AU687553B2 - Process for the production of microparticles - Google Patents

Description

Regulation 3 2

AUSTRALIA

Patents Act 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT

(ORIGINAL)

s 104 tU

C)

Name of Applicant: 8andezs-L4 1 -t MO\ rQC AG Actual Inventors: Address for Service: Invention Title: BODMER, David FONG, Jones Wing KISSEL, Thomas MAULDING, Hawkins Valliant NAGELE, Oskar PEARSON, Jane Edna DAVIES COLLISON CAVE, Patent Attorneys, 1 Little Collins Street, Melbourne, 3000.

"Process for the production of microparticles" The following statement is a full description of this invention, including the best method of performing it known to me/us: -1la- PROCESS FOR THE PRODUCTION OF MICROPARTICLES 0 o This invention relates to a process for the production of microparticles comprising a drug Sin a biodegradable, biocompatible polymeric carrier.

Conventional techniques for producing microparticles include organic phase separation spray drying and triple emulsion, wherein the polymer is precipitated together with the drug, followed by hardening of the resulting product, when phase separation or triple ."emulsion are used.

95O629,poper~dab,4 1985.div, I -I I M We have found an especially useful modification of the triple emulsion technique for preparing microparticles of any drug.

Accordingly the present invention provides a process for producing microparticles which comprises: intensively mixing a water-in-oil emulsion formed from an aqueous medium and a water-immiscible organic solvent containing in one phase the drug and in the other a biodegradable, biocompatible polymer, with an excess of an aqueous medium containing an emulsifying substance or a protective colloid to form a water-in-oil-in-water emulsion, without adding any drug retaining substance to the water-in-oil emulsion or applying any intermediate viscosity increasing step; (ii) desorbing the organic solvent therefrom; (iii) isolating and drying the resultant microparticles.

The present invention additionally provides the microparticles obtained according to the process of the present invention.

The drugs of use in the processes of the invention are preferably water soluble drugs, e.g.

peptides.

The peptides of use in the processes of this invention may be a calcitonin, such as salmon calcitonin, lypressin, and the naturally occurring somatostatin and synthetic analogs thereof.

The naturally occurring somatostatin is one of the preferred compounds and is a tetradecapeptide having the structure:- 950616,p:\operdab,41985.div2

I

3 Ala-Gly-Cys-Lys-Asn-Phe-Phe-Trp Cys-Ser-Thr-Phe-Thr-Lys This hormone is produced by the hypothalmus gland as well as other organs, e.g. the GI tract, and mediates, together with GRF, q.v. the neuroregulation of pituitary growth hormone release. In addition to inhibition of GH release by the pituitary, somatostatin is a potent inhibitor of a number of systems, including central and peripheral neural, gastrointestinal and vascular smooth muscle. It also inhibits the release of insulin and glucagon.

The term "somatostatin" includes its analogues or derivatives thereof. By derivatives and analogues is understood straight-chain, bridged or cyclic polypeptides wherein one or more amino acid units have been omitted and/or replaced by one or more other amino radical(s) of and/or wherein one or more functional groups have been replaced by one or more other functional groups and/or one or more groups have been replaced by one or several other isosteric groups. In general, the term covers all modified derivatives of a biologically active peptide which exhibit a qualitatively similar effect to that of the ."unmodified somatostatin peptide.

Agonist analogs of somatostatin are thus useful in replacing natural somatostatin in its effect on regulation of physiologic functions.

