Continuous release formulations

The present invention relates to pharmaceutical compositions of pharmacologically active polypeptides which permit continuous release of polypeptide over an extended period when the composition is placed in physiological type aqueous medium.

It has long been understood that the continuous release of certain products over an extended period following simple administration could have significant practical advantages in clinical practice, and compositions have been developed to allow the sustained release of a certain number of pharmaceutical products. clinically useful after oral administration (see for example Remington's Pharmaceutical Sciences, published by Mack Publishing Company, Caston, Pennsylvania, US, A., 15th edition, 1975, p. 1618-1631) after oral administration (ibid, pp. 1631-1643), and after topical administration (see for example UK Patent No. 1,351,409). A suitable method of parenteral administration is subcutaneous injection or implantation of a solid body, for example a

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Λ;

pellet ου a film containing the substance, and a wide variety of such implantable devices have already been described. It is known in particular that for many substances suitable implantable devices to ensure prolonged release of the substance can be obtained by encapsulating the substance in a biodegradable polymer, or dispersing the substance in a matrix of a polymer of this species, so that the substance is released as degradation of the polymer matrix occurs. '

Biodegradable polymers suitable for use in these controlled release formulations are known, and comprise polyesters that gradually degrade by hydrolysis when placed in a physiological type aqueous medium. Particular polyesters that have been used are hydroxycarboxylic acid derivatives, and much of the current art has been directed to polymers derived from acidic and hydroxycarboxylic acids, especially lactic acid in their racemic and optically active forms, and glycolic acid, and their copolymers. see for example U.S. Pat. Nos. 3,773,919 and 3,887,699; Jacknacicz et al., Contraception, 1973, 13, 227-234; Anderson et al., Ibid., 1976, 11, 375-384; Vise et al., Life Sciences, 1976, 14, 867-874; Woodland et al., Journal of Medicinal Chemistry, 1973, 16, 897-981; Yolles et al., Bullatin of the Parenteral Drug Association, 1976, 30, 306,312; Wise et al., Journal of Pharmacy and Pharmacology, 1978, 301, 686-689 and 1979, 31, 201-204.

United Kingdom Patent No^and 1,325,209 (equivalent to US Patent No.^and 3,773,919) and U.S. Pat.^and 3,887,699 refer to the prolonged or slow release of polypeptides. The eighth specification mentions only insulin, but contains no particular example of any of these formulations, and the reference to polypeptides is apparently absolutely speculative, with only an extensive list of many different classes of substances allegedly being incorporated into formulations of the types described therein. In fact, essentially all other types of substances referred to in that specification apart from

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polypeptides, are relatively hydrophobic in character and have relatively low molecular weights, and the description of that specification does not refer to the knowledge of the difficulties we encountered when seeking satisfactorily slow release polypeptide formulations, many of which are relatively hydrophilic, and of weight. relatively high molecular weight »

It should be noted that constant or prolonged release of a substance may be either continuous or discontinuous. We have now found that in many cases, when prior art experience, and in particular experience of British Specification No. 1,325,209, is applied to the preparation of a formulation of a polypeptide, the release of the polypeptide from the formulation, although occurring throughout an extended period of time can also be discontinuous. For example, the release of a polypeptide from a polylactide polymer as described in said specification is often preceded by a significant induction period, during which no polypeptide is released, or is polyphasic and comprises an initial period during which some polypeptide is released, a second period during which no or virtually no polypeptide is released, and a third period during which most of the remainder of the polypeptide is released. In contrast to this, it is an object of the present invention to disclose polypeptide compositions from which, except perhaps from a relatively short initial induction period, the polypeptide is continuously released, without periods during which little or no polypeptide is released. . The terms continuous release are used in this specification only to describe a release profile that is essentially single phase, although it may have an inflection point, but certainly does not have a plateau phase.

United Kingdom Patent No^s 1,388,580 describes. insulin-containing constant release formulations which are based on hydrogels formed by reacting a flanaiut '♦' polymer

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soluble in water with a chelating agent, then cross-linking the polymer-chelating agent chains by reaction with a polyvalent metal ion in an aqueous solution to form a hydrogel. Insulin was incorporated into a preformed hydrogel in aqueous solution, the whole was homogenized and injected subcutaneously or intramuscularly.

