NL9001537A - PREPARATIONS OF WATER-SOLUBLE PEPTIDES WITH SLOW DELIVERY. - Google Patents

Description

PREPARATIONS OF WATER-SOLUBLE PEPTIDES WITH SLOW DELIVERY.

This invention relates to slow-release preparations (depot preparations), in particular water-soluble peptides, for example somatostatin or somatostatin analogues, such as patent, in a biodegradable and biocompatible polymeric carrier, for example a matrix or a coating, for example in the form of an implant or preferably a microparticle (also known as a microcapsule or a microsphere).

The invention also relates to such compositions having peptide release profiles that are satisfactory for a special period of time.

Peptide drugs often show poor bioavailability in the blood after oral or parenteral administration, for example due to their short biological half-lives caused by their metabolic instability. When administered orally or through the nose, they often show poor absorption by the mucous membranes. A therapeutically relevant blood level over a long period of time is difficult to achieve.

The parenteral administration of peptide drugs as a depot preparation in a biodegradable polymer, for example as microparticles or implantations, has been proposed, which, after a residence time in the polymer protecting the peptide from enzymatic and hydrolytic influences of the biological media, with delayed release can be released.

While some parenteral depot preparations or peptide drugs are known in a microparticle polymer or implantation, only in some cases satisfactory peptide release profiles are obtained in practice. Special measures must be taken to provide a continuous peptide release for serum levels of a therapeutically active medicinal product and, if desired, to avoid excessive serum concentrations of the medicinal product causing undesirable pharmacological and adverse reactions.

The release pattern of a peptide drug depends on numerous factors, for example, on the type peptide and, for example, whether it is present in its free form or in another form, for example in its salt form, which can affect its solubility in water. Another important factor is the choice of polymer, from an extensive list of possibilities described in the literature.

Each polymer type has its characteristic biological decomposition rate. Free carboxyl groups can be formed which contribute to the pH value in the polymer and thus further affect the water solubility of the peptide and thus its release pattern.

Other factors affecting the release pattern of the depot composition are the drug loading of its polymeric carrier, its mode of distribution into the polymer, its particle size and, in the case of an implantation, additionally its shape. The place of the preparation in the body also has an influence.

To date, no somatostatin formulation in sustained-release form for parenteral administration has been marketed, probably because no formulation showing a satisfactory serum level profile could be obtained.

Polymer formulations containing drugs intended to provide a sustained or delayed release of the drug are known in the art.

U.S. Patent 3,773,919 describes compositions from which the drug is released at a controlled rate, wherein the drug, for example, a water-soluble peptide drug, is dispersed in a biodegradable and biocompatible linear polylactide or polylactide. co-glycolide polymer. However, no drug release patterns have been described and there is no reference to somatostatin. In U.S. Patent 4,293,539, microbial antibacterial compositions are described.

U.S. Patent 4,675,189 discloses sustained-release preparations of the LHRH analog decapeptide nafareline and analogous LHRH relatives in polylactide co-glycolide polymers. No delivery pattern has been described.

T. Chang, J. Bioeng., Vol. 1, pp. 25-32, 1976 describe the sustained release of biological materials, enzymes and vaccines from microparticles.

Polymers copolymers of lactic acid and lactide-glycolide copolymers and related preparations for use in surgical applications and for the delayed release and biological decomposition are described in U.S. Pat. Nos. 3,991,776; 4,076,798 and 4,118,470.

European patent application 0.203.031 describes a series of somatostatin octapeptide analogues, for example compound RC-160 with formula * * D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2, with a bridge between the -Cys- sections, in columns 15-16.

The ability of the somatostatins to be encapsulated in micro-form with polylactide-co-glycolide polymer is set forth in claim 18, but no guidance is given on how to obtain a continuous therapeutically active serum level.

U.S. Pat. No. 4,011,312 discloses that a continuous release of an anti-microbial drug, for example, the water-soluble polymyxin B, from a polylactide-co-glycolide matrix has a low molecular weight (less than 2000) and a relatively high glycolide content in the implantation form can be obtained if the implant is inserted into a cow's teat canal. The drug is released in a short period of time, due to the high glycolide content and low molecular weight of the polymer, both of which stimulate rapid biological decomposition of the polymer and thus corresponding rapid drug release. Moreover, a relatively high drug loading contributes to a rapid release of the drug. No somatostatins and no drug delivery patterns have been described.

European Patent 58481 describes that a continuous release of a water-soluble peptide from a polylactide polymer implant is stimulated by decreasing the molecular weight of at least a portion of the polymer molecules, by introducing glycolide units into the polymer molecule, by increasing the block polymer character of the polymer-polymer when polylactide. glycolide molecules are used, by increasing the drug load of the polymer matrix and by increasing the surface area of the implant.

Although somatostatins have been referred to as water-soluble peptides, no somatostatin release profiles have been described, nor has any indication been given as to how all these parameters can be combined to obtain, for example, a continuous somatostatin serum level for at least a week, e.g., a month.

European Patent 92918 describes that a continuous release of peptides, preferably hydrophilic peptides, can be obtained over a long period of time if the peptide is incorporated into a conventional hydrophobic polymer matrix, for example of a polylactide, which has been made more accessible to water by molecule into a hydrophilic unit, for example, of polyethylene glycol, polyvinyl alcohol, dextran, polymethacylamide. The hydrophilic contribution to the amphipathic polymer is imparted to all ethylene oxide groups in the case of a polyethylene glycol unit, through the free hydroxyl groups in the case of a polyvinyl alcohol unit or of a dextran unit, and through the amide groups in the case of a polymethyl acrylamide unit. Due to the presence of the hydrophilic unit in the polymer molecules, the implantation will acquire hydrogel properties after the absorption of water. Somatostatin is referred to as a hydrophilic peptide, but no release profile has been described, nor has any indication been given as to which polymer type is recommended for this peptide and which molecular weight and how many hydrophilic groups it will have.

U.S. Pat. No. 2,145,422 Bis discloses that a sustained release of different types of drugs, for example vitamins, enzymes, antibiotics and antigens, can be obtained over a prolonged period of time if the drug is incorporated in an implant, for example of the size of microparticles, made from a polymer of a polyol, for example glucose or mannitol, with one or more, preferably at least 3, polylactide ester groups. The polylactide ester groups preferably contain, for example, glycolide units. No peptides, for example somatostatins, are listed as drugs and no serum drug levels have been described.

This invention relates to sustained release preparations, for example preparations of microparticles of a drug, in particular of a hormonally active, water-soluble, somatostatin or anomatostatin analog, such as octreotide, providing a satisfactory drug plasma level and, for example in a biologically decomposable, biocompatible polymer, for example, in an encapsulating polymer matrix. The polymer matrix can be a synthetic or a natural polymer.

The microparticles of this invention can be obtained by any conventional method, for example, an organic phase separation method, a spray drying technique, or a triple emulsion method, whereby the polymer is precipitated together with the drug, followed by curing the obtained product, if the phase separation or triple emulsion method is added suits.