Preferred known somatostatins are:a) (D)Phe-Cys-Phe-(D)Trp-Lys-Thr-Cys-Thr-ol (Generic name Octreotide) b) (D)Phe-Cys-Tyr-(D)Trp-Lys-Val-Cys-ThrNH2 ~II -4 c) (D)Phe-Cys-Tyr-(D)Trp-Lys-Val-Cys-TrpN12 k* d) (D)Trp-Cys-Phe-(D)Trp-Lys-Thr-Cys-ThrNH 2 e) (D)Phe-Cys-Phe-(D)Trp-Lys-Thr-Cys-ThrNH 2 f) 3-(2-(Naphthyl)-(D)Ala-Cys-Tyr-(D)Trp-Lys-Val-Cys-ThrNl 2 g) (D)Phe-Cys-Tyr-(D)Trp-Lys-Val-Cys--Nal-Nl 2 h) 2-naphthyl)-Ala-Cys-Tyr-(D)Trp-Lys-Val-Cys--Nal-Nl 2 i) (D)Phe-Cys-o-Nal-(D)Trp-Lys-Val-Cys-Thr-Nl 2 wherein in each of compounds a) to i) there is a bridge between the amino acids marked with a as indicated in the next formula.

Other preferred somatostatins are:- H-Cys-Phe-Phe- (D)Trp-Lys -Thr-Phe-Cys-OH (See Vale et al., Metabolism, 27, Supp.1, 139 (1978)).

Asn-Phe-Phe- (D)Trp-Lys-Thr-Phe-Gaba (See European Pat.Publication No. 1295 and Appln.No. 78 a....100 994.9).

:MeAla-Tyr-(D)Trp-Lys-Val-Phe (See Verber et al., Life Sciences, 34, 1371-1378 (1984) and European Pat.Appln.No. 82106205.6 (published as No.

021)) also known as cyclo 5 (N-Me-Ala-Tyr-D-Trp-Lys-Val-Phe).

NMePhe-His-(D)Trp-Lys-Val-Ala (See R.F.Nutt et Klin.Wochenschr. (1986) 64 (Suppl.VII) H-Cys-His-His-Phe-Phe-(D)Trp-Lys-Thr-Phe-Thr-Ser-Cys-OH (see EP-A-200,188).

X-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH 2 and X-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-ol wherein X is a cationic anchor especially Ac-hArg(Et 2 -Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-NH2 (See EP 0363589A2) wherein in the above mentioned amino acids there is a bridge between the amino acids marked with a The contents of all the above publications including the specific compounds are specifically incorporated herein by reference.

The term derivative includes also the corresponding derivatives bearing a sugar residue.

When somatostatins bear a sugar residue, this is preferably coupled to a N-terminal amino group and/or to at least one amino group present in a peptide side chain, more preferably to a S. N-terminal amino group. Such compounds and their preparation are disclosed, e.g. in WO 88/02756.

The term octreotide derivatives includes those including the I 6 moiety -D-Phe-Cys-Phe-DTrp-Lys-Thr-Cys- having a bridge between the Cys residues.

Particularly preferred derivatives are N-[ac-glucosyl- (1-4-deoxyfructosyl]-DPhe-Cys-Phe-DTrp-Lys-Thr-Cys-Thr-ol and N -deoxyfructosyl-DPhe-Cys-Phe-DTrp-Lys-Thr-Cys-Thr-ol, each having a bridge between the -Cys- moieties, preferably in acetate salt form and described in Examples 2 and 1 respectively of the above mentioned application.

The somatostatins may exist e.g. in free form, salt form or in the form of complexes thereof. Acid addition salts may be formed with e.g. organic acids, polymeric acids and inorganic acids.

Acid addition salts include e.g. the hydrochloride and acetates.

Complexes are e.g. formed from somatostatins on addition of inorganic substances, e.g. inorganic salts or hydroxides such as Ca- and Zn-salts and/or an addition of polymeric organic substances.

The acetate salt is a preferred salt for such formulations, especially for microparticles leading to a reduced initial drug burst. The present invention also uses the pamoate salt, which is useful, particularly for implants and the process for its preparation.

The pamoate may be obtained in conventional manner, e.g. by reacting embonic acid (pamoic acid) with octreotide e.g. in free base form as described in our co-pending Australian Patent Application No. 58746/90. The reaction may be effected in a polar solvent, e.g. at room temperature.

