CA1297627C - Biologically degradable polymers for depot preparations havingcontrolled release of the active compound - Google Patents

Abstract

Abstract of the disclosure Polyamides in which amino acids are incorporated in the polymer backbone via two amino or carboxyl groups and which carry in the .alpha.-position to the amide structure a functional group which is responsible for degradation and active compound release are highly suitable for the preparation of biologically degradable active compound depot preparations having controlled release of the active compound.

Description

~297627 HOECHST AKTIENGESELLSCHAFT Dr.S~/gm HOE ~7/~ o7o ~iologically degradable polymers for depot preparations having controlled release of the active compound Long-duration controlled release of the active compound is of great topicality due to the increasing importance of chronic disorders and long-term oriented therapy con-cepts in human and veterinary medicine.

Medicament release systems in which the active compound is dispersed in a nondegradable polymer matrix and is liberated by diffusion are described in American Patent 4,069,307. ~hen the active compound reservoir is ex-hausted, such implants must, however, be removed surgic-ally from the organism.
In biologically degradable medicament release systems, such as specified in American Patent 4,093,709, the active compound is dispersed in a biodegradable polymer which releases the act;ve compound Gn degradation. Typical bio-logically degradable polymers which have been most investi-gated according to the state of the art are homopolyesters and copolyesters, in particular of lactic acid and glycolic acid, as are described in US Patents 3,773,919 and 3,297,033 respectively. A disadvantage is, inter alia, the low or poorly controllable s~ellability of the polyesters in the physiological environment, which hinders permeation of the active compounds incorporated in the implant and causes an only low liberation rate after the initial "burst effect".
Recently, polyacetals and polyketals have been described in 3D US Patent 4,304,767, polyanhydrides have been described by H.G. Rosen et al., 3iomaterials 4, 131 ~1983), and polyortho-esters have been described in US Patent 4,180,646; all these compounds were developed as biologically degradable polymers for use as implant materials. Due to the lack of further functional groups, similar to the polyesters mentioned, the degradation of these polymers is only determined by the hydro-lytic resistance of the carbonyl function in the ma;n polymer chain. In addition, such polymers do not have adequate stab;l;ty for ;mplantation periods of months. As further classes of polymers, polyamides, in particular polyamino acids, have been described in American Patent 3,371,069 as bioresorbable implant materials. Ho~ever, the industrial preparation of polyamino acids requires the use of expensive protected amino acids, relatively large amounts of highly toxic phosgene, the removal of the proteceing groups and the chem;cal mod;ficat;on of the polymers obta;ned.
Surprisingly, ;t has been found that polyam;des ;n wh;ch amino acids are incorporated ;n the polymer backbone v;a t~o am;no or carboxyl groups and ~h;ch carry ;n the ~-pos;tion to the am;de structure a funct;onal group wh;ch is responsible for degradat;on and act;ve compound release are highly suitable for use as degradable medicament im-plants having controlled release of the active compound.
These biologically degradable polymers are obtained by polycondensation of physiologically and pharmacologically acceptable diamines ~ith just such dicarboxylic acids.
In vivo, these polymers are metabolized into nontoxic, nonallergenic and nonimmunogenic compounds and are excreted.

The invention thus relates to:
1) A biolog;cally degradable polyamide in which am;no ac;ds are incorporated into the polymer backbone v;a two am;no or carboxyl groups and ~hich carry in the ~-pos;t;on to the am;de structure a funct;onal group ~hich is responsible for degradation and active com-pound release, ~ith I) repeat;ng un;ts of the d;am;no compound from the group compris;ng - the monomeric compound of the general formula Ia, NH
H N- ( CH ) - CH- CORl Ia 2 2 n ~29762~

in which R1 denotes a physiologically acceptable, hydrolyzable alkoxy group, having up to 18 carbon atoms, ~hich can optionally be substituted by physio-logically acceptable side groups, or denotes a physiologically accept-able, hydrolyzable alkylam;no or aralkylamino group, or denotes a hydroxyl group, and n is 3 or 4, and/or - the monomeric compound which is produced by esterification of aminoethanol ~ith the di-carboxylic acids of the citrate cycle, and/or - the monomeric compound of the general formula Ib, _ N~
2 1 2 Cl H2 3 N Ib in uhich R2 and R3, independently of one another, denote hydrogen or methyl, and II) repeating units of the dicarboxylic ac;d compounds from the group comprising :~ - the monomeric compound of the general formula IIa, R4 C=O
N-H IIa HOOC- CH- ( C~2 )n~ C~

