GB1573459A

GB1573459A - Absorbable polymer drug compositions

Info

Publication number: GB1573459A
Application number: GB15755/78A
Authority: GB
Original assignee: Ethicon Inc
Current assignee: Ethicon Inc
Priority date: 1977-05-20
Filing date: 1978-04-20
Publication date: 1980-08-20
Also published as: FR2390962B1; CA1098443A; AU3560978A; ZA782880B; AU517229B2; FR2390962A1; JPS53145905A; DE2821949A1

Description

(54) ABSORBABLE POLYMER-DRUG COMPOSITIONS (71) We, ETHICON, INC., a Corporation organised and existing under the laws of the State of New Jersey, United States of America, of Somerville, State of New Jersey, United States of America, do hereby declare the invention for which we pray that a patent may be granted to us and the method by which it is to be performed to be particularly described in and by the following statement:- The present invention relates to polymerdrug compositions and their use in providing sustained release drug delivery to human and other warm-blooded animals.

The polymer-drug compositions provide a mechanism whereby the rate of release and availability of the drug may be regulated so that the quantity of a drug which is released at a particular time or at a particular site is relatively constant and uniform over extended periods of time.

Drugs are conventionally administered orally or by injection, often at a site remote from the target. Over a relatively short period of time, the drug diffuses into the circulation system of the patient and is distributed to the various organs, at least one of which is the intended target for the drug. The action of the drug on organs other than the target may result in undesirable side effects. Finally, the drug is metabolized or otherwise irreversibly removed from the organism by excretion or chemical deactivation.

When drugs are delivered orally or by injection, the level and duration of availability of the drug cannot be controlled independently: only the size and frequency of the dose can be manipulated. Typically, there is an initially high concentration of available drug at the site of injection or in the circulatory system which then decreases gradually as the drug is distributed and consumed within the body of the patient.

In controlled sustained delivery, a formulation of the drug and a carrier is administered to the patient by injection or implantation. The carrier forms a drug reservoir that protects the stored drug from extraneous removal mechanisms and releases the drug to the biological reservoir at a predetermined rate. Controlled sustained delivery of a drug. prevents undesirable peaking of blood levels and makes the drug available at an optimum and uniform concentration over an extended period of time. Only the released drug is subject to removal via metabolism and excretion.

U.S. Patents Nos. 3,773,919, 3,755,558, and 3,997,512 describe formulations of various polylactides, polyglycolides and copolymers of glycolide and lactide with some well-known drugs in order to achieve slow release of the drugs when implanted or applied topically to humans. These compositions are designed to release the drug over an extended period of time as the polymer of the mixture is slowly absorbed in the system. The polymer itself is nonreactive to body tissue and degrades into harmless products which are metabolized or excreted by the host body.

We have discovered that polymers of pdioxanone are also absorbed slowly in animal tissue without significant adverse tissue reaction. Such polymers and their method of preparation are known in the art.

U.S. Patents No. 3,063,967 and 3,063,968, for example, describe the polymerization of p-dioxanone and the preparation of films and fibers therefrom. There was, however, no appreciation in the prior art of the absorbability of p-dioxanone polymers, and fibers of such polymers were reported to be resistent to the effects of saline and distilled water.

Other references dealing with the polymerization of p-dioxanone include, but are not limited to U.S. Patents Nos.

3,190,858, 3,391,126 and 3,645,941 which disclose various catalysts for the polymerization of lactones such as pdioxanone, and U.S. Patent No. 3,020,289 which describes the polymerization of pdioxanone in the presence of sulfuric acid.

None of these references suggest that polymers of p-dioxanone are useful in the preparation of absorbable polymer-drug compositions in accordance with the present invention.

Accordingly, the present invention provides a pharmaceutical composition for parenteral administration of effective amounts of a drug released slowly over an extended period of time which comprises a combination of: a) from 1% to 99% by weight of the composition of a drug, and b) a solid, absorbable polymer which is nonreactive towards body tissue and which undergoes boidegradation in the presence of body fluids into products which are metabolized or excreted by the body with our adverse body reaction, the absorbable polymer being a polymer of p-dioxanone having the formula

wherein each R individually is hydrogen, methyl, or ethyl and x is the degree of polymerization resulting in a polymer having an inherent viscosity of at least 0.20 measured at 250C in a 0.10/n solution in tetrachloroethane, and having a crystallinity of at least 20% as determined by X-ray diffraction.

