WO1994022424A1

WO1994022424A1 - Biodegradable, water-permeable membrane for fluid-imbibing pump

Info

Publication number: WO1994022424A1
Application number: PCT/US1994/003394
Authority: WO
Inventors: Patrick S.-L. Wong; Felix Theeuwes; Brian L. Barclay; Michael H. Dealey
Original assignee: Alza Corporation
Priority date: 1993-03-29
Filing date: 1994-03-29
Publication date: 1994-10-13
Also published as: AU6526694A

Abstract

A fluid-imbibing pump employing a membrane having water permeability and structural integrity sufficient to effect agent delivery, which membrane biodegrades upon exposure to gastrointestinal fluids and disintegrates within 90 days after the agent delivery period. The membrane preferably comprises poly(d,l-lactide-co-glycolide) and hydrophilic polymer. Methods of coating a fluid-imbibing pump with poly(lactide-glycolide) copolymers and hydrophilic polymers are also disclosed.

Description

BIODEGRADABLE, WATER-PERMEABLE MEMBRANE FOR FLUID-IMBIBING PUMP

TECHNICAL FIELD

This invention relates to controlled agent delivery devices. More particularly, this invention relates to orally administered fluid- imbibing pump devices for gastrointestinal drug delivery. Still more particularly, this invention relates to water-permeable, biodegradable membranes for fluid-imbibing pumps.

BACKGROUND OF THE INVENTION

Controlled delivery of drugs has received substantial attention in the pharmaceutical field. "Delivery agents", "agents", or "drugs" are used interchangeably herein to refer to any substance which is delivered to a living organism or plant to produce a desired, usually beneficial, effect. Many forms of controlled drug delivery devices are currently being practiced and further developed. Examples of such drug delivery devices include intravenous devices such as in U.S. 4,857,052, transdermal devices such as in U.S. 4,725,272, electrotransport devices such as in U.S. 5,080,646, and osmotic pump devices such as in U.S. 3,916,899. Many of these devices employ coatings, films, or membranes which function as a means of controlling the drug delivery rate.

A fluid-imbibing pump, also referred to as an osmotic pump, is one type of device which utilizes one or more membranes in controlling drug delivery rates. As used herein, "fluid-imbibing pump" refers to a device which imbibes fluid from the surroundings through a membrane, thereby generating an internal pressure useful in expelling a substance from within the membrane. One type of fluid-imbibing pump, commonly referred to as an elementary osmotic pump, generates an internal pressure when water surrounding the device diffuses through the semi- permeable membrane and dissolves the drug. The driving force for osmosis, or water diffusion into the device, is the drug concentration gradient across the membrane. Since the membrane is impermeable to drug, more water diffuses into the device than out of the device, thereby generating a pressure sufficient to deliver drug solution through one or more orifices in the membrane. Another type of fluid-imbibing pump does not require water-soluble agent to function. In these devices, water diffusing across a semi-permeable membrane contacts a hydrophilic polymer. The hydrophilic polymer expands upon contact with water, thereby generating a pressure inside the device sufficient to deliver drug through one or more orifices in the membrane.

In addition to water permeability and drug impermeability, other factors should be examined when selecting a membrane for an fluid-imbibing pump. Examples of other factors to consider are structural strength and integrity, biocompatibilitγ, chemical stability with respect to the drug, hydrophilic polymer and surrounding body fluids, shelf life, processing constraints, and aesthetic appeal. One aspect of design related both to chemical stability in the body fluids and structural integrity is biodegradability. "Biodegradation", as used herein, relates to the chemical and/or mechanical degradation resulting in disintegration of a membrane upon exposure to animal body fluids, e.g. gastrointestinal (Gl) fluids.

Generally, fluid-imbibing pumps either are designed to be naturally expelled from an animal or are designed to be manually removable. However, problems may arise when a pump is neither naturally expelled or manually removable after drug delivery has ceased. For example, although typically an orally administered pump will pass through a human gastrointestinal system in less than about 24 hours, it is possible for a device to become lodged in the Gl tract. In order to eliminate remnants of the fluid-imbibing pump after the useful life has expired, it would be desirable for the membrane to disintegrate after delivery is accomplished. Therefore, an improved membrane for an fluid- imbibing pump would biodegrade at a predetermined time after exposure to body fluids, thereby diminishing the structural integrity of the membrane to a point at which the membrane separates or ruptures. Biodegradable materials known in the drug delivery art include poly(d,l-lactide-co-glycolide) copolymers, as disclosed in U.S. 4,897,268 and "Biodegradable Polymers as Drug Delivery Systems", Drugs and the Pharm. Sci., vol. 45, ch. 1 (1990). Poly(d,l-lactide-co- glycolide), also referred to as polydactide-glycolide) or PLG, is used herein to describe generally copolymers of lactic and glycolic acids. Although polydactide-glycolide) copolymers are biodegradable, these copolymers allow insufficient water permeability for use as membranes for fluid-imbibing pumps. Alternatively, hydrophilic polymers, such as cellulose acetates, are known for use in membranes of osmotic delivery devices, as disclosed in U.S. 3,916,899. Such hydrophilic polymers are useful in allowing water permeation into the device while preventing drug permeation out of the device, except through pre-formed orifices in the membrane. However, hydrophilic polymers do not biodegrade at a sufficient rate to function as a biodegradable membrane for a fluid-imbibing pump.