If desired, the delayed release formulations may be in the form of an implant.

A particularly useful modification of a phase separation method to prepare microparticles of each drug has now been found.

Thus, the present invention provides a method of preparing or manufacturing a microparticle containing a drug in a biologically decomposable, biocompatible carrier, comprising the following steps: a) dissolving the polymeric carrier material in a suitable solvent, wherein the drug carrier bond is insoluble, b) addition and dispersion of a solution of the drug compound in a suitable solvent, for example an alcohol, which is not a solvent for the polymer, in the solution of step a), c) addition of a phase- inducing agent to the dispersion of step b), to induce microparticle formation, d) adding an oil-in-water emulsion to the mixture of step c), to cure the microparticle, and e) recovering the microparticle.

Also, a particularly useful modification of the triple emulsion method for preparing microparticles of each drug has been found.

Thus, the present invention provides: a method of preparing microparticles, which comprises (i) intimately mixing a water-in-oil emulsion formed from an aqueous medium and a water-immiscible organic solvent which in one phase contains the medicament and in the other phase contains a biodegradable, biocompatible polymer, with an excess of an aqueous medium containing an emulsifying material or a protective colloid to form a water-in-oil-in-water emulsion, without adding any material drug contains to the water-in-oil emulsion or application of any intermediate viscosity enhancing step, (ii) desorbing the organic solvent thereof, (iii) isolating and drying the microparticles obtained.

The present invention additionally provides microparticles obtained by these methods.

The present invention also provides: a) a sustained-release composition containing a peptide drug compound in a 40/60 to 60/40 polylactide co-glycolide ester of a polyol, wherein the polyol moiety is selected from the group of an alcohol with a carbon chain of 3-6 carbon atoms and 3-6 hydroxyl groups and a mono- or di-saccharide and the esterified polyol contains at least 3 polylactide co-glycolide chains.

b) a sustained release preparation comprising a peptide drug compound selected from the group of moncitonin, lypressin or a somatostatin in a 40/60 to 60/40 polylactide co-glycolide polymer with linear chains of molecular weight Mw between 25,000 and 100,000, a polydispersibility Mw / Mn between 1.2 and 2 at a concentration of 0.2, preferably 2-10% by weight, of the peptide drug compound therein.

c) a sustained release preparation containing octootreide or a salt or a derivative thereof in a biodegradable, biocompatible, polymeric carrier.

It has been found that a new salt of octreotide is the pamoate, which is very stable in such preparations.

The present invention accordingly provides (i) octreotide pamoate and (ii) a method of preparing octreotide pamoate, which comprises reacting octreotide with embonic acid (or a reactive derivative thereof).

The present invention additionally provides:

A method of administering a peptide to a subject, which comprises administering a predefined depot composition parenterally to a subject in need of such treatment, particularly for the treatment of acromegaly or breast cancer.

The medicaments which can be used in the method according to the invention are preferably water-soluble, for example peptides.

The peptides which can be used in the methods and formulations of this invention may be a calcitonin such as salmon calcitonin, lypressinene naturally occurring somatostatin and synthetic analogues thereof.

The naturally occurring somatostatin is one of the recommended compounds and is a tetradecapeptide with formula

Ala-Gly-Cys-Lys-Asn-Phe-Phe-Trp

I I

Cys-Ser-Thr-Phe-Thr-Lys.

This hormone is produced by the hypothala musk gland as well as other organs, for example the GI system and mediates, together with GRF, q.v. the neuroregular system and mediates, together with GRF, q.v. the neuroregulation of pituitary growth hormone release. In addition to inhibition of GH release by the pituitary gland, somatostatin is a potent inhibitor of a number of systems, including the central and peripheral neural, gastrointestinal and vascular smooth muscle. It also inhibits the release of insulin and glucagon.

The term "somatostatin" includes its analogs or derivatives. Derivatives and analogs are understood to mean straight chain, bridge or cyclic polypeptides in which one or a number of deamino acid units have been omitted and / or have been replaced by one or a number of other amino group (s) and / or in which one or a number of the functional groups have been replaced by one or a number of other functional groups and / or one or a number of groups have been replaced by one or a number of other isosteric groups. In general, the designation includes all modified derivatives of a biologically active peptide that exhibits a qualitatively similar effect to that of the unmodified somatostanin peptide.

Thus, agonist analogues of somatostatin can be used to replace natural somatostatin in terms of its effect on the regulation of physiological functions.

Recommended 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 * * c) (D) Phe-Cys-Tys- (D) Trp-Lys-Val-Cys-TrpNH2 * * d) (D) Trp-Cys-Phe- (D) Trp-Lys-Thr-Cys-ThrNH2 * * e) (D) Phe-Cys-Phe- (D) Trp-Lys-Thr-Cys-ThrNH2 * * f) 3- (2- (naphthyl) - (D) -Ala-Cys-Tyr- (D) Trp-Lys-Val-Cys-ThrNH2 * * g) (D) Phe-Cys-Tyr- (D) Trp-Lys-Val-Cys-jB-Nal- NH2 * * h) 3- (2-naphthyl) -Ala-Cys-Tyr- (D) Trp-Lys-Val-Cys-jS-Nal-NH2 * * i) (D) Phr-Cys-jS-Nal- (D) Trp-Lys-Val-Cys-Thr-NH2 wherein in each of compounds a) to i) there is a bridge between the amino acids labeled with * as indicated in the following formula.

Other recommended somatostatins are:

(see Vale and med., Metabolism, 27, Supp. 1, 139 (1978)).

* *

Asn-Phe-Phe- (D) Trp-Lys-Thr-Phe-Gaba (see European Patent Publication No. 1295 and Application No. 78100 994.9).

* *

MeAla-Tyr- (D) Trp-Lys-Val-Phe (see Verber and med., Life Sciences, 34, 1371-1378 (1984) and European patent application 82106205.6 (published as no. 70 021)) also known as (N-Me-Ala-Tyr-D-Trp-Lys-Val-Phe).

* * NMePhe-His (D) Trp-Lys-Val-Ala (see RFNutt and med., Clinic 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-NH2en * * X-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-ol where X is a cationic anchor, in special * *

Ac-hArg (Et2) -Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-NH2 (see EP 0363589A2) in which in the aforementioned amino acids there is a bridge between the amino acids labeled with a *.

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

If somatostatins contain a sugar residue, it is preferably linked to an N-terminal amino group and / or to at least one amino group present in a peptide side chain, more particularly to an N-terminal amino group. Such compounds and their preparation are described, for example, in WO 88/02756.

Octreotide derivatives include those derivatives which contain a * * -D-Phe-Cys-Phe-DTrp-Lys-Thr-Cys group bridged between Cys residues.