The pharmaceutical compositions of the invention comprise mixtures and combinations of one or more drugs with absorbable polymers of p-dioxanone, or methyl or ethyl substituted p-dioxanone.

The polymers may be conveniently prepared by known polymerization techniques. The polymers and drugs may be combined as physical mixtures or, in some instances, as chemical combinations. The polymer-drug composition may be administered to the patient by implantation as a solid pellet, by injection as a suspension in a biologically acceptable fluid, or by other convenient means.

The formulations of this invention are absorbable, non-irritating pharmaceutical compositions consisting of one or more drugs intimately mixed with or coated by an absorbable polymer designed to release effective amounts of a drug over a predetermined period of time. The invention is of particular value for drugs that require prolonged administration or slow sustained release, for example, certain fertility-control drugs or hormones used for hormone-replacement therapy. The absorbable polymer may be considered as a carrier or matrix for the drug.

The novel formulation permit prolonged release of drugs for a controlled period of time from the sites of parenteral administration and minimize the frequency and thus the discomfort and inconvenience associated with conventional injection formulations. Unlike conventional depot injections, the formulations of this invention undergo biodegradation in the body into products which are nonreactive toward body tissue, and can be designed, by controlling molecular weight and composition, to undergo hydrolysis and to release drug from the depot at a desired rate.

The term "drug" as used herein is intended in its broadest sense as defined in the United States Federal Food, Drug and Cosmetic Act, Section 201(2)g: 1) Articles recognized in the official United States Pharmacopoeia, official Homeopathic Pharmacopoeia of the United States, or official National Formulary, or any supplement of any of them; and 2) articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals; and 3) articles (other than food) intended to affect the structure or any function of the body of man or other animals; and 4) articles intended for use as a component of any article specified in clauses 1, 2 or 3; but does not include devices or their components, parts, or accessories.

Classes of drug which may be specifically mentioned include agents affecting the central nervous system, e.g., narcotics, such as, for example, morphine; narcotic antagonists, such as naloxome; antipsychotic agents, such as chlorpromazine and molindone; antianxiety agents, such as sodium pentobarbital, chlorpromazine, and molindone; antidepressives, such as imipramine hydrochloride; stimulants, such as methyl phenadate and nikethamide; hallucinogens; analgesics, such as numorphan, meperidine, and morphine; and anorexigenic agents.

Other classes are pharmacodynamic agents, e.g., anti-hypertensive agents as reserpine, and chlorisondamine chloride, and antianginal agents, such as papaverine, and drugs for therapy of pulmonary disorders, such as theophylline ethylenediamine salt and epinephrine.

Additional classes are chemotherapeutic agents, e.g., antiviral; antiparasitic, such as emetine hydrochloride and stibophen; antifungal agents, such as cycloheximide; and antineoplastic agents, such as triethylene thiophosphoramide; agents affecting metabolic diseases and endocrine functions, e.g., prostaglandins; athersclerosins, such as heparin; steroids and biologically related compounds; polypeptides, such as bacitracin, polymixin B sulfate, and sodium colistimethate; natural and synthetic hormones, such as estradiol dipropionate, progesterone, and hydroxy progesterone caproate; steroid and nonsteriodal antiinflammatory agents, such as gold sodium thiomalate and hydrocortisone sodium succinate; and agents affecting thrombosis, such as crystalline trypsin; vitamins, such as vitamin B12; and anti-epilepsy agents, such as phenobarbital. It should be understood that the specific drugs mentioned by name are illustrative and not limitative.

Endrocrine agents comprise a particularly useful class of compounds in this invention and can be defined either as natural hormones or as synthetic drugs that to some extent act like, or antagonize, natural hormones. Endocrine agents include, but are not limited to, both steroids and nonsteroids that function as fertility-control agents; progestogens, estrogens, androgens, antiandrogens, corticoids, anabolic agents, and anti-inflammatory agents.

Examples of specific endocrine agents that can be used in the formulations of the invention are described in U.S. Patent No.

3,773,919.