The somatostatins are indicated for use in the treatment of disorders wherein long term application of the drug is envisaged, e.g. disorders with an aetiology comprising or associated with excess GH-secretion, e.g. in the treatment of acromegaly, for use in the treatment of gastrointestinal

L-

7 disorders, for example, in the treatment or prophylaxis of peptic ulcers, enterocutaneous and pancreaticocutaneous fistula, irritable bowel syndrome, dumping syndrome, watery diarrhea syndrome, acute pancreatitis and gastroenteropathic endocrine tumors vripomas, GRFomas, glucagonomas, insulinomas, gastrinomas and carcinoid tumors) as well as gastro-intestinal bleeding, breast cancer and complications associated with diabetes.

The polymeric carrier may be prepared from biocompatible and biodegradable polymers, such as linear polyesters, branched polyesters which are linear chains radiating from a polyol moiety, e.g. glucose: Other esters are those of polylactic acid, polyglycolic acid, polyhydroxybutyric acid, polycaprolactone, polyalkylene oxalate, polyalkylene glycol esters of acids of the Kreb's cycle, e.g. citric acid cycle and the like and copolymers thereof.

The preferred polymers of this invention are the linear polyesters, and the branched chain polyesters.

The linear polyesters may be prepared from the alphahydroxy carboxylic acids, e.g. lactic acid and glycolic acid, by the condensation of the lactone dimers, see for example US Pat.No.

3,773,919.

Linear polylactide-co-glycolides which are preferably used according to the invention conveniently have a molecular weight between 25,000 and 100,000 and a polydispersibility Mw/Mn e.g.

between 1.2 and 2.

The branched polyesters preferably used according to tue invention may be prepared using polyhydroxy compounds e.g.

polyol e.g. glucose or mannitol as the initator. These esters of a polyol are known and described in UK Patent GB 2,145,422 B.

The polyol contains at least 3 hydroxy groups and has a molecular weight of up to 20,000, with at least 1, preferably at la~- I L 8 least 2, e.g. as a mean 3 of the hydroxy groups of the polyol being in the form of ester groups, which contain poly-lactide or co-poly-lactide chains. Typically 0.2X glucose is used to initiate polymerisation. The structure of the branched polyesters is star shaped. The preferred polyester chains in the linear and star polymer compounds preferably used according to the invention are copolymers of the alpha carboxylic acid moieties, lactic acid and glycolic acid, or of the lactone dimers. The molar ratios of lactide: glycolide is from about 75:25 to 25:75, e.g. 60:40 to 40:60, with from 55:45 to 45:55, e.g. 55:45 to 50:50 the most preferred.

The star polymers may be prepared by reacting a polyol with a lactide and preferably also a glycolide at an elevated temperature in the presence of a catalyst, which makes a ring opening polymerization feasible.

We have found that an advantage of the star polymer type in the formulations of the present invention is, that its molecular weight can be relatively high, giving physical stability, e.g. a certain hardness, to implants and to microparticles, which avoids their sticking together, although relatively shrt polylactide chains are present, leading to a controllable biodegradation rate of the polymer ranging from several weeks to one or two months and to a corresponding sustained r~.,.tse of the peptide, which make a depot formulation made the ,'rom suitable for e.g. a one month's release.

The star polymers preferably have a main molecular weight My in the range of from about 10,000 to 200,000, preferably 25,000 to 100,000, especially 35,000 to 60,000 and a polydispersity e.g.

of from 1.7 to 3.0, e.g. 2.0 to 2.5. The intrinsic viscosities of star polymers of M 35.000 and M. 60.000 are 0.36 resp. 0.51 dl/g in chloroform. A star polymer having a M, 52.000 has a viscosity of 0.475 dl/g in chloroform.