Thus, there is a need for a biodegradable, water-permeable membrane for a fluid-imbibing pump which disintegrates after exposure to gastrointestinal fluids for a predetermined time. A related need exists for a biodegradable membrane for an fluid-imbibing pump which provides adequate structural integrity and water permeability during drug delivery periods, while disintegrating prior to potential problems occurring from the device being lodged in the gastrointestinal tract. Similarly, a method is needed for forming a water-permeable membrane for an osmotic drug delivery device which will disintegrate after a predetermined time of exposure to Gl fluids.

DISCLOSURE OF THE INVENTION

Satisfaction of the previously described needs and other advantages of the invention will become apparent from the disclosure of the membranes and fluid-imbibing pumps of the present invention. The pump includes a core comprising a delivery agent. The core is at least partially enclosed by a biodegradable, water-permeable membrane. The membrane has sufficient water permeability and structural integrity to deliver the agent during a predetermined period. Membrane structural integrity decreases with time of exposure to gastrointestinal fluids. Structural integrity decreases to the point at which the membrane disintegrates. This disintegration occurs within about 90 days after the predetermined delivery period. The biodegradable membrane is preferably formed from a hydrophilic polymer and a poly(d,l-lactide-co-glycolide) copolymer. In a one embodiment of the pump, the volume further includes a hydrophilic polymer which expands upon contact with water, thereby causing a positive pressure inside the device. In a preferred embodiment, the fluid-imbibing pump is designed for oral administration to a human. Agent delivery is initiated by surrounding water diffusing through the membrane as the pump passes through the gastrointestinal tract. Water in the gastrointestinal tract is osmotically imbibed through the surrounding membrane as a result of a concentration gradient. An agent is delivered through one or more orifices in the membrane as a result of pressure generated by water within the device and/or expansion of a hydrophilic polymer. After contact with gastrointestinal fluids for a predetermined time period, the polydactide-glycolide) biodegrades, thereby allowing the membrane to disintegrate and the residual device contents to disperse. This minimizes lodging of solid remnants of the device in the gastrointestinal tract.

BRIEF DESCRIPTION OF THE DRAWINGS

This invention will be described in further detail with reference to the accompanying drawings wherein:

FIGURE 1 is a schematic side view of one embodiment a fluid-imbibing pump of the present invention prior to agent delivery. This embodiment illustrates use of a hydrophilic polymer delivery means.

FIGURE 2 is a schematic side view of the device of FIG. 1 wherein agent delivery has been initiated.

MODES FOR CARRYING OUT THE INVENTION

The fluid-imbibing pump of the present invention employs a biodegradable, water-permeable membrane which biodegrades in the gastrointestinal tract. Preferably, the membrane comprises poly(d.l-lactide-co-glycolide), also referred to as polydactide-glycolide) or PLG, and a hydrophilic polymer. The hydrophilic polymer component allows water passage through the membrane which activates the agent delivery mechanism, while the polydactide-glycolide) component degrades upon exposure to gastrointestinal fluids, thereby effectively disintegrating the membrane after a predetermined time. This biodegradation of the membrane minimizes potential problems associated with device lodging in the delivery environment, e.g. in crevices of the Gl tract.

While complete degradation of the entire membrane may be desirable in certain embodiments, it is not necessary in all applications of the present invention. Degradation of the polydactide-glycolide) component is sufficient to break or separate the membrane into smaller portions, thereby dislodging the remnants of the fluid-imbibing pump from inadvertent retention in the delivery environment. Thus, membrane compositions and dimensions are selected so as to allow for disintegration within about 90 days after agent delivery has been accomplished, while providing sufficient water permeability rates to effect agent delivery. This disintegration time is chosen sufficiently short to avoid problems from developing if the device inadvertently lodges in the delivery environment, e.g. in crevices of the human Gl tract.

FLUID-IMBIBING PUMP t

Referring now to the drawings, one embodiment of the fluid-imbibing pump 10 of the present invention includes a agent distribution means 12, a delivery agent 14, and a rate-controlling semipermeable membrane 16 having at least one delivery orifice 18, which is sized to permit agent distribution at the desired rate, as illustrated in FIG. 1. The agent distribution means 12 is composed of at least one hydrophilic polymer. The semipermeable membrane 16 surrounds or encapsulates the agent distribution means 12 and the agent 14. The semipermeable membrane 16 must be permeable to surrounding water to some extent, while impermeable to agent passage. In addition, the semipermeable membrane of the present invention is biodegradable, i.e., the membrane decomposes or disintegrates over a predetermined time period of exposure to gastrointestinal fluids. A delivery orifice 18 is formed through the semipermeable membrane 16. The orifice 18 must be sufficiently large to allow agent passage at the desired delivery rate. The agent layer 14 is positioned adjacent to the delivery orifice 18. Although the agent 14 is commonly in solid form, a liquid form of the agent may be utilized.

