DE4021517A1 - FORMULATIONS WITH SLOW RELEASE OF WATER-SOLUBLE PEPTIDES - Google Patents

Description

Background of the invention

This invention relates to slower formulations Release of active substances, especially water-soluble Peptides, e.g. Somatostatin or somatostatin analogs such as Octreotide, in a biodegradable and biocompatible polymer Carrier material, for. B. as a matrix or enclosure, which as Implant or preferably may be present as a microparticle (also indicated as microcapsule or microsphere).

The invention also relates to formulations which a satisfactory peptide release profile during some Have time.

Peptide agents often show a low bioavailability in the Plasma when administered orally or parenterally what the short biological half-life by metabolic Attributable to instability. If she is oral or nasal are usually found only a small absorption through the mucosa instead. That's why one is therapeutically relevant blood levels over a longer period of time difficult to realize and became the parenteral application of peptide active ingredients as depot formulations in one biodegradable polymer, e.g. As a microparticle or implant, proposed which their slow release after a  Allow stay in a polymeric carrier. This carrier protects the active ingredient against enzymatic and hydrolytic Influences of the biological media in which he is located.

Although parenteral depot formulations of peptide drugs in a polymer carrier in microparticle or implant form from the Literature are known to be in practice only in very few Cases were obtained satisfactory peptide releases. Specific Measures must be taken to be continuous To enable peptide release, which is based on a therapeutically effective level and yet not so high plasma concentrations allows that undesirable pharmacological side reactions arise.

The peptide drug release profile is different Factors dependent, z. B. of the peptide type and whether the peptide in its free form or any other form, e.g. B. the salt form, which affects its water solubility. Another important factor is the selection of polymers, one of which extensive list of possibilities described in the literature is.

Each polymer type has its characteristic degradation rate. Free carboxyl groups can be formed during degradation which the pH in the polymer and thereby the water solubility of the peptide and, consequently, its release profile influence.

Other factors influencing the release profile of the Depot formulation affect are the drug loading level of the polymeric carrier material, the active ingredient distribution in Polymers, the particle size of the polymer and, in the case of a Implant, in addition to its shape. In the further is the place in Body, where the formulation is located, co-determining.

So far no somatostatin compositions are slower  Release of the active ingredients for parenteral use on the Market appeared, maybe because no compositions with one satisfactory plasma level profile could be obtained.

Description of the Prior Art

Polymer formulations with slowed or delayed Drug release are known. U.S. Patent No. 3,773,919 describes formulations with controlled Release of active ingredient in which the active ingredient, eg. B. a water-soluble peptide, in a biodegradable and biocompatible linear polylactide or polylactide-co-glycolydolymer is dispersed. However, none were Drug release profiles described and no evidence given a somatostatin. U.S. Patent No. 4,293,539 antibacterial formulations in the form of microparticles.

U.S. Patent No. 4,675,189 describes formulations of decapeptide LHRH analogue nafarelin and analog LHRH relative in polylactide-co-glycolydiene polymers. There were no release profiles described.

T. Chang, J. Bioeng., Vol. 1, pp. 25-32, 1976, describes the slowed release of biological products, enzymes and Vaccines of microparticles.

Polymers / copolymers of lactic acid and lactide / glycolic copolymers and related products for surgical application and for slow release and biodegradation are described in the US patents No. 39 91 776; 40 76 798 and 41 18 470 described.

European Patent Application No. 02 03 031 describes a series of somatostatin octapeptide analogs, e.g. B. Connection RC-160 with the formula

which has a bridge between the two Cys units, in columns 15-16.

The possibility of somatostatins with polylactide-co-glycolydopolymers to microencapsulate in claim 18 However, no clues are given on how to a continuous, therapeutically effective plasma level comes.

US Patent No. 4 01 11 312 describes that a continuous release of an antimicrobial agent, z. B. of the water-soluble polymyxin B from a Low molecular weight polylactide-co-glycolyd matrix (below 2000) and a relatively high glycolic content in the form an implant can be obtained when the implant in the Udder tube of a cow cattle is pushed. The active ingredient will then released within a short period of time, which is the high Glycolydgehalt and the low molecular weight of the polymer is to owe. The factors stimulate a rapid Polymer degradation and associated rapid release. On In addition, a relatively high degree of active substance loading contributes to a rapid release at. However, no somatostatins and no drug release profiles described.

European Patent No. 58,481 describes that a continuous Release of a water-soluble peptide from a polylactide polymer Implant by reducing the molecular weight at least a portion of the polymer molecules, by uptake of Glycolydeinheiten in the polymer molecule, by amplifying the Block polymer character of the polymer when Polylactide-co-glycolydmolecules are used by increase the drug loading level of the polymeric matrix and by Surface enlargement of the implant is stimulated. Even though Somatostatins are named as water-soluble peptides no somatostatin release profiles have been described Hints given how to combine all these parameters,  during a continuous somatostatin release profile during at least one week, eg B. of a month to obtain.

European Patent No. 92,918 describes that a continuous Release of peptides, preferably of hydrophilic peptides, can be obtained for a longer period of time if that Peptide into a conventional hydrophobic polymeric matrix, e.g. B. a polylactide, which is more accessible to water has been made by which in their molecules a hydrophilic Unit, z. B. a polyethylene glycol, polyvinyl alcohol, Dextrans or a polymethacrylamide is recorded. The hydrophilic contribution to the amphipathic polymer is in the case a polyethyleneoxy moiety through the ethylene oxide groups, in the Case of a polyvinyl alcohol unit or a dextran unit by free hydroxyl groups and in the case of a Polymethacrylamide unit supplied by the amide group. By the presence of a hydrophilic moiety in the polymer molecules After implantation of water, the implant becomes the property of a hydrogel. Somatostatin is considered a hydrophilic Peptide indicated, however, no release profile and no indication was given which Polymer type is suitable for this peptide and which Molecular weight and how many hydrophilic groups it should have.

The UK Patent GB 21 45 422 B describes that a slow Release of different types of drugs, eg. B. vitamins, Enzymes, antibiotics, antigens over a longer period of time can be achieved when the active ingredient in an implant, z. B. of microparticle size, is incorporated and that from a Polymer of a polyol, e.g. As glucose or mannitol, is built, one or more, preferably at least three Contains polylactide ester groups. The polylactide ester groups preferably contain z. B. Glycolydeinheiten. No peptides, z. As somatostatins are called as active ingredients and none Plasma mirror profiles are described.  

Summary of the invention

This invention relates to slower formulations Drug release, z. B. microparticle formulations of a Active substance, especially one of hormonally active, water-soluble Somatostatin or a somatostatin analog, such as octreotide sufficient plasma level and z. B. in a biodegradable biocompatible polymers, eg. B. in an enveloping polymer Matrix. The matrix can be made of a synthetic or natural Consist of polymers. The microparticles of this invention can by using conventional techniques, e.g. B. the organic Phase separation method, the spray-drying method or the Tripelemulsionsmethode be obtained. According to the first and the The third method is to use the polymer together with the active ingredient Microparticles precipitated and the resulting product hardened. However, if desired, the formulations may also be be made in the form of an implant.

