SE512992C2 - Delayed-release preparations of water-soluble peptides - Google Patents

Abstract

A sustained release formulation of a peptide drug compound, preferably a somatostatin like octreotide, e.g. as a pamoate salt. The drug compound is present in a polymeric carrier, preferably a polylactide-co-glycolide especially a poly(lactide-co-glycolide)glucose. The formulation is preferably a depot formulation in the form of a monolithic microparticle.

Description

5,122,992 2 known, satisfactory peptide release profiles can in practice be obtained only in very few cases. Special measures must be taken to achieve continuous peptide release for a therapeutically active drug serum level and, if desired, to avoid excessive drug serum concentrations, which cause undesirable pharmacological side or side reactions.

The pattern of peptide drug release is dependent on numerous factors, e.g. peptide type and for example whether it is present in its free or some other form, e.g. salt form, which may affect its water solubility. Another important factor is the choice of polymer from the very extensive list of possibilities that have been described in the literature.

Each type of polymer has its characteristic rate of biodegradation. Free carboxyl groups can be formed, which contribute to the pH of the polymer and thus also affect the water solubility of the peptide and consequently its release pattern.

Other factors which may affect the release pattern of the depot preparation are the amount of polymeric carrier filled with drug, the method of its distribution in the polymer, the particle size and, in the case of an implant, also its shape. Furthermore, the place of preparation in the body is important.

To date, no somatostatin composition in a form with delayed release for parenteral administration has entered the market, probably due to the fact that no composition showing a satisfactory serum level profile has been obtained. 10 15 20 25 30 35 512 9.92 3 DESCRIPTION OF THE PRIOR ART Polymer preparations with drugs, which are designed to give prolonged or delayed release of the drug, are known in the art.

U.S. Patent 3,773,919 discloses controlled release formulations of the drug, wherein the drug, e.g. 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 a somatostatin. U.S. Patent 4,293,539 discloses antibacterial preparations in microparticle form.

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

T. Chang, J. Bioeng., Vol.1, pages 25-32, 1976 have described sustained release of biological compounds, enzymes and vaccines from microparticles.

Polymers / copolymers of lactic acid and lactide / glycolide copolymers and related compositions for use in surgical applications and for sustained release and biodegradation have been disclosed in U.S. Patent Nos. 3,991,776, 4,076,798 and 4,118,470.

European Patent Application 0 203 031 describes a series of somatostatin octapeptide analogs, e.g. compound RC-160 of the formula D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH 2 with a bridge between the -Cys units in columns 15-16.

The possibility of microencapsulating somatostatins with polylactide-co-glycolide polymer has been mentioned in claim 18, but no instructions or details have been given on how to obtain a continuously therapeutically active serum level.

U.S. Patent 4,011,312 discloses that continuous release of an antimicrobial drug, e.g. the water-soluble polymyxin B from a polylactide-co-glycolide matrix with low molecular weight (in 2000) and relatively high glycolide content in the form of an implant can be obtained when the implant is inserted into the teat canal of a cow. The drug is released in a short time due to the high glycolide content and the low molecular weight of the polymer, both of which stimulate rapid polymer biodegradation and thus correspondingly rapid release of the drug. A relatively high content of drugs also contributes to rapid drug release. No somatostatins and no drug release patterns have been described.

European Patent No. 58,481 discloses that continuous release of a water-soluble peptide from a polylactide polymer implant is stimulated by lowering the molecular weight of at least a portion of the polymer molecules by introducing glycolide moieties into the polymer molecule, thereby increasing the segment polymer nature of the polymer. of drugs in the polymer matrix is increased and thereby the surface of the implant is increased. Although somatostatins are referred to as water-soluble peptides, no somatostatin release profiles have been described and no indication has been given on how to combine all these parameters to obtain, for example, a continuous somatostatin serum level for at least one week, e.g. one month.

European Patent No. 92,918 discloses that continuous release of peptides, preferably hydrophilic peptides, over a long period of time can be obtained if the peptide is incorporated into a conventional hydrophobic polymer matrix, e.g. of a polylactide, which is made more accessible to water by incorporating into its molecule a hydrophilic moiety, for example of polyethylene glycol, polyvinyl alcohol, dextran, polymethacrylamide. The hydrophilic contribution to the amphipathic polymer comes from all the ethylene oxide groups in the case of a polyethylene glycol moiety, from the free hydroxyl groups in the case of a polyvinyl alcohol moiety or a dextran moiety and from the amide groups in the case of a polymethacrylamide moiety. Depending on the presence of the hydrophilic moiety in the polymer molecules, the implant acquires hydrogel properties after absorption of water. Somatostatin is referred to as a hydrophilic peptide, but no release profile has been described and no information has been given as to the type of polymer preferred for this peptide or what molecular weight and how many hydrophilic groups it should have.

British Patent Specification GB 2 145 422 B describes that delayed release of drugs of various types, e.g. of vitamins, enzymes, antibiotics, antigens, can be obtained over a long period of time if the drug is incorporated into an implant, e.g. of microparticle size, made of a polymer of a polyol, e.g. glucose or mannitol, having one or more, preferably at least 3, polylactide ester groups. The polylactide ester groups preferably contain, for example, glycolide units. No peptides, e.g. somatostatins, are referred to as drugs and no serum drug levels have been described.

SUMMARY OF THE INVENTION The present invention relates to sustained release formulations, e.g. microparticle preparations, of a drug, in particular of a hormonally active water-soluble somatostatin or a somatostatin analogue, such as octreotide, which give satisfactory plasma drug levels and, e.g. in a biodegradable, biocompatible polymer, for example in an encapsulating polymer matrix. The polymer matrix can be a synthetic or natural polymer.

The microparticles of the present invention can be prepared by any conventional technique, e.g. an organic phase separation technique, a spray drying technique or a triple emulsion technique, where the polymer is precipitated together with the drug, followed by a curing or curing of the resulting product, when phase separation or triple emulsion technique is used.

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

We have found a particularly useful modification of the phase separation technique for the production of microparticles of any drug.