The terms microsphere, microcapsule and microparticle are considered to be interchangeable with respect to the invention, o.-sm IY I 9 and denote the encapsulation ot 1 peptides by the polymer, preferably with the peptide distributed throughout the polymer, which is then a matrix for the peptide. In that case preferably the terms microsphere or more generally microparticle are used.

Using the phase separation technique of the present invention the formulations of this invention may be prepared for example by dissolving the polymeric carrier material in a solvent, which is a nonsolvent for the peptide, following by the addition and dispersing a solution of the peptide in the polymer-solvent composition. A phase inducer e.g. a silicone fluid is then added to induce encapsulation of the peptide by the polymer.

The drug burst effect can be significantly reduced by insitu precipation of ultra fine drug particules, by adding a drug solution to the polymer solution prior to phase separation. The prior art method involves adding dry particles directly to the polymer solution.

The therapeutic duration of peptide release can be increased by hardening/washing the microparticles with an emulsion of buffer/heptane. The prior art method involves a hardening step followed by either no subsequent washing, or a separate aqueous washing step.

An emulsion of the type oil-in-water O/w) may be used to wash and harden the microspheres and remove non-encapsulated peptide.

The wash aids in the removal of non-encapsulated peptide from the surface of the microspheres. The removal of excess peptide from the microspheres diminishes the initial drug burst, which is characteristic of many conventional encapsulation formulations. Thus, a more consistent drug delivery over a period of time is possible with the present microsphere formulation..

The emulsion also aids in the removal of residual polymer solvent and the silicone fluid. The emulsion may be added to the 10 polymer peptide mixture, or the mixture added to the emulsion.

It is preferred that the polymer peptide mixture be added to the emulsion.

The o/w emulsion may be prepared using a emulsifier such as sorbitan mono-oleate (Span 80 ICI Corp.) and the like, to form a stable emulsion. The emulsion may be buffered with a buffer which is non-detrimental to the peptide and the polymer matrix material. The buffer may be from pH 2 to 8 with a pH 4 preferred. The buffer may be prepared from acidic buffers such as phosphate buffer, acetate buffer and the like. Water alone may be substituted for the buffer.

Heptane, hexane and the like may be used as the organic phase of the buffer.

The emulsion may contain dispersing agents such as silicone oil.

A preferred emulsion may comprise heptane, pH 4 phosphate buffer, silicone oil and sorbitan mono-oleate. When an initial drug release may be desirable, a single non-solvent hardening step may be substituted for the emulsion hardening. Heptane, hexane and the like, may be used as the solvent.

Other alternatives to the o/w emulsion may be used for hardening the microcapsules, such as:- Solvent plus emulsifier for hardening the microcapsules without washing; and solvent plus emulsifier for hardening followed by a separate washing step.

The o/w emulsion may be used without the dispersing agent. The dispersing agent, however, avoids aggregation of the dry particles of microcapsules due to static electricity, and helps to reduce the level of residual solvent.

Examples of the solvent for the polymer matrix material include methylene chloride, chloroform, benzene, ethyl acetate, and the like. The peptide is preferably dissolved in an alcoholic II~BPI~SIII~IOI11~ lRI~III--~- 11 solvent, e.g. methanol, which is miscible with the polymer solvent.

The phase inducers (coacervation agents) are solvents which are miscible with the polymer-drug mixture, and cause the embryonic microcapsules to form prior to hardening; silicone oils are the preferred phase inducers.

The o/w emulsion may be prepared in a conventional manner using heptane, hexane and the like for the organic phase.

The microparticles of this invention may also be prepared by the .generally known spray-drying procedure. According to this method the somatostatin, or a solution of the peptide in an organic solvent, e.g. methanol, in water or in a buffer, e.g of pH 3-8 and a solution of the polymer in an organic solvent, not miscible with the former one, e.g. methylene chloride, are thoroughly mixed.