Agent delivery is initiated when water penetrates the membrane 16 because of the agent and/or polymer concentration gradient between inside and outside the device. As water diffuses through the semipermeable membrane 16, solid agent 14 may be dissolved. Agent 14 is delivered to the surroundings through the delivery orifice 18 via pressure generated from the expanding hydrophilic polymer in the delivery means 12. The rate of water influx is controlled by proper selection of the composition, thickness, porosity, and surface area of the semipermeable rate-controlling membrane 16. Furthermore, the composition and amount of the hydrophilic polymer in the agent distribution means 12 has an impact on the agent delivery rate.

BIODEGRADABLE MEMBRANE

The membranes of the fluid-imbibing pumps of the present invention are designed so as to be biodegradable after a predetermined time. "Biodegradable" is used herein to describe those membranes which will decompose and disintegrate over a relatively short time upon exposure to an animal gastrointestinal system. "Disintegration", as used herein, means either a separation of the membrane, caused by chemical decomposition of one or more membrane components, and/or a rupture, resulting from mechanical forces. Thus, "disintegration" describes a loss of structural integrity in the membrane which is manifested in membrane deformation, cracking, fragmentation, dissolution, and/or erosion.

Disintegration of the membrane allows expulsion of the membrane and associated core from the gastrointestinal tract after agent delivery is completed. Exemplary of mechanical forces aiding in membrane disintegration are physical contact with the walls of the gastrointestinal tract or with particulates passing through the Gl tract. Also, mechanical forces aiding in disintegration may include a pressure differential across the membrane caused by the fluid-imbibing characteristics of the pump, such as the expansion pressure generated by the optional hydrophilic polymer distribution means. Thus, biochemical decomposition weakens the membrane over time, while the mechanical forces eventually complete disintegration of the weakened membrane.

Disintegration of the membranes of the present invention may occur from the time of cessation of agent delivery to about 90 days. 5 Delivery of agent preferably occurs over a period of about one to about 48 hours, more preferably about one to about 24 hours. Preferably, the structural disintegration of the membranes occurs less than about 30 days after the delivery period. More preferably, membrane disintegration occurs within about 14 days after the agent delivery o period. Disintegration of the membrane is desirable after agent delivery is completed but before problems associated with potential lodging in the Gl tract can occur.

The materials chosen for the membrane of the present invention must decompose at a relatively predictable rate in the human s gastrointestinal tract, i.e., the stomach and the large and small intestines. In addition, the materials and corresponding degradation products cannot be toxic to humans, and preferably, do not cause any detrimental side effects, such as irritation or sensitization. Preferably, the biodegradable component of the membranes of this invention includes poly(d,l-lactide- o co-glycolide) copolymers. More preferably, the membrane is composed, in part, of a poly(d,l-lactide-co-glycolide) copolymer having a weight percent of lactide of about 40% to about 60%, based on total polymer weight.

Since the water permeability of poly(d,l-lactide-co-glycolide) 5 (PLG) membranes of suitable thicknesses is insufficient for osmotic agent delivery, one or more other materials, such as hydrophilic polymers, must be mixed with the PLG copolymer to achieve a desired water permeability level. For example, hydrophilic polymer materials suitable for the membranes of the present invention include, without limitation, cellulose 0 acetates, poly(vinyl alcohol), hydrophilic polyurethane, poly(vinylpyrrolidone), hγdroxypropylmethyl celluloses, hγdroxypropγl cellulose, hydroxyethyl cellulose, methylcellulose, poly(ethylene oxides), and acid carboxy polymers having a molecular weight of about 450,000 to about 4,000,000. Other suitable hydrophilic polymers components of the membrane of this invention are disclosed in U.S Pat. No. 3,916,899 (Theeuwes), which is incorporated herein by reference. Preferably, cellulose acetate is mixed with the biodegradable material to improve water permeability. Cellulose acetates having an acetate content of about 32% to about 43% by weight have preferred mechanical properties and water permeability characteristics. The ratios of poly(d,l-lactide-co-glycolide) to hydrophilic polymer in the membranes may vary depending on the desired rate of water permeability and rate of membrane degradation. In order to provide a biodegradation rate of greater than about 7 days but less than about 90 days after agent delivery, and to provide sufficient water permeability to effect agent delivery, a composition of about 20% to about 60% polydactide-glycolide) and 40% to 80% hydrophilic polymer by weight, based on total membrane weight, is preferred. At high polydactide-glycolide) concentrations, the membrane may degrade before agent delivery is completed or water permeation rates may be insufficient to achieve desired agent delivery rates. In contrast, lower polydactide- glycolide) concentrations may result in an insufficient biodegradation rate. The degradation rate of the membrane is also a function of the molecular weight of the polydactide-glycolide). Increasing the PLG molecular weight reduces the degradation rate, i.e. increases the degradation time. Preferably, the polydactide-glycolide) has a number average molecular weight in the range of about 1000 to about 20,000. The hydrophilic polymer component of the membrane may be a mixture of hydrophilic polymers. By mixing hydrophilic polymers having different water permeation rates, the permeation rate can be modulated without affecting the overall ratio of biodegradable component, e.g. polydactide-glycolide), to hydrophilic polymer in the membrane. For instance, preferably poly(methyl methacrylate) (PMMA) is added to cellulose acetate to reduce the water permeation rate. Alternatively, poly(vinylpyrrolidone) is preferred for enhancing water permeation rates in cellulose acetate membranes. Thus, a preferred biodegradable, water-permeable membrane of this invention includes polydactide-glycolide), cellulose acetate, and poly(vinyipyrrolidone). The preferred composition for these components is about 20% to 60% polydactide-glycolide), about 10% to 70% cellulose acetate, and about 10% to 30% poly(vinylpyrrolidone) by weight, based on total membrane weight.