The polymers used in the preparation of polymer-drug compositions of the present invention are those having the formula

wherein each R is individually hydrogen methyl or ethyl and x is the degree of polymerization resulting in a polymer having an inherent viscosity of at least 0.20 measured at 250C in a 0.1% solution in tetrachloroethane, and having a crystallinity of at least 20% as determined by X-ray diffraction. Particularly preferred polymers are those derived from p-dioxanone, methylp-dioxanone and dimethyl-p-dioxanone.

A particularly preferred polymer is poly(p-dioxanone), and the following description and Examples presented by way of illustration are directed primarily to the preparation of that polymer, it being understood that certain variations may apply to the preparation of other polymers encompassed by the above formula as will be readily apparent to those skilled in the art. In these Examples all parts and percentages are by weight unless otherwise states.

EXAMPLE I Highly purified p-dioxanone monomer is polymerized in the presence of an organometallic catalyst such as diethyl zinc or zirconium acetyl acetonate to obtain high molecular weight polymers according to the following typical procedure: 0.1 M (10.2 g) of dry, 99+% pure p-dioxanone monomer is weighed into a dry flask under an inert atmosphere of dry nitrogen and 0.36 ml of 0.138 m diethyl zinc in heptane are added. The monomer to catalyst ratio is calculated as 2000:1. After completely mixing the catalyst and monomer, the flask is swirled at intervals over a period of about one hour or less at room temperature until initiation and polymerization is evident by the occurrence of gelation. The flask is then connected to a vacuum of about 14 inches of Hg. The sealed flask is maintained at 800C in a constant temperature bath for about 72 hours to complete the polymerization. The resulting polymer is characterized by an inherent viscosity (I.V.) of 0.70 measured on a 0.1% solution of polymer in tetrachloroethane at 250 C, a glass transition temperature T9 of -16"C, a melting temperature Tm of 1100 C, and a crystallinity of 37 percent.

In the polymerization procedure, the initial one hour hold time for polymerization initiation is required only when using volatile catalysts which would be lost if the polymerization mixture was immediately placed under vacuum. When non-volatile catalysts such as zirconium acetyl acetonate are used, this hold time may be omitted and the polymerization reaction mixture placed under vacuum immediately following addition and mixing of catalyst. As a further alternative, the entire polymerization reaction may be conducted under an inert atmosphere at atmospheric pressure.

EXAMPLE II The method of Example I was repeated using 0.13 ml of zirconium acetyl acetonate catalyst (7500:1 monomer to catalyst ratio) in the polymerization reaction. Properties of polymer were as follow: I.V. 0.71 Tg -16"C Tm 111"C Crystallinity 49% EXAMPLE III The method of Example I was repeated at a monomer to catalyst ratio of 4000:1 and with a polymerization reaction of three days at 80"C. The resulting polymer had an inherent viscosity of 0.86 and crystallinity of 30 percent.

EXAMPLE IV The method of Example I was repeated using tetraoctylene glycol titanate as the polymerization catalyst. The monomer to catalyst ratio was 12,300: 1 based on titanium content, and the polymerization reaction was maintained at 800C for six days. The resulting polymer had an inherent viscosity of 0.86 and a crystallinity of 33 percent.

EXAMPLE V In Vivo Absorption The absorbability of poly(p-dioxanone) in animal tissue at a desirable rate and without adverse tissue reaction was demonstrated by melt extruding the polymer into filaments and implanting the filaments in test animals as follows: Two 2 cm segments of monofilament extruded from the polymer of Example I and having a diameter of approximately 0.30 mm were implanted aseptically into the left gluteal muscles of 24 female Long Evans rats. The implant sites were recovered after periods of 60, 90, 120 and 180 days and examined microscopically to determine the extent of absorption.

After 60 days the filament cross sections were still transparent and intact. The tissue reactions were slight and most filamentswere encapsulated with fibrous tissue. The filaments at this period remained birefringent under polarized light.

At 90 days the filaments were becoming translucent and had lost some of their birefringent properties. A few of the filament cross sections stained pink (eosinophilic) around the periphery and the edges were indistinct, indicating the onset of absorption. The tissue reactions generally consisted of a fibrous capsule and a layer of macrophages interposed between it and the filament surface.

At 120 days the filaments were translucent, most cross sections had taken on an eosinophilic stain, and the material appeared to be in the process of active absorption. The tissue reaction consisted of an outer layer of fibroblasts with an interface of macrophages several cell layers thick. Absorption at 120 days was estimated to be approximately 70 percent complete.