Particularly recommended derivatives are N '- [α-gluco-syl- (1-4-deoxyfructosyl] -DPhr-Cys-Phe-DTrp-Lys-Thr-Cys-Thr-ol and Na - [/ 3-deoxyfructosyl-DPhe -Cys-Phe-DTrp-Lys-Thr-Cys-Thr-ol, each with a bridge between the -Cys portions, in particular in acetate salt form and described in Examples 2 and 1 of the aforementioned application, respectively .

The somatostatins can occur, for example, in free form, in salt form or in the form of complexes thereof. Acid addition salts can be formed with, for example, organic acids, polymeric acids and inorganic acids. Acid addition salts include, for example, hydrochloride and acetates. For example, complexes are formed from somatostatins by the addition of inorganic materials, for example inorganic salts or hydroxides, such as calcium and zinc salts and / or addition of polymeric organic materials.

The acetate salt is a recommended salt for such preparations, especially for microparticles that lead to a reduced explosion of drug at the beginning. The present invention also provides the pamoate salt which is useful, in particular pre-implantations and a method for its preparation.

The pamoate can be obtained in a conventional manner, for example by reacting embonic acid (pamoic acid) metoctreotide, for example in the form of a free base. The reaction can be carried out in a polar solvent, for example at room temperature.

The somatostatins are indicated for use in the treatment of diseases in which the long-term administration of the drug must be taken into account, for example diseases with an etiology including or associated with an excess of GH secretion, for example treatment of acromegaly, for use in the treatment of gastrointestinal disorders, for example treatment or prevention of gastric ulcers, enterocutaneous and pancreatic futels, irritable bowel syndrome, dumping syndrome, watery diarrhea syndrome, acute pancreatitis and gastroenteropathic endocrine tumors (eg vipomas, GRFomas, glucagonomas, insulinomas, gastrinomas and carcinoid tumors), as well as bleeding in the gastrointestinal tract, breast cancer and complications associated with diabetes.

The polymeric carrier can be obtained from biocompatible and biodegradable polymers, such as linear polyesters, branched polyesters, which are linear chains radiating from a polyol portion, for example glucose. Other esters are those of polylactic acid, polyglycolic acid, polyhydroxybutyric acid, polycaprolactone, polyalkylene oxalate, polyalkylene glycol esters of Kreb's cycle acids, for example, the citric acid cycle, etc., and copolymers thereof.

The recommended polymers of this invention are the linear polyesters and the single-branched polyesters.

The linear polyesters can be prepared from de -hydroxycarboxylic acids, e.g., lactic acid and glycolic acid, by condensation of the lactone dimers, see, for example, U.S. Patent 3,773,919.

Linear polylactide co-glycolides, which are preferably used according to the invention, suitably have a molecular weight between 25,000 and 100,000 and a polydispersibility Mw / Mn of, for example, between 1.2 and 2.

The branched polyesters which are preferably used according to the invention can be obtained using polyhydroxy compounds, for example polyol, for example glucose or mannitol, as initiators. These esters of a polyol are known and described in British patent GB 2,145,422 B. The polyol contains at least 3 hydroxyl groups and has a molecular weight of up to 20,000, with at least 1, preferably at least 2, for example, an average of 3 of the hydroxyl groups of the polyol in the form of ester groups, dipoly-lactide or co-poly-lactide chains. Typically, 0.2% glucose is used to initiate the polymerization. The structure of the branched polyester is star-shaped. The preferred polyester chains in the linear and star-shaped polymer compounds which are preferably used according to the invention are copolymers of the α-carboxylic acid moieties, lactic acid and glycolic acid, or of delactone dimers. The molar ratios of lactide: glycolide is about 75:25 to 25:75, e.g. 60:40 to 40:60, with 55:45 to 45:55, e.g. 55:45 to 50:50 being the most recommended.

The star-shaped polymers can be obtained by reacting a polyol with a lactide, and preferably also a glycolide, at an elevated temperature and in the presence of a catalyst which makes a polymerization under opening possible.

It has been found that an advantage of the star-type polymer in the compositions of the present invention is that its molecular weight may be relatively high, thereby imparting physical stability, e.g., a certain hardness, to implants and mica particles, avoiding their sticking together, although relatively short polylactide chains are present, leading to a controllable decomposition rate of the polymer ranging from a few weeks to 1 or 2 months and to a corresponding delayed release of the peptide, which makes a depot preparation thereof suitable, for example, for delivery during a month.

The star-shaped polymers preferably have an average molecular weight Mw in the range of about

10,000 to 200,000, preferably 25,000 to 100,000, in particular 35,000 to 60,000 and a polydispersibility of, for example, 1.7 to 3.0, for example 2.0 to 2.5. Intrinsic viscosities of star-shaped polymers with MH

35,000 and 60,000 MH are 0.36 and 0.51 dl / gin chloroform, respectively. A star-shaped polymer with an Mw 52,000 has a viscosity of 0.474 dl / g in chloroform.

The designations "microsphere, microcapsule and microparticle" are interchangeable with regard to the invention and indicate encapsulation of the peptides by the polymer, preferably with the peptide distributed by the polymer, which is then a matrix for the peptide. preferably the designation "microsphere" or more generally "microparticle" is used.

For example, using the phase separation method of the present invention, the compositions of this invention can be prepared by dissolving the polymeric carrier material in a solvent, which is not a solvent for the peptide, followed by addition and dispersion of a solution of the peptide in the polymer solvent product. A phase inducer, for example a silicone liquid, is then added to induce encapsulation of the peptide by the polymer.

The effect of the explosive release of the drug can be greatly reduced by in situ precipitation of the ultrafine drug particles, by adding a drug solution to the polymer solution, for phase separation. The prior art method involves adding dry particles directly to the polymer solution.

The therapeutic duration of the peptide release can be extended by curing washing of the microparticles with an emulsion of buffer heptane. The prior art method involves a hardening step after which no washing is carried out or which is followed by a separate aqueous washing step.

An oil-in-water emulsion (= ° / w) can be used to wash and cure the microspheres and to remove unencapsulated peptides. The wash promotes removal of the unencapsulated peptide from the surface of the microspheres. Removing the excess peptide from the microspheres reduces the initial drug explosion, which is characteristic of many common encapsulation formulations. Thus, with the present microsphere preparations, a more consistent release of the drug over a period of time is possible.

The emulsion also promotes the removal of residual polymer solvent and silicone fluid. Deemulsion can be added to the polymer peptide mixture or the mixture can be added to the emulsion. It is recommended that the polymer peptide mixture be added to the emulsion.

The 0 / W emulsion can be prepared using an emulsifying agent, such as sorbitan monooleate (Span 80 ICI Corp.) or the like, to form a stable emulsion. The emulsion can be buffered with a buffer that is not harmful to the peptide and polymer polymer material. The buffer can have a pH between 2 and 8, with a pH of 4 being recommended. The buffer can be prepared from acidic buffers, such as a phosphate buffer, acetate buffer, etc. Water can replace the buffer.

Heptane, hexane, etc. can be used as the organic phase of the buffer.

The emulsion may contain dispersants, such as silicone oil.