Accordingly, the present invention also provides a process for the preparation of a microparticle comprising a drug in a biodegradable, biocompatible carrier, which comprises the steps of: a) dissolving the polymeric carrier material in a suitable solvent, wherein the drug compound is insoluble, b ) adds and disperses a solution of the drug compound in a suitable solvent, e.g. an alcohol, which is a non-solvent for the polymer, in the solution of step a), c) adds a phase inducer to the dispersion of step b) to induce or effect microparticle formation, d) adds a oil-in-water emulsion to the mixture from step c) to cure the microparticle or cause the microparticle to cure, and e) recover the microparticle.

We have also found a particularly useful modification of the triple emulsion technique for the preparation of microparticles of any drug.

Accordingly, the present invention provides: A process for the preparation of microparticles, which comprises (i) intensively mixing a water-in-oil emulsion formed of an aqueous medium and a water-immiscible organic solvent, the drug being present in one phase and a biodegradable, biocompatible polymer is present in the second, with an excess of an aqueous medium containing an emulsifying substance or a protective colloid to form a water-in-oil-in-water e-emulsion, without any drug preserving or retaining substance is added to the water-in-oil emulsion or any intermediate viscosity enhancing step is used, (ii) desorbing the organic solvent therefrom, (iii) isolating and drying the resulting microparticles.

The present invention further relates to the microparticles obtained according to these processes.

The present invention also provides: a) a sustained release formulation comprising 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 containing a (C3-5) carbon chain and having from 3 to 6 hydroxyl groups and a mono- or disaccharide, and wherein the esterified polyol has at least 3 polylactide co-glycolide chains, b) A sustained release formulation comprising a peptide drug compound selected from the group a calcitonin, lypressin or a somatostatin in a 40/60 to 60/40 polylactide-co-glycolide polymer with linear chains with a molecular weight MW of between 25,000 and 100,000, a polydispersity MW / Mn of between 1.2 and 2 in a concentration of from 0.2 or preferably from 2 to 10% by weight of the peptide drug compound therein. c) a sustained release formulation comprising octreotide or a salt or derivative thereof in a biodegradable, biocompatible polymeric carrier.

We have found that a new salt of octreotide is the pamoate, which is very stable in such preparations.

Accordingly, the present invention provides (i) octreotide pamoate and (ii) a process for the preparation of octreotide pamoate, which comprises reacting octreotide with embonic acid (or a reactive derivative thereof).

Furthermore, the present invention provides: A method of administering a peptide to an individual, which comprises parenteral administration to an individual in need of such treatment of a depot preparation as defined above, in particular for the treatment of acromegaly or breast cancer. DESCRIPTION OF THE PREFERRED EMBODIMENTS The drugs used in the methods of the invention are preferably water-soluble drugs, e.g. peptides.

The peptides used in the methods and in the formulations of the present invention may be a calcitonin such as salmon calcitonin, lypressin and a naturally occurring somatostatin and synthetic analogs thereof.

The naturally occurring somatostatin is one of the preferred compounds and is a tetradecapeptide having the structure: Ala-Gly-Cys-Lys-Asn-Phe-Phe-Trï Cys-Ser-Thr-Phe-Thr-Lys This hormone is produced by the hypothalamic gland as well as other organs, e.g. GI area, and mediates, together with GRF, q.v. the neuroregulation of the pituitary gland's release of growth hormone. In addition to inhibiting pituitary GH release, somatostatin is a potent or potent inhibitor of a number of systems, including central and peripheral neural, gastrointestinal, and vascular smooth muscle. It also inhibits the release of insulin and glucagon.

The term "somatostatin" includes its analogs or derivatives thereof. Derivatives and analogs are understood to mean straight-chain, conjugated or cyclic polypeptides in which one or more amino acid moieties have been omitted and / or replaced by one or more other amino radicals and / or in which one or more * functional groups have been replaced by one or more other functional groups and / or one or more groups have been replaced by one or more other isosteric groups. In general, the term covers all modified derivatives of a biologically active peptide which have a qualitatively similar effect to that of the unmodified somatostatin peptide.

Agonist analogues of somatostatin are thus useful in replacing natural somatostatin in terms of its effect on the regulation of physiological functions.

Preferred known somatostatins are: a) (D) Phe-Cys-Phe- (D) Trp-Lys-Thr-Cys-Thr-ol (Generic name Octreotide) b) (D) Phe-Cys-Tyr- (D) Trp -Lys-Val-Cys-ThrNH2 c) (D) Phe-Cys-Tyr- (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-fl Naphthyl) - (D) C1a-Cys-Tyr- (D) Trp-Lys-Val-Cys-ThrNH2 g) (D) Phe-Cys-Tyr- (D) Trp-Lys-Val-Cys-B-Na1-NH2 h) 3- (2-naphthyl) -Ala-Cys- Tyr- (D) Trp-Lys-Va1-Cys-B-Nal-NH2 i) (D) Phe-Cys-ß-Nal- (D) Trp-Lys-Val-Cys-Thr-NH2 where in each of compounds a) to i) there is a bridge between the amino acids marked with an *, as indicated in the next formula.

Other preferred somatostatins are: * -----------------------------x II H-Cys ~ Phe-Phe- (D) Trp -Lys-Thr-Phe-Cys-OH 10 15 20 25 30 35 512 992 ll (See Vale et al., Metabolism, 27, Supp. 1, 139 (1978)). i i 'Asn-Phe-Phe- (D) Trp-Lys-Thr-Phe-Gaba (See European patent with publ. no. 1295 and application no. 78100994.9).

: E: k MeAla-Tyr- (D) Trp-Lys-Val-Phe (See Verber et al., Life Sciences, 34, 1371-1378 (1984) and European Patent Application No. 82106205.6 (published as No. 70 021) also known as cyclo (N-Me-Ala-Tyr-D-Trp-Lys-Val-Phe). * x NMePhe-His- (D) Trp-Lys-Val-Ala (See RF Nutt et al., Klin.Wochenschr. (1986) 64 (Suppl.VII) ki H-Cys-His-His-Phe-Phe- (D) Trp-Lys-Thr-Phe-Thr-Ser-Cys-OH (see EP-A-200 188) * * X-Cys-Phe-Q-Trp-Lys-Thr-Cys-Thr-NH2 and * * X-Cys-Phe-Q-Trp-Lys-Thr-Cys-Thr-ol wherein X is a cationic "anchor" , especially Ac-hArg (Et 2) -Gly-Cys-Phe-Q-Trp-Lys-Thr-Cys-NH 2 (see EP 0363589A2) where there is a bridge between amino acids in the above amino acids the acids marked with an *.

