system, comprising: a drug in liquid form stored within a pressurized reservoir; a viscosity altering agent in combination with the drug, and a flow path within the pressurized reservoir through which the drug is delivered at a rate of between about 0.05 and about 100 cc/day. Preferably, the flow path is an aperture The present invention also provides a method for delivering a drug, comprising the steps of: combining a drug in liquid form and a viscosity-altering agent; pressurizing the drug and the viscosity-altering agent; pressurizing the drug and the viscosity-altering agent; and delivering the drug through a valve at a rate of between about 0.05 and about 100 cc/day. Preferably, the flow altering agent is a viscosity enhancing agent
Another embodiment of the invention is the use of a liquid drug in combination with a flow-altering agent in the preparation of a medicament for intravesical delivery Preferably, the flow-altering agent is a viscosity enhancing agent. In one aspect of this preferred embodiment, the delivery is accomplished by infusing the drug through a flow regulator and then into the bladder of a patient.
Brief Description of the Drawing Figure 1 is a schematic diagram of a drug delivery system of the present invention
Detailed Description of the Preferred Embodiments The present invention provides a controlled drug delivery system comprising an energy source and a drug in liquid form which comprises a flow-altering agent. The flow-altering agent affects the rate at which the drug is delivered by changing the dynamic properties of the liquid drug mixture. In a preferred embodiment, the flow-altering agent is a viscosity enhancing agent.
It is recognized that various buffers, salts, osmotic agents, and the like are common ingredients in liquid drug formulations, and that these agents may have some minor impact on viscosity For purposes of the present invention, these ingredients would not be considered "viscosity enhancing agents " Rather, a viscosity enhancing agent is a material that is either (a) added primarily to enhance viscosity, and not for another pharmacological or formulation purpose, or (b) increases the viscosity by at least 0.5, and preferably by at least 1 centipoise.
For example, if a drug delivery device such as the intravesical infuser described in U. S. Patent Application Serial No. 09/041,475 is provided in combination with a liquid or solid drug, a viscosity-altering agent can be added to the drug by the physician to alter the drug delivery rate thereof. A drug in condensed form (solid or liquid) is present in the infuser in the deflated state. After placement in a body cavity, a solution comprising a viscosity-altering agent is added to the infuser Addition of the solution inflates the infuser, generating an internal pressure on the drug solution, and activates the drug, resulting in inflation of the infuser and activation of the drug. Once activated, the drug gradually effluxes from the infuser The pressure of the infuser, the structure and design of the flow valve, and the dynamic properties of the drug solution affect the flow rate of the drug. The drug delivery system of the invention can be used to treat, for example, bladder disorders and diseases including urge incontinence, interstitial cystitis, bladder infection, cystitis, and bladder cancer. The system may be useful in treating diseases affecting the surrounding tissues and organs such as recurrent or chronic urinary tract infection (UTI), lower urinary tract symptom (LUTS), endometπosis, prostatitis, benign prostatic hyperplasia (BPH) and prostate cancer. Furthermore, the system may be able to deliver pharmaceutical compounds to treat systemic conditions such as chronic pain and neuralgia. Drugs contemplated for these uses include, for example, anticholinergics (such as, for example, oxybutynm), vanilloids, hepaπn, antibiotics, hormones, alpha blockers, diagnostic agents, anticancer drugs, chemotherapeutics compounds, antidepressants narcotics, analgesics and non- steroidal anti-inflammatory drugs (NSAID) and the like. In the present invention, more controlled delivery rates are obtained by changing the dynamic properties of the drug solution. The dynamic properties of the drug solution may be changed by adding an agent that alters the viscosity of the drug solution, affects the interaction of the drug solution and the surfaces of the flow valve, or otherwise affects the action of particles within the drug solution. The net result of changing the dynamic properties of the drug solution is to affect the flow of the drug solution. Flow is governed by laws relating the physical and dynamic properties of the fluid. The Navier-Stokes equation relates the flow to the forces acting upon the fluid as functions of the physical properties of the fluid such as the density and viscosity. The addition of a viscosity-altering agent affects the coefficient of viscosity of the drug solution. In the case of a steady flow of an incompressible, viscous fluid in a two dimensional channel, the Navier Stokes equation reduces to a simple relationship where the flow rate is directly proportional to the pressure and inversely proportional to the coefficient of viscosity. For example, if it is desirable to quickly deliver a high dose of drug, a relatively low viscosity agent, having a viscosity coefficient in the range of about 0.1 to about 1.0 centipoise, is added to the drug. In contrast, if one wants to slowly deliver a low dose of drug, a relatively high viscosity agent providing a coefficient of viscosity in the range of about 1 to about 100 centipoise, is added to the drug. In preferred embodiments, the viscosity of the liquid drug composition is increased by at least about 1, 2, or 3 centipoise, or alternatively by at least about 5, 10, or 15 centipoise. Altering fluid properties allows the operator to affect flow rates without changing the design or function of a fluid delivery system Thus, by adding an agent that affects the dynamic properties of the fluid, the rate of fluid delivery can be changed without changing the design or function of the fluid delivery system.