A recommended emulsion may contain heptane, pH 4 phosphate buffer, silicone oil, and sorbitan monooleate. If a drug release is desirable initially, a single solvent-free curing step may be used in place of the emulsion curing. As the solvent, heptane, hexane, etc. can be used.

Other alternatives to the emulsion can also be used to cure the microcapsules, such as: solvent plus emulsifier for curing demicrocapsules without washing, and solvent plus emulsifier for curing followed by a separate washing step.

The O / w emulsion can be used without dispersant. However, the dispersant avoids aggregation of the dry particles of the microcapsules due to static electricity and promotes the reduction of the residual solvent content.

Examples of the solvent for the polymeric matrix material include methylene chloride, chloroform, benzene, ethyl acetate, etc. The peptide is preferably dissolved in an alcoholic solvent, for example, methanol, which is miscible with the polymer solvent.

The phase inducers (coacervatives) are solvents that are miscible with the polymer-drug mixture and cause the embrional micro-capsules to form before curing; silicone oils are recommended phase inducers.

The 0 / w emulsion can be prepared as an organic phase in a conventional manner using heptane, hexane, etc.

The microparticles of this invention can also be obtained by the well known spray drying method. 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., pH 3-8, and a solution of the polymer in an organic solvent, which is immiscible with the former, e.g. methylene chloride, intimately mixed.

The former solution, suspension or emulsion, is then sprayed in a stream of air, preferably warm air. The microparticles obtained are collected, for example with a cyclone, and optionally washed, for example, in a buffer solution with a pH of, for example, between 3.0 and 8.0, preferably of 4.0, or distilled water and dried under reduced pressure, for example at a temperature of 20-40 ° C. The washing step can be used if the particles give a drug explosion in vivo and the extent of this explosion is undesirable. An acetate buffer can be used as a buffer.

As a result, microparticles can be obtained which display a better somatostatin release profile in vivo.

Thus, the invention also relates to microparticles prepared by this method. The invention further provides a delayed release preparation prepared by a somatostatin or a solution of a somatostatin in methanol or water or a buffer containing pH3-8 and a solution of the polylactide co glycolide in methylene chloride and spray the formed solution, emulsion or suspension of somatostatin in a stream of warm air into the polymer solution, collect the microspheres and wash them in a buffer solution with pH 3.0-8 or distilled water and drying them under reduced pressure at a temperature of from 20 to 40 ° C. Compared with microparticles prepared by the phase separation method, they do not contain any silicone oil, even in trace amounts, since no silicone oil is used in the spray drying process.

The compositions according to the invention can also be prepared by a triple emulsion method. According to a typical method, peptide, for example octreotide, is dissolved in a suitable solvent, for example water and intensively in a solution of the polymer, for example 50/50 poly (D, L-lactide-co-glycolide) emulsified glycose in a solvent, which is not a solvent for the peptide, for example in methylene chloride. Examples of the solvent for the polymer matrix material include methylene chloride, chloroform, benzene, ethyl acetate, etc. The obtained water-oil (w / o) emulsion is further emulsified in excess water containing an emulsifying material, for example an anionic or non-ionic surfactant or lecithin or a protective colloid, for example, gelatin, dextrin, carboxymethyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, emulsified to give a continuous formation of the triplet (w / o / w) emulsion. The microparticles are formed by spontaneous precipitation of the polymer and cured by evaporation of the organic solvent. Gelatin serves to prevent agglomeration of the microspheres. After sedimentation of the microspheres, the supernatant is decanted and the microparticles are washed with water and then with acetate buffer. Finally, the microparticles are filtered and dried.

The peptide can also be dispersed directly in the polymer solution, after which the resulting suspension is mixed with the gelatin-containing water phase.

The triple emulsion process is known from U.S. Patent 4,652,441. According to this patent, in a first step, a solution of a drug (1), for example somatostatin in water (column 2, lines 31-32), is intimately mixed with an excess of a polylactide-co-glycolide solution (2) in another solvent , in which the first solvent is insoluble, for example methylene chloride, thereby obtaining a water-in-oil type (w / 0) emulsion (3) of fine drug-containing droplets of (1) in solution (2) . In solution (1), a so-called drug-containing material (column 1, line 31), for example gelatin, albumin, pectin or agar, is dissolved.

In a second step, the viscosity of the internal phase (1) is increased by using suitable measures, such as heating, cooling, change of depH, addition of metal ions or cross-linking of, for example, gelatin with aldehyde.

In a third step, an excess of water is mixed thoroughly with the H / O emulsion (3) (column 7, lines 52-54), resulting in a H / 0 / w "type ternary layer emulsion. The excess water may optionally contain a so-called emulsifying agent (column 7, line 56) selected from the group of, for example, an anionic or nonionic surfactant, or, for example, polyvinylpyrrolidone, polyvinyl alcohol or gelatin.

In a fourth step, the w / 0 / h emulsion is subjected to "drying in water" (line 52). This means that the organic solvent is desiccated in the oil layer to develop microparticles. The desorption is according to a known per se manner (column 8, lines 3-5), for example, by decreasing the pressure with stirring (column 8, lines 5-7), or, for example, by blowing nitrogen gas through the oil layer (for example, methylene chloride) (line 19).

The microparticles formed are collected by centrifugation or filtering (lines 26-27) and the components not included in the polymer are removed by washing with water (line 29). If desired, the microparticles are heated under reduced pressure to obtain a better removal of water and of solvent (eg methylene chloride from the microparticle wall (lines 30-32).

Although the above-described method is satisfactory for the preparation of the compositions of the invention, however, the so-called drug-containing material, mentioned above, for example, gelatin, albumin, pectin or agar, is still present in the microparticles obtained.

It has now been found that if the addition of the drug-containing material (= in solution (1)) and the step of increasing the viscosity of the internal phase are avoided and in the excess water of the ternary w / 0 / w emulsion the measure of adding an emulsifying material or a protective colloid, such as gelatin, is maintained, yet satisfactory microparticles can be obtained, while, moreover, the microparticles contain no drug-containing material and only a very small amount of methylene chloride.

The invention thus provides a method for preparing microparticles obtained by intimately mixing: a) a solution of a medicament, preferably a somatostatin, in particular octreotide, in an aqueous medium, preferably water or a buffer, preferably in w / v. ratio of 0.8-4.0 g / 1-120 ml, in particular 2.5 / 10 and in a buffer with pH 3-8, in particular an acetate buffer, and b) a solution of a polymer, preferably a polylactide co-glycolide, as aforementioned, in an organic solvent immiscible with the aqueous medium, for example methylene chloride, preferably in w / v. ratio of 40 g / 90 to 400 ml, in particular 40/100, preferably in such a way that the w / w. drug to polymer ratio is between 1/10 to 50, in particular 1/16 and the volume / volume ratio of the aqueous medium / organic solvent is 1 / 1.5 to 30, in particular 1/10, intimate mixing the w / O emulsion of a) in b) together with c) an excess of an aqueous medium, preferably water or a buffer, for example an acetate or phosphate buffer, preferably together pH 3-8, which is an emulsifying material or contains a protective colloid, preferably in a concentration of 0.01 to 15.0%, in particular gelatin, especially in a concentration of 0.1 to 3%, especially 0.5% by weight, preferably in a vol./vol. mixing rate of ab) / c) from 1/10 to 100, especially 1/40, without adding any drug-containing material to the water-in-oil emulsion or using any intermediate viscosity increasing step, curing the embryonic microparticles in the formed w / 0 / H emulsion by desorption, preferably evaporation, of the organic solvent, preferably methylene chloride, and by isolation, optionally washing and drying the obtained microparticles.