We have a special, well usable modification of the Phase separation method developed according to which with each Active microparticles can be produced.

The invention relates to a process for the preparation of Microparticles containing an active ingredient in a biodegradable, contain biocompatible carrier material, according to which

• a) the polymeric carrier material in a suitable Solvent is dissolved in which the active ingredient is not is soluble,
• b) a solution of the active ingredient in a suitable Solvent, for. As an alcohol, the polymer is not dissolved in the solution of step a),
• c) a phase - inducing agent to the dispersion of the Step b) is added, whereby microparticles be formed
• d) an oil-in-water emulsion to the mixture of the step c) is added, whereby the microparticles hardened and
• e) the microparticles are deposited.

We also have a particularly useful modification of Triple emulsion developed according to which with each Active microparticles can be produced.

The invention is therefore also a method for Production of microparticles by

• (i) a water-in-oil emulsion from an aqueous medium and a water immiscible solvent, the in one phase the active substance and in the other one contain biodegradable biocompatible polymer, intensively with an excess of an aqueous medium, which contains an emulsifier or a protective colloid a water-in-oil-in-water emulsion is mixed without any drug-retaining Substance added to the water-in-oil emulsion or any viscosity-increasing measures to be hit,
• (ii) removing the solvent therefrom and
• (iii) The microparticles formed are isolated and dried become.

The invention also relates to the microparticles, after produced this method.

The subject of the invention is also:

• a) a slow release formulation of a peptide active in a 40/60 to 60/40 polylactide-co-glycolide ester of a polyol in which the polyol residue is that of an alcohol having a (C _3-6 ) carbon chain and having 3 to 6 Hydroxyl groups or from a mono- or disaccharide and the esterified polyol has at least 3 polylactide-co-glycolide chains.
• b) a slow release formulation with a peptide active ingredient from the group of a calcitonin, Lypressins or a somatostatin in a linear 40/60 to 60/40 polylactide-co-glycolide polymers from chains having a Mw of 25,000 to 100,000, a polydispersity Mw / Mn of 1.2 to 2 and in a concentration of 0.2, preferably 2 to 10% by weight of peptide active ingredient on the polymers.
• c) a slow release formulation octreotide or a salt or a derivative in one biodegradable biocompatible polymeric carrier material.

We have found that the new salt octreotide pamoate in such Formulations is very stable. The subject of the invention is therefore, (i) octreotide pamoate and (ii) a method of preparation of octreotide pamoate, by adding octreotide with embonic acid (or a reactive derivative) is reacted.

The subject of the invention is additionally:
A method for the medical application of the peptide drug by using a depot formulation of the active ingredient, especially for the treatment of acromegaly or breast cancer.

Description of the Preferred Embodiments

The active ingredients which are used in the process according to the invention are used, are preferably water-soluble active ingredients, z. B. water-soluble peptides.

The peptide active ingredients which are used in the process according to the invention and formulations can be used a calcitonin, such as Salmcalcitonin, Lypressin and the natural somatostatin and  its synthetic analogues.

The natural somatostatin is one of the preferred active ingredients and is a tetradecapeptide having the structure:

This hormone is released both through the hypothalamus and as well through other organs, eg. B. the digestive tract, produced and mediates, together with GFR, the neuroregulation of Growth hormone release in the pituitary gland. In addition to Inhibition of growth hormone release in the pituitary causes Somatostatin a powerful inhibition of other systems, such as the central and peripheral nervous system, the gastrointestinal System and smooth muscle vessels. It also inhibits the Release of insulin and glucagon.

The term somatostatin includes the analogs and the derivatives. Derivatives and analogs are straight chain, through internal or external disulfide bridges characterized polypeptides by a or more amino acid units omitted and / or by a or several other amino radicals have been replaced and / or one or more functional groups by one or more others functional groups and / or one or more groups replaced one or several other isosteric groups were. In general, the term includes all modified ones Derivatives of a biologically active peptide, which have a qualitatively comparable effect as the unmodified peptide show.

Agonistan analogs of somatostatin are useful in the replacement of natural somatostatin as to its physiological effect To regulate functions. Preferred known somatostatins are:  

In each of the compounds a) to i) is a bridge between the amino acid units marked with a * are. The bridge is in the following formula located.

Other preferred somatostatins are:

Also in the above connections there is a bridge between the amino acid units marked with a *.

The content of all publications mentioned above, especially the Specifically listed somatostatins, as to this Description belonging to considered.  

The term "derivative" also includes the corresponding derivatives, which have a sugar residue.

If somatostatins have a sugar residue, this is preferably with an N-terminal amino group and / or with at least one amino group in a peptide side chain connected, but preferably with an N-terminal Amino group. Such compounds, including their production, have been described, for. In WO 88/02745.

The name "octreotide derivatives" includes those with the remainder

with a bridge between the Cys units.

Particularly preferred derivatives are:

N ^α - [α-glucosyl- (1-4-deoxyfructosyl] -DPhe-Cys-Phe-DTrp-Lys-Thr-Cys-Thr-ol and
N ^α - [β-deoxyfructosyl] -DPhe-Cys-Phe-DTrp-Lys-Thr-Cys-Thr-ol,

each with a bridge between the Cys units, preferably in the form of the acetate salt and in Examples 2 and 1 of the above mentioned patent application.

The somatostatins can z. B. in free form, salt form or in Form of these complexes are present. Acid addition salts can with z. As organic acids, polymeric acids and inorganic Be formed acids. Acid addition salts are z. B. the Hydrochloride and acetate salts. Complexes are for. B. off Somatostats by addition with inorganic substances, eg. B. inorganic salts or hydroxides, such as the calcium and Zinc salts and / or by addition of polymeric organic Substances formed. The acetate salt is used for formulations, especially microparticles, which have a reduced incipient Show drug release, preferred. Subject of the Invention is also the pamoate salt, which also, especially for Implants is useful, and the method for its  Production. The pamoate can be obtained in a conventional manner be, for. B. by embonic acid (pamoic acid) with octreotide z. B. is implemented in free form. The reaction can be in one polar solvents, for. B. at room temperature become.

The somatostatins are for use in the treatment of Diseases suitable if long-term Target drug application is targeted, z. B. in disorders which caused by excessive GH secretion, e.g. B. at the treatment of acromegaly, of gastrointestinal Disturbances, e.g. B. in the treatment or prophylaxis of Gastric ulcers, enterocutaneous and pancreaticcutaneous fistulas, of intestinal inflammations, the dumping syndrome, the aqueous Diarrheal syndrome, acute pancreatitis and gastrointestinal, Hormones secreting tumors, z. B. Vipomas, GRFomas, Glucagonomas, insulinomas, gastrinomas and carcinoids Tumors, as well as gastrointestinal bleeding, breast cancer and Complications associated with diabetes.