At 180 days, absorption of the material was substantially complete. The incision healed with minimal adverse tissue reaction.

While the preceding examples have been directed to the preparation of homopolymers of p-dioxanone, these examples are for purposes of illustration only and are not limiting of the invention.

Polymers of methyl-p-dioxanone, dimethylp-dioxanone, copolymers of two or more of these monomers, copolymers of these monomers with up to about 50 ,, by weight of other copolymerizable monomers which produce nontoxic and absorbable polymers, and mixtures of these polymers with other absorbable polymers are likewise included within the present invention. For example, mixtures of p-dioxanone with lactide and/or glycolide are useful in the preparation of absorbable copolymers, . and the physical and chemical properties of such polymers including the rate of absorption can be controlled by varying the relative proportions of the monomer constituents. In addition, such copolymers may be prepared by random, block or graft polymerization techniques in order to obtain particular combinations of compositions and physical and chemical properties. In certain applications where the rate of absorption of poly(p-dioxanone) is less than desired, copolymers of pdioxanone with from about 5 to 25 percent or more glycolide which have a faster rate of absorption may be preferred.

Polymers of the present invention are adversely affected by moisture and are accordingly preferably prepared and stored in a substantially moisture free environment and in hermetically sealed packages.

Polymers which have been dried under vacuum at elevated temperatures and subsequently stored under vacuum or in a dry nitrogen environment are found to be quite storage stable.

The drug and the polymer can be mixed, and the intimacy of mixing, particle size, and particle shape of the formulations of varied, by any of a number of known methods. Intimacy of mixing, particle size, and particle shapw of the formulations of the invention will depend to some extent on the intended use. High homogeneity can be obtained by mixing the components in the molten state, cooling, and grinding the resulting solid. A formulation so obtained is suitable for injection as 0.1 p to 1000 p particles suspended in saline solution or a pharmaceutically acceptable oil. In some cases particles with cores of pure drug coated with various thicknesses of polymer can be preferred for delayed and/or sustained release. Relatively large pellets (1--10 mm) may be preferred for reversible implantation in animals by surgery or by injection as projectiles. For this use adequate homogeneity can usually be realized by grinding or milling the drug and the polymer together before forming pellets under pressure. Known techniques of encapsulation, including microencapsulation, can be used to mix the polymer and the drug. The formulations of this invention provide a slow, steady release of drug in contradistinction to conventional preparations which generally produce a rapid surge followed by a fairly quick decline in drug effect.

Polymer-drug mixtures of the invention may contain pharmaceutically acceptable inert additives such as plasticizers. Typical plasticizers are Carbowax (registered Trade Mark) polyethylene glycols, glycerides and ethylcellulose.

The relative proportions of the drug and p-dioxanone polymer can be varied over a wide range depending on the desired effect.

The drug can be present in an amount which will be released over controlled periods of time. This necessarily implies a quantity of drug greater than the conventional single dose and requires that the polymer must not break down or become absorbed by the body so rapidly as to release undue quantities of drug. Proportions may range from 1 percent of drug and 99 percent of the polymer to 99 percent of drug and 1 percent of the polymer. Preferred ratios include 1 part of drug to from 4 to 20 parts of polymer.

These formulations can be injected as fluid suspensions by syringe into subcutaneous cellular tissue or muscular tissue, or implanted in pellet form subcutaneously or intramuscularly. Liquid vehicles useful for suspensions of the drugpolymer formulation include water or aqueous solutions such as normal sodium chloride solution or sodium carboxymethyl cellulose in water. Oils such as sesame oil or peanut oil containing, if desired, dissolved adjuvants such as benzyl alcohol, may also be used to prepare suspensions of the polymer-drug formulation.

Drug compounds of the classes mentioned earlier may be coated, embedded, or intimately mixed in or with a matrix of one or a combination of different chain-length biodegradable polymers to give a drug-polymer mixture which will provide a controlled sustained release of the drug compound over a period of 8 hours to 2 months or longer when administered parenterally.

The compositions of the present invention may be prepared by coating, embedding or intimately mixing a drug in or with a solid, absorbable polymer as above defined.