The invention also provides the process variant in which the drug is dispersed directly in the polymer solution, after which the obtained dispersion is mixed with the gelatin-containing water phase.

The invention also provides the microparticles obtained by these methods. Like microparticles obtained by the spray-drying method, they do not contain silicone oil. Compared to the microparticles prepared according to the known triple emulsion process type, they do not contain a protective colloid.

The sustained-release preparations can also be prepared by other methods known per se, for example - if the peptide is sufficiently stable for the manufacture of an implantation, by heating microparticles containing the peptide, for example a somatostatin in a polylactide-co-glycolide, in particular as described above, or a mixture thereof obtained by mixing the peptide and the polymer, at a temperature of for instance 70 to 100 ° C and extruding and cooling the compact mass, after which the extrudate is cut and if desired is washed and dried.

Suitably, the compositions of the invention are prepared or prepared under aseptic conditions.

The compositions according to the invention can be used in a deposition form, for example as injectable microspheres or implantations.

They can be administered in a conventional manner, for example, subcutaneously or by intramuscular injection, for example for indications known for the drug contained therein.

The sustained-release preparations containing octreotide may be administered for any known indications of the octreotide or derivatives thereof, for example, those described in British Pat. No. 2,199,829A, pages 89-96, as well as for acromegaly and breast cancer.

The microparticles of this invention may have a size ranging in diameter from about 1 to 250 microns, preferably from 10 to 200, especially 10 to 130 microns, for example from 10 to 90 microns. For example, implants may have a size from about 1 to 10 mm 3. The amount of drug, ie peptide, present in the composition depends on the desired daily dose delivered and thus the biological decomposition rate of the encapsulating polymer. The exact amount of peptide can be determined by bioavailability studies. The compositions can contain peptide in an amount of at least 0.2, preferably 0.5 to 20% by weight, relative to the polymer matrix, preferably 2.0 to 10, especially 3.0 to 6% by weight.

The release time of the microparticle peptide can be from 1 to 2 weeks to about 2 months.

Suitably, the delayed release preparation contains a somatostatin, e.g., octreotide, in a biologically decomposable, biocompatible polymer carrier which, administered subcutaneously at a dose of 10 mg somatostatin per kg body weight of the animal to a rat, contains a concentration of a somatostatin in the blood plasma of at least 0.3 ng / ml and preferably less than 20 ng / ml over a 30 day period or suitably a 60 day period.

It is also possible that the sustained-release preparation contains a somatostatin, for example octreotide, in a biologically decomposable, biocompatible polymeric carrier which, administered intramuscularly at a dose of 5 mg / kg body weight, to a concentration of somatostatin of at least 0.3 ng / ml for a period of 50 days and suitably gives a concentration of at most 20 ng / ml.

Other recommended properties of the obtaining somatostatin, for example octreotide-containing depot preparations, depend on the preparation methods used:

Phase separation method

Koniin 5 mg somatostatin / kg, intramuscular delay (0-42 days) 76% mean plasma level (cp, ideal) (0-42 days) 4 ng / ml AUC (0-42 days) 170 ng / mlx days

Spray drying method

Rat 10 mg somatostatin / kg, subcutaneous delay (0-42 days)> 75% mean plasma level (cp, ideal) (0-42 days) 4-6 ng / m.

AUC (0-42 days) 170-210 ng / ml x days

Koniin 5 mg somatostatin / kg, intramuscular delay (0-43 days)> 75% mean plasma level (Cp.ideal) (0-43 days) 4-6 ng / ml AUC (0-43 days) 200-240 ng / ml x days

Triple emulsion method

Rat 10 mg somatostatin / kg, subcutaneous delay (0-42 days)> 75% mean plasma level (CP ideal) (0-42 days) 4-6.5 ng / ml AUC (0-42 days) 170- 230 ng / ml x days.

Koniin 5 mg somatostatin / kg, intramuscular delay (0-42 / 43 days)> 74% mean plasma level (CP ideal) (0-42 / 43 days) 3.5-6.5 ng / ml AUC (0-42 / 43 days 160-270 ng / ml x days

Thus, the invention provides somatostatin, preferably octreotide and octreotide analog formulations, having the following properties: 1. a delay of at least 70%, preferably at least 74%, for example at least 75%, 80%, 88% or at least 89% over a period of O up to 42 or 43 days, and / or 2. an average plasma level (Cp <ideal) of 2.5-6.5, preferably 4-6.5 ng / ml over a period of 0 to 42 days, in rats, if 10 mg somatostatin is administered subcutaneously and / or an average plasma level of 3.5-6.5, for example 4-6.5 ng / ml, for a period of 0 to 42 or 43 days in a rabbit when 5 mg somatostatin is administered intramuscularly , and / or 3. an AUC over a period of 0 to 42 days of at least 160, preferably from 170-230 ng / ml x days for a rat, if 10 mg somatostatin is administered subcutaneously / or an AUC over a period of 0 to42 or 43 days of at least 160, preferably from 180-275, for example from 200 to 275ng / ml x days for a rabbit, if 5 mg somatostatin is administered intramuscularly.

For the quantitative characterization of the sustained-release preparations described above, use is made of the surface deviation (AD) method of F. Nimmerfall and J. Rosenthaler; Intern. J. Pharma-ceut. 32, 1-6 (1986). Briefly, according to the AD method, the surface deviations from the experimental plasma profile of an ideal profile that a constant mean plasma level (= c ideal) are obtained by converting the experimental surface under the plasma mirror time curve (AUC) into a rectangle with the same surface calculated. From the percentage surface deviation (indicated by AUC) the percentage delay is calculated as follows:% delay = 100 x (1 - AD / AUC).

According to this method, the complete plasma profile is determined during a preselected time period characterized by a single number index.

In Proc. natl. Acad.Sci.USA 85 (1988) 5688-5692 is a plasma level profile of the octapeptide analogous to somatostatin of formula * * D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2 in rats in Figure 4. described.

However, a clear comparison cannot be made with the plasma level values of the compositions according to the invention in rats, as mentioned above, since the plasma level profile described is based on a different method of administration (intramuscular injection) and, more importantly, the loading level of the microcapsules (between 2 and 6%) and the dosage amount for administration (25 to 50 mg aliquots of microcapsules for 30 days, although assays were performed for at least 45 days) are not accurately indicated. In addition, the type of poly (D1-lactide-co-glycolide) used has not been accurately described.