The contents of all the above-mentioned publications, including the specific associations, are hereby incorporated specifically into the present text by the references in question.

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

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

The term octreotide derivative includes those containing the moiety: k i -D-Phe-Cys-Phe-DTrp-Lys-Thr-Cys- with a bridge between the Cys residues.

Particularly preferred derivatives are Na- [G-glucosyl- (1-4-deoxy-fructosyl-DPhe-Cys-Phe-DTrp-Lys-Thr-Cys-Thr-ol and Nu- [β-deoxyphructosyl-DPhe-Cys -Phe-DTrp-Lys-Thr-Cys-Thr-ol, each of which has a bridge between the Cys units, preferably in acetate salt form and described in Examples 2 and 1, respectively, in the above-mentioned application.

The somatostatins may exist, for example, in free form, in salt form or in complex form thereof. Acid addition salts can be formed with, for example, organic acids, polymeric acids and inorganic acids. Acid addition salts include e.g. the hydrochloride and acetates. Complexes are formed, for example, by somatostatins by the addition of inorganic substances, e.g. inorganic salts or hydroxides, such as Ca and Zn salts, and / or addition of polymeric organic substances.

The acetate salt is a preferred salt for such formulations, especially for microparticles, as it results in reduced initial or initial drug deficiency. The present invention also provides the pamoate salt, which is useful especially for implants, and a process for its preparation.

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

The somatostatins are intended for use in the treatment of disorders or diseases where long-term application of the drug is desired or needed, e.g. conditions with an etiology involving or associated with excessive GH secretion, e.g. in the treatment of acromegaly, for use in the treatment of gastrointestinal disorders or diseases, e.g. in the treatment or prophylaxis of peptic ulcers, enterocutaneous and pancreatic cutaneous fistulas, irritable bowel syndrome, dumping syndrome, water diarrhea syndrome, acute pancreatitis and gastroenteropathic endocrine tumors (eg vipoma, GRF as well as gastrointestinal bleeding, breast cancer and complications associated with diabetes.

The polymeric support can be made of biocompatible and biodegradable polymers, such as linear polyesters, branched polyesters which are linear chains which radiate from a polyol unit or core, e.g. glucose; other esters are those of polylactic acid, polyglycolic acid, polyhydroxybutyric acid, polycaprolactone, polyalkylene oxalate, polyalkylene glycol esters of acids from Krebs cycle, e.g. the citric acid cycle and the like, and copolymers thereof.

The preferred polymers of the present invention are the linear polyesters and the branched chain polyesters. The linear polyesters can be prepared from the alpha-hydroxycarboxylic acids, e.g. lactic acid and glycolic acid, by condensation of the lactone dimers, see e.g. U.S. Patent No. 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 preferably used according to the invention can be prepared using polyhydroxy compounds, e.g. polyol, for example glucose or mannitol, as initiator. These esters of a polyol are known and are described in English patent GB 2 145 422 B. The polyol contains at least three hydroxy groups and has a molecular weight of up to 20,000, wherein at least 1, preferably at least 2, e.g. on average 3, of the hydroxy groups in the polyol are in the form of ester groups which contain polylactide or co-polylactide chains. Typically 0.2! glucose to initiate the polymerization. The structure of the branched polyesters is star-shaped. The preferred polyester chains in the linear polymer compounds and star polymer compounds preferably used in the invention are copolymers of alpha-carboxylic acid units, lactic acid and glycolic acid, or of the lactone dimers. The molar ratios lactide: glycolide are from about 75:25 to 25:75, e.g. 60:40 to 40:60, with from 55:45 to 45:55, e.g. from 55:45 to 50:50 are the most preferred.

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

We have found that an advantage of the star polymer type in the formulations of the present invention is that its molecular weight can be relatively high, which imparts physical stability, e.g. a certain hardness, to implants and to microparticles, which prevents them from sticking together or sticking together, even if relatively short polylactide chains are present, leading to a controllable or controllable biodegradation rate of the polymer in the range of several weeks to one or more two months and to a correspondingly delayed release of the peptide, which makes a depot preparation made therefrom suitable for, for example, one month of release.

The star polymers preferably have an average molecular weight MW in the range from about 10,000 to 200,000, preferably from 25,000 to 100,000, in particular from 35,000 to 60,000, and a polyydispersibility of, for example, from 1.7 to 3.0, e.g. . from 2.0 to 2.5. The intrinsic viscosities of star polymers with MW 35,000 and MW 60,000 are 0.35 and 0.51 dl / g, respectively, in chloroform. A star polymer with a MW of 52,000 has a viscosity of 0.475 dl / g in chloroform.

The terms microsphere, microcapsule and microparticle dye are considered to be equivalent or interchangeable with each other in connection with the invention and indicate encapsulation of the peptides of the polymer, preferably with the peptide distributed in the polymer, which is thereby a matrix for the peptide. In this case, the terms microsphere or more generally microparticle are preferably used.

Using the phase separation technique of the present invention, the formulations of the invention may be prepared, for example, by dissolving the polymeric carrier material in a solvent which is a non-solvent for the peptide, followed by the addition and dispersion of a solution of 10 The peptide in the polymer solvent composition. A phase inducing agent, e.g. a silicone fluid, is then added to induce encapsulation of the peptide of the polymer.

The drug deficiency effect can be significantly reduced by in situ precipitation of ultrafine drug particles by adding a drug solution to the polymer solution before phase separation. The previously known method involves the addition of dry particles directly to the polymer solution.