The polymeric carrier material may be biocompatible and biodegradable polymers such as linear polyesters or branched ones Polyesters with linear chains, which have a central Polyol, such as glucose esterified, are produced. Other Esters are those of polylactic acid, polyglycolic acid, Polyhydroxybutyric acid, polycaprolactone, polyalkylene oxalate or are polyalkylene glycol esters of Krebs cycle acids, e.g. B. of Citric acid cycle and its copolymers.

The preferred polymers of the invention are the linear ones Polyester and the branched polyester with linear chains (Star) polymers. The linear polyesters can through Condensation of the alphahydroxycarboxylic acids, eg. For example, lactic acid and glycolic acid or by polymerization of the lactone dimers be prepared, see, for. See, for example, U.S. Patent No. 3,773,919.

Preferred polylactide-co-glycolides have  suitably a molecular weight between 25,000 and 100,000 and a polydispersibility Mw / Mn z. B. from 1.2 to 2.

Preferably usable branched polyesters can be prepared from Polyhydroxy compounds such as a polyol such. B. glucose or Mannitol be prepared as an initiator. These polyol esters are known and have been described in UK Patent GB 21 45 422 B. The polyol contains at least 3 hydroxyl groups and has one Molecular weight up to max. 20,000 and at least 1, preferably at least 2, z. B. an average of 3 hydroxyl groups in the form ester groups consisting of polylactide or co-polylactide chains consist. To start the polymerization is for a Representative polyol ester 0.2 weight percent glucose used. The structure of the branched polyester has the form a star. The preferred polyester chains of the linear and star polymers are co-polymers of the alpha-carboxylic acid units of lactic acid and glycolic acid or from the lactone dimers. The molar ratios of lactide and Glycolide are preferably from 75:25 to 25:75, e.g. Eg 60:40 to 40: 60, especially from 55: 45 to 45: 55, z. 55: 45 to 50: 50 as the most preferred conditions. The star polymers can in which a polyol with a lactide and preferably also with a glycolide at elevated temperature in Presence of a catalyst that undergoes polymerization Lactonringöffnung makes possible, is implemented.

We have found that the advantage of a star polymer in it is that its molecular weight can be relatively high, whereby physical stability, eg. B. a certain hardness Implants and microparticles is present, thereby Sticking together is avoided. Nevertheless, however, then his Polylactide chains relatively short, resulting in a fast, controllable biodegradation rate of the polymers leads. The degradation is sufficient z. From a few weeks to one or two Months, which, if the polymer contains a peptide, of one corresponding peptide release is accompanied and a  Depot formulation, eg. For one month release allows. The star polymers preferably have one average molecular weight Mw of about 10,000 to 200,000, especially 25,000 to 100,000, especially 35,000 to 60,000 and a polydispersity z. From 1.7 to 3.0, such as 2.0 to 2.5.

The intrinsic viscosities of star polymers with Mw 35,000 and Mw 60,000 are 0.36 and 0.51 dl / g in chloroform, respectively. On Star polymer with Mw 52,000 has a viscosity of 0.475 dl / g in chloroform.

The terms microsphere, microcapsule and microparticles are used in the context of the invention considered as confused and refer to the encapsulation of the peptides in the polymers, wherein the peptide is preferably distributed in the polymer and a Represents matrix for the peptide. In this case will be preferably the terms microsphere or, more generally, Used microparticles.

When applying the phase separation technique of the invention the resulting formulations can be prepared be prepared by the polymeric carrier material in a Solvent in which the peptide can not dissolve dissolved after which a solution of the peptide in the polymer-containing Solution is dispersed. To encapsulate the peptide by to bring about the polymeric carrier becomes one Phase induction agents such as silicone oil added.

The strong at the beginning of application strong Drug release can be considerably reduced by Production of ultrafine drug particles by the Drug solution prior to phase separation to the polymer solution is supplied.

However, you can also dry fine drug particles directly Add the polymer solution.  

The therapeutic peptide effect can according to the invention be extended by adding the microparticles with an emulsion hardened by buffer / heptane and washed. The is known Methodology, whereby one hardens, without afterwards to wash or only with washes an aqueous medium. For washing and curing the Microparticles, wherein non-encapsulated, left-behind peptide is removed, an emulsion of the oil-in-water type (= o / w) be used. When washing, non-encapsulated, Peptide particles adhering to the microparticle surface away. The removal of these excess peptide lowers the high plasma level at the beginning of the application, which for many conventionally encapsulated products are characteristic and additionally promotes a more even drug release. The buffer heptane emulsion also removes the solvent that was needed for the solution of the polymer and the Phase induction agents, such as the silicone oil.

The emulsion may be attached to the polymer / peptide mixture or mixture be added to the emulsion. The last variant will be prefers.

The o / w emulsion can, if stability is required, under With the aid of an emulsifier, such as sorbitan monooleate (Span 80 ICI Corp.). You can use a buffer, which is not harmful to the peptide and polymer matrix, be buffered. The buffer may be one with pH 2 to 8, preferably pH 4 and may be of the type of acidic buffers, like a phosphate buffer or an acetate buffer. Instead of a buffer Water can also be used.

Solvents such as heptane or hexane can be used as the organic phase the emulsion can be used. The emulsion can Dispersants, such as silicone oil included. The preferred Emulsion contains heptane, phosphate buffer pH 4, silicone oil and Sorbitan. If an immediate release drug is desired, the curing / washing of the emulsion by the  Hardening with the organic solvent, such as heptane or hexane, be replaced.

Other alternatives than the o / w emulsion for curing the microparticles are:
The use of a solvent with emulsifier for curing without washing, or the use of a solvent with emulsifier for curing, after which a separate washing treatment can be switched on.

The o / w emulsion can be used without dispersant. The The advantage of a dispersant is that it prevents the clumping of dry microparticles prevented by static electricity and helps to reduce the amount of residual solvent. Examples of solvents for the polymeric matrix material are methylene chloride, chloroform, benzene, ethyl acetate. The Peptide is preferably in an alcoholic solvent, z. As methanol dissolved, with the solvent of the polymer is immiscible.

The phase-inducing agents (coacervating agents) are Solvents miscible with the polymer / drug mixture are. They cause embryonic microparticles to form afterwards to be hardened. Silicone oils are the preferred ones Phase induction means.

The o / w emulsion can be prepared in a conventional manner What are solvents such as heptane or hexane for the organic phase can be used.