in ~hich R4 denotes an alkyl group hav;ng 1 to 3 carbon atoms, and n denotes 1 or 2, and/or - the monomeric straight-chain, saturated or mono-unsaturated dicarboxylic acids having 2-10 carbon ~:~ atoms, and/or :
~ " ' ' ' ~ , ~297627 - the monomeric compound wh;ch is produced by esterification of the dicarboxylic acids of the citrate cycle with diols of the general formula IIb, HO(CH- 7)mH IIb ~ R
in ~hich R6 and R7, independently of one another, denote hydrogen or a methyl group, and m is a number in the range 1 to 100, or by amidation with diamines of the general formula Ib mentioned.

2) The process for the preparation of the abovementioned polyamide, wherein one or more of the diamino and dicarboxylic acid compounds mentioned under 1) are polycondensed.

3) The use of the abovementioned polyamide for encapsu-lation of b;olog;cally active substances.

4) The use of the abovementioned polyam;de as a degrad-able depot preparat;on of the act;ve compound hav;ng controlled release of the active compound.

In the following, the invention is described ;n deta;l and defined in the claims.

As diam;no compound of the formula Ia, esters of orn;-thine and lysine with physiologically acceptable, hydro-lyzable alkoxy groups which have up to 18 carbon atoms are employed. Although esters w;th higher alkoxy groups can also be used, the polymerization becomes more dif-; 35 f;cult w;th increasing chain length. These alkoxy grouPs can, if appropriate, be subst;tuted by hydroly~able, physiolog;cally acceptable side groups. The following alkoxy groups are su;table, for example:
- n- or iso-(Cl-C1g)alkoxy~ preferably methoxy, ' ' ' ' ~ .

- . ' ~ ' . .
' ' ' - .

12~7627 ethoxy, butyloxy, octadecyloxy and isopropyloxy;
- methoxytC2-C4)alkoxy, preferably methoxypoly-ethyleneoxy and methoxypolypropyleneoxy;
- hydroxytC2-C4)alkoxy, preferably 2-hydroxy-1-propyl-S oxy and 2-hydroxy-3-butyloxy;
- trichloroisobutyloxy;
- tC2-C4)alkoxycarbonylalkyleneoxy, preferably ethoxy-carbonylmethyleneoxy and butoxycarbonylmethyleneoxy.

The methoxy, ethoxy and n-butoxy groups are part;cularly preferably used.

In place of the alkoxy groups, hydrolyzable, physiologi-cally acceptable alkylamino or aralkylamino groups are also suitable, such as, for example, the following groups:
- hydroxy(C2-C6)alkylamino, preferably 2-hydroxyethyl-amino, tris(hydroxymethylene)methylamino and glycosyl-amino;
- (C2-C4)alkanoyloxyethylamino, preferably 2-acetoxy-ethylamino and 2-butanoyloxyethylamino;
- mercapto(C2-C4)alkylamino, preferably 2-mercapto-ethylamino;
- the methyl esters of natural ~-amino acids, preferably the methyl ester of phenylalanine and the methyl ester of leucine.

As indicated above, the group R1 can be very variable, in particular since it only occurs as a side group in the actual polymer according to the invention. It can, for example, 3lso be a hydroxyl group if copolyamides or polymer mixtures are employed.

~y esterification of aminoethanol with the dicarboxylic acids of the citrate cycle, in particular succinic acid and fumaric acid, diamines which are employed according to the invention are likewise obtained. Furthermore, pharmacologically acceptable piperazines of the formula Ib can be used.