It is an object of the present invention to provide an implantable or injectable pharmaceutical or veterinary formulation for pharmacologically useful polypeptides which is in solid form and which absorbs water from the animal after implantation to form a hydrogel from which the polypeptide is released. continuously for an extended period of time.

Thus, according to the present invention there is disclosed a pharmaceutical composition comprising a pharmacologically useful polypeptide and a linear, uncrossed, amphipathic, pharmaceutically or veterinarily acceptable graft or branched block copolymer which has a minimum average molecular weight of 5000, in which the hydrophobic component is biodegradable or hydrolytically unstable under normal physiological conditions, and the hydrophilic component may or may not be biodegradable, the composition being capable of absorbing water to form a hydrogel when placed in water or an aqueous physiological medium.

The present invention is applicable to polypeptides in general, without any limitation of structure or molecular weight, but is more useful for polypeptides that are relatively hydrophilic and the following list, which is not intended to be exhaustive, is indicative of polypeptides that may be employed. in the formulations of the present invention:

oxytocin, vasopressin, adrenocorticotropic hormones (ACTH), epidermal growth factor (EGF), prolactin, luliberin or luteinizing hormone releasing hormone (LHRH), growth hormones, growth hormone releasing factors insulin, somatostatin, qlucagunin, gastrone, interferon , = 4 =

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tetragastrin, pentagastrin, urogastrone, secretin, calcifonin, encephalin, endorphin, angiotensin, renin, bradykinin bacitracin, polymyxin, colistrin, thyridine, gramicidins, and synthetic analogues, and pharmaceutically active fragments and fragments thereof, monoclonal antibodies and soluble vaccines .

A particular LH-RH-like compound to which the present invention is applicable is ICI.118,630, Glu-HisTrp-5 er-Tyr-D-5 er- (0-tBu) -L eu-Ar- Pro-Azgly-1 \ IH 2.

Aqueous physiological type * means the body, particularly the musculature or circulatory system, of a warm-blooded animal, although without laboratory investigations such a medium may be materialized by aqueous liquids, possibly buffered to a physiological pH, at a temperature between 35 and 40 ° C^sÇ.

The sustained release composition of the present invention may be placed in a body of an animal to be treated with a polypeptide, for example by intramuscular or subcutaneous injection, or by subcutaneous surgical implantation, in a clinically or veterinarily conventional manner.

A pharmaceutically or veterinarily acceptable amphipathic copolymer may be for example a linal block copolymer of formula A (BA) or B (AB) wherein m is 0 mmnmn or 1, but an integer, A is A pharmaceutically or veterinarily acceptable hydrophobic polymer and B is a pharmaceutically or veterinarily acceptable hydrophilic polymer, or the amphipathic copolymer may be a branched or graft block copolymer of formula AB or BA, wherein A, B en have the meanings indicated above, and wherein respectively either A or B is a polymeric backbone with n units of a monomer or polymer B or A, respectively, grafted onto it.

hydrophobic polymer A pharmaceutically or veterinarily acceptable polymer may be, for example, poly (acid D, L, or

<img file="PT76576B_D0005.tif" />

DL-lactic acid), poly (D, L, DL-lactides), polyglycolic acid, polyglycolides, poly-caprolactone, poly (3-hydroxybutyric acid) or a non-therapeutically hydrophobic polypeptide, for example polybenzylglutamate. Alternatively the hydrophobic polymer A may be a polyacetal of general formula in or

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where R is a hydrocarbon radical, polyorthoester of general formula or a polycarbonate

I

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wherein R is a hydrocarbon radical as described in U.S. Pat.^s No. 4,093,709, which is cited herein by reference, or may be a copolymer comprising said acetal, carbonate or orthoester units, alternating with diC1 units, or may be a copolymer of formula

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which is obtained by reacting pentaerythritol with ketenes to form 3,9-bis (methylene) -2,4,8,10-tetraoxaspiro / 5,5,77-undecane which is then copolymerized with a diol of formula HO-R- OH, as described in Journal of 1980 pages. 619-624. The example diol a polyethylene glycol mixes it with species of a randomized structure. 0 ι

Polymer Science, Polymer Letters formula HQ-R-QH may be of high molecular weight or low molecular weight, yielding □ hydrophobic polymer may also, el = 6 =

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itself, be a copolymer derived from 2 or more monomers from which the above polymers are derived.