In addition, chemical additives may be mixed with the polydactide-glycolide) and hydrophilic polymer, for example, to improve the processing characteristics, structural stability, or aesthetic appeal of the biodegradable, water-permeable membrane. For example, binders or colorants may be added to the membrane forming mixture. Suitable binders are disclosed in U.S. Pat. No. 4,135,514, which is incorporated herein by reference.

A factor relating to disintegration of the membrane in the gastrointestinal tract is the elongation of the membrane at the break point. "Elongation" or "elongation at break", as used herein, refer to the increase in a membrane dimension from the point of initial load application to the point of membrane rupture in a tension test, typically expressed as a percentage increase. The measurement of elongation at break of the membrane may be determined by commercially available instrumentation, such as the Instron Universal Testing Instrument, model no. TM-S, available from Instron Corp., Instron, Massachusetts. The membranes of the present invention preferably have an elongation at break of less than about 10% of the original membrane dimension. More preferably, the elongation at break is less than about 4%. Even more preferably, the elongation at break is less than about 2%. Another factor relating to disintegration of the membrane in the gastrointestinal tract is the tensile strength at break. The initial membrane tensile strength at break is preferably about 1 x 10^'3 psi to about 10 x 10^'3 psi. Tensile strength may be measure by a variety of means, more preferably by an Instron Universal Testing Instrument. Exposure of the membrane to gastrointestinal fluids causes degradation of the membrane, thereby reducing the tensile strength. Within about 90 days after the delivery period, the tensile strength at break is preferably less than about 1 x 10^"3 psi. The membranes of the present invention may be applied by any means known in the art. Some methods of coating an osmotic device of the present invention involve first dissolving the poly(d,l-lactide- co-glycolide) and selected hydrophilic polymer in a solvent. The membrane components preferably represents about 1 % to about 10% by weight of the resulting mixture. More preferably, the membrane components represent about 3% to about 5% by weight of the resulting mixture. The resulting mixture may be applied to the osmotic device by such processes as spray coating, dip coating, or air suspension coating. Air suspension coating processes may be preferred due to a balancing of factors, including economic and coating precision concerns. The air suspension procedure is disclosed in U.S. Pat. No. 3,207,824 and in J. Am. Pharm. Assoc, vol. 48, pp. 451-59 (1958) and vol. 49, pp. 82-84 (1960). These references are hereby incorporated by reference. Commercially available air suspension coaters include the WURSTER^® and AEROMATIC^® coaters.

The solvents chosen for dissolving the polydactide-glycolide) and membrane hydrophilic polymer should not react substantially with the selected agent or hydrophilic polymer of the agent delivery means. The selection of solvent is also dependent upon the rate of solvation of the poly(d,l-lactide-co-glycolide) and hydrophilic polymer to be incorporated in the membrane. For example, for a poly(d,l-lactide-co- glycolide) and cellulose acetate mixture, suitable solvents include, without limitation, ethylene chloride, ethanol, methylene chloride, methanol, water, and mixtures thereof. More specifically, methylene chloride/methanol, ethylene chloride/methanol and acetone/water mixtures are preferred solvents for poly(d,l-lactide-co-glycolide) and cellulose acetate membrane coating formulations.

Another factor affecting the biodegradation rate of the membrane is the thickness of the membrane. If a membrane is too thin, structural integrity may be compromised before or during agent delivery. On the other hand, excessively thick membranes can impede water permeation or slow biodegradation rates. Preferably, the membranes of the present invention have a thickness of about 0.001 to about 0.025 inches (about 25 to about 625 microns). Membrane thicknesses of about 0.002 inches to about 0.010 inches (about 50 to about 250 microns) are more preferred.

Typically subsequent to membrane formation, one or more delivery orifices are formed in an area of the membrane adjacent to the agent layer. The orifices or holes may be formed by any available means, including mechanical drilling, punching, and laser drilling. Laser drilling is usually preferred for precision and accuracy reasons. It is also possible to form the orifices in situ by processes which include the step of forming the membrane around a removable mold, wire, fiber or the like, which is subsequently removed from the membrane. Examples of such processes are disclosed in U.S. Pat. No. 3,916,899, which is herein incorporated by reference.