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

An oil-in-water (= o / w) emulsion can be used to wash and cure the microspheres and remove unencapsulated peptide. The washing helps to remove unencapsulated peptide from the surface of the microspheres. The removal of excess peptide from the microspheres reduces the initial drug deficiency, which is characteristic of many conventional encapsulation formulations. Thus, a more even delivery of drugs with time is possible with the present microsphere preparations.

The emulsion also facilitates the removal of residual polymer solvent and silicone fluid. The emulsion may be added to the polymer peptide mixture, or the mixture may be added to the emulsion. It is preferred that the polymer peptide mixture be added to the emulsion. The o / w emulsion can be prepared using an emulsifier, such as sorbitan monooleate (Span 80 ICI Corp.) and the like, to obtain a stable emulsion. The emulsion can be buffered with a buffer which is not harmful to the peptide and the polymer matrix material. The buffer may be from pH 2 to 8, with pH 4 being preferred. This buffer can be prepared from acidic buffer substances, such as phosphate buffer, acetate buffer and the like. Only water can replace the buffer in question. Heptane, hexane and the like can be used as the organic phase in the buffer in question. The emulsion may contain dispersants, such as silicone oil.

A preferred emulsion may include heptane, pH 4 phosphate buffer, silicone oil and sorbitan monooleate. When an initial drug release may be desired, a single curing step with non-solvent may replace the emulsion curing.

Heptane, hexane and the like can be used as solvents.

Other alternatives to the o / w emulsion can be used to cure the microcapsules, or to cause them to cure, such as: Solvents plus emulsifiers for curing the microcapsules without washing and solvents plus emulsifiers for curing followed by a separate washing step.

The o / w emulsion can be used without the dispersant. With the help of the dispersant, however, aggregation of the dry microcapsule particles due to static electricity is avoided, and it also helps to reduce the level of residual solvent.

Examples of solvents for the polymer matrix material include methylene chloride, chloroform, benzene, ethyl acetate and the like. The peptide is preferably dissolved in an alcoholic solvent, e.g. methanol, which is miscible with the polymer solvent. Phase inducers (coacervatives) are solvents that are miscible with the polymer-drug mixture and cause the embryonic microcapsules to form before curing or curing; Silicone oils are the preferred phase inducers.

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

The microparticles of the present invention can also be prepared by the well-known spray-drying procedure. According to this method, the somatostatin, or a solution of the peptide, is thoroughly mixed in an organic solvent, e.g. methanol, in water or in a buffer, e.g. with pH 3-8, and a solution of the polymer in an organic solvent which is immiscible with the former, e.g. methylene chloride.

The solution, suspension or emulsion formed is then sprayed into a stream of air, preferably hot air. The formed microparticles are collected, e.g. with a cyclone, and, if desired, they are washed, e.g. in a buffer solution with for example pH 3.0 to 8.0, preferably with pH 4.0, or distilled water and dried in vacuo or under pressure, e.g. at a temperature of from 20 to 40 ° C. The washing step can be applied if the particles have so-called in vivo drug deficiency and the extent of the drug deficiency in question would be undesirable. An acetate buffer can be used as a buffer.

Microparticles can be obtained in this way, which show improved somatostatin release profile in vivo.

The invention thus also relates to the microparticles produced by this process. Accordingly, the invention further provides a sustained release formulation which is prepared by mixing a somatostatin or a solution of a somatostatin in methanol or water or a buffer of pH 3- 8 and a solution of the polylactide-co-glycolide in methylene chloride and injecting the resulting solution, emulsion or suspension of somatostatin into the polymer solution in a stream of hot air, collecting the microspheres and washing them in a buffer solution of pH 3 , 0 to 8.0 or distilled water and drying them in a vacuum or negative pressure at a temperature of from 20 to 40 ° C. Compared to microparticles prepared according to the phase separation technique, they do not contain any silicone oil, and this is not even in trace amounts, since no silicone oil was used in the spray drying technique.

The formulations of the invention may also be prepared using a triple emulsion procedure. In a typical technique, peptide is dissolved, e.g. octreotide, in a suitable solvent, e.g. water, and is intensively emulsified in a solution of the polymer, e.g. 50/50 poly (D, L-lactide-co-glycolide) glucose in a solvent which is a non-solvent for the peptide, for example in methylene chloride. Examples of the solvent for the polymer matrix material are methylene chloride, chloroform, benzene, ethyl acetate and the like. The resulting water / oil (w / o) emulsion is further emulsified in an excess of water, which contains an emulsifying substance, e.g. an anionic or non-ionic surfactant or lecithin or a protective colloid, e.g. gelatin, dextrin, carboxymethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, which gives continuous formation of the triple (w / o / w) emulsion. The microparticles are formed by spontaneous precipitation of the polymer and harden by evaporation of the organic solvent. Gelatin helps prevent agglomeration of the microspheres. After sedimentation of the microparticles, the supernatant is decanted, and the microparticles are washed with water and then with acetate buffer. The microparticles are filtered and then dried. The peptide can also be dispersed directly in the polymer solution, after which the resulting suspension is mixed with the gelatinous aqueous phase.

The triple emulsion procedure is known from U.S. Patent No. 4,652,441. According to this patent specification, in a first step, a drug solution (1) is thoroughly mixed in a solvent, e.g. somatostatin in water (column 2, lines 31-32), with an excess of a polylactide-co-glycolide solution (2) in another solvent, wherein the first solvent is insoluble, e.g. methylene chloride to give a water-in-oil (w / o) emulsion (3) of fine drug-containing droplets of (1) in solution (2). In solution (1), a so-called drug-retaining substance (column 1, line 31), e.g. gelatin, albumin, pectin or agar.

In a second step, the viscosity of the inner phase (1) is increased in a suitable manner, such as by heating, cooling, pH change, addition of metal ions or crosslinking of, for example, gelatin with an aldehyde.

In a third step, an excess of water is thoroughly mixed with the w / o emulsion (3) (column 7, lines 52-54), resulting in a W / O / W type ternary layer emulsion. In the excess of water, a so-called emulsifiers be present, if desired, (column 7, line 56), which is selected from the group of, for example, an anionic or non-ionic surfactant or e.g. polyvinylpyrrolidone, polyvinyl alcohol or gelatin.