1297~27 Dicarboxylic acids accord;ng to the ;nvent;on are N-acy-lated glutam;c ac;d and aspart;c ac;d of the formula lIa whose am;no group is protected by a (C2-C~)acyL
group. Preferred acyl groups are acetyl and butyryl, in S particular acetyl. The acyl groups can also have longer chains, but, with increasing chain length, it becomes more complicated to introduce them into the dicarboxyl;c acid.
In addition, the reactivity of the carbonyl group in the ~-position is reduced by a longer-chain acyl group.
1û
Furthermore, straight-chain, saturated or monounsaturated d;carboxylic acids having 2-10, preferably 4-8, particu-larly preferably 4-6 carbon atoms can also be used for the polycondensation. In this case, glutaric ac;d and fumaric acid are again very particularly preferred. It is furthermore possible to prepare, by esterificat;on of these dicarboxylic acids with pharmacologically acceptable diols of the formula Ilb or by amidation with d;amines of the formula Ib, dicarboxyl;c acid compounds wh;ch can likewise be used according to the invention. Suitable dioLs are, for exampLe, propanedioL and ethyLene gLycoL, and the polymers thereof having up to 100 repeating units.
2,3-butanedioL is preferably used. In this connection, suitabLe diamines are piperazine and the physiologicalLy acceptabLe methyLhomoLogs thereof. However, piperazine is preferabLy used.

The biologicaLLy degradabLe poLyamides according to the invention are condensed by methods which are known per se (P.~. Morgan "Condensation PoLymers: by InterfaciaL and Solution Methods", Interscience PubL., New York 1965).
These products are easy to prepare by interfacial poLy-condensation of the free diamines with dicarboxyLic acid chLorides or by solution polycondensation of the diamines, or the bis-silyl derivatives thereof, with chlorides or active esters of the dicarboxyLic acids in an aprotic di-polar solvent.

To this purpose, the diamino component is dissolved in ~' .'' ' , . , ~297627 water which contains excess diamine and organic or inor-ganic bases, such as, for example, tr;alkylamines or al-kali metal hydroxides or alkali metal carbonates, as acid S scavengers. The dicarboxylic acid component, preferably the dicarboxylic acid dichloride, is dissolved in water-immiscible organic solvents, such as, for example, ali-phatic, cycloaliphatic and aromatic hydrocarbons, or halogenated aliphatic and aromatic hydrocarbon. This solution is added to the diamine solution with vigorous stirring, and the polymer produced is isolated by fil-tration or centrifugation. The polyamide is washed with water and ethanol or acetone and dried in vacuo at eLe-vated temperature.
50% of the polyamide prepared in this fashion are repeat-ing units of the diamino compounds and 50% are repeating units of the dicarboxylic acid compounds. Homopolymers can be built up, that is to say each one of the diamino compounds mentioned reacts with one of the dicarboxylic acid compsunds mentioned, but also copolymers in which two or more compounds from the group comprising the di-amino compounds and two or more compounds from the group comprising the dicarboxylic acid compounds are contained can also be built up.

~hen using the amino compound of the general formula Ia and fumaric acid or a mixture of fumaric acid/glutaric acid as the dicarboxylic acid for the polycondensation, the corresponding products are open, via the ester function of the lysine or ornithine radical, to polymer-analogous reactions vith amines, in particular with aminoethanol, or amino-functional pharmaceuticals, or, via the double bonds of the fumarate, are open to free-radical cross-linking. In this fashion, physical properties~ for examplesolubiLity and hydrophilia, and physiological properties, such as stability towards hydrolytic degradation, toler-ance or pharmacological activity, can subsequently be modified on the polymer.

The carbonyl or aminoacyl function which is in the -position to the amide structure influences, by means of inductive and steric effects, the degradation of the poly-mer and the release of the active compound. For example, the hydrophilia of the polymer, and thus its swellability (water resorption) and solubility in the physiological environment, are increased by the carboxyl group produced after known enzymatic or hydrolytic ester cleavages in the body. The undesired, steep decrease in the liberation rate which occurs after the initial "burst effect" in the implant materials described is thereby compensated for.

From the polyamides according to the invention, implantable particles, in particular microcapsules and microspheres, and, by compacting macroscopic molded elements of any geometry, in particular tablets and rods, can be prepared by known methods.

The polyamide can be dissolved, for example, ~ith the active compound in a suitable polar aprotic solvent, for example dimethyl sulfoxide or dimethylacetamide. The solution is emulsified, with addition of an emulsifier, into an oil phase at a temperature at which the polymer solution is liquefied. After several minutes, solidification of the individual solvent/polymer droplets is initiated by cooling the emulsion. The polymer beads are hardened by washing with a suitable solvent in which the solvent employed for dissolving the polyamide and the oil phase dissolve, but not the polymer droplets. The volume of the polymer beads is reduced during this, but the shape does not change.