The minimum delivery orifice area is an area large enough to permit sufficient flow of agents and excipients out of the device to achieve desired agent delivery rates. Also, inadequate orifice dimensions may cause excessive pressure resulting in premature membrane rupture. Discussion of the variables affecting delivery orifice sizing are more fully discussed in U.S. Pat. No. 3,916,899, which is incorporated herein by reference. Typically, the preferred orifice diameter of the semi-permeable membrane will range from about 0.4 mm to about 1.0 mm.

After semipermeable membrane formation, other coatings may be applied which do not substantially impede the function of the device in osmotic agent delivery. For instance, colorants may be applied for aesthetic or identification purposes. Also, markings denoting such informational items as manufacturer, ingredients, and active agent quantities may appear on the membrane without significantly affecting agent delivery rates.

DELIVERY AGENT

This invention has utility in connection with the delivery of agents within the broad class normally delivered through the gastrointestinal tract. As used herein, the expressions "agent" or "drug" are used interchangeably and are intended to have their broadest interpretation as any substance which is delivered to a living organism to produce a desired, usually beneficial, effect. In general, this includes therapeutic agents in all of the major therapeutic areas including, but not limited to, anti-infectives such as antibiotics and antiviral agents; analgesics such as fentanyl, sufentanil, and burprenorphine, and analgesic combinations; anesthetics; anorexics; antiarthritics; antiasthmatic agents such as terbutaline; anticonvulsants; antidepressants; antidiabetics agents; antidiarrheals; antihistamines; anti-inflammatory agents; antimigraine preparations; antimotion sickness preparations such as scopolamine and ondansetron; antinauseants; antineoplastics; antiparkinsonism drugs; antipruritics; antipsychotics; antipyretics; antispasmodics including gastrointestinal and urinary; anticholinergics; sympathomimetrics; xanthine derivatives; cardiovascular preparations including calcium channel blockers such as nifedipene; beta-agonists such as dobutamine and ritodrine; beta blockers; antiarrythmics; antihypertensives such as atenolol; ACE inhibitors such as rinitidine; diuretics; vasodilators including general, coronary, peripheral and cerebral; central nervous systems stimulants; cough and cold preparations; decongestants; diagnostics; hormones such as parathyroid hormones; 5 hypnotics; immunosuppressives; muscle relaxants; parasympatholytics; parasympathomimetrics; prostaglandins; proteins; peptides; psychostimulants; sedatives and tranquilizers.

If the agent is soluble in water, agent delivery may be accomplished without a separate agent delivery means. Thus, the fluid- o imbibing pump could consist solely of a biodegradable, water-permeable membrane surrounding a water soluble delivery agent. Exemplary agents that are very soluble in water and that can be delivered by the devices of this invention include nystatin, chlorhexidine, clonidine, sodium fluoride, prochlorperazine adisylate, ferrous sulfate, aminocaproic acid, potassium s chloride, mecamylamine hydrochloride, amphetamine sulfate, benzphetamine hydrochloride, isoproterenol sulfate, methamphetamine hydrochloride, phenmetrazine hydrochloride, bethanechol chloride, methacholine chloride, pilocarpine hydrochloride, atropine sulfate, methascopolamine bromide, isopropamide iodide, tridihexethyl chloride, o phenformin hydrochloride, methylphenidate hydrochloride, oxprenolol hydrochloride, metoprolol tartrate, cimetidine hydrochloride, and the like.

On the other hand, fluid-imbibing pumps for delivery of agents having poor solubility in water generally require a separate agent delivery means, as described above. Such agents may also be 5 administered by the fluid-imbibing pump of the instant invention. Exemplary agents having poor water solubility include nicotine base, retin A, ibuprofen, diphenidol, meclizine hydrochloride, prochlorperazimine maleate, phenoxybenzamine, thiethylperazine maieate, anisindone, diphenadione erythrityl tetranitrate, dizoxin, isofuraphate, reserpine, o acetazolamide, methazolamide, bendrofiumethiazide, chlorpropamide, tolzamide, chlormadinone acetate, phenaglycodol, allopurinol, aluminum aspirin, methotrexate, acetyl sulfisoxazole, erythromycin, progestins, esterogenic progestational hormones, corticosteroids, hydrocortisone, hydrocorticosterone acetate, cortisone acetate, triamcinolone testosterone, testosterone esters, methyltestosterone 17β-estradiol, ethinyl estradiol, ethinyl estradiol 3-methyl ether, prednisolone, 17β-hydroxyprogesterone acetate, 19-nor-progesterone, norgestrel, norethindone, norethiderone, progesterone, norgesterone, norethynodrel, and the like.