A pharmaceutically or veterinarily acceptable hydrophilic polymer B may be, for example, polyvinyl alcohol, polyvinyl pyrrolidone, polyethylene oxide, polyethylene glycol, polyacrylamide, polymethacrylamide, dextran, alginic acid, sodium alginate, gelatin, or a copolymer of 2 or more of the monomers from which the above polymers are derived.

In another alternative hydrophilic polymer B may itself be a copolymer, for example a polyoxyethylene / polyoxypropylene block copolymer of the type known as pluronic (trademark) or Synperonics (trademark)

Several mechanisms by which substances are released from biodegradable polymers are described in Controlled RelBase of Biactive Materials, edited by R. Baker, Academic Press 19BQ, in particular chapters 1, pages 1 to 17, by J. Heller and RW Baker.

In the present invention, when the dry amphipathic copolymer containing a polypeptide is immersed in water or placed in an aqueous physiological medium in the animal's body, water absorption is a function of the hydrophilic or water-interactive parts of the copolymer, and the material dims. This water absorption, however, renders the water-insoluble parts of the copolymer incompatible, and these hydrophobic parts of the copolymer then serve as the crushing points, and thus limit the subsequent absorption of water. »In this hydrated, swollen state, the matrix it is permeable to water-soluble polypeptides incorporated within the matrix, and these polypeptides are thus progressively displaced from the matrix »

In the swelling process, and when swollen to some equilibrium state, hydrolytic degradation of the hydrophobic part of the copolymer begins to occur. Partially degraded copolymer has higher swelling capacity, so continued hydrolysis leads to water absorption = 7 =

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subsequent increase in polypeptide desorption, which compensates for the decrease in its concentration and maintains its continuous release. Thus, upon careful planning of the copolymer material the initial swelling for hydrogel formation and the consequent desorption of the active material, and the rate of subsequent hydrolytic degradation to increase the subsequent desorption of the active material to compensate for its decrease in concentration in the active material. matrix can be controlled to give continuous release of the active substance over an extended period of time as defined above.

This ideal release profile of the active substance can also be obtained by linking different copolymers each having their own defined properties (e.g. molecular weight, molecular weight distribution, block structure, and hydrophilicity, degradation properties, diffusion properties). and by appropriate combination of several of these materials, the release rate and release duration of the active material may vary as desired.

Also by appropriate choice of the above parameters, and / or appropriate bonding, a copolymer material can be obtained which allows processing in implantable materials at relatively low temperatures, always below 1 ° C, and in some cases even at room temperature, and is thus suitable for manufacturing implantable materials incorporating heat sensitive or solvent sensitive polypeptide active materials. For example, polyethylene glycol block copolymers and amorphous hydrophobic polymers having a glass transition temperature above 37 ° C are particularly useful.^sC, because the polyethylene glycol block plasticizes the hydrophobic block, giving rise to a material that is processed rapidly at relatively low temperatures, even at room temperature, while in the subsequent state the crystallizing polyethylene glycol block yields a hard product that can be easily handled.

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The block copolymers defined above are themselves new and useful materials. Thus, according to a further feature of the invention, a pharmaceutically or veterinarily acceptable linear branched or graft block copolymer is disclosed, which has a minimum molecular weight of 5,000, in which the hydrophobic component is biodegradable or hydrolytically unstable under normal physiological conditions, and the hydrophilic component may or may not be biodegradable, copolymer that is capable of absorbing water to form a hydrogel when placed in water or an aqueous medium.

Particular cases of these copolymers are defined above.