The polyamides according to the invention can also be employed as mixtures and in blends with other b;odegrad-able polymers or physiologically acceptable auxiliaries (for example polymer plasticizers).

In vitro degradation experiments with the polyamides ac-cord;ng to the invention have shown that the degradation .... .

``` ~Z97627 rate can be regulated in a controlled manner via the functional side groups.

The invention is described in detail in the following 5 examples. Percentage data refer to the weight unless otherwise stated.

Example 1 Preparation of poly(L-lys;ne ethyl ester fumaramide) (LEF) 0.76 9 of fumaryl chloride in 100 ml of ethanoL-free chloro-form is added, ~ith rapid stirring, to a solution of 2.47 9 of L-lysine ethyl ester dihydrochloride and 2.~2 9 of sodium carbonate in 100 ml of ice-cold water. After 15 stirring for ten minutes at room temperature, 100 ml of 1N hydrochloric acid are added, and the mixture is stirred for a further minute. The resultant Polymer is filtered otf under suction through a glass filter frit, and washed first with hot water, then with cold water and subsequently Z0 with acetone. After drying in vacuo over phosphorus pentoxide, 0.8 - 0.95 g ~63 - 75~ of theory) of white poly(L-lysine ethyl ester fumaramide) are obtained. (Mw 23,ûO0, water resorption 9.5Z by ~eight, TG 75C).

25 ExampLe 2 Preparation of poly(L-lysine methyl ester fumaramide) (LMF) û.76 9 of fumaryl chloride is polycondensed with 2.34 9 of L-lysine methyl ester dihydrochloride analogously to 30 Example 1. 0.8 9 of white poly(L-lysine methyl ester fumaramide) (LMF) is obtained.

Example 3 Preparation of poly(L-lysine butyl ester fumaramide) (LBF) 1.52 9 of fumaryl chloride in 200 ml of methylene chlor;de, distilled over phosphorus pentoxide, are poured, ~ith : ~tirring with an Ultra Turrax*, into a ~olution of 5.5 g of X ~denotei trade ~rrk lZ97~27 L-lysine butyl ester dihydrochloride and 4.24 9 of sodium carbonate in 200 ml of ice-cold water. After stirring for two minutes with ice cooling, 100 ml of 1N hydrochloric acid are added, and the mixture is stirred for a further S minute. The methylene chloride is expelled from the re-action mixture by passing in steam, and the polycondensate is subsequently filtered off under suction through a frit.
After ~ashing with hot water, cold water and ethanol, the polymer is dried in vacuo at 60C. 1.8 9 (64% of theory) of white, fibrous poly(L-lysine butyl ester fumaramide) are obtained.

Example 4 Preparation of copoly(L-lysine methyl ester-piperazine fumaramide) 0.76 9 of fumaryl chloride in 100 ml of methylene chloride is polycondensed, analogously to Example 2, with 1.2 9 of L-lysine methyl ester dihydrochloride and 0.93 9 of piper-azine in 100 ml of water which contains 2.12 9 of sodiumcarbonate. 0.7 g ~6~X of theory) of the copolyamide, which dissolves in concentrated sulfuric acid and formic acid, is obtained.

Example 5 Preparation of copoly(L-lysine ethyl-butyl ester fumaramide) 1.52 9 of fumaryl chloride in 200 ml of methylene chloride are polycondensed, analogously to Example 2, with 2.47 9 of lysine ethyl ester dihydrochLoride and 2.75 9 of lysine butyl ester dihydrochloride in 200 ml of water which con-tains 5.5 g of potassium hydroxide. 2.5 g ~71~ of theory) of white, fiber-like copolycondensate are obtained.

Example 6 (LMEF 75/25) 1.52 g of fumaryl chloride are polycondensed, analogously to Example 4, with 3.45 9 of lysine methyl ester dihydro-- ~zg7~27 chloride and 1.30 9 of lysine ethyl ester dihydrochloride.
2.0 g t70% of theory) of a ~hite, fiber-like copolyconden-sate are obtained.

S Example 7 Preparation of poly(diethylene succinate fumaramide) 1.75 g of di-N-hydroxybenzotriazole fumarate and 1.02 9 of 2-aminoethyl succinate in 10 ml of dry N-methylpyr-rolidone are stirred at room temperature for 48 hourswith exclusion of moisture. The reaction mixture is sub-sequently added dropwise to 100 ml of water, and the polycondensate is centrifuged off and, after washing with hot water, dried in vacuo at 60C.