Examples of other agents that can be delivered by the fluid-imbibing pump of the present invention include, without limitation, aspirin, indomethacin, naproxen, fenoprofen, sulidac, diclofenac, ibuprofen, indoprofen, nitroglycerin, propranolol, metoprolol, valproate, oxprenolol, timolol, atenolol, alprenolol, cimetidine, clonidine, imipramine, levodopa, chlorpromazine, reserpine, methyl-dopa, dihydroxyphenylalanine, pivaloyloxyethyl ester of α-methyldopa hydrochloride, theophylline, calcium gluconate, ferrous lactate, vincamine, diazepam, phenoxybenzamine, α-blocking agents, polypeptides, proteins, and the like.

AGENT DELIVERY MEANS

The optional osmotic delivery means 12 of the present invention is a material which absorbs water, thereby expanding and causing a pressure increase inside the delivery device. This expansion pressure causes or enhances agent delivery through the delivery orifice(s) 18. Typically, this material is a hydrophilic polymer comprising noncross- linked hydrogels and lightly cross-linked hydrogels, such as those cross- linked by covalent or ionic bonds. These hydrophilic hydrogels exhibit about a 2 to 50 fold volume increase. Suitable hydrophilic polymers useful in agent delivery means according to the present invention include, without limitation, acidic carboxy polymers having a molecular weight of about 450,000 to about 4,000,000; poly(hydroxyalkyl methacrylate) polymers having a molecular weight of about 30,000 to about 5,000,000; poly(vinyl pyrrolidone) polymers having a molecular weight of about 10,000 to about 360,000; polyacrylic acid having a molecular weight of about 80,000 to about 200,000; polyethylene oxide) polymers having a molecular weight of about 100,000 to about 5,000,000, and the like. Representative polymers that form hydrogels and that are useful as agent delivery means in the present invention are disclosed in U.S. Pat. Nos. 3,865,108 (Hartop); 4,002,1 73 (Manning); 4,207,893 (Michaels); 4,327,725 (Cortese et al); and in Handbook of Common Polymers by Scott and Roff, published by CRC, Cleveland, Ohio. These references are hereby incorporated by reference.

As disclosed earlier, this invention is not limited to those fluid-imbibing pumps having a delivery means separate from the delivery agent to be delivered. Thus, the membranes of the present invention are also useful in those fluid-imbibing pumps consisting of a water soluble agent surrounded by the membrane, i.e. in absence of a hydrophilic polymer delivery means. These delivery devices are also referred to as elementary osmotic pumps. Having thus generally described our invention, the following examples will illustrate the feasibility of biodegradable, water-permeable membranes for oral osmotic delivery devices. The effects of variations in composition and exposure time to gastrointestinal fluid on the strength of the membranes of the present invention are explored in these examples.

EXAMPLE I

A coating solution was prepared by dissolving poly(d,l-lactide-co-glycolide) (50:50), having a number average molecular weight of about 10,000, and cellulose acetate in about equal weight portions in a methylene chloride:methanol solvent (80:20 weight ratio) using about a six hour mixing time. The resulting solution contained about 3% by weight poly(d,l-lactide-co-glycolide) and cellulose acetate. Films were formed on one inch diameter plastic disks using an Aeromatic Coater (a modification of model STREA-1 ). About 400 gram, 5/16 inch (about 7.94 mm) diameter saccharide cores were used as fillers. The resulting film thicknesses ranged from about 0.005 to about 0.012 inches (about 127 to 305 microns). Films were dried overnight at about 50 °C.

After drying, the films were continuously immersed in artificial gastric fluid (no enzymes) at about 37 °C. An Instron Universal Testing Instrument was utilized to determine modulus, tensile stress at break and percent elongation at 0, 1 , 2, 3, 4, and 7 days after immersion in gastric fluid.

Tabular data for the mechanical properties of the membrane as a function of immersion time in artificial gastric fluid appear in TABLE 1 . Elastic modulus, tensile strengths at break point, and elongation at break were evaluated to correlate with membrane biodegradability potential.

TABLE 1 MECHANICAL PROPERTIES AS A FUNCTION OF IMMERSION TIME

IN ARTIFICIAL GASTRIC FLUID COMPOSITION: 50% polydactide-glycolide) / 50% cellulose acetate

IMMERSION ELASTIC TENSILE PERCENT TIME MODULUS STRENGTH ELONGATION (days) psi x 10^"6 AT BREAK AT BREAK psi x 10^'3

0 1.25 4.4 6.0

1 1 .28 3.9 3.9

2 1.25 3.8 4.0

3 1.24 3.6 4.1

4 1.28 3.6 3.6

7 0.85 2.4 3.2

As the data demonstrates, there is a substantial degradation in the physical properties of the membrane over the 7 day period of exposure to artificial gastric fluid. Further, TABLE 1 demonstrates that the elongation at break for the poly(lactide-glycolide)/cellulose acetate membranes ranged from about 3% to about 6% of the initial membrane length.