The formed solution, suspension or emulsion is then sprayed in a stream of air, preferably of warm air. The generated microparticles are collected, e.g. by a cyclon and if desired w: ashed, e.g. in a buffer solution of e.g. pH 3.0 to preferably of pH 4.0 or distilled water and dried in a vacuum e.g. at a temperature of 20 to 40 0 C. The vashing step can be applied, if the particles exhibit a drug burst in vivo, and the extent of the drug burst vould be undesired. As a buffer an acetate buffer can be used.

Microparticles can accordingly be obtained, exhibiting an improved somatostatin release profile in vivo.

The invention thus also relates to the microparticles prepared by this process.

The triple emulsion procedure is known from the US-Patent No.

12 4,652,441. According to this patent in a first step a drug solution in a solvent, e.g. somatostatin in water (Column 2, lines 31-32), is thoroughly mixed with an excess of a polylactide-co-glycolide solution in another solvent, in which the first solvent is not soluble, e.g. methylene chloride, giving a water-in-oil type emulsion of fine drug-containing droplets of in solution(2).

In solution is additionally dissolved a so-called drug-retaining substance (Column 1, line 31), e.g. gelatin, albumin, pectin, or agar.

In a second step the viscosity of the inner phase is increased by appropriate means, like heating, cooling, pH change, addition of metal ions, or cross linking of e.g. gelatin with an aldehyde.

In a third step, an excess of water is thoroughly mixed with the /o-emulsion (Column 7, lines 52-54), leading to a W/o/w-type ternary-layer emulsion. In the excess of water a so-called emulsifying agent may if desired be present (Column 7, line 56), choosen from the group of e.g. an anionic or nonionic surfactant or e.g. polyvinyl pyrrolidone, polyvinyl alcohol or gelatine.

In a fourth step the "/o/w-emulsion is subjected to "in-water S. drying", (line 52). This means that the organic solvent in the oil layer is desorbed to generate microparticles.

The desorption is accomplished in a manner known per se (Column 8, lines e.g. by pressure decrease while stirring (Column 8, lines 5-7) or e.g. by blowing nitrogen gas through the oil layer methylene chloride) (line 19).

The formed microparticles are recovered by centrifugation or filtration (lines 26-27) and the components which are not incorporated in the polymer are removed by washing with water (line 29). If desired, the microparticles are warmed under reduced pressure to achieve) better removal of water and of solvent methylene chloride from the microparticle wall (lines 30-32).

Whilst the above process is satisfactory for the production of 13formulations according to the invention, however, the so-called drug-retaining substance mentioned above, e.g. gelatine, albumin, pectin or agar, is still enclosed in the resultant microparticles.

We have now found that when the addition of the drug retaining substance in solution and the step of increasing the viscosity of the inner phase is avoided, and in the excess of water of the ternary w/o/w-emulsion, the measure of adding an emulsifying substance or a protective colloid, like gelatine is maintained, satisfactory microparticles can still be obtained.

additionally, the microparticles do not contain any drug retaining substance, and only a very small quantity of methylene chloride.

Therefore the invention provides a process for the production of microparticles prepared by intensively mixing:a) a solution of a drug, preferably a somatostatin, especially octreotide in an aqueous medium, preferably water or a buffer, preferably in a weight/volume ratio of 0.8 to 4.0 g 1 to 120 ml, especially 2.5 10 and in a buffer of pH 3-8, especially an acetate buffer, and b) a solution of a polymer, preferably a polylactideco-glycolide, such as mentioned above, in an organic solvent, not miscible with the aqueous medium, e.g. methylene chloride, preferably in a weight/volume ratio of 40g/90 to 400ml, especially 40/100, preferably in such a manner that the weight/weight ratio of the drug to the polymer is from 1/10 to 50, especially 1/16 and the volume/volume ratio of the aqueous medium/organic solvent is 1/1.5 to 30, especially 1/10, intensively mixing the W/o-emulsion of a) in b) together with c) an excess of an aqueous medium, preferably water or a buffer, ~IAl Bl~ar~ l~ 14 e.g. an acetate or phosphate buffer, preferably of a pH 3-8, containing an emulsifying substance or a protective colloid, preferably in a concentration of 0.01 to 15.OX, particularly gelatine, especially in a concentration of 0.1 to 3 X, particularly 0.5% of weight, preferably at a volume/volume mixing speed ratio of ab) c) of from 1/10 to 100, especially 1/40, without adding any drug retaining substance to the water-in-oil emulsion or applying any intermediate viscosity increasing step, hardening the embryonic microparticles in the formed /o/w-emulsion by desorption, preferably by evaporation, of the organic solvent, preferably methylene chloride, and by isolating, optionally washing and drying the generated microparticles.