The microparticles according to the invention can also be obtained by use prepared by the well-known spray-drying method become. These are somatostatin or a solution of this Peptids in an organic solvent, eg. As methanol, or in water or in a buffer, e.g. B. with pH 3 to 8 and a Solution of the polymer in an organic solvent containing the first is immiscible, z. As with methylene chloride, good mixed together.  

The resulting solution, suspension or emulsion is then poured into sprayed an air stream. Preferably, the air is warm. The forming microparticles are collected, eg. In one Cyclone and, if desired, washed. As a washing liquid serves z. B. a buffer solution with z. PH 3.0 to 8.0, preferably pH 4.0 or distilled water. The microparticles are dried in a vacuum, z. B. at temperatures of 20-40 ° C.

The washing can be used if the microparticles during The beginning of an application a sudden sharp increase of released drug that is undesirable is. As a buffer z. As an acetate buffer can be used.

The microparticles of the invention show an improved Somatostatin release profile. The invention relates thus also on the microparticles following this procedure getting produced.

The invention thus also relates to a formulation with slowed down drug release, prepared by a Somatostatin or a solution of somatostatin in methanol or water or a buffer of pH 3 to 8 with a solution of the polylactide-co-glycolide in methylene chloride and the formed solution, emulsion or suspension of somatostatin in the polymer solution is sprayed in a warm air stream, the formed microparticles in a buffer solution with pH 3.0 to 8.0 or washed with distilled water and in a vacuum be dried at a temperature of 20 to 40 ° C. Compared with microparticles according to the phase separation method Made, they do not contain silicone oil, either by the trace, as in the spray-drying technology no silicone oil is used.

The formulations according to the invention can also be mentioned under Application of the triple-emulsion process can be produced. In a representative procedure is z. B. a peptide, such as  Octreotide, in a suitable solvent, e.g. Water, dissolved and the solution intensively in a solution of the polymer, z. B. 50/50 poly (D, L-lactide-co-glycolide) glucose in one Solvent that can not dissolve the peptide, e.g. In Methylene chloride, emulsified. As a solvent for the polymeric Matrix material can z. Methylene chloride, chloroform, benzene, Ethyl acetate can be used. The resulting water-in-oil (w / o) emulsion is then dissolved in an excess of water, the an emulsifier, e.g. As an anionic or non-ionic Detergent or lecithin or a protective colloid, such as gelatin or dextrin, carboxymethylcellulose, polyvinylpyrrolidone, Contains polyvinyl alcohol, emulsified. This procedure allows a continuous formation of the triple (w / o / w) emulsion. while now the organic solvent from this emulsion Evaporation is removed by spontaneous precipitation of the polymer microparticle formed and cured. It will gelatin is preferably used to agglomerate the To prevent microparticles. After sedimentation of Microparticles, the supernatant liquid is decanted off and the microcapsules washed with water and with acetate buffer. The Microparticles are finally filtered off and dried.

The peptide can also, without previously dissolve, directly to the Polymer solution are added, after which the resulting Suspension with the gelatin-containing aqueous phase is mixed.

The triple-emulsion process is known from US Pat. No. 4,652,441 known. According to this patent, in a first step, a Active ingredient solution (1) in a solvent, for. B. somatostatin in Water (column 2, lines 31-32) in detail with an excess a polylactide-co-glycolide solution (2) in another Solvent in which the first solvent is insoluble, z. As methylene chloride, mixed, creating a water-in-oil type (w / o) emulsion (3) of fine drug-containing droplets of (1) in solution (2). In the solution (1) is additional  a so-called drug-retaining substance (column 1, Line 31), z. Gelatin, albumin, pectin or agar. In in a second step, the viscosity of the inner phase (1) by suitable measures, such as heating, cooling, pH change, Addition of metal ions or crosslinking, e.g. Of gelatin enlarged with an aldehyde. In a third step will be an excess amount of water completely with the w / o emulsion (3), (col. 7, lines 52-54), whereby a three-layer w / o / w type emulsion is formed. In the Excess amount of water may be a so-called emulsifier be present (column 7, line 56), from the group of a anionic or nonionic detergent, or z. B. Polyvinylpyrrolidone, polyvinyl alcohol or gelatin selected becomes. In a fourth step, the w / o / w emulsion of a Treated as "dry in water" (line 52) is presented. In this step, the organic Solvent "desorbs" (removes), causing microparticles be formed. The desorption is in a known manner executed (column 8, line 3-5), z. B. by reducing pressure during stirring (column 8, lines 5-7) or by Nitrogen gas through the emulsion, its oil layer out Methylene chloride consists (line 19) is blown. The educated Microparticles are made by centrifugation or filtration Isolated (lines 26-27). Component parts, which are not in the Polymer were incorporated by washing with water (line 29). If desired, the microparticles are submerged heated to a reduced pressure, causing the particles adhesive water and solvents, eg. As methylene chloride, better can be removed (lines 30-32). Although the above described method for the formulations according to the invention is satisfactory, the so-called drug is restrained Substance, e.g. Gelatin, albumin, pectin or agar still in the microparticles present. If, as we found, that Adding the restrained substance (in solution 1) and the Increasing the viscosity of the inner phase avoids it but the measure is an emulsifier or a protective colloid, such as  Gelatin, to the excess water of the ternary w / o / w emulsion remain to be maintained, it remains possible to qualitatively good To obtain microparticles. The advantage of these microparticles is that they are no drug-retaining substance and only one very small amount of solvent, such as methylene chloride, contain.

The invention relates to a process for the preparation of Microparticles that are obtained by

• a) a solution of an active ingredient, preferably a Somatostatin, especially octreotide, in an aqueous solution Medium, preferably water or a buffer, preferably in a weight / volume ratio of 0.8 to 4.0 g / 1-120 ml, preferably 2.5 / 10 and in one Buffers of pH 3-8, preferably an acetate buffer, and
• b) a solution of a polymer, preferably one Polylactide-co-glycolide as mentioned above in one organic solvent, not with an aqueous Medium, such as methylene chloride, is miscible, preferably in a weight / volume ratio of 40 g / 90-400 ml, especially 40/100, are mixed intensively with each other, preferably in such a way that the weight / weight Ratio of active ingredient to polymer 1 / 10-50, preferably 1/16 and the volume / volume ratio from aqueous medium to organic Solvent 1 / 1.5-30, preferably 1/10 and the w / o emulsion of a) in b) intensively with
• c) an excess of an aqueous medium, preferably Water or a buffer, e.g. As an acetate or Phosphate buffer, preferably with pH 3-8, which contains a Contains emulsifier or a protective colloid, preferably in a concentration of 0.01-15.0%, especially Gelatin, preferably in a concentration of 0.1-3%,  especially 0.5% by weight, preferably in one Volume / volume mixing rate ratio of from / c of 1 / 10-100, especially 1/40,

without any drug-retaining substance to the Add water-in-oil emulsion or viscosity-increasing Apply measure, according to which the embryonic formed Microparticles in the formed w / o / w emulsion by removal of the organic solvent, preferably from Methylene chloride is cured by evaporation and the microparticles are isolated and possibly afterwards be washed and dried.