EXAMPLE II

Three water permeability enhancement additives, i.e. hydrophilic polymers, were evaluated in conjunction with poly(d,l-lactide- co-glycolide) and cellulose acetate membranes. The weight percentage of the membranes were about 40% polydactide-glycolide), 40% cellulose acetate, and 20% permeation enhancer. The enhancers chosen for evaluation were hydroxypropyl methylcellulose, poly(vinyl pyrrolidone), and hydroxypropyl cellulose. Coatings were applies to potassium chloride tablets with an Aeromatic^® coater (modified model STREA-1 ). As in EXAMPLE I, the coating solution contained about 3% solids by weight in a methylene chloride/methanol solvent (80:20 ratio by weight). Mixing times were about two to three hours.

Coated tablets were dried overnight at about 50°C prior to collapse pressure testing. Potassium chloride concentrations were determined from electrical conductivity measurements of the solution surrounding the tablets. Membranes surrounding potassium chloride tablets were tested for casing rigidity after nearly all the potassium chloride had been delivered from the device. Membrane casing rigidity was analyzed by applying increasing pressure to the fluid-imbibing pump until membrane deformation was visually detected. This deformation pressure is termed "collapse pressure" herein.

Tabular data for agent flux as a function of oven time for the three enhancers appears in TABLE 2. Tabular data for collapse pressures as a function of immersion time appear in TABLE 3.

TABLE 2 AVERAGE KCI DELIVERY RATE AS A FUNCTION OF TIME IN

50 °C OVEN FOR THREE PERMEATION ENHANCING COMPOSITIONS AVERAGED OVER A 4-10 HOUR PERIOD AFTER DEVICE IMMERSION

PERMEATION HYDROXYPROPYL POLY(VINYL HYDROXYPROPY ENHANCER → METHYL PYRROLIDONE) CELLULOSE -

CELLULOSE KLUCEL EF^®

OVEN KCI Delivery KCI Delivery KCI Delivery Rate

TIME -i Rate Rate (mg/hr)

(hours) (mg/hr) (mg/hr)

20 4.0 44.0 4.1

90 3.3 38.3 3.1

373 3.2 35.7 3.6

1097 4.1 38.3 5.4

Delivery rate measurements as a function of oven time at a constant 20% enhancer demonstrates poly(vinyl pyrrolidone) is the produces higher delivery rates than hydroxypropylmethyl cellulose and hydroxypropyl cellulose for 40% polydactide-glycolide) / 40% cellulose acetate membranes. TABLE 3

COLLAPSE PRESSURE AS A FUNCTION OF IMMERSION TIME

FOR 40% polydactide-glycolide) / 40% cellulose acetate /

20% poly (ethylene glycol) with KCI cores

IMMERSION Number COLLAPSE TIME of PRESSURE (days) samples (mm Hg)

0 4 130

2 4 135

6 5 140

7 5 120

9 5 95

14 1 1 10

30 8 88

TABLE 3 illustrates a general decrease in the pressure required to collapse a poly(lactide-glycolide)/cellulose acetate/poly(ethylene glycol) membrane over a 30 day exposure period to artificial Gl fluid. After 30 days, the collapse pressure of the membrane had dropped over 30%. Having thus generally described our invention and described in detail certain preferred embodiments thereof, it will be readily apparent that various modifications to the invention may be made by workers skilled in the art without departing from the scope of this invention, which is limited only by the following claims.

Claims

CLAIMSWhat is claimed is:

1. A fluid-imbibing pump for delivering an agent to a gastrointestinal tract in a predetermined manner over a predetermined, extended delivery period, said pump comprising:

(1 ) a core, comprising said agent; and

(2) a biodegradable membrane enclosing at least a portion of said core, said membrane having sufficient water permeability and structural integrity to deliver said agent over said delivery period and said membrane being biodegradable in the gastrointestinal tract at a rate such that said membrane disintegrates within 90 days after the end of said delivery period.

2. A fluid-imbibing pump as recited in claim 1 , wherein said predetermined, extended delivery period is about one to about 48 hours.

3. A fiuid-imbibing pump as recited in claim 2 wherein said predetermined, extended delivery period is about six to about 24 hours.

4. A fluid-imbibing pump as recited in claim 1 , wherein said membrane is biodegradable in the gastrointestinal tract at a rate such that said membrane disintegrates within 30 days after the end of said delivery period.

5. A fluid-imbibing pump as recited in claim 4, wherein said membrane is biodegradable in the gastrointestinal tract at a rate such that said membrane disintegrates within 14 days after the end of said delivery period.

6. A fluid-imbibing pump as recited in claim 1 , wherein said membrane has an initial tensile strength less than about 10 x 10^'3 psi and a tensile strength less than about 1 x 10^'3 psi within about 90 days after said predetermined delivery period.

7. A fluid-imbibing pump as recited in claim 1 , wherein said membrane has an elongation at break of less than about 3% within about 90 days after said predetermined delivery period.

8. A fluid-imbibing pump as recited in claim 1 , wherein said membrane comprises:

(a) a poly(d,l-lactide-co-glycolide) copolymer; and

(b) at least one hydrophilic polymer.

9. A fluid-imbibing pump as recited in claim 8, wherein said core further comprises a means for delivering said agent, comprising a hydrophilic polymer, wherein said delivery means expands upon contact with water.