According to a further feature of the invention a blend of 2 or more of these copolymers as defined above is disclosed.

These copolymers and copolymer blends are also useful, more generally for the continuous release of non-peptide pharmaceutical substances by oral administration, including intra-ruminal, parenteral, ocular, rectal or vaginal route.

Accordingly, in accordance with other features of the present invention, pharmaceutical or veterinary compositions comprising a pharmacologically active non-peptide compound and a block copolymer as defined above are disclosed, and the use of these block copolymers for the continuous release of a nonpeptide compound of the said type, pharmacologically active.

According to another feature of the invention there is disclosed a process for the preparation of a pharmaceutically or veterinarily acceptable linear, amphipathic, branched or graft block copolymer as defined above comprising copolymerization of a monomer A and a monomer B by conventional techniques such as copolymerization = 9 =

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Jf

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graft, polycondensation and polyaddition *, optionally with a suitable catalyst, for example zinc oxide, zinc carbonate, basic zinc carbonate, diethyl zinc, organotin compounds, for example stannous octoate (stannous 2-ethylhexanoate) tributylaluminum, magnesium or barium, or lithium, and among these, stannous octaoa is preferred.

In the remainder copolymerizations are carried out in a conventional manner known in the polymerization art with respect to time and temperature.

The invention is illustrated below but not limited by the following examples:

Example 1

Polyethylene glycol of 20,000 molecular weight (30g) was stirred and heated under vacuum (0.1mm mercury) at 120 ° C for 3 hours. D, L-lactide (15g) and glycolide (15g) were added and the mixture was stirred under nitrogen until the solids had melted. The temperature was raised to 160 ° C and stannous octoate (stannous 2-ethylhexanoate) (0.1 ml) was added. The mixture was kept at 160 ° C for 3 hours, and at that time it had become quite viscous, and was then cooled and dissolved in acetone (200 ml). This acetone solution was slowly added under vigorous stirring to ethanol (1500 ml) and the precipitate thus formed was filtered off and dried under vacuum for 3 hours at room temperature and then overnight at 40 ° C.

NMR spectrum of this copolymer in deuterochloroform showed that it had the 2: 1: 1 oxyethylene: lactic acid glycolic acid composition.

This copolymer was molded at about 60 ° C as a transparent, plastic, calcium film. One sample = 10

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(39 mg) rapidly swelled when placed in water, soaking up to 135 mg of water for 4 hours to give a clear hydrogenol which subsequently disintegrated over a period of 2 weeks at 37 ° C^sÇ.

Example 2 polymer described in example 1 (20.2 mg) and bovine growth hormone (BGH), (5.1 mg) were mixed together at about 40 ° C.²An opaque mixture was obtained which was formed into a strip of one millimeter thick. This strip was immersed in a ph 8.6 buffer solution (M / 15 buffer, ph 8.6, containing 0.01% sodium azide) and released about 22,000 molecular weight material which had the same retention time. in high pressure liquid chromatography than BGH over a period of at least 12 days.

Example 3

Using the procedure described in example 2 the copolymer / BGH mixture was formed into discs weighing about 45 mg and containing about 20% of BGH. These discs were each implanted in a rat pituitary-removed, and the weight of the animals was observed to increase by an average of 25% for 7 days, while the weights of the control animals each received a inert implant, remained virtually unchanged.

Example 4 copolymer described in example 1 (13.5 mg) and monoclonal mouse immunoglobulin A (IgA) with a defined antigen specificity and a molecular weight of 180.00D (1.5 mg) were homogeneously mixed at 50 ° C.²A homogeneous mixture of IgA in the copolymer was obtained, and this protein / copolymer mixture was molded to give a 2 mm diameter bead. In vitro release of IgA was assessed by emerging the protein copolymer in a buffer (buffered saline) = 11.

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phosphate, ph 7.2) at 37 ° C²C. Using an enzyme-linked immunoassay technique, the aqueous medium was assayed for active IgA, and release of the biologically active protein was found to begin about 2 days later and continue for at least 9 days.