The descriptive value of the publication is very small to consider it as a prepublishing which is inconvenient for the invention.

The following examples illustrate the invention.

The Mh of the polymers is the average molecular weight determined by GLPC using polystyrene as a standard.

EXAMPLE 1

1 g of poly (D, L-lactide-co-glycolide) (50/50 molar, MH 45,000; polydispersity about 1.7) was dissolved under magnetic stirring in 15 ml of methylene chloride, after which 75 mg of octreotide acetate were dissolved in 0.5 ml of methanol was added. Then, 15 ml of silicone oil (Dow brand 360 Medical Fluid 1000 cs) (silicone fluid) was added to the polymer peptide mixture. The resulting mixture was added to a stirred emulsion containing 400 ml n-heptane, 100 ml pH 4 phosphate buffer, 40 ml Dow 360 Medical Fluid, 350 cs and 2 ml Span 80 (emulsifier). Stirring was then continued for a minimum of 10 minutes. The obtained microparticles were collected by filtration under reduced pressure and dried in a vacuum oven overnight. The yield was about 90% of microparticles with a size of 10-40 microns.

The microparticles were suspended in a carrier and administered intramuscularly at a dose of 4 mg octreotide to New Zealand rabbits. Blood samples were taken periodically to measure plasma levels of 0.5 to 1.0 ng / ml for 30 days as measured by radioimmunoassay (RIA) analysis.

EXAMPLE 2

1 g of poly (D, L-lactide-co-glycolide) glucose (Mw = 45,000) (55/45 molar, obtained according to the method of British Patent Specification 2,145,422 B, polydispersibility of about 1.7) was prepared from 0.2% glucose) under magnetic stirring in 25 ml of ethyl acetate, followed by adding 75 mg of octreotide dissolved in 3 ml of methanol. 25 ml of silicone oil (Dow360 Medical Fluid brand, 1000 cs) was then added to the polymer-peptide mixture. The resulting mixture was added to the emulsion described in Example 1. Stirring was then continued for a minimum of 10 min. The obtained microparticles were collected by vacuum filtration and dried in a vacuum oven overnight. The yield was greater than 80% microparticles in the range of 10-40 microns.

The microparticles were suspended in a carrier and administered at a dose of 4 mg octreotide intramuscularly to white New Zealand rabbits. Blood samples were taken periodically to show that plasma levels were between 0.5 and 2 ng / ml for 21 days as measured by RIA.

EXAMPLE 3

A solution of 1.5 g of octreotide. acetate in 20 ml of methanol was added with stirring to a solution of 18.5 g of poly (D, L-lactide-co-glycolide) glucose (50:50 molar, molecular weight 45,000) in 500 ml of methylene chloride. Phase separation was performed by adding 500 ml Dow 360 Medical Fluid (1000 cs) and 800 ml Dow 360 Medical Fluid (350 cs) to the peptide polymer suspension. The resulting mixture was added to a stirred emulsion consisting of 1800 ml n-heptane, 2000 ml of sterile water and 40 ml of Span 80. After stirring for 10 min, the microspheres were collected by filtration under reduced pressure.

Half of the product was dried in a vacuum oven at 37 ° C.

The residual methylene chloride level was 1.2%.

The other half of the product was washed by stirring with 1000 ml of ethanol containing 1 mg of Span 80. After stirring for 1 hour, the ethanol was decanted and the microparticles were stirred for 1 hour with 1000 ml of n-heptane containing 1 ml of Span 80. After stirring for 1 hour, the microparticles were collected by filtration under reduced pressure and dried in a vacuum oven at 37 ° C overnight. The residual methylene chloride level of the microparticles washed in this way was lowered from 1.2% to 0.12%.

The combined yield of the product was 18.2 g (91%) of microparticles containing 5.6% octreotide, with an average diameter of 24 microns and 1.5% residual heptane.

The microparticles were suspended in a carrier and administered intramuscularly at a dose of 5 mg / kg dose octreotide to white rabbits. Blood samples were taken periodically to show that during 49 day plasma levels were between 0.3 and 7.7 ng / ml, measured with RIA, EXAMPLE 4

1 g of poly (D, L, lactide-co-glycolide) glycose, molecular weight 46,000 (50:50) molar prepared by the method of British Patent Specification 2,145,422 B, polydispersibility about 1.7, prepared from 0, was dissolved (2% glucose) under magnetic stirring in 10 ml of methylene chloride, followed by addition of 75 mg of octreotide dissolved in 0.133 ml of methanol. The mixture was intimately mixed for 1 minute, for example, using an Ultra-Turax at 20,000 revolutions per minute to obtain a suspension of very small crystals of octreotide in the polymer solution.

The suspension was sprayed using a high speed turbine (Niro Atomizer) and the small droplets were dried in a stream of warm air to yield microparticles. These microparticles were collected with a "zyclone" and dried overnight in a vacuum oven at room temperature.

The microparticles were washed with 1/15 molar acetate buffer, pH 4.0 for 5 min and dried again in a vacuum oven at room temperature. After 72 hours, the microparticles were sieved (0.125 mm mesh) to obtain the final product.

The microparticles were suspended in a carrier and administered at a dose of 5 mg / kg octreotide intramuscularly to white rabbits (chinchille hybrid) and subcutaneously at a dose of 10 mg / kg to male rats. Periodic samples were taken that showed plasma levels between 0 , 3 and 10.0 ng / ml (5 mg dose) in rabbits and rat rats between 0.5 and 7.0 ng / ml for 42 days, measured by radioimmunoassay (RIA) analysis.

EXAMPLE 5

Microparticles were prepared by spray drying in the same manner as described for Example 4, the only change being that octreotide was suspended directly in the polymer solution, without the use of methanol.

The microparticles were suspended in a vehicle and administered to male rats at a dose of 10 mg / kg octreotide subcutaneously. Blood levels were taken periodically to show that plasma levels were between 0.5 and 10.0 ng / ml for 42 days as measured by radioimmunoassay (RIA) analyzes.

EXAMPLE 6

1 g of poly (D, L, lactide-co-glycolide) glucose, molecular weight 46,000 (50:50 molar, prepared according to the method of British Patent Specification 2,145,422 B, polydispersibility about 1/7, prepared from 0) was dissolved 2% glucose) in 2.5 ml of methylene chloride and 75 mg of octreotide dissolved in 0.125 ml of deionized water are added. The mixture was intimately mixed for 1 min, for example with an Ultra-Turax at 20,000 rpm (internal W / O phase).