In a fourth step, the w / 0 / W emulsion was subjected to "in-water drying" (line 52). This means that the organic solvent in the oil layer is desorbed to form microparticles. The desorption is effected in a manner known per se (column 8, lines 3-5), e.g. by depressurizing while stirring (column 8, lines 5-7) or e.g. by blowing nitrogen gas through the oil layer (eg methylene chloride) (line 19). The microparticles formed are recovered by centrifugation or filtration (lines 26-27) and the components not incorporated in the polymer are removed by washing with water (line 29). If desired, the microparticles are heated under reduced pressure to achieve better removal of water and of solvents (eg methylene chloride from the microparticle wall) (rows 30-32). Although the above process is satisfactory for the preparation of preparations according to the invention, the above-mentioned so-called drug-retaining substance, e.g. gelatin, albumin, pectin or agar, still entrapped in the formed microparticles.

We have now found that, while avoiding the addition of the drug-retaining substance (= in solution (1)) and the step of increasing the viscosity of the inner phase, and in excess water of the ternary w / 0 / W emulsion, and retains the action of adding an emulsifying substance or a protective colloid, such as gelatin, satisfactory microparticles can still be obtained. In addition, the microparticles do not contain any drug-retaining substance and only a very small quantity of methylene chloride.

The invention therefore provides a process for the preparation of microparticles, which means that these microparticles are prepared by intensive mixing of: a) a solution of a drug, preferably a somatostatin, especially octreotide, in an aqueous medium, preferably water or a buffer , preferably in a weight / volume ratio of 0.8 to 4.0 g / l to 120 ml, in particular 2.5 / 10, and in a buffer of pH 3-8, in particular an acetate buffer, and B) a solution of a polymer, preferably a polylactide-co-glycolide, as mentioned above, in an organic solvent which is immiscible with the aqueous medium, e.g. methylene chloride, preferably in a weight / volume ratio of 40 g / 90 to 400 ml, in particular 40/100, preferably in such a way that the weight / weight ratio between the drug and the polymer is from 1/10 to 50, in particular 1/16, and the volume / volume ratio of aqueous medium / organic solvent is 1 / 1.5 to 30, in particular 1/10, and intensive mixing of the w / o emulsion of a) ib) together with c) an excess of an aqueous medium, preferably water or a buffer, e.g. an acetate or phosphate buffer, preferably having a pH of 3-8, containing an emulsifying substance or a protective colloid, preferably in a concentration of from 0.01 to 15.02, in particular gelatin, in particular in a concentration of from 0.1 to 3 % by weight, in particular 0.5% by weight, preferably at a volume / volume mixing rate of ab) / c) of from 1/10 to 100, in particular 1/40, without the addition of any drug-retaining substance to the water-in-oil emulsion or use of any intermediate viscosity enhancing step, curing of the embryonic microparticles in the w / O / W emulsion formed by desorption, preferably by evaporation or evaporation, of the organic solvent, preferably methylene chloride, and isolation, optionally washing and drying of the formed microparticles.

The invention also provides the process variant in which the drug is dispersed directly in the polymer solution, after which the resulting dispersion is mixed with the gelatinous aqueous phase. The invention also provides the microparticles produced by these methods. In the same way as microparticles produced according to the spray-drying technique, they do not contain any silicone oil. Compared to microparticles prepared according to the known tripen emulsion process technique, they do not contain any protective colloid.

The sustained release formulations can also be prepared by other per se known methods, e.g. if the peptide is sufficiently stable for the manufacture of an implant, by heating microparticles containing the peptide, e.g. 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 example from 70 to 100 ° C and extruding or extruding and cooling the compact, after which the extrudate is cut and, if necessary, washed and dried.

The formulations of the invention are conveniently prepared under aseptic conditions.

The preparations according to the invention can be used in depot form, e.g. in the form of injectable microspheres or implants.

They can be administered in a conventional manner, e.g. subcutaneous or intramuscular injection, for example for indications known for the medicinal product contained therein.

The sustained release formulations containing octreotide may be administered for all known indications for the octreotide or derivatives thereof, e.g. those described in GB 2 199 829A, pages 89-96, as well as for acromegaly and for breast cancer. The microparticles of the present invention may have a size range of from about 1 to 250 microns in terms of diameter, preferably from 10 to 200, in particular from 10 to 130, e.g. from 10 to 90, um. Implants can be, for example, from about 1 to 10 mm 3. The amount of drug, ie peptide, present in the preparation depends on the desired daily release dose and thus on the biodegradation rate of the encapsulating polymer. The exact amount of peptide can be determined using bioavailability tests. The formulations may contain peptide in an amount of from at least 0.2, preferably from 0.5, to 20% by weight relative to the polymer matrix, preferably from 2.0 to 10, in particular from 3.0 to 6,% by weight. .

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

Suitably the sustained release formulation comprises a somatostatin, e.g. octreotide, in a biodegradable biocompatible polymeric carrier, which upon administration subcutaneously at a dose of 10 mg somatostatin per kg body weight of the animal has a concentration of a somatostatin in the blood plasma of at least 0.3 ng / ml and preferably less than 20 mg. ng / ml for a 30-day period or preferably a 60-day period.

Alternatively, the sustained release formulation suitably comprises a somatostatin, e.g. octreotide, in a biodegradable biocompatible polymeric carrier which, when administered to rabbits intramuscularly at a dose of 5 mg per kg body weight, gives a somatostatin concentration of at least 0.3 ng / ml over a 50 day period and preferably a concentration of not more than 20 ng / ml.