Example 5

Polyethylene glycol having a molecular weight of 20,000 (50 g) was dissolved in chloroform (150 mg) and washed 6 times with distilled water (~ 300 ml) by rinsing the aqueous phases of the wash. Chloroform was evaporated under reduced pressure and the purified polyethylene glycol was dried at 160 ° C / 0.05 mm Hg for 1 hour.

Stannous octoate (2-ethylhex; stannous yearate) (~ 5 g) was purified by heating to 140 ° C / 0.055 mm Hg to remove impurities. Purified polyethylene glycol (14.3 g) was heated to 160 ° C.²C under vacuum (0.05 mm Hg) in a 100 ml round bottom flask for 1 hour. Freshly prepared pure D-Lactidium (42.9) was added under nitrogen and melted at 160 ° C. Stannous octoate (0.2 ml) was then added and the mixture was stirred until the viscosity no longer allowed stirring. After 3 hours a highly viscous product was obtained. The mixture was allowed to cool, the flask was broken, the contents dissolved in acetone (~ 300 ml) and the solution filtered. 0 The filtrate was slowly added to ethanol (~ 1000 ml) with vigorous stirring to give a fibrous precipitate which was collected and dried at 30 ° C in a vacuum oven overnight. Analysis of the product by NMR spectrography showed that the product had a composition oxyethylene: ls3 lactic acid and the intrinsic viscosity in chloroform was 1.055.

The product was molded into a thin, soft transparent plastic film (0.2 mm). By immersion in water the film (0.54 g) increased in weight to 0.95 g on a day at 37 ° C.²C. The hydrated transparent filmB had rigidity and strength superior to that of the initial dry copolymer. Past 35 days = 12

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the film was intact and had good mechanical properties, evidencing that the copolymer had been degraded only slowly as shown by change in composition by NMR spectrum.

When bovine growth hormone is incorporated into the dry copolymer at 60 ° C²C, the resulting polypeptide / polymer mixture releases a 22 DOO molecular weight product in a buffer solution (M / 15 phosphate buffer, pH 8.6) for at least 7 days.

Example 6

Polyethylene glycol having a molecular weight of 6,000 (50 g) was purified using the method described above in Example 5. Purified dry polyethylene glycol (7.5 g) and stannous chloride dihydrate (15 mg) were mixed at room temperature and then heated under stirring to 155²Under high vacuum (0.1-0.01 mmHg) and kept at this temperature for 2 h while adding to the mixture under freshly prepared nitrogen D, L-lactide (22.5 g), and merged. The reaction temperature was maintained at 155-160 ° C.²For 3 hours, a viscous product was obtained which was poured onto polytetrafluoroethylene film and allowed to cool. The polymer product was dissolved in acetone (80 ml) with moderate heating, and the polymer was isolated by pouring the acetone solution in ethanol (600 ml). The precipitate was dried in a vacuum oven overnight at 60 ° C.²C. The polymer had an intrinsic chloroform viscosity of 0.41. When compressed into a thin film (0.2 mm) and immersed in water, the polymer absorbed approximately its own weight of water at 37 ° C.²C for 24 h giving a rigid hydrogel.

Example 7 mg of a block copolymer as prepared = 13

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Example 6 containing 25 parts of polyethylene glycol (molecular weight 6000) and 75 parts of poly (DL-lactide) was dissolved in 4.5 ml anhydride-free glacial acetic acid and 0.5 ml distilled water. To the 200yal polymer solution was added a solution containing 1.1 mg rat epidermal growth factor (EOF) and the mixture was homogenized. This homogenized solution was frozen and then lyophilized for 18 h, and the product was molded at 50 ° C.²C-to obtain an implant weighing 40 mg C 8 mm x 4 mm χ 1 mm). The implant was placed in 1 ml of human serum at 37 ° C.^sThe release of EGF was measured by radioimmunoassay on aliquots of serum. Results showed a continuous release of peptide for at least 3 days.