The invention also provides the process variant, in which the drug is dispersed directly in the polymer solution, whereafter the resulting dispersion is mixed with the gelatine containing water phase.

The invention also provides to the microparticles, produced by these processes. Like microparticles prepared according to the spray drying technique, they do not contain silicon oil.

Compared with microparticles prepared according to the known triple emulsion process type, they do not contain any amount of a protective colloid.

The microparticles of this invention may have a size range from about 1 to 250 microns diameter, preferably 10 to 200, especially 10 to 130, e.g. 10 to 90 microns.

"Implants may be e.g. from about 1 to 10 cubic mm. The amount of drug i.e. peptide present in the formulation depends on the desired daily release dosage and thus on Sthe biodegradation rate of the encapsulating polymer. The exact amount of peptide may be ascertained by bioavailability trials. The formulations may contain peptide in an amount from at least 0.2, preferably 0.5 to 20 per cent by weight relative to the polymeric matrix, preferably 2.0 to 10, especially 3.0 to 6% of weight

I

15 The release time of the peptide from the microparticle may be from one or two weeks to about 2 months.

The following examples illustrate the invention.

M. of polymers is the mean molecular weight as determined by GLPC using polystyrene as standard.

EXAMPLE 1: One g of poly(D,L,-lactide-co-glycolide)glucose, M, 46,000 (50:50 molar produced according to the process of GB 2,145,422 B, Polydispersity ca. 1.7, produced from 0.2X glucose) was dissolved in 2.5 ml of methylene chloride followed by the addition of 75 mg of Octreotide dissolved in 0.125 ml of deionized water. The mixture was intensively mixed e.g. by means of an Ultra-Turax for one minute at 20,000 rpm (inner V/0-phase).

One g of Gelatine A vas dissolved in 200 ml of deionized water at 50 oC and the solution cooled down to 20 0 C (outer V-phase).

The V/0- and the V-phases were intensively mixed. Thereby the Sinner V/0-phase was separatoo into small droplets which were dispersed homogenously in the outer V-phase. The resulting e *o *~e 950616,p:%opcdab,4198,div, -16 triple emulsion was slowly stirred for one hour. Hereby the methylene chloride was evaporated and the microcapsules were hardened from the droplets of the inner phase. After sedimentation of the microparticles the supernatant was sucked off and the microparticles were recovered by vacuum filtration and rinsed with water to eliminate gelatine.

Drying, sieving, washing and secondary drying of the microparticles was conducted.

The microparticles were suspended in a vehicle and administered i.m. in 5mg/kg dose of Octreotide to white rabbits (chinchillabastard) and s.c. in a 10 mg/kg dose to male rats. Blood samples were taken periodically, indicating plasma levels of 0.3 :to 15.0 ng/ml (5 mg dose) in rabbits and 0.5 to 8.0 ng/ml in rats for 42 days as measured by Radiolmmunoassay (RIA) analysis.

EXAMPLE 2: Microparticles were prepared by the triple-emulsion technique in the same way as desribed for example 1 with three changes:- 1. 0.25 ml of acetate buffer pH 4.0 vere used instead of 0.125 ml of water to prepare the inner W/0-phase.