The method variant according to the invention also belongs to the invention which disperses the active ingredient directly in the polymer solution and the formed dispersion with the gelatin-containing Water phase is mixed.

The invention also relates to the microparticles according to be prepared by this method.

Like the microparticles, which according to the spray-drying technique produced, they contain no silicone oil. Compared to the microparticles, which according to the known Triple emulsion technology produced, included the new Microparticles no protective colloid.

The slow release formulations can also be prepared according to other known methods. Eg when the peptide drug for the preparation of an implant stable enough, microparticles containing the peptide, e.g. B. contain a somatostatin in a polylactide-co-glycolide, or a mixture of polymer and peptide, at a temperature of z. B. heated to 70 ° C to 100 ° C and extruded, after which the cooled compact mass, cut the extrudate and possibly still washed and dried.

The formulations of the invention are useful under aseptic conditions.  

The formulations may be in depot form, e.g. B. as injectable Microparticles or used as an implant. You can in a conventional manner, e.g. B. subcutaneous or intramuscular at Indications in which the peptide active ingredients are used apply.

The formulations with slowed octreotide release can in all known indications where octreotide or its Salts or derivatives are used, for. B. in such, which in GB 21 99 829 A, pages 89 to 96 have been described or be applied to agromegaly or breast cancer.

The microparticles of this invention may be about 1 in size to 250 microns, preferably 10 to 200, z. 10 to 130, as 10 to 90 microns have.

Implants can have a size of 1 to 10 mm³.

The amount of active ingredient of the formulations depends on the desired daily release amount and therefore of the Biodegradation rate of the polymer. The exact amount of peptide can be determined by bioavailability regulations, however In general, the formulations contain a quantity of peptide from at least 0.2, preferably 0.5 to 20 weight percent, based to the polymeric matrix material, especially 2.0 to 10, especially 3.0 to 6 percent by weight.

The peptide release period can be from 1 to 2 weeks to about 2 Months.

Useful are the slow release formulations those containing a somatostatin, e.g. B. octreotide in one biodegradable, biocompatible polymeric carrier material Contain and which, when given to a rat subcutaneously in a crowd of 10 mg of somatostatin per kg of body weight , a plasma somatostatin concentration of at least 0.3 ng / ml and preferably less than 20 ng / ml for 30 days or expediently for 60 days. Also are the formulations according to the invention with a slower rate Drug release those containing a somatostatin, e.g. Octreotide in a biodegradable, biocompatible polymeric carrier material  and when given to a rabbit intramuscularly in administered in an amount of 5 mg / kg body weight, one Plasma concentration of somatostatin of at least 0.3 ng / ml and expediently have a maximum of 20 ng / ml for 50 days.

Further preferred properties of somatostatin, e.g. Octreotide Depot formulations contained are dependent on the used Manufacturing process, the following:

Phase separation method Rabbit 5 mg somatostatin / kg, intramuscularly Retardation (0-42 days) | 76% Average plasma level (Cp, ideal) (0-42 days) 4 ng / ml AUC (0-42 days) 170 ng / ml x days

Spray-drying process Rat 10 mg somatostatin / kg, subcutaneously Retardation (0-42 days) | <75% Average plasma level (Cp, ideal) (0-42 days) 4-6 ng / ml AUC (0-42 days) 170-210 ng / ml × days

Rabbit 5 mg somatostatin / kg, intramuscularly Retardation (0-43 days) | <75% Average plasma level (0-43 days) 4-6 ng / ml AUC (0-43 days) 200-240 ng / ml × days

Triple emulsion method Rat 10 mg somatostatin / kg, subcutaneously Retardation (0-42 days) | <75% Average plasma level (Cp, ideal) (0-42 days) 4-6.5 ng / ml AUC (0-42 days) 170-230 ng / ml × days

Rabbit 5 mg somatostatin / kg, intramuscularly Retardation (0-42 / 43 days) | <74% Average plasma level (Cp, ideal) (0-42 / 43 days) 3.5-6.5 ng / ml AUC (0-42 / 43 days) 160-270 ng / ml × days

The invention thus also relates to somatostatin, preferably octreotide and octreotide analogues containing Compositions which have the following properties:

• 1. a retardation of at least 70%, preferably at least 74%, z. At least 75%, 80%, 88% or at least 89% for a period of 0 to 42 days or 43 days and or
• 2. An average plasma level (Cp, ideal) of 2.5 to 6.5, preferably 4 to 6.5 ng / ml for a period of time from 0 to 42 days in the rat when 10 mg of somatostatin administered subcutaneously and / or an average Plasma levels of 3.5 to 6.5, z. B. 4-6.5 ng / ml during a period of 0 to 42 or 43 days, in the rabbit when 5 mg of somatostatin is administered intramuscularly and or
• 3. an AUC during a period of 0 to 42 days from at least 160, preferably from 170 to 230 ng / ml x days, for the rat when 10 mg somatostatin administered subcutaneously and / or an AUC over a period of 0 to 42 or 43 days of at least 160, preferably from 180 to 275, e.g. B. from 200 to 275 ng / ml x days for the rabbit when 5 mg Somatostatin is administered intramuscularly.

For the quantitative characterization of the invention Formulations, we use the method of area deviation (AD) by F. Nimmerfall and J. Rosenthaler, published in Intern. J. Pharmaceut. 32, 1-6 (1986).

In short, the AD method determines the deviation of the area of a experimental plasma profile of an ideal profile in shape a constant average plasma concentration (= Cp, ideal) by placing the experimental surface under the plasma curve (AUC) is converted into a rectangle with the same surface. The percentage of retardation will now be percentage Surface deviation relative to the AUC calculated according to the following formula:

% Retardation = 100 × (1-AD / AUC)

According to this method, the entire plasma profile is measured numerically over a predetermined period of time single index.

In Proc. natl. Acad. Sci. USA 85 (1988) 5688-5692 was shown in FIG. 4 a plasma profile of the octapeptide analogue of somatostatin the formula

described in the rat.

However, no clear comparison can be made with those above reproduced plasma profile data of the invention Compositions are drawn in the rat as the described Plasma profile on another application method (intramuscular Injection) and - more importantly - the degree of loading (between 2 and 6%) and the dosage amount for the application (25 to 50 mg Portions of microparticles for 30 days, though during for at least 45 days) were not accurate  were specified. In addition, the poly (D, L-lactide-co-glycolide) type also became not exactly described. The The disclosure content of the publication is therefore too low to Publication as a pre - publication, which the Could affect the invention.

The following examples illustrate the invention.