0.7 g (49% of theory) of polymer are obtained as a sticky, viscous material.

Example 8 (LMFG 50/S0) Preparation of poly(L-lysine methyl ester fumaramide/L-lysine methyl ester glutaramide) Copolymer 50 : 50 (LMFG 50 : S0) 0.7 g of glutaryl d;chlor;de and 0.84 9 of fumaryl di-chlor;de are dissolved ;n 170 ml of CH2Cl2. This solution is added at room temperature with vigorous stirring to a solution of 2.91 9 of L-lysine methyl ester and 3.0 9 of Na2C03 in 120 ml of HzO. The polycondensation, which occurs suddenly, is terminated after 15 minutes by adding 120 ml of 1N aqueous HCl. The methylene chloride is then expelled by passing in steam. The hot aqueous mixture is filtered, and the solid product is washed several times with water and tr;turated w;th bo;l;ng ethanol.
Yield: 1.3 g (60X of theory) after vacuum drying (20 hours).

..: . , .

lZ97~27 Example 9 tLMFG 60/40) Preparation of poly (L-lysine methyl ester fumaramide/L-lysine methyl ester glutaramide) S Copolymer 60 : 40 (LMFG 60 : 40) 0.56 9 of glutaryl dichloride and 0.77 9 of fumaryl di-chloride are dissolved in 170 ml of CH2Cl2 and polycon-densed, as described ;n Example 7, with a solution of 2.91 9 of L-lysine methyl ester and 3 9 of Na2C03 in 120 ml of H20.
Yield: 1.3 9 (60% of theory).

Example 10 Preparation of monolithic microspheres from LEF

460 mg of octadecanol are dissolved in 100 ml of viscGus paraffin (Riedel de Haen) by ultrasound treatment, warmed to 50C and stirred. 70 mg of LEF, which has been pre-pared according to Example 1, and 30 mg of LHRH-analogous peptide hormone are dissolved ;n dimethyl sulfoxide by ultra-sound treatment. The solution is added dropwise to the stirred paraffin solution, and the mixture is emulsified for 10 minutes.
The emulsion is stirred into 300 ml of n-butanol at 40C, the paraffin matrix dissolving and the polymer beads pre-cipitating. After about 6 hours, the supernatant liquid is decanted off, and the polymer beads are taken up in 1ûO ml of butanol, hardened for 16 hours and then centrifuged off.
Polymer beads having a size distribution between 20 and 100 ~m are obtained.

Example 11 Preparation of monolithic microspheres from LMFG 60 : 40 (from Example 9) 90 mg of LMFG 60 : 40 from Example 9 are dissolved in 1297~27 small portions in 1 ml of dimethyl sulfoxide. The solution is added dropwise to about 50 ml of liquid nitrogen from a syringe wieh a f;ne cannula (external cannula d;ameter 0.4 - 1.2 mm: depending on the desired bead s;ze). The frozen beads thus produced are separated from the nitrogen by decanting and added to about 500 ml of water. After 2 hours, the DMS0 has diffused out of the beads, and the beads have hardened. They are freeze-dried for 20 hours.

Example 12 Preparation of m;crospheres ~ith act;ve compound 56 mg of LMF from Example 2 and 14 mg of RPluron;c F 68 (manufacturer Fluka AG, Neu-Ulm) are dissolved in 1 ml of d;methyl sulfox;de at 50C. 30 mg of buserelin (manu-facturer Behringwerke AG, Marburg) are then dissolved by brief treatment w;th ultrasound. The polymer and act;ve compound solution is added drop~ise to a prepared amount of liquid nitrogen (100 ml) using a cannula (disposable syringe, external cannula diameter 0.6 mm).

The resultant m;crospheres are transferred into 200 ml of water, and the residual solvent is extracted for 2 hours.
Excess water is decanted off and the microspheres are lyophilized ~diameter after lyophilization 1-Z mm).

Example 13 Preparation of microspheres 70 mg of LMF from Example 2 and 30 mg of maize starch SF
type Snowflake~05063 (manufacturer Maizena lndustrie-produkte GmbH, Hamburg) are dissolved in 1 ml of dimethyl sulfoxide at 50C. The polymer solution is added drop-wise to a prepared amount of liquid nitrogen (100 ml) using a cannula (disposable syringe, external cannula diameter 0.6 mm).