Coating, embedding or intimately mixing the drug compound with the polymer can be accomplished in the following ways: (A) Coating the discrete drug particles or drug-particle aggregates, agglomerates or flocs by: (1) Spray drying: Finely divided drug particles are suspended in a solvent system in which the drug is not soluble containing the dissolved polymer and other agents, e.g., extenders, plasticizers, dyes, etc., in the drug/polymer ratio from 1/99 to 99/1, followed by spray drying. For example: Drug particles 0.2 to 10 microns in size and equal to the weight of polymer used are suspended in a solvent solution of polymer in such a concentration so as to give a liquid viscosity suitable for atomizing. The drugpolymer mixture is spray-dried using conventional method of atomizing, e.g., centrifugal wheel, pressure, and two-fluid nozzle using appropriate drying conditions and temperatures that do not exceed the softening point of the polymer and do not exceed the melting point or decomposition point of the drug. Solvents useful in preparing solutions of the polymers of the present invention include, but are not limited to, hexafluoroisopropyl alcohol, hexafluoroacetone, trichloroethane, tetrachloroethane and trifluoroacetone.

(2) Pan coating or fluid-bed coating: Place granules or pellets, 5 microns to 20 mm, preferably between 0.25 and 10 mm diameter, in a rotating coating pan or 'fluid-bed drier, and apply polymer (dissolved in a carrier to a suitable viscosity for spraying) by spraying until a suitable coating quantity has been deposited to give the required release-rate characteristics. For example: Granules of drug are prepared by extrusion of a wet granulation or other suitable methods known to the art, and dried. 16-to-40-Mesh granules are placed in a rotating coating pan and a solution of polymer, dissolved in a suitable nonaqueous volatile solvent, is sprayed onto the moving granules with a continuous fine spray under conditions known to the art, until a coating giving the desired release rate has been applied. The granules are then dried.

(3) Microencapsulation: Suspend drug particles, granules or pellets (.1 to 2000 microns diameter) in a solvent system in which the drug is not soluble, and which contains the polymer in solution. Add an agent incompatible with the polymer solvent system, such as an incompatible polymer, a nonsolvent for the polymer, or a salt, or vary conditions such as temperature and pressure. One or a combination of the above will precipitate the polymer, coating the drug particles, granules or pellets. For example: 0.5 to 25 micron drug particles are suspended in a low viscosity solution of the polymer in a suitable solvent in which the drug is not soluble. A miscible solvent in which the polymer is not soluble, such as hexane, is then added slowly to precipitate the polymer. The coated particles are filtered and washed with hexane and allowed to dry. The powder is stored for use in the suitable dosage form.

(B) Embedding The polymer or polymer mixture is melted and a nonheatlabile drug is suspended and thoroughly dispersed in the melt. The melt is congealed by spraying, or in a mass and ground into small particles to give a polymer matrix with the drug embedded. For example: the poly(pdioxanone) polymer is melted and 0.5-to400-micron (preferably 0.5 to 25 micron) drug particles are suspended and thoroughly dispersed in the molten polymer in a concentration necessary to give the desired release rate patterns. The polymer is solidified by cooling and ground into small pieces 1 to 200 microns in size.

(C) Intimate mixing The drug and polymer are dissolved in a common solvent and the solvent is removed in some suitable way (spray-drying, flashevaporation, etc.). For example: the drug and polymer are dissolved in the solvent in a 1:1 ratio and to a concentration of 2%. The solvent is flash-evaporated and the resulting film is scraped from the flask and powdered.

The above sustained-release powder, granular or pellet forms may be included in the following type formulations: (1) Suspensions: Active ingredients of low solubility which have been embedded in or coated with the polymer and are in a finely divided state, 200 microns diameter or less, preferably 50 microns or less, may be suspended in a suitable pharmaceutical vehicle for injection. This vehicle may also contain suspending and thickening agents, e.g., methyl cellulose, and preservatives.

These ingredients are combined to give a stable suspension which will release the active ingredient over the time period desired.

(2) Emulsions: Active ingredients insoluble in oil in fine powder form, preferably 10 microns or less, are thoroughly dispersed in a suitable oil, which is, in turn, emulsified in an external aqueous phase (oil in water) using suitable emulsifying agents, e.g., triethanolamine oleate, polyoxyethylene sorbitan monooleate, acacia, gelatin, etc. The aqueous phase may also contain agents such as protective colloids and preservatives, formulated to give a stable emulsion which will provide a controlled release of the active ingredient over the time period desired.