1 g of gelatin A was dissolved in 200 ml of deionized water at 50 ° C and the resulting solution was cooled to 20 ° C (outer W phase). The W / O and W phases were intimately mixed. The W / O inner phase was thereby separated into small droplets, which were homogeneously dispersed in the W outer phase. The resulting triple emulsion was slowly stirred for 1 hour. The methylene chloride was evaporated and the microcapsules were cured from the droplets of the inner phase. After depositing the microparticles, the supernatant was aspirated and the microparticles were collected by filtration under reduced pressure and rinsed with water to remove gelatin.

Drying, sieving, washing and drying of the microparticles was performed as described in Example 4. The microparticles were suspended in a vehicle and administered at a dose of 5 mg / kg octreotide intramuscularly to white rabbits (chinchilla hybrid) and in a dose of 10 mg / kg administered subcutaneously to male rats. Blood samples were taken periodically to show that plasma levels were between 0.3 and 15.0ng / ml (5 mg dose) in rabbits and were between 0.5 and 8.0 ng / ml in rats for 42 days as measured by radioimmunoassay ( RIA) analyzes.

EXAMPLE 7

Microparticles were prepared by the triple emulsion method, in the same manner as described for Example 6, with three changes: 1. 0.25 ml acetate buffer pH 4.0 was used instead of 0.125 ml water to prepare the W / O- inner phase.

2. Rinsing after collection of the microparticles was performed with a 1/45 molar acetate buffer pH 4.0 instead of water.

3. further washing of the microparticles was omitted.

EXAMPLE β

Microparticles were prepared by the triple emulsion method, in the same manner as described for Example 7, with the only change that the W / O inner phase was obtained by using water containing 0.7% (w / v) sodium chloride in instead of acetate buffer.

EXAMPLE 9

Microparticles were prepared in the same manner as described in Example 6 except that the drug compound was suspended directly in the polymer solution and the resulting dispersion was mixed with the gelatin-containing aqueous phase.

EXAMPLE 10

Octreotideoamate

10.19 g (10 mM) octreotide free base and 3.88 g (10 mM) embonic acid are dissolved in 1 liter of a mixture of equal parts water and dioxane. The reaction mixture was filtered and lyophilized to give a yellow powder [α] D = + 7.5 ° (C = 0.35, m DMF) of octreotide pamoate hydrate. The factor is 1.4, where factor is the weight of lyophilisate weight of the octreotide contained therein.

The pamoate can replace the octreotide acetate present in the microparticles of Examples 1-9 and has excellent stability.

EXAMPLE 11

A solution of 1 g of poly (D, L-lactide-co-glycolide) (50:50 molar, molecular weight 36,100) in 20 ml of methylene chloride was added with stirring to a solution of 100 mg of calcitonin in 1.5 ml of methanol. Phase separation was performed by adding 20 ml of silicone liquid (Dow 360 Medical Fluid, 1000 cs). The resulting mixture was added to a stirred emulsion consisting of 100 ml pH 4 phosphate buffer, 400 ml n-heptane, 4 ml Span 80 and 40 ml silicone liquid (Dow 360 Medical Fluid, 1000 cs). After stirring for 10 min, the microspheres were collected by filtration under reduced pressure and dried in a vacuum oven overnight at 37 ° C. The yield was 1.1 g of microspheres containing 5.9% calcitonin.

EXAMPLE 12

A solution of 9.9 g of poly (D, L-lactide-co-glycolide) (50:50 molar, Mw = 44,300) in 140 ml of methylene chloride was added to 100 mg of lypressine. The dispersion was stirred magnetically for one hour before adding 140 ml of silicone liquid (Dow 360 Medical Fluid, 1000 cs) and 2.5 ml of Span 80. The mixture was added to 2000 ml of heptane and stirred for 10 min. The resulting microcapsules were collected by filtration under reduced pressure, washed three times with heptane and dried under suction for 10 min. Half of the sample was washed by stirring in water for 10 min and the other half was not washed. Both samples were dried in a vacuum oven at 30 ° C overnight. The total yield was 10.65 g of micro-capsules. Analysis of the washed sample was 0.5% lypresins and 0.6% for the sample that had not been washed with water.

Claims (43)