~he resultant microspheres were transferred into 200 ml 3~ de~o+G~ ~r~ ~

.

lZ976Z7 of water, the residual solvent was extracted for 2 hours, and the microspheres were lyophilized (diameter after lyophilization 1-2 mm).

Example 14 Degradation exper;ments 5 samples each of 100 mg of poly(lysine ethyl fumaramide), which has been prepared according to Example 1, are in each case introduced into a semimicro dialysis tube made from regenerated cellulose (Spectra/Por No. 1326QO, Spectrum Medical Ind., Inc., L.A., U.S.A.). The tube segments (length 80 mm, flat width 2.5 mm) are sealed with a wire loop and incubated, with stirring, in a phosphate buffer solution comprising 0.00205 mol of Na2HP04 and 0.0045 mol of NaH2P04 (pH 7.4) at 37C and a partial pressure of oxygen of 50 mm Hg.

0.108 mol of NaCl and 0.030 mol of NaHC03 are added to the phosphate buffer, wh;ch ;s then stab;l;zed against attack by m;croorganisms by 0.0078 mol of NaN3. The buffer is exchanged with a throughput of 50 ml/d.

Over a period of 120 days, a sample is taken after each 30 days and washed with dist;lled ~ater, and the degradat;on behavior, as shown in the following table, character;zed as follo~s by means of the polymer remaining:
a) dry weight after storage for 50 hours in vacuo over b) water resorption after storage for 74 hours at a relative atmospheric humid;ty of 92X
c) molecular weight (about Mw) by gel permeat;on chrom-atography in dimethyl sulfoxide with the aid of an allyl dextran ((R)Sephacryl S-200, Pharmacia, Uppsala) which is covalently crosslinked with N,N'-methylene bisacrylamide.

1297~27 Days 30 _60 90 120 Dry weight (mg) 85 79 68 55 ~ater resorption t% by weight) 17 25 32 38 Molecular weight (Dalton)25000 22000 2000û 19000 Example 15 The water resorption (% by weight) of various homopoly-amides and copolyamides after storage for 74 hours at a relative atmospheric humidity of 92% and the duration of hydrolysis of the aLkyl ester sidegroup (hours) until com-pLete solubilization of each 100 mg of polymer powder in 10 ml of aqueous NaOH (pH 13) are determined.
Polyamide according water duration of to Example resorption solubilization ~h]
Poly(lysine 20 methyl ester fumaramide) 2 13.8 3 Poly(lysine ethyl ester fumaramide) 1 9.2 48 25 Poly(lysine butyl ester fumaramide) 3 5.7 864 Poly(lysine methyl/ethyl ester 30 fumaramide) Molar proport;on of comonomers 10.1 30 75:25 molar 6 Molar proportion 35 of comonomers 9.7 55 25:75 molar 6 .

lZ97~27 Polyamide according water duration of to Example resorption solub;lization Ch]
. .
Polytlysine ethyl/
5 Ibutyl ester fumaramide):
Molar proportion 8.2 528 of comonomers 75:25 molar 5 10 Molar proportion of comonomers 7.0 696 50:50 molar 5 Example 16 Polymer degradation The water resorption (in % by weight) after storage for 74 hours at a relative atmospheric humidity of 92% and the durat;on of hydrolysis of the side groups ~in hours) until complete solubil;zat;on of each 100 mg of polymer powder ;n 100 ml of aqueous NaOH (pH 13) are determined.

The degradation ;n buffer at the physiolog;cal pH ;s car-ried out as follows.
In each case 500 mg of polymer are incubated ;n 30 ml of a phosphate buffer solution comprising 0.00205 mol of Na2HP04 and 0.0045 mol of NaH2P04 (pH 7.4) and stirred at 37C ;n sealed glass bottles (50 ml).
The phosphate buffer ;s stabil;zed against microb;al attack using 0.0078 mol of NaN3, and the pH ;s adjusted after each 7 days.

After a per;od of 150 days, the weight losses of the polymer samples are measured: the buffer solution with incubated polymer is filtered through a tared glass frit, the residue is dried for 24 hours in vacuo over phosphorus pentoxide, and the weight loss is determined.

lZ97~`27 Polymer accord;ng water re- solub;l;z- we;ght to Example sorption,X ation,h loss,%

LMF/Pluronic F 68 12 16 0.5 55 LMF/starch SF 13 18 1 43 Example 17 Release of buserelin from LMF/Pluronic F 68/buserelin microspheres from Example 12 The microspheres investigated have the composition: 12%