Example 8 g of a copolymer containing equimolar proportions of D, L-lactide and glycolide, and having an intrinsic viscosity in chloroform 0.20, were dissolved in 50 ml of anhydrous ethyl acetate, and this solution was heated to reflux under stirring and under nitrogen atmosphere. 0.25g of lauroyl peroxide was dissolved in freshly distilled vinyl pyrrolidone (25ml). The mixture was added dropwise to the refluxed polymer for 2 h, and the final mixture was refluxed for a further 6 h. After cooling the gel mixture was frozen. Purification of the amphipathic block graft copolymer by removal of the polyvinylpyrolidone homopolymer using precipitation techniques was difficult as precipitation often resulted in colodal suspensions, and this indicated that the polyvinylpyrolidone graft had occurred in the lactide / glycolide copolymer. .

The ethyl acetate mixture was then heated to 70 ° C.²C and 50 ml of ethanol were added to give a colloidal suspension from which the polymer was isolated by precipitation in n-hexane (21). The polymer thus obtained was dried at 90 ° C.²C overnight and under vacuum to give a brittle product consisting of copolymer after cooling = 14 =

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Graft Polyvinylpyrrolidone Good Polymer The product had an intrinsic viscosity of 0.29 in chloroform, and had approximately 50% polyvinylpyrrolidone as the homo-copolymer and graft block copolymer.

The polymer thus obtained (0.45 g) and ICI.11B 630 (0.05 g) were dissolved in anhydride-free glacial acetic acid (5 ml) and lyophilized at 0.01 mm of mercury for 22 h.

was molded to 110^sC for 20 sec. obtaining a strip (~ 0.8 cm x 1.2 mm x 2 mm, weighing 30 mg) which after immersion in aqueous buffer pH 7.4 at 37 ° C^sC, released the peptide over a period of several days.

Example 9 g of polyvinyl alcohol having a molecular weight of 14,000 was dissolved in 500 g of commercial D, L-lactic acid (containing approximately 12% water) under stirring and under a nitrogen atmosphere. The mixture was heated to 140 ° C.^sC and water was distilled off for 8 h, during which time the mixture became progressively more viscous and its temperature rose to 190 ° C.^andC. When water was no longer separated by distillation the pressure was reduced to approximately 25 cm @ 3 of mercury and the mixture was heated for a further 8 h. Finally the pressure was reduced to 0.1 mm of mercury and the mixture was heated at 2002 for 8 h to give a highly viscous amber product.

The polymer was allowed to cool and the balloon was broken. The product was triturated into small pieces and was dissolved in methanol (1.5 l) and the product was isolated by precipitation in 10 l of distilled water. The precipitated product was washed with an additional 5 l of water and dried under vacuum at room temperature for 8 h, and finally at 100 ° C for 16 h, yielding an amber glass product consisting essentially of a polyvinyl alcohol backbone containing chains. acid = 15

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low molecular weight polylactic compounds bound thereto having an intrinsic viscosity of 0.65 in chloroform. The product contained approximately B5% polylactic acid and this bound polylactic acid had an average chain length of approximately 3.5, polymer was molded at 100 ° C to obtain a strip of 1 cm x 0.2 cm x 0.2 cm that was immersed in water at 37²C. The product absorbed water and became flexible and degraded to soluble products over a period of 2 months. '

Example 10

Rat epidermal growth factor (285 æl of a 21 mg / ml solution of distilled water) was added to a solution of an 80 / 20.poli (D, L-lactid) / PEG 6000 copolymer with intrinsic viscosity 0, 36 in chloroform (45 mg) in 2.5 ml 90% aqueous acetic acid. The peptide and polymer solution was frozen and then lyophilized at about 0.01 mm Hg for 24 h to give a dry product. The lyophilized product was molded at 60 ° C.²C, obtaining implants weighing 13.5 mg and 15.3 mg, containing 1.3 and 1.5 mg peptide, respectively.

These were implanted subcutaneously in 2 cats each having a gastric fistula. Blood samples were collected and gastric acid releases measured in response to histamine stimuli. Peptide was detected in the blood by radioimmunoassay for a minimum of 3 days following implantation, and gastric acid responses showed an inhibition of 3 to 6 days following implantation.