2. rinsing after collection of the microparticles was carried out with 1/45 molar acetate buffer pH 4.0 instead of water.

3. further washing of microparticles was omitted.

EXAMPLE 3: Microparticles were prepared by the triple-emulsion technique in Sthe same way as described for example 2 with the only change that the inner V/0-phase was prepared by using water containing sodium chloride instead of acetate buffer.

I

i \MPI 4 Microparticles were prepared in the same manner as described in ,xample 1, vith the only difference, that the drug compound is dispersed directly in the polymer solution, whereafter the resulting dispersion is mixed with the gelatine containing water phase.

[XAMPI.L ,ctreotide pamoate 10.19 g of octreotide free base (10 iH) and 3.88 embonoic acid mrn) are dissolved in 1 litre of vater/dioxane The reaction mixture is filtered, and lyophilized to give a yellow powder [aj]2D 7.50 (C 0.35, in DMF), of octreotide pamoate hydrate. Factor 1.4 wherein the factor weight of lyophilizate/veight of octreotide contained therein.

The pamoate may replace the octreotide acetate present in the microparticles of Examples 1-4 and has an excellent stability.

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising', will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.

I

Claims (1)

18- THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS: I A process for producing microparticles comprising a drug in a biodegradable, biocompatible carrier, which comprises intensively mixing a water-in-oil emulsion formed from an aqueous medium and a water-immiscible organic solvent containing in one phase the drug and in the other a biodegradable, biocompatible polymer with an excess of aqueous medium, containing an emulsifying substance or a protective colloid, to form a water-in-oil-in-water emulsion without adding any drug retaining substance to the water-in-oil emulsion or applying any intermediate viscosity increasing step, (ii) desorbing the organic solvent therefrom, (iii) isolating and drying the resultant microparticles. 2. A process for producing microparticles comprising a drug compound in a biodegradable, biocompatible polymer, which comprises intensively mixing a drug compound suspension formed from a drug compound and a water-immiscible organic solvent containing a biodegradable, biocompatible polymer with an excess of aqueous medium, containing an emulsifying substance or a protective colloid, to form an oil-in- water emulsion, the drug compound being dispersed in the oil component, without adding any drug retaining substance or applying any intermediate viscosity increasing step, (ii) desorbing the organic solvent therefrom, (iii) isolating and drying the resultant microparticles. S9710 r\ 195.iv, -\Cd 9 7 to 3 0, p: ut p rviab,4 19 8 5. div, 1 19 3. A process for the production of microparticles according to claim I which comprises intensively mixing:- a) a solution of a drug in an aqueous medium and b) a solution of a polymer in an organic solvent, not miscible with the aqueous medium, intensively mixing the "/o-emulsion of a) and b) together vith c) an excess of an aqueous medium containing a protective colloid, without adding any drug retaining substance to the water-in-oil emulsion or applying any intermediate viscosity increasing step, hardening the embryonic microparticles in the formed /o4,-emulsion by desorption, and isolating the generated microparticles. 4. A process according to any one of the preceding claims, in which the drug is a somatostatin. A process according to any one of claims 1 to 3, in which the drug is octreotide. 6. A process according to any one of claims 1 to 3, in which the drug is octreotide 20 pamoate salt. 7. A process according to any one of claims 1 to 3, in which the polymer is a polylactide-co-glycolide. 8. A process according to any one of claims 1 to 3, in which the aqueous medium is water or a buffer. 9. A process according to any one of claims 1 to 3, in which the aqueous medium is a buffer of pH 3-8. A process according to any one of claims 1 to 3, in which the organic solvent is methylene chloride. 