10. A fluid-imbibing pump as recited in claim 9, wherein said membrane has at least one delivery orifice, said orifice being sized to permit passage of said delivery agent through said membrane.

1 1 . A fluid-imbibing pump as recited in claim 8, wherein said membrane comprises about 20% to about 60% poly(d,l-lactide-co- glycolide) copolymer and about 40% to about 80% hydrophilic polymer by weight, based on total membrane weight.

12. A fluid-imbibing pump as recited in claim 1 1 , wherein said copolymer has a number average molecular weight of about 1000 to about 20000 grams/gram-mole.

13. A fluid-imbibing pump as recited in claim 12, wherein said copolymer comprises about 40% to about 60% by weight lactide, based on total copolymer weight.

14. A fluid-imbibing pump as recited in claim 8, wherein said hydrophilic polymer is selected from the group consisting of cellulose acetates, ethylcellulose, poly(vinyl alcohol), hydrophilic polyurethane, poly(vinyl pyrrolidone), hydroxypropylmethyl celluloses, hydroxypropyl cellulose, methylcellulose, hydroxyethγl cellulose, poly(ethylene oxides), acid carboxy polymers having a molecular weight of about 450,000 to about 4,000,000, and mixtures thereof.

15. A fluid-imbibing pump as recited in claim 14, wherein said hydrophilic polymer comprises cellulose acetate.

16. A fluid-imbibing pump as recited in claim 15, wherein said cellulose acetate comprises about 32% to about 43% acetate by weight, based on total cellulose acetate weight.

17. A fluid-imbibing pump as recited in claim 15, wherein said membrane further comprises poly(vinylpyrrolidone).

18. A fluid-imbibing pump as recited in claim 15, wherein said membrane further comprises poly(methyl methacrylate).

19. A fluid-imbibing pump as recited in claim 17, wherein said membrane comprises:

(1 ) about 20 weight % to about 60 weight % poly(d,l-lactide-co-glycolide);

(2) about 10 weight % to about 70 weight % hydrophilic polymer; and

(3) about 10 weight % to about 30 weight % poly (vinyl pyrrolidone).

20. A fluid-imbibing pump as recited in claim 19, wherein said membrane is about 50 microns to about 250 microns thick.

21 . A fluid-imbibing pump for delivering an agent to a gastrointestinal tract over a predetermined delivery period, said pump comprising:

(1 ) a core, comprising: (a) said agent; and (b) a hydrophilic polymer delivery means which expands upon contact with water; and

(2) a membrane enclosing at least a portion of said core, said membrane having sufficient water permeability and structural integrity to effect delivery of said agent during exposure to gastrointestinal fluid for said predetermined delivery period, wherein said structural integrity decreases with time of exposure to gastrointestinal fluid, such that said membrane disintegrates and substantially all pump components are expelled from the gastrointestinal tract less than 90 days after said predetermined delivery period, said membrane comprising:

(a) about 20 to about 60 weight percent 5 poly(d,l-lactide-co-glycolide) copolymer, wherein said copolymer comprises about 40 to about 60 weight percent lactide;

(b) about 10 to about 70 weight percent cellulose acetate, wherein said cellulose acetate comprises about 32 to about 43 weight percent acetate; and o (c) about 10 to about 30 weight percent poly (vinylpyrrolidone) .

22. A method of coating a core comprising an agent in order to form a fluid-imbibing pump with a biodegradable membrane, comprising the steps of: s (a) contacting a polydactide-glycolide) copolymer and a hydrophilic polymer with a solvent, thereby forming a solution; and (b) contacting said core with said solution under conditions sufficient to form a biodegradable, water-permeable membrane enclosing at least a portion of said core, said membrane having sufficient o water permeability and structural integrity to deliver said agent over a predetermined, extended delivery period and said membrane being biodegradable in the gastrointestinal tract at a rate such that said membrane disintegrates within 90 days after the end of said delivery period. 5

23. A method as recited in claim 22, wherein said hydrophilic polymer is cellulose acetate.

24. A method as recited in claim 23, wherein said solvent comprises ethylene chloride and methanol.

25. A method of coating a core comprising an agent in order to form a fluid-imbibing pump with a biodegradable membrane, comprising

the steps of:

(a) milling polydactide-glycolide) copolymer with a hydrophilic polymer, thereby forming particles of less than about

40 micron diameter;

(b) mixing said particles with a solvent, thereby forming a suspension; and

(c) contacting said suspension with said core under conditions sufficient to form a biodegradable, water-permeable membrane enclosing at least a portion of said core, said membrane having sufficient water permeability and structural integrity to deliver said agent over a predetermined, extended delivery period and said membrane being biodegradable in the gastrointestinal tract at a rate such that said membrane disintegrates within 90 days after the end of said delivery period.

26. A method as recited in claim 25, wherein said hydrophilic polymer is ethyl cellulose.

27. A method as recited in claim 26, wherein said solvent comprises ethanol and water.