The molecular weight Mw of the polymer is the average Molecular weight determined by GPC being polystyrene as Standard was used.

example 1

1 g of poly (D, L-lactide-co-glycolide) (50/50 molar, Mw = 45,000; Polydispersity about 1.7) was added with stirring magnetic stirrer dissolved in 15 ml of methylene chloride, after which first a solution of 75 mg octreotide acetate in 0.5 ml methanol and then 15 ml of silicone oil (brand Dow 360 Medical Fluid 1000 cs) (silicone fluid) was added. The resulting mixture was with stirring to an emulsion of 400 ml of n-heptane, 100 ml of pH 4 Phosaphate buffer, 40 ml Dow 360 Medical Fluid, 350 cs and 2 ml Span 80 (emulsifier) was added and stirring at least 10th Followed up minutes. The microparticles formed were through Vacuum filtration isolated and overnight in a vacuum oven dried. The yield was about 90% microparticles in the Diameter range from 10 to 40 microns.

The microparticles were suspended in a carrier and in a Dosage of 4 mg octreotide intramuscularly on white New Zealand rabbits applied. Periodically, blood samples were taken, in those with RIA analysis (RIA = Radio Immuno Assay) for 30 days Plasma levels of 0.5 to 1.0 ng / ml were measured.

Example 2

1 g of poly (D, L-lactide-co-glycolide) glucose (Mw = 45,000, 55/45 molar; prepared by the method GB 21 45 422 B from 0.2% glucose, Polydispersity about 1.7) was added with stirring magnetic stirrer dissolved in 25 ml of ethyl acetate, after which 75 mg Octreotide in 3 ml of methanol and then 25 ml of silicone oil (Dow 360 Medical Fluid 1000 cs) was added. The mixture was on the emulsion described in Example 1 was added. The Stirring was continued for at least 10 minutes, the formed microparticles were by vacuum filtration isolated and dried overnight in a vacuum oven. The Yield exceeded 80% microparticles. The diameter range was from 10 to 40 microns.

The microparticles were suspended in a carrier and in a Dosage of 4 mg octreotide in white New Zealand rabbits applied intramuscularly. Periodically, blood samples were taken in those with RIA analysis (RIA = Radio Immunoassay) during 21 Plasma levels of 0.5 to 2 ng / ml were measured.

Example 3

On a solution of 18.5 g Poly (D, L-lactide-co-glycolide) glucose (50/50 molar, Mw 45,000) in 500 ml of methylene chloride with stirring, a solution of 1.5 g Octreotide acetate added in 20 ml of methanol. Thereafter, 500 ml Dow 360 Medical Fluid (1000 cs) and 800 ml Dow 360 Medical Fluid (350 cs) was added to the peptide-polymer suspension to give a Phase separation took place. The resulting mixture was added Stir to an emulsion of 1800 ml of n-heptane, 200 ml of sterile Water and 40 ml Span 80 added. Continue stirring for 10 minutes The microspheres were isolated by vacuum filtration. The half of the product was overnight in a vacuum oven at 37 ° C dried. The residual content of methylene chloride was 1.2%. The other half of the product was stirred with 1000 ml Methanol containing 1 ml Span 80, washed. After 1 hour Further stirring, the ethanol layer was decanted and the  Microparticles for 1 hour with 1000 ml of n-heptane containing 1 ml of Span 80, stirred.

The microparticles were isolated by vacuum filtration and transferred Dried overnight in a vacuum oven at 37 ° C. The residual content Methylene chloride of the microparticles washed in this way was reduced from 1.2% to 0.12%. The total yield of the Product was 18.2 g (91%) microparticles containing 5.6% octreotide contained. Average diameter 24 microns, residual content Heptane 1.5%.

The microparticles were suspended in a carrier and in a Dosage of 5 mg / kg octreotide to white rabbit intramuscular applied. Periodically, blood samples were taken in which RIA analysis during 49 days plasma levels of 0.3 to 7.7 ng / ml were measured.

Example 4

1 g of poly (D, L-lactide-co-glycolide) glucose (Mw 46,000, 50:50 molar, according to the method according to GB 21 45 422 B from 0.2% glucose prepared, polydispersity about 1.7) was added with stirring a magnetic stirrer in 10 ml of methylene chloride, followed by a solution of 75 mg of octreotide in 0.133 ml of methanol was added has been. The mixture was stirred for 1 minute z. B. by means of a Ultra-Turax stirred intensively at 20,000 revolutions per minute, whereby a suspension of very small Octreotidkristallen in the polymer solution was formed. The suspension was purified by means of a Turbine developing a high speed, (Niro Atomizer) spray-dried; the little droplets were in one warm air stream dried to microparticles. They were in collected a cyclone and overnight at room temperature in dried in a vacuum oven for 5 minutes with a 1/15 Acetate buffer pH 4.0 and washed again at room temperature in dried in a vacuum oven. After 72 hours, the Microparticles sieved (0.125 mm mesh). The sifted Microparticles were suspended in a carrier and in a Dose of 5 mg octreotide / kg body weight intramuscularly  white rabbit (chinchilla bastard) and in a 10 mg / kg Dose administered subcutaneously to male rats. Periodically Blood samples taken in those during 42 days plasma levels of 0.3 to 10.0 ng / ml (5 mg dose) in rabbits and 0.5-7.0 ng / ml in Rats were measured (RIA analysis).

Example 5

In the same manner as described in Example 4 Microparticles produced by spray drying. Only was in the present case Octreotide directly, without application of Methanol suspended in the polymer solution. The microparticles were suspended in a vehicle and subcutaneously in one dose of 10 mg octreotide per kg body weight in male rats applied. In blood samples, which periodically during 42 days plasma levels could be determined by RIA analysis 0.5-10.0 ng / ml.

Example 6

1 g of poly (D, L-lactide-co-glycolide) glucose (Mw 46,000, 50:50 molar; according to the method according to GB 21 45 422 B from 0.2% glucose prepared, polydispersity about 1.7) was dissolved in 2.5 ml Methylene chloride, after which 75 mg octreotide in 0.125 ml of Ion was added to liberated water. The resulting mixture was at 20,000 by means of an Ultra-Turax for 1 minute Revolutions / minute intensively mixed (inner w / o phase). 1 g of gelatin A was dissolved at 50 ° C in 200 ml of ion-free water solved; the solution was cooled to 20 ° C (outer w phase). The w / o and w phases were mixed thoroughly. While This process became the inner w / o phase as small droplets homogeneously dispersed in the outer w phase. The resulting Triple emulsion was stirred slowly for 1 hour, whereby the methylene chloride evaporated and hardened microcapsules from the Droplets of the inner phase emerged. To Sedimentation of the microparticles was the excess  Sucked liquid by filtration. The microparticles were isolated by vacuum filtration and rinsed with water, whereby the gelatin was removed. After that, the Microparticles dried, sieved, washed and a second time dried as described in Example 4. The microparticles were suspended in a vehicle and at a dose of 5 mg Octreotide per kg body weight intramuscularly on white rabbits (Chinchilla bastard) and at a dose of 10 mg per kg Body weight administered subcutaneously to male rats. In Periodically taken blood samples were used for 42 days RIA analysis Plasma levels of 0.3 to 15.0 ng / ml (5 mg dose) in Rabbit and 0.5 to 8.0 ng / ml in rats.