A method of preparing a microparticle containing a drug in a biodegradable, biocompatible polymeric carrier, which comprises: a) dissolving the polymeric carrier material in a suitable solvent in which the drug compound is insoluble, b) adding and dispersing a solution of the drug compound in a suitable solvent, which is not a solvent for the polymer in the solution of step a), c) adding a phase inducing agent to the dispersion of step b), to induce microparticle formation, d adding an oil-in-water emulsion to the mixture of step c) to cure the microparticle, and e) recovering the microparticle. The microparticle obtained according to claim 1. A method of preparing microparticles containing a medicament in a biodegradable, biocompatible carrier, comprising: (i) intimately 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 phase a biologically decomposable biocompatible polymer with an excess of aqueous medium containing an emulsifying material or a protective colloid to form a water-in-oil-in-water emulsion, without adding any drug-containing material to the water-in-oil emulsion or using an intermediate viscosity increasing step, (ii) desorbing the organic solvent therefrom, (iii) isolating and drying the obtained microparticles. 4. A method of preparing microparticles containing a drug compound in a biodegradable, biocompatible polymer, comprising: i) intimately mixing a suspension of a drug compound formed from a drug compound and a water-immiscible organic solvent that contains a biologically decomposable, biocompatible polymer containing an excess of an aqueous medium containing an emulsifying material or a protective colloid to form an oil-in-water emulsion, wherein the drug compound is dispersed in the oil component without adding a material adding a drug containing or applying an intermediate viscosity enhancing step, ii) desorbing the organic solvent therefrom, and iii) isolating and drying the obtained microparticles. A method of preparing microparticles which comprises intimately mixing: a) a solution of a drug in an aqueous medium, and b) a solution of a polymer in an organic solvent, which is immiscible with the aqueous medium, intimately mixing together the water-oil emulsion of a) and b) with c) an excess of an aqueous medium containing a protective colloid, without adding a drug-containing material to the water-in-oil emulsion or an intermediate viscosity increasing, using step, curing the embryonic microparticles in the w / O / M emulsion formed by desorption and separation of the obtained microparticles. 6. A method according to claim 5, characterized in that the medicament is a somatostatin. 7. A method according to claim 5, characterized in that the medicament is octreotide. 8. A method according to claim 5, characterized in that the medicament is octreotide pamoate salt. 9. Process according to claim 5, characterized in that the polymer is a polylactide co-glycolide. 10. A method according to claim 5, characterized in that the aqueous medium is water or a buffer. 11. Process according to claim 5, characterized in that the aqueous medium is a buffer with pH 3-8. 12. Process according to claim 5, characterized in that the organic solvent is methylene chloride. A method of preparing microparticles which comprises intimately mixing: a) a solution of a somatostatin in water or a buffer in a weight to volume ratio of 0.8 to 4.0 g / l to 120 ml and b) a solution of a polylactide co-glycolide in an organic solvent that is immiscible with the aqueous medium, in a weight / volume ratio of 40g / 90 to 400ml, in such a way that the weight / weight ratio of the drug to the polymer is between 1/10 to 50 and the volume to volume ratio of the aqueous medium / organic solvent is 1 / 1.5-30, intensively mixing the water-oil emulsion of a) and b) together with c) an excess of water or a buffer containing a protective colloid in a volume / volume mixing rate ratio of ab) / c) from 1/10 to 100, without a material containing a drug to the water-in oil emulsion or applying an intermediate viscosity enhancing step, hardening the embryonic micro particles in the w / O / H ~ emulsion formed by evaporation of the organic solvent and separation of the obtained microparticles. A method according to claim 13, characterized in that the protective colloid is gelatin. A method of preparing microparticles, comprising intimately mixing a) a solution of a somatostatin in an aqueous medium in a w / v ratio of 2.5 g / 10 ml, and b) a solution of a polylactide co-glycolide in an organic solvent, which is immiscible with the aqueous medium in a weight / volume ratio of 40g / 100ml, in such a way that the weight / weight ratio of the drug to the polymer 1 / 16 and the volume / volume ratio of the aqueous medium / organic solvent is 1/10, intimately mixing the water-oil emulsion of a) in b) together with c) an excess of an aqueous medium containing a protective contains colloid at a concentration of 0.01 to 15.0% in a volume-volume mixing rate ratio of ab) / c) of 1/40, without adding a drug containing material to the water-in-oil emulsion or application of an intermediate viscosity increasing step, the curing of the embryonic microparticles in the form The water / oil / water emulsion was evaporated by evaporation of the organic solvent and isolation of the microparticles obtained. A method of preparing microparticles, which comprises intimately mixing: a) a solution of octreotide in a w / v ratio of 2.5 g per 10 ml in a buffer with a pH of 3-8, and b) a solution of a polylactide-co-glycolide inmethylene in a w / v ratio of 40 g / 100 ml, in such a way that the w / w ratio of the drug to the polymer and the volume / volume ratio of the aqueous medium / organic solvent is 1:10, intimately mixing the water-oil emulsion of a) in b) together with c) an excess of a buffer having a pH of 3-8 containing gelatin at a concentration of 0.5% by weight at a volume / volume mixing ratio of ab) / c) of 1:40, without adding a material containing a drug to the water-in-oil emulsion or using an intermediate viscosity enhancing step, curing the embryonic microparticles in the formed H / O / w emulsion by evaporation of the methylene chloride, and separating, washing and drying the microparticles obtained. The microparticle obtained according to claim 3. 18. A sustained release preparation containing octoootide or a salt or a derivative thereof in a biologically decomposable, biocompatible polymeric carrier. A sustained-release preparation according to claim 18, wherein the polymer is poly (DL-lactide-co-glycolide) glucose. A preparation according to claim 18 in microparticle form in which the surface contains practically no drug compound. A sustained-release preparation according to claim 18 prepared by mixing the drug compound or a solution thereof in methanol or water or a buffer of pH 3-8 and a solution of a polylactide co-glycolide in methylene chloride and spraying the formed suspension. solution or emulsion of the drug compound in the polymer solution in a stream of dry air, collecting the microspheres and washing these spheres in a buffer solution with a pH of 3.0 to 8.0 or distilled water and drying the spheres under pressure at a temperature of 20-40 ° C. Sustained-release preparation according to claim 18, characterized in that the octreotide concentration is between 2.0 and 10% by weight. The sustained release formulation of claim 18 in microparticulate form having a diameter of 1 - 250 microns. Sustained-release preparation containing a peptide drug compound in a 40/60 to 60/40 polyacti-de-co-glycolide ester of polyol, wherein the polyol unit is selected from the group of an alcohol or a carbon chain of 3-6 carbon atoms with 3-6 hydroxyl groups and a mono- or di-saccharide and the esterified polyol contains at least 3-polylactide-co-glycolide chains. 25. Delayed-release preparation containing a peptide drug compound selected from the group of monocitonin, lypressin or a somatostatin in a linear 40/60 to 60/40 polylactide co-glycolide polymer with chains having a molecular weight between 25,000 and 100,000 and a polydispersibility Mw / Hn between 1, 2 and 2 in a concentration of 0.2 to 20% by weight of the peptide drug compound contained therein. A sustained release preparation according to claim 24 having an average molecular weight Mw of 10,000 to 200,000 and a polydispersibility Mw / Hn of 1.7 to 3.0. A sustained-release preparation according to claim 24 wherein Mw is between 35,000 and 60,000. A sustained release formulation according to claim 24 wherein Mw / Hn is between 2.0 and 2.5. A sustained release preparation according to claims 18, 24 or 25 which, when administered subcutaneously to a rat at a dose of 10 mg drug compound per body weight, has a drug compound concentration in the blood plasma of at least 0.3 ng / ml and less than 20ng / ml for a period of 30 days. A sustained-release preparation according to claims 18, 24 or 25, which, administered intramuscularly at a dose of 5 mg drug compound per kg body weight to a rabbit, has a drug compound concentration of at least 0.3 ng / ml and at most 20 ng / ml Gives a period of 50 days. The sustained-release composition of claims 18, 24 or 25, which, administered intramuscularly at a dose of 5 mg drug compound per kg body weight to a rabbit, provides a delay of at least 70% over a period of 0-42 or 43 days. A sustained release preparation according to claims 18, 24 or 25 which, administered to a rat subcutaneously at a dose of 10mg drug compound per kg body weight, has an average plasma level (Cp ideal) of 2.5 to 6.5 ng / ml for gives a period of 0-42 days. The sustained release formulation of claims 18, 24 or 25, which is administered intramuscularly to a rabbit at a dose of 5 mg drug compound per kg body weight, gives an average plasma level (Cp ideal) of 3.5 to 6.5 ng / ml. The sustained release composition according to claims 18, 24 or 25, which, administered subcutaneously at a dose of 10mg drug compound per kg body weight to a rat, over a period of 0-42 or 43 days, an AUC of 160-230 ng / ml x days gives. The sustained release composition according to claims 18, 24 or 25, which, administered intramuscularly at a dose of 5 mg drug compound per kg body weight to a rabbit, over a period of 0-42 or 43 days, an AUC of 160-275 ng / ml x days gives. The sustained-release composition of claim 18 for use in the treatment or prevention of acromegaly or breast cancer. A method of administering a peptide drug to a patient, characterized in that men parenterally administering a depot composition according to claim 18 to a patient in need of such treatment. 38. A method according to claim 37 for the treatment of acromegaly or breast cancer. 39. Octreotide pamoate. 40. A method of preparing octreotide paroate wherein octreotide is reacted with embonic acid or a reactive derivative thereof. 41. The sustained release composition comprising a peptide drug compound selected from the group of encalcitonin and lypressin, and the pharmaceutically acceptable salts thereof, in a biodegradable, biocompatible polymer matrix. The sustained release composition according to claim 25, which contains a peptide drug compound selected from the group of a calcitonin and a lypressin. 43. Method as described in the descriptions / or examples.