One significant advantage of the apparatus and method of the present invention is that a single device with a single design may be manufactured by a single manufacturing process which has many applications for drug delivery at a variety of desired flow rates. The flow rate is simply adjusted by the physician by the selection of an appropriate flow-altering agent which is combined with the drug
The addition of one or more flow altering agents to a concentrated drug now makes metered drug delivery from an energy source, such as a pressurized source, simple and reproducible, a method which was not previously feasible. In a preferred embodiment, the flow altering agent is a viscosity altering agent which increases the viscosity of the liquid drug and changes the dynamic character of the fluid flow, thus slowing down its rate of delivery.
Viscosity-enhancing agents contemplated for use in the present invention include glycol cosolvents such as glycerol or propylene glycol; cellulosic viscosity-enhancing agents such as carboxymethylcellulose, hydroxypropylmethylcellulose; or any other viscosity enhancing agent well known in the art.
In an alternative embodiment, if a drug solution properties cause it to flow too fast, a viscosity decreasing agent such as water or other aqueous solution is added which actually increases the flow rate. In another embodiment, a drug in solid form (i.e., powdered or lyophi zed) is provided with the drug delivery system and reconstituted with a pharmaceutically acceptable excipient or diluent such as phosphate buffered saline (PBS) or lactated Ringer's solution and a viscosity-altering agent.
A schematic diagram of a drug delivery system 2 of the invention is shown in Figure 1. An energy source 4 acts on liquid drug reservoir 6 which contains a viscosity altering agent. The liquid drug then flows through valve 8 at a controlled rate.
The energy source may be a spring, piston, syringe, balloon, gravitational source, and the like, that generates a pressure on the liquid. In a preferred embodiment, the drug reservoir is an elastic membrane that, when inflated, generates a pressure on the liquid drug. The liquid drug exits the drug reservoir through a flow controller or flow restπctor/regulator (e.g. valve) that controls the rate of flow of the drug out of the reservoir. For example, several pressure responsive valves are disclosed in U. S. Patent Application Serial No. 09/041,475. The drug reservoir may be any shaped article capable of holding a liquid drug in combination with a flow-altering agent, and configured with an energy source such that the source exerts pressure on the liquid drug contained within the article. The drug delivery system may also comprise a valve assembly for accurately metering the dosage of a drug.
In a preferred embodiment, the system also comprises a flow path through which the drug is delivered at a rate of about 0.05 to about 100 cc/day, more preferably between about 0.25 and about 50 cc/day. In a preferred embodiment, the flow path comprises an aperture. The aperture is preferably a valve or microflow valve. Typically, the viscosity of the liquid drug is between about 0.1 and about 100 centipoises (cps); more preferably between about 1 and about 10 cps; and most preferably, between about 1 and 5 cps. The viscosity of any desired liquid drug solution and its flow rate from a reservoir can be determined using standard analytical techniques. Thus, a particular constant flow rate can be obtained by determining flow rates of drug solutions having different viscosities which requires only routine experimentation by one of ordinary skill in the art. In another preferred embodiment, the drug delivery system comprises an energy source; a drug in liquid form within a reservoir operably connected to the energy source; and a flow-altering agent in combination with the drug.
In yet another preferred embodiment, the drug delivery system comprises a drug in liquid form stored within a pressurized source; a flow-altering agent in combination with the drug; and an aperture within the pressurized source through which the drug is delivered at a rate of about 0.05 to about 100 cc/day Preferably, the flow altering agent is a viscosity enhancing agent In another embodiment, the drug delivery method comprises the steps of combining a drug in liquid form and a flow altering agent, pressurizing the drug and the flow altering agent, and delivering the drug through a microflow valve at a rate of about 0 05 to about 100 cc/day
The pressurized drug delivery system and method of the invention may be used to deliver any desired drug to any desired location In a preferred embodiment, a drug such as oxybutynm chloride, which is used to treat urge incontinence, is placed in the drug reservoir of an intravesical infuser such as the one described in U. S. Patent Application Serial No 09/041,475, in combination with glycerol, to decrease the flow rate of oxybutynm chloride through the flow restricted exit port of the infuser This allows prolonged drug release over time and reduces the number of times the infuser must be refilled with drug It should be noted that the present invention is not limited to only those embodiments describe in the Detailed
Description. Any embodiment that retains the spirit of the present invention should be considered to be within its scope. However, the invention is only limited by the scope of the following claims