Example 7

Microparticles were prepared by the triple emulsion technique as in Example 6, but with the following Process changes made:

• 1. Instead of 0.125 ml of water, 0.25 ml of acetate buffer pH 4.0 used to make the inner w / o phase.
• 2. After isolation of the microparticles, rinsing with a 1/45 molar acetate powder pH 4 instead of water carried out.
• 3. The further washing of the microparticles was omitted.

Example 8

Microparticles were prepared by the triple emulsion technique in prepared as described in Example 7, with the Difference that the inner w / o phase was made by Application of water, which instead of acetate powder 0.7% (Weight / volume) contained sodium chloride.  

Example 9

Microparticles were prepared in the same manner as in Example 6 described, prepared, with the difference that the active ingredient dispersed directly in the polymer solution and the resulting Dispersion mixed with the gelatin-containing water phase has been.

Example 10 Octreotidpamoat

10.19 g of octreotide free base (10 mM) and 3.8 g embonic acid (10 mM) are dissolved in 1 L of water / dioxane (1: 1). The Reaction mixture is filtered and lyophilized to give a yellow powder (C = 0.35, in DMF) Octreotidpamoat hydrate. The factor is 1.4. As a factor is the weight of the lyophilisate / the weight of the contained Octreotids indicated. Octreotide acetate in Examples 1 to 9 can be replaced by octreotide pamoate and has one excellent stability.

Example 11

A solution of 1 g of poly (D, L-lactide-co-glycolide) (50:50 molar, MW = 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 was added and the Phase separation by adding 20 ml of silicone oil (Dow 360 Medical Fluid, 1000 cs). The resulting mixture was added with stirring to an emulsion of 100 ml of pH 4 Phosphate buffer, 400 ml n-heptane, 4 ml Span 80 and 40 ml Silicone fluid (Dow 360 Medical Fluid, 1000 cs) added. After 10 minutes of stirring, the microspheres were passed through Vacuum filtration isolated and overnight in a vacuum oven at Dried 37 ° C. The yield was 1.1 g of microspheres, which was 5.9%. Contained 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 lypressin added. The dispersion was stirred magnetically for 1 hour, after which 140 ml of silicone oil (Dow 360 Medical Fluid, 1000 cs) and 2.5 ml Span 80 was added. The mixture was added to 2,000 ml of heptane added and stirred for 10 minutes. The resulting Microcapsules were isolated by vacuum filtration, 3 times with Washed heptane and dried under suction for 10 minutes. The Half of the product incurred was in for 10 minutes Water washed; the other half was not washed. Both Samples were dried overnight in a vacuum oven at 30 ° C. The total yield was 10.65 g of microparticles. In the washed sample was 0.5% and in the non-washed sample 0.6% Lypressin present.

Claims (43)

A process for producing microparticles containing an active ingredient in a biodegradable, biocompatible polymeric carrier according to which

• a) the polymeric carrier material in a suitable solvent in which the active ingredient is not soluble,
• b) a solution of the active ingredient in a suitable solvent, which can not dissolve the polymer, is added to the solution of step a) and dispersed therein
• c) adding a phase-inducing agent to the dispersion of step b), thereby forming microparticles,
• d) an oil-in-water emulsion is added to the mixture of step c), whereby the microparticles are cured and
• e) the microparticles are isolated.

2. Microparticles obtained by the process according to claim 1. 3. A process for the preparation of microparticles containing an active ingredient in a bioerodable, biocompatible carrier by

• (i) a water-in-oil emulsion of an aqueous medium and a water-immiscible solvent containing in one phase the active ingredient and in the other a biodegradable biocompatible polymer intensively with an excess of an aqueous medium containing an emulsifier or a protective colloid is mixed to a water-in-oil-in-water emulsion, without any drug-retaining substances added to the water-in-oil emulsion or any viscosity-increasing measures are taken,
• (ii) the solvent is removed therefrom and
• (iii) the microparticles formed are isolated and dried.

4. A process for the preparation of microparticles containing an active ingredient in a biodegradable, biocompatible carrier in which

• (i) an active substance suspension of an active substance and a water-immiscible organic solvent which contains a biodegradable, biocompatible polymer dissolved intensively with an excess of an aqueous medium which contains an emulsifier or a protective colloid to an oil-in-water Emulsion is mixed, which contains the active ingredient dispersed in the oil component, without in the oil component, any drug-retaining substances are present or any viscosity-increasing measures are taken,
• (ii) removing the solvent therefrom and
• (iii) the microparticles formed are isolated and dried.

5. Process for the preparation of microparticles, in which

• a) a solution of an active ingredient in an aqueous medium and
• b) a solution of a polymer in an organic solvent, which is not miscible with the aqueous medium, are thoroughly mixed together and the w / o-emulsion of a) in b),
• c) is intensively mixed with an excess of an aqueous medium containing a protective colloid, without adding to the water-in-oil emulsion any active substance restraining substances or any viscosity enhancing measures are taken, the embryonic microparticles in the w / o formed / w emulsion hardened by removal of the solvent and the microparticles formed are isolated.

6. The method according to claim 5, with a somatostatin as Active ingredient. 7. The method according to claim 5, with octreotide as the active ingredient. 8. The method according to claim 5, with the Octreotidpamoat salt as Active ingredient. 9. The method according to claim 5, comprising a polylactide-co-glycolide as Polymer. 10. The method according to claim 5, with water or a buffer as aqueous medium. 11. The method according to claim 5, with a buffer of pH 3-8 as aqueous medium. 12. The method according to claim 5, with methylene chloride as organic Solvent. 13. A process for the preparation of microparticles, in which

• a) a solution of a somatostatin in water or a buffer in a weight / volume ratio of 0.8 to 4.0 g / 1 to 120 ml and
• b) a solution of a polylactide-co-glycolide in an organic solvent, which is not miscible with the aqueous medium, in a weight / volume ratio of 40 g / 90 to 400 ml are intensively mixed together in such a way that the weight / Weight ratio of the active ingredient to the polymer 1/10 to 50 and the volume / volume ratio of the aqueous medium to the organic solvent 1 / 1.5 to 30 and the w / o emulsion of a) in b) intensively with
• c) an excess of water or buffer, containing a protective colloid, in a volume / volume velocity ratio of a) b) / c) of 1/10 to 100 is mixed,

without any drug-retaining substances to the Water-in-oil emulsion added or any viscosity-increasing measures are taken, the embryonic microparticles in the formed w / o / w emulsion Evaporation of the organic solvent cured and the formed microparticles are isolated. 14. The method according to claim 13 with gelatin as a protective colloid. 15. Process for the preparation of microparticles by