by weight of buserelin, 25% by weight of Pluronic F 68 and 63% by we;ght of LMF.

The release of active compound in a buffer solution was measured by UV spectroscopy. ~Buffer: 2.91 g of Na2HP04;
0.540 g of NaH2P04; û.4 9 of NaN3, 6.328 g of NaCl;
2.52 g of NaHC03 in 1 liter of water). In the figure~
the total released amount of buserelin is shown in % as a function of the time (in days).

Claims (11)

1. A biologically degradable polyamide in which amino acids are incorporated into the polymer backbone via two amino or carboxyl groups and which carry in the .alpha.-position to the amide structure a functional group which is responsible for degradation and active com-pound release, with I) repeating units of the diamino compound from the group comprising - the monomeric compound of the general formula Ia, Ia in which R1 denotes a physiologically acceptable, hydrolyzable alkoxy group, having 1 to 18 carbon atoms, which can be unsub-stituted or substituted by physio-logically acceptable side groups, or denotes a physiologically accept-able, hydrolyzable alkylamino or aralkylamino group, or denotes a hydroxyl group, and n is 3 or 4, and/or - the monomeric compound which is produced by esterification of aminoethanol with the di-carboxylic acids of the citrate cycle, and/or - the monomeric compound of the formula lb, Ib in which R2 and R3, independently of one another, denote hydrogen or methyl, and II) repeating units of the dicarboxylic acid compounds from the group comprising - the monomeric compound of the formula IIa, IIa in which R4 denotes an alkyl group having 1 to 3 carbon atoms, and n denotes 1 or 2, and/or - the monomeric straight-chain, saturated or mono-unsaturated ditarboxylic acids having 2-10 carbon atoms, and/or - the monomeric compound which is produced by esterification of the dicarboxylic acids of the citrate cycle with diols of the formula IIb, IIb in which R6 and R7, independently of one another, denote hydrogen or a methyl group, and m is a number in the range 1 to 100, or by amidation with diamines of the formula Ib mentioned.

2. A polyamide as claimed in claim 1, wherein the side group R1 denotes n- or iso-(C1-C18)alkoxy, methoxy(C2-C4)-alkoxy, hydroxy(C2-C4)alkoxy, (C2-C4)alkoxycarbonyl-alkyleneoxy, trichloroisobutoxy, hydroxy(C2-C6)alkylamino, (C2-C4)alkanoyloxyethylamino, mercapto(C2-C4)alkylamino or methyl esters of natural .alpha.-amino acids.

3. A polyamide as claimed in claim 1, wherein R1 denotes a methoxy, ethoxy or n-butoxy group.

4. A polyamide as claimed in claim 1, wherein the dicarboxylic acids employed are straight-chain, saturated or monoun-saturated dicarboxylic acids having 4-8 carbon atoms.

5. A polyamide as claimed in claim 1, wherein the dicarboxylic acids employed are fumaric acid and glutaric acid.

6. A polyamide as claimed in claim 1, wherein the formula IIb denotes 2,3-butanediol.

7. A process for the preparation of a polyamide as claimed in claim 1, wherein one or more compounds from each of the groups comprising the diamino and dicarboxylic acid compounds are polycondensed.

8. The use of a polyamide as claimed in claim 1 for encapsu-lation of biologically active substances.

9. The use of a polyamide as claimed in claim 1 for the pre-paration of biologically degradable active compound depot preparations having controlled release of the active com-pound.

10. The use of a polyamide as claimed in claim 1 in blends with other biodegradable polyamides or physiologically acceptable auxiliaries, for encapsulation of biologically active substances.

11. The use of a Polyamide as claimed in claim 1 in blends with other biodegradable polyamides or physiologically acceptable auxiliaries for the preparation of biologically degradable active compound depot preparations having con-trolled release of the active compound.