Other preferred properties of the resulting depot preparations containing somatostatin, e.g. octreotide, is, depending on the manufacturing processes used: 15 20 25 30 512 992 25 aa 'onste' Kanig 5 mg somatostatin / kg, intramuscular (0-42 days) 76% (0-42 days) retardation mean plasma level 4 ng / ml (cp, ideal) AUC (0-42 days) 170 ng / ml x days Sgraytgrkniggstgkgikg Correct 10 mg somatostatin / kg subcutaneous retardation (0-42 days)> 75% mean plasma level (cp, ideal) (0-42 days) 4-6 ng / ml AUC <0-42 days) 170-210 ng / ml x dgr ßanig 5 mg somatostatin / kg, intramuscular retardation (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 dgr r 'le ul' nk passed; 10 mg somatoatatin / kg, subcutaneous retardation (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 dgr Kggig 5 mg somatoatatin / kg intramuscular retardation (0-43 / 43 dgr)> 74 % mean plasma level (cp, ideal) (0.42 / 43 dgr) 3.5-6.5 ng / ml AUC (0.42 / 43 dgr) 160-270 ng / ml x dgr 10 15 20 25 30 35 51 The invention thus also provides somatostatin compositions, preferably compositions of octreotide and octreotide analogs, having the following properties: 1. a retardation of at least 70%, preferably at least 74%, e.g. at least 75%, 80%, 88% or at least 89% over a period of from 0 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 for a period of from 0 to 42 days, in rats, when 10 mg of somatostatin is administered subcutaneously, and / or an average plasma level of 3.5-6.5, e.g. 4-6.5, ng / ml for a period of from 0 to 42 or 43 days in rabbits, where 5 mg of somatostatin is administered intramuscularly, and / or 3. an AUC for a period of from 0 to 42 days of at least 160, preferably 170-230, ng / ml x days, for rat, when 10 mg of somatostatin is administered subcutaneously, and / or an AUC for a period of from 0 to 42 or 43 days of at least 160, preferably from 180 to 275, e.g. . from 200 to 275, ng / ml x days for rabbit, when 5 mg of somatostatin is administered intramuscularly.

For quantitative characterization of the above-described sustained release formulations, we use the area deviation (AD) method published by F. Nimmerfall and J. Rosenthaler; Intern.J.Pharmaceut. 12, 1-6 (1986).

Briefly, the AD method calculates the area deviations of the experimental plasma profile from an ideal profile, which is a constant mean plasma level (= cp, ideal) produced by converting the experimental area under the plasma level time curve (AUC) to a rectangle. with 10 15 20 25 30 35 512 992 27 equal area. From the percentage area deviation (referred to as AUC), the percentage deceleration is calculated as follows: 1 deceleration = 100 x (1 - AD / AUC) Using this method, the entire plasma profile is measured measured over a predetermined time period by a single numerical index.

In Proc.natl. Acad.Sci.USA go (1989B) 5688-5692 is described in Figure 4 a plasma level profile of the octapeptide analog of somatostatin of the formula * x D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp- NH2 and ratta.

However, no clear comparison can be made with the plasma level data for the compositions according to the invention in the steering wheel, as has been discussed immediately above, since the described plasma level profile is based on another method of administration (intramuscular injection) and that - which is essential gare - the filling level of the microcapsules (between 2 and 6%) and the dosage amount for administration (25 to 50 mg portions of microcapsules for 30 days, even if determinations were made for at least 45 days) are not specified. In addition, the type of poly used (D1-lactide-co-glycolide) is not exactly described.

The value of the publication in terms of description is thus too great for it to be regarded as a prepublication which anticipates the invention.

The following examples illustrate the invention.

MW for the polymers is the average molecular weight or average molecular weight determined using GLPC using polystyrene as standard. EXAMPLE 1: One g of poly (D, L-lactide-co-glycolide) (50/50 molar, Mw = 45,000; polydispersibility about 1.7) was dissolved in 15 ml of methylene. chloride by magnetic stirring followed by the addition of 75 mg of octreotide acetate dissolved in 0.5 ml of methanol. Fifteen ml of silicone oil (trade name Dow 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 of n-heptane, 100 ml of phosphate buffer pH 4, 40 ml of Dow 360 Medical Fluid, 350 cs, and 2 ml of Span 80 (emulsifier). Stirring was continued for at least 10 minutes. The microparticles formed were recovered by vacuum filtration and dried overnight in a vacuum oven. The yield was approximately 90% microparticles in the size range of 10 to 40 μm.

The microparticles were suspended in a vehicle and IM was administered in a 4 mg dose of octreotide to white New Zealand rabbits. Blood samples were taken periodically, which gave plasma levels of pa from 0.5 to 1.0 ng / ml for 30 days measured by radioimmunoassay (RIA).

EXAMPLE 2: One g of poly (D, L-lactide-co-glycolide> glucose (MW = 45,000; 55/45 molar prepared according to the process in GB 2 145 422 B; polydispersibility about 1.7; prepared from 0.21 glucose) was dissolved in 25 ml of ethyl acetate with magnetic stirring followed by the addition of 75 mg of octreotide dissolved in 3 ml of methanol 25 ml of silicone oil (trade name Dow 360 Medical FLuid, 1000 cs) was added to the polymer-peptide mixture. Stirring was continued for at least 10 minutes The microparticles obtained were recovered by vacuum filtration and dried in a vacuum oven overnight, yielding more than 80% microparticles in the size range of 10 to 40 microns. The microparticles were suspended in a vehicle and IM was administered at a dose of 4 mg octreotide to white New Zealand rabbits. ng / ml for 21 days measured with RIA ššE! EšL_â¿ A solution of 1 5.5 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, Mw 45,000) in 500 ml of methylene chloride. Phase separation was accomplished by adding 500 ml of Dow 360 Medical FLuid (1000 cs) and 800 ml of Dow 360 Medical Fluid (350 cs) to the peptide polymer suspension. The resulting mixture was added to a stirred emulsion consisting of 1800 ml of n-heptane, 2000 ml of sterile water and 40 ml of Span 80.

After stirring for 10 minutes, the microspheres were collected by vacuum filtration.

Half of the product was dried overnight in a vacuum oven at 37 ° C. The residual methylene chloride content was 1.21.