Example 11

Rat epidermal growth factor (120 æl of a solution of 10.5 mg peptide in 320 ml of distilled water) was added to a solution of a 85/15 = 16 = copolymer =

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poly (D, L-lactide) / PEG 6000 with intrinsic viscosity 0.39 in chloroform (36 mg) in 1.8 ml of 90% aqueous acetic acid. The resulting solution was frozen and lyophilized overnight. The lyophilized product was molded at 70 ° C to obtain an implant weighing 16.9 mg (dimensions approximately 1 χ 1 χ 5 mm).

Peptide was released from this implant continuously for at least 15 days in 10% huinane serum in water containing 0.1% sodium azide.

Example 12

To show the effect of block copolymer composition and hydrophility on releasing the polypeptide from the implants, the following comparison assays were performed.

In separate experiments, implants were prepared using

a) a block copolymer with 0.39 intrinsic viscosity in chloroform containing 25% w / w polyethylene glycol having a molecular weight of 6,000 and 75% w / w poly (D, L-lactidio).

b) Intrinsic viscosity block copolymer 0.79 in chloroform containing 5% w / w polyethylene glycol having a molecular weight of 6,000 and 95% w / w poly (D, L-lactide).

76.2 mg of polymer and ICI 11B 630 (23.8 mg as acetate salt, equivalent to 20 mg of pure peptide) were dissolved in anhydride-free glacial acetic acid (1.5 ml). The solution was frozen and lyophilized for 18 h, and the lyophilized product was molded at approximately 7Â ° C, yielding implants weighing about 45-50 mg (dimensions approximately 0.2 cm x 0.2 cm χ 1 cm).

These implants were immersed in 1 ml of pH 7.4 Mollvains buffer at 37 ° C.²C, and samples of 1 ml of the aqueous medium were taken at certain time intervals, and their content in substance was determined by high pressure liquid chromatography. The aqueous medium removed was reconstituted from = 17 =

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each time by one ml of fresh buffer.

These release experiments show that implants prepared using the most hydrophilic polymers containing 25% polyethylene glycol released the compounds for about 18 days.

In contrast, implants prepared using less hydrophilic copolymers containing 5% polyethylene glycol continuously released the compounds for at least 250 days.

Example 13

Pali- (ethylene glycol methyl ester) having a molecular weight of 5000 was purified as in example 5.

g of this purified poly (ethylene glycol methyl ether) was dried at 160 ° C / 0.01 mm Hg for 1 h. 80 g of freshly prepared, dried DL-lactide was added and the mixture was stirred under nitrogen at 16D20. When all of the D, L-lactide had melted 0.15 ml of stannous octoate (stannous 2-ethylhexanoate) was added and the mixture was kept at 160 ° C for 6 hours during which time a highly viscous product formed. The mixture was allowed to cool, the flask was broken and the contents dissolved in 200 ml of acetone. The acetone solution of this polymer was added under vigorous stirring to 2000 ml of hexane to precipitate the polymer. The precipitated polymer was dried at 70 ° C under reduced pressure for 24 hours to give a block copolymer having a structure A3 wherein A is a polylactide and D is poly (ethylene glycol methyl ether).

This copolymer is particularly useful for preparing water-in-oil dispersions that can be used to prepare microcapsules or in microencapsulation processes.

For example 5 g of the copolymer was dissolved in

200 methylene chloride and 1 ml of an aqueous solution of ICI 110 630 containing 20 mg of compound = 10

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vigorous stirring to produce a stable water-in-oil dispersion.

The water-in-oil emulsion was stirred vigorously and a non-solvent such as hexane (2,000 ml) was added slowly to produce microcapsules which were isolated by filtration and dried, yielding a substance / polymer mixture which even in these microcapsules or in the form. The microencapsulated material resulted in continuous release over a period of several days.

The poly (ethylene glycol methyl ether) used in the above process has been replaced by other poly (ethylene glycol) derivatives to prepare similar block copolymers, and suitable examples are monomethyl ethers (keto macrogol) and stearate esters.