(3) Aqueous suspensions: The active ingredient embedded and/or coated with the polymer in a particle size no greater than 200 microns and preferably no greater than 50 microns is suspended in an aqueous solution which may contain thickening agents, e.g., carboxymethylcellulose; preservatives, e.g., phenol; suspending agents, e.g., polyvinylpyrrolidone; surface active agents; buffers and dextrose or saline to adjust for isotonicity.

(4) Nonaqueous suspensions: The active ingredient embedded and/or coated with the polymer in a particle size usually no greater than 200 microns and preferably no greater than 50 microns is suspended in a suitable oil, etc. The suspension may contain preservatives, e.g., chlorbutanol or methylparaben and propylparaben mixtures, and suspending agents such as aluminum monostearate.

In both the aqueous and nonaqueous preparations, the final product is sterilized by heat, radiation, ethylene oxide or other suitable means prior to use.

The present invention includes within its scope a method for the parenteral administration to a non-human animal of a drug released slowly over an extended period of time a composition of the invention to the said animal.

The use of absorbable polymer-drug formulations in the controlled administration of fertility control agents over extended periods of time is wellknown. U.S. Patent No. 3,773,919, for example, describes the combination of poly L-lactide polymers with endocrine agents such as 17p-estradiol; 2a, 1 7diethynyl-A- nor-5a-androstane-2A,17,B-diol; 17p- estradiol; 6,6-difluoro- 1 7ethynyl- 1 7- hydroxyestr-4-en-3-one; and 17p- hydroxyestr-4-en-3-one adamantane- 1 '- methanolcarbonate. The poly(p-dioxanone) polymers of the present invention are effectively substituted for the poly-L-lactide polymers of U.S. Patent No. 3,773,919 to obtain an alternative polymer-drug composition of similar effect.

WHAT WE CLAIM IS: 1. A pharmaceutical composition for parenteral administration of a drug released slowly over an extended period of time which comprises a combination of: a) from 1% to 99% by weight of the composition of a drug, and b) a solid, absorbable polymer which is nonreactive towards body tissue and which undergoes biodegradation in the presence of body fluids into products which are metabolized or excreted by the body without adverse body reaction, the absorbable polymer being a polymer of pdioxanone having the formula

wherein each R individually is hydrogen, methyl or ethyl and x is the degree of polymerization resulting in a polymer having an inherent viscosity of at least 0.20

**WARNING** end of DESC field may overlap start of CLMS **.

Claims

**WARNING** start of CLMS field may overlap end of DESC **. melt. The melt is congealed by spraying, or in a mass and ground into small particles to give a polymer matrix with the drug embedded. For example: the poly(pdioxanone) polymer is melted and 0.5-to400-micron (preferably 0.5 to 25 micron) drug particles are suspended and thoroughly dispersed in the molten polymer in a concentration necessary to give the desired release rate patterns. The polymer is solidified by cooling and ground into small pieces 1 to 200 microns in size. (C) Intimate mixing The drug and polymer are dissolved in a common solvent and the solvent is removed in some suitable way (spray-drying, flashevaporation, etc.). For example: the drug and polymer are dissolved in the solvent in a 1:1 ratio and to a concentration of 2%. The solvent is flash-evaporated and the resulting film is scraped from the flask and powdered. The above sustained-release powder, granular or pellet forms may be included in the following type formulations: (1) Suspensions: Active ingredients of low solubility which have been embedded in or coated with the polymer and are in a finely divided state, 200 microns diameter or less, preferably 50 microns or less, may be suspended in a suitable pharmaceutical vehicle for injection. This vehicle may also contain suspending and thickening agents, e.g., methyl cellulose, and preservatives. These ingredients are combined to give a stable suspension which will release the active ingredient over the time period desired. (2) Emulsions: Active ingredients insoluble in oil in fine powder form, preferably 10 microns or less, are thoroughly dispersed in a suitable oil, which is, in turn, emulsified in an external aqueous phase (oil in water) using suitable emulsifying agents, e.g., triethanolamine oleate, polyoxyethylene sorbitan monooleate, acacia, gelatin, etc. The aqueous phase may also contain agents such as protective colloids and preservatives, formulated to give a stable emulsion which will provide a controlled release of the active ingredient over the time period desired. (3) Aqueous suspensions: The active ingredient embedded and/or coated with the polymer in a particle size no greater than 200 microns and preferably no greater than 50 microns is suspended in an aqueous solution which may contain thickening agents, e.g., carboxymethylcellulose; preservatives, e.g., phenol; suspending agents, e.g., polyvinylpyrrolidone; surface active agents; buffers and dextrose or saline to adjust for isotonicity. (4) Nonaqueous suspensions: The active ingredient embedded and/or coated with the polymer in a particle size usually no greater than 200 microns and preferably no greater than 50 microns is suspended in a suitable oil, etc. The suspension may contain preservatives, e.g., chlorbutanol or methylparaben and propylparaben mixtures, and suspending agents such as aluminum monostearate. In both the aqueous and nonaqueous preparations, the final product is sterilized by heat, radiation, ethylene oxide or other suitable means prior to use. The present invention includes within its scope a method for the parenteral administration to a non-human animal of a drug released slowly over an extended period of time a composition of the invention to the said animal. The use of absorbable polymer-drug formulations in the controlled administration of fertility control agents over extended periods of time is wellknown. U.S. Patent No. 3,773,919, for example, describes the combination of poly L-lactide polymers with endocrine agents such as 17p-estradiol; 2a, 1 7diethynyl-A- nor-5a-androstane-2A,17,B-diol; 17p- estradiol; 6,6-difluoro- 1 7ethynyl- 1 7- hydroxyestr-4-en-3-one; and 17p- hydroxyestr-4-en-3-one adamantane- 1 '- methanolcarbonate. The poly(p-dioxanone) polymers of the present invention are effectively substituted for the poly-L-lactide polymers of U.S. Patent No. 3,773,919 to obtain an alternative polymer-drug composition of similar effect. WHAT WE CLAIM IS:

1. A pharmaceutical composition for parenteral administration of a drug released slowly over an extended period of time which comprises a combination of: a) from 1% to 99% by weight of the composition of a drug, and b) a solid, absorbable polymer which is nonreactive towards body tissue and which undergoes biodegradation in the presence of body fluids into products which are metabolized or excreted by the body without adverse body reaction, the absorbable polymer being a polymer of pdioxanone having the formula

measured at 250C in a 0.10/, solution in tetrachloroethane, and having a crystallinity of at least 20% as determined by X-ray diffraction.

2. A composition as claimed in claim 1 wherein the polymer is poly(p-dioxanone).

3. A composition as claimed in claim 1 wherein the polymer is poly(methyl-pdioxanone).

4. A composition as claimed in claim 1 wherein the polymer is poly(dimethyl-pdioxanone).

5. A composition as claimed in any one of the preceding claims wherein the drug is an endocrine agent.

6. A composition as claimed in claim 5 wherein the drug is a fertility control agent.

7. A composition as claimed in any one of the preceding claims in the form of injectable particles dispersed in a saline solution or a pharmaceutically acceptable oil.

8. A composition as claimed in claim 7 wherein the injectable particles range in size from 0.1 to 200 microns.

9. A composition as claimed in any one of claims 1 to 6 in the form of pellets for implantation.

10. A composition as claimed in any one of the preceding claims wherein the polymer is a mixture of a polymer of pdioxanone and at least one other absorbable polymer.

11. A composition as claimed in claim 10 wherein the other absorbable polymer is a homopolymer of a lactide or a glycolide or a copolymer thereof.

12. A composition as claimed in any one of claims 1 to 9 wherein the absorbable polymer is a copolymer of p-dioxanone and at least one other monomer copolymerizable therewith.

13. A composition as claimed in claim 12 wherein the other monomer is a lactide or a glycolide.

14. A composition as claimed in any one of the preceding claims wherein the ratio of drug to polymer is from 1:4 to 1:20 by weight.

15. A composition as claimed in claim 1 substantially as hereinbefore described.

16. A process for the preparation of a composition as claimed in any one of the preceding claims which process comprises coating, embedding or intimately mixing a drug in or with a solid, absorbable polymer as defined in claim 1.

17. A process as claimed in claim 16 substantially as hereinbefore described.

18. A pharmaceutical composition as claimed in claim 1 whenever prepared by a process as claimed in claim 16 or claim 17.

19. A method for the parenteral administration to a non-human animal of a drug released slowly over an extended period of time which method comprises administering a composition as claimed in any one of claims 1 to 14 or claim 18 to the said animal.