The other half of the product was washed with stirring with 1000 ml of ethanol containing 1 ml of Span 80. After stirring for one hour, the ethanol was decanted, and the microparticles were stirred with 1000 ml of n-heptane containing 1 ml of Span 80. After stirring for 1 hour the microparticles were collected by vacuum filtration and dried overnight in a vacuum oven at 37 ° C. The residual methylene chloride content of the microparticles washed in this way was reduced from 1.21 to 0.12%.

The combined yield of the product was 18.2 g (91%) of microparticles containing 5.6 X octreotide, mean diameter 24 μm, 1.51 residual heptane. The microparticles were suspended in a vehicle and injected intramuscularly at a dose of 5 mg / kg of octreotide into white rabbits. Blood samples were taken periodically, which gave plasma levels from 0.3 to 7.7 ng / ml for 49 days measured by RIA.

EXAMPLE Q: One g of poly (D, L-lactide-co-glycolide) glucose with MW 46,000 (50:50 molar) prepared according to the process described in GB 2 145 422B, polydispersibility about 1.7, prepared from 0.21 glucose ) was dissolved in 10 ml of methylene chloride with magnetic stirring followed by the addition of 75 mg of octreotide dissolved in 0.133 ml of methanol. The mixture was mixed intensively, e.g. using an Ultra-Turax, for one minute at 20,000 rpm, giving 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 droplets were dried in a stream of hot air to form microparticles. These microparticles were collected with a “cyclone” and dried overnight at room temperature in a vacuum oven.

The microparticles were washed with 1/15 molar acetate buffer, pH 4.0, for 5 minutes and dried again at room temperature in a vacuum oven. After 72 hours, the microparticles (0.125 mm mesh size) were sieved to give the final product. The microparticles were suspended in a vehicle and administered i.m. in a dose of 5 mg / kg octreotide to white rabbits (chinchilla bastard) and s.c. at a dose of 10 mg / kg for male rats.

Blood samples were taken periodically, giving plasma levels ranging from 0.3 to 10.0 ng / ml (5 mg dose) in rabbits and from 0.5 to 7.0 ng / ml in rats for 42 days as measured by radioimmunoassay (RIA). ). EXAMPLE 5: Microparticles were prepared by spray drying in the same manner as described for Example 4 with the only change that octreotide was suspended directly in the polymer solution without the use of methanol.

The microparticles were suspended in a vehicle and administered s.c. in a dose of 10 mg / kg octreotide for male dishes. Blood samples were taken periodically, giving plasma levels ranging from 0.5 to 10.0 ng / ml in rats for 42 days as measured by radioimmunoassay (RIA).

EXEHEEL §; A single poly (D, L-lactide-co-glycolide) glucose, MW 46,000 (50:50 molar prepared according to the process from GB 2 145 4225, polydispersibility about 1.7, produced from 0.2 X glucose) was dissolved in 2.5 ml of methylene chloride followed by the addition of 75 mg of octreotide dissolved in 0.125 ml of deionized water. The mixture was mixed intensively, e.g. using an Ultra-Turax, for one minute at 20,000 rpm (internal W / O phase).

One g of Gelatin A was dissolved in 200 ml of deionized water at 50 ° C and the solution was cooled to 20 ° C (outer W phase). The WIO and W phases were mixed intensively. Thereby, the inner W / O phase was separated into small, fine droplets, which were homogeneously dispersed in the outer W phase. The resulting triple emulsion was stirred slowly for one hour. This evaporated the methylene chloride and the microcapsules were cured from the fine droplets of the inner phase. After sedimentation of the microparticles, the supernatant was filtered off with suction and the microparticles were recovered by vacuum filtration and rinsed with water to remove gelatin. Drying, sieving, washing and secondary drying of the microparticles were performed as described for Example 4. The microparticles were suspended in a carrier and administered i.m. in a dose of 5 mg / kg octreotide to white rabbits (chinchilla bastard) and s.c. in a dose of 10 mg / kg for male rats. Blood samples were taken periodically, giving plasma levels ranging from 0.3 to 15.0 ng / ml (5 mg dose) in rabbits and from 0.5 to 8.0 ng / ml in rats for 42 days as measured by radioimmunoassay (RIA). ).

EXAMPLE 7: Microparticles were prepared using the triple emulsion technique in the same manner as described in Example 6 but with three changes: 1. 0.25 ml of acetate buffer, pH 4.0, was used instead of 0.125 ml of water to prepare the internal W / The O phase. 2. Rinsing after collecting the microparticles was performed with 1/45 molar acetate buffer, pH 4.0, instead of water. Additional washing of the microparticle clays was omitted.

EXAMPLE Q: Microparticles were prepared using the triple emulsion technique in the same manner as described for Example 7, with the only change that the inner W / O phase was prepared using water containing 0.71 (w / v) sodium chloride instead. for acetate buffer.

Microparticles were prepared in the same manner as described in Example 6, except that the drug compound was dispersed directly in the polymer solution, after which the resulting dispersion was mixed with the gelatinous aqueous phase.

EXAMPLE 10: Octreotide gammogt 10.19 g of octreotide in the form of free base (10 mM) and 3.88 embononic acid (10 mM> are dissolved in 1 liter of water / dioxane (lzl). yellow powder, ra12 ° D = + 7.5 °, of oxtreotide pamoate hydrate Factor = 1.4, where the factor = the weight of lyphilisate / the weight of octreotide contained therein.

The pamoate can be replaced by octreotide acetate present in the microparticles from Examples 1-9 and has excellent stability.

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. The reaction was carried out by adding 20 ml of silicone fluid (Dow 360 Medical Fluid, 1000 cs), the resulting mixture was added to a stirred emulsion consisting of 100 ml of pH 4 phosphate buffer, 400 ml of n-heptane, 4 ml of Span 80 and 40 ml of silicone fluid. (Dow 360 Medical Fluid, 1000 cs.) After stirring for 10 minutes, the microspheres were collected by vacuum filtration and dried overnight in a vacuum oven 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 subjected to magnetic stirring for 1 hour 34 hours before adding 140 ml of silicone fluid (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 minutes. The resulting microcapsules were collected by vacuum filtration, washed three times with heptane and tufted for 10 minutes under suction. Half of the sample was washed by stirring in water for 10 minutes; 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 microcapsules. Analysis of the washed sample gave 0.5 lypressin and 0.61 for the sample that was not washed with water.