• a) a solution of a somatostatin in an aqueous medium in a weight / volume ratio of 2.5 / 10 ml and
• b) a solution of a polylactide-co-glycolyds in an organic solvent, which is not miscible with the aqueous medium, in a weight / volume ratio of 40 g / 100 ml are intensively mixed together in such a way that the weight / weight Ratio of the polymer is 1/16 and the volume / volume ratio of the aqueous medium to the organic solvent is 1/10 and the w / o emulsion of a) in b) intensively with
• c) an excess of an aqueous medium containing a protective colloid in a concentration of 0.01 to 15.0 weight percent, in a volume / volume ratio of a) b) / c) of 1/40 is mixed without any drug-retaining substances are added to the water-in-oil emulsion or any viscosity-increasing measures are taken, the embryonic microparticles cured in the formed w / o / w emulsion by evaporation of the organic solvent and the microparticles formed are isolated.

16. A process for the preparation of microparticles in the

• a) a solution of octreotide in a weight / volume ratio of 2.5 g / 10 ml in a buffer of pH 3 to 8 and
• b) a solution of a polylactide-co-glycolide in methylene chloride in a weight / volume ratio of 40 g / 100 ml are intensively mixed together in such a way that the weight / weight ratio of the active ingredient to the polymer is 1/16 and the Volume / volume ratio of the aqueous medium to the organic solvent is 1/10 and the w / o emulsion of a) in b) intensively with
• c) an excess of a buffer of pH 3 to 8, containing gelatin in a concentration of 0.5% by weight, in a volume / volume ratio of a) b) / c) of 1/40 is mixed without any drug-retaining substances to the water-in-oil emulsion or any viscosity-increasing measures are taken, the embryonic microparticles in the formed w / o / w emulsion hardened by evaporation of the methylene chloride and the microparticles formed are isolated, washed and dried.

17. Microparticles obtained by the process according to claim 3. 18. Formulation with slow release of octreotide or a salt or a derivative as an active ingredient in one biodegradable, biocompatible polymeric carrier. 19. Formulation with slow release in accordance with Claim 18, wherein the polymer is poly (D, L-lactide-co-glycolide) glucose is. 20. A formulation according to claim 18 in microparticle form, the Surface is substantially free of active ingredient. 21. Formulation with slow release in accordance with Claim 18, obtained by mixing the active ingredient or its solution in methanol or water or in a pH 3 buffer to 8 with a solution of a polylactide-co-glycolide in Methylene chloride, spraying the suspension formed, solution or emulsion of the active ingredient in the polymer solution in one warm air stream, separating the microparticles with a Buffer solution pH 3.0 to 8.0 or with distilled water and Dry the microparticles in a vacuum oven at 20 ° C to 40 ° C. 22. Slow release formulation according to Claim 18 having an octreotide concentration of 2.0 to 10 Percent by weight, based on the polymeric carrier material. 23. Formulation with slow release in accordance with Claim 18 in microparticle form with a diameter of 1 to 250 microns. 24. A slow release formulation containing a peptide active in a 40/60 to 60/40 polylactide-co-glycolide ester of a polyol, and the polyol of the group consisting of a (C _3-6 ) carbon chain-containing alcohol having 3 to 6 hydroxyl groups and a mono- or disaccharide is selected and the esterified polyol contains at least 3 polylactide-co-glycolide chains. 25. Formulation with sustained-release, which a Peptidwirkstoff from the group of a calcitonin, lypressin or a somatostatin in a linear 40/60 to 60/40 Containing polylactide-co-glycolide polymers, the polymer chains with a molecular weight Mw of 25,000 to 100,000 and a Polydispersity Mw / Mn has from 1.2 to 2 and the Peptide loading of the polymer of 0.2 to 10 weight percent is. 26. Formulation with slow release in accordance with Claim 24, having a molecular weight Mw of the ester of 10,000 to 200,000 and a polydispersity Mw / Mn of 1.7 to 3.0. 27. Formulation with slow release in accordance with Claim 24, wherein the molecular weight Mw of the ester is 35,000 to 60,000. 28. Slow release formulation according to Claim 24, in which the polydispersity Mw / Mn of the ester 2.0 bis 2.5. 29. A sustained-release formulation according to claim 18, 24 or 25, which, if taken subcutaneously in an amount of 10 mg Active substance per kg body weight is administered to a rat, a plasma level of the active substance of at least 0.3 ng / ml and less than 20 ng / ml for 30 days. 30. A sustained-release formulation according to claim 18, 24, 25, which when given subcutaneously in an amount of 5 mg Active substance per kg body weight is administered to a rabbit, a plasma level of at least 0.3 ng / ml and at most 20 ng / ml during 50 days.   A sustained-release formulation according to claim 18, 24 or 25, which, when given intramuscularly in an amount of 5 mg Active ingredient per kg of body weight applied to a rabbit is a retardation of at least 70% over a period of 0 to 42 or 43 days. 32. Slow release formulation according to Claim 18, 24 or 25 which, when administered subcutaneously in an amount of 10 mg of active ingredient per kg of body weight applied to a rat , an average plasma level (Cp, ideal) of 2.5 to 6.5 ng / ml for a period of 0 to 42 days having. 33. Slow release formulation according to Claim 18, 24 or 25 which, when intramuscularly in an amount of 5 mg of active ingredient per kg of body weight in a rabbit applied, an average plasma level (Cp, ideal) from 3.5 to 6.5 ng / ml. 34. Slow release formulation according to Claim 18, 24 or 25 which, when administered subcutaneously in an amount of 10 mg per kg of body weight is administered to a rat AUC from 160 to 230 ng / ml x days for a period from 0 to 42 or 43 days. 35. Slow release formulation according to Claim 18, 24 or 25 which, when intramuscularly in a Amount of 5 mg of active ingredient per body weight in a rabbit An AUC of 160 to 275 ng / ml x days is administered over one Period from 0 to 42 or 43 days. 36. Slow release formulation according to Claim 18 for the treatment or prevention of acromegaly or Breast cancer. 37. Method for the application of a peptide active ingredient, characterized  by the parenteral administration of a depot formulation according to Claim 18. 38. Method according to claim 37 for the treatment of acromegaly or Breast cancer. 39. octreotide pamoate. 40. Process for the preparation of octreotide pamoate in which octreotide is reacted with embonic acid or with a reactive derivative. 41. Slow release formulation containing a Peptidwirkstoff from the group of a calcitonin and lypressin and their pharmaceutically acceptable salts in one biodegradable, biocompatible polymeric matrix. 42. Slow release formulation according to Claim 25, which is a peptide active ingredient from the group of Contains calcitonins and lypressin.