950619,p.opcr\dab,41 98S.d5v, 19 20 11. A process for the production of microparticles according to claim 1 which comprises intensively mixing;- a) a solution of a somatostatin in water or a buffer in a weight/volume ratio of 0.8 to 4.0g/l to 120 ml and b) a solution ofa polylactide-co-glycolide in an organic solvent, not miscible with the aqueous medium in a weight/volume ratio of 40g/90 to 400 ml in such a manner that the weight/weight ratio of the drug to the polymer is from 1/10 to 50 and the volume/volume ratio of the aqueous medium/organic solvent is 1/1.5 to 30, intensively mixing the "/o-emulsion of a) in b) together with c) an excess of water or a buffer containing a protective colloid at a volume/volume mixing speed ratio of ab)/c) of from 1/10 to 100, without adding any drug retaining substance to the water-in-oil emulsion or applying any intermediate viscosity increasing step, hardening the embryonic microparticles in the formed W/ow-emulsion by evaporation of the organic solvent and isolating the generated microparticl 20 12. A process according to claim 11, in which the protective colloid is gelatine. 13. A process for the production of microparticles according to claim 1 which comprises intensively mixing:- a) a solution of a somatostatin in an aqueous medium in a weight/volume ratio of 2.5g/10 ml and b) a solution of a polylactide-co-glycolide in an organic solvent, not miscible with the aqueous medium in a weight/volume ratio of 40g/100 ml in such a manner that the weight/weight ratio of the drug to the polymer is 1/16 and the volume/volume ratio of the aqueous medium/organic solvent is 1/10, intensively mixing the '"/-emulsion of a) in b) together with 950619, pAoper\dab,4 I985. c L -21 c) an excess of an aqueous medium containing protective colloid in a concentration of 0.01 to 15.0% at a volume/volume mixing speed ratio of ab)/c) of 1/40, without adding any drug retaining substance to the water-in-oil emulsion or applying any intermediate viscosity increasing step, hardening the embryonic microparticles in the formed /o/w-emulsion by evaporation of the organic solvent and isolating the generated microparticles. 14. A process for the production of microparticles according to claim 1 which comprises intensively mixing:- a) a solution of octreotide in a weight/volume ratio of 2.5g/10 ml in a buffer of pH 3-8 and b) a solution of a polylactide-co-glycolide in methylene in a weight/volume ratio of 40g/100 ml in such a manner that the weight/weight ratio of the drug to the polymer is 1/16 and the volume/volume ratio of the aqueous medium/organic solvent is 1/10, intensively mixing the "/o-emulsion of a) in b) together with 20 c) an excess of a buffer of a pH 3-8, containing gelatine in a concentration of 0.5% of weight at a volume/volume mixing speed ratio of ab)/c) of 1/40, without adding any drug retaining substance to the water-in-oil emulsion or applying intermediate viscosity increasing step, hardening the embryonic microparticles in the formed w/ow-emulsion by evaporation of the methylene chloride and by isolating, washing and drying the generated microparticles. The microparticle obtained according to claim 1 or claim 2. 950619,pgopcrab,41985.di,21 22 16. A process for the production of rnicroparticles, substantially as hecreinbefore described with reference to the Examples. Dated this 29th day of June, 1995 gffldei-h. N&oirt AqC By Its Patent Attorneys E SC 1- S104 u DAVIES COLLISON CAVE 9506 29, p,\kp\dab,4 19 8 5div,22 -23 ABSTRACT The present invention relates to a process for producing microparticles compris'ng a drug in a biodegradable, biocompatible carrier, which comprises intensively mixing a water-in-oil emulsion formed from an aqueous medium and a water-immiscible organic solvent containing in one phase the drug and in the other a biodegradable, biocompatible polymer with an excess of aqueous medium, containing an emulsifying substance or a protective colloid, to form a water-in-oil-in-water emulsion without adding any drug retaining substance to the water-in-oil emulsion of applying any intermediate viscosity increasing step, (ii) desorbing the organic solvent therefrom, (iii) isolating and drying the resultant microparticles. e 950619,p:\opr\b,4198S.div,23