Claims (17)

10 15 20 25 30 35 AT 1. 512 992 35 TKR V Process for the preparation of a microparticle comprising a drug in a biodegradable, biocompatible polymer carrier, man! a) b) c) then e) 2. characterized in that it comprises the steps of dissolving the polymeric carrier material in a suitable solvent, wherein the drug compound is insoluble, adding and dispersing a solution of the drug compound in a suitable solvent, which is a non-solvent for the polymer, in the solution of step a ), adds a phase inducer to the dispersion from step b) to induce microparticle formation, adds an oil-in-water emulsion to the mixture from step c) to cure the microparticle or cause it to cure, and recovers the microparticle. Process for the preparation of microparticles comprising a drug in a biodegradable, biocompatible carrier, (i) characterized by intensively mixing a water-in-oil emulsion formed of an aqueous medium and a water-immiscible organic solvent, wherein the drug is present in one phase and a biodegradable, biocompatible polymer is present in the other, with an excess of aqueous medium containing an emulsifying substance or a protective colloid, to form a water-in-oil-in-water emulsion without adding any drug-retaining substance to said water-in-oil emulsion or using any intermediate viscosity enhancing step, (ii) desorbing the organic solvent therefrom, (iii) isolating and drying the resulting microparticles. Process for the preparation of microparticles comprising a drug compound in a biodegradable, biocompatible polymer, characterized in that (i) intensively mixing a drug compound suspension formed by a drug compound and a water-immiscible organic solvent containing a biodegradable , biocompatible polymer, with an excess of aqueous medium containing an emulsifying substance or a protective colloid, to form an oil-in-water emulsion, the pharmaceutical compound being dispersed in the oil component, without the addition of any drug-retaining substance or the use of any intermediate viscosity enhancing steps, (ii) desorbing the organic solvent therefrom, (iii) isolating and drying the formed microparticles. Process according to claim 2, characterized in that the drug is present in the aqueous medium, that the polymer is present in the organic solvent, that said water-in-oil emulsion is formed by intensive mixing of said aqueous medium containing the drug and said organic solvent containing the polymer, and that said excess aqueous medium contains a protective colloid. »- J = o: 10 15 20 25 30 35 512 992 37 Process according to Claim 2 or 4, characterized in that the medicament is a somatostatin. Process according to claim 5, characterized in that intensively mixing: a) a solution of said somatostatin in water or a buffer in a weight / volume ratio of 0.8 to 4.0 g / l to 120 ml and b) a solution of a polylactide co-glycolide in said organic solvent, which is immiscible with the aqueous medium, in a weight / volume ratio of 40 g / 90 to 400 ml in such a way that the weight / weight ratio of drug to polymer is from 1/10 to 50 and the volume / volume ratio of aqueous medium / organic solvent is 1 / 1.5 to 30, and that the w / o emulsion of a) ib) is intensively mixed together with c) said excess water or a buffer containing the protective colloid at a ratio volume / volume mixing rate for ab) / c) of from 1/10 to 100. Sustained-release formulation, characterized in that it comprises octreotide or a salt or a derivative thereof in a biodegradable, biocompatible polymeric carrier. Sustained-release preparation, characterized in that it comprises a peptide drug compound in a 40/60 to 60/40 polylactide co-glycolide ester of polyol, wherein the polyol moiety is selected from the group of an alcohol containing a (C3-5) carbon chain having from 3 to 6 hydroxyl groups and a mono- or disaccharide, and wherein the esterified polyol has at least 3 polylactide co-glycolide chains. Sustained-release preparation, characterized in that it comprises a peptide drug compound selected from the group of a calcitonin, lypressin or a somatostatin in a linear 40/60 to 60/40 polylactide co-glycolide polymer with chains with a molecular weight MW of between 25,000 and 100,000, a polydispersibility MW / Mn between 1.2 and 2 at a concentration of from 0.2 to 10% by weight of the peptide drug compound therein. Sustained-release formulation according to claim 7, 8 or 9, which when administered subcutaneously to a rat at a dose of 10 mg of drug compound per kg of body weight gives a concentration of the drug compound in the blood plasma of at least 0.3 ng / ml and less than 20 ng / ml over a 30-day period. Sustained-release formulation according to claim 7, 8 or 9, which when administered to a rabbit intramuscularly at a dose of 5 mg of drug compound per kg of body weight gives a concentration of drug compound of at least 0.3 ng / ml and at most ng / ml over a 50 day period. Sustained-release formulation according to claim 7, 8 or 9, which upon administration to a rabbit intramuscularly in a dose of 5 mg of drug compound per kg of body weight gives a retardation of at least 70% over a period of from 0 to 42 or 43 days. Sustained-release formulation according to claim 7, 8 or 9, which when administered to rats subcutaneously at a dose of 10 mg of drug compound per kg of body weight gives an average plasma level (Cp ideal) of from 2.5 to 6.5 ng / ml for a period of from 0 to 42 days. The sustained release formulation according to claim 7, 8 or 9, which when administered to the rabbit intramuscularly in a dose of 5 mg of drug compound per kg of body weight gives an average plasma level (Cp ideal) of from 3.5 to 6.5 ng / ml. The sustained release formulation according to claim 7, 8 or 9, which upon administration to the rat subcutaneously at a dose of 10 mg of drug compound per kg of body weight gives an AUC of 160-230 ng / ml x days for a period of from 0 to 42 or 43 days. The sustained release formulation according to claim 7, 8 or 9, which upon administration to the rabbit intramuscularly at a dose of 5 mg of drug compound per kg of body weight gives an AUC of from 160 to 275 ng / ml x days for a period of from 0 to 42 or 43 days. 17. Octreotide pamoate. l8i. Sustained-release preparation, characterized in that it comprises microproparticles prepared according to any one of claims 1-6, which comprise a peptide drug compound selected from the group of calcitonin and lypressin and pharmaceutically acceptable salts thereof in a biodegradable, biocompatible polymeric matrix.