IT9048113A1 - PROTRACT SALE FORMULATIONS OF WATER SOLUBLE PEPTIDES (CASE 600-7110) - Google Patents

Description

The present invention relates to formulations with prolonged release of medicaments.

In particular, the invention relates to formulations with prolonged release of water-soluble peptides, for example of somatostatin or an analogue thereof such as octreotide, in a biodegradable and biocompatible carrier polymer, for example a matrix or a coating, for example in the form of 'an implant or preferably of microparticles (also known under the name of microcapsules or microspheres).

The invention also relates to such formulations which exhibit satisfactory peptide release profiles over a particular time period.

Peptides often have after their administration, for example orally or parenterally, a poor bioavailability in the blood, for example due to their high biodegradability in the body. When administered orally or nasally, they also often show poor resorption through mucous membranes. It is difficult to obtain a therapeutically active blood peptide rate over a long period of time. The parenteral administration of peptides has been proposed in the form of a formulation deposited in a biodegradable polymer, for example in the form of microparticles or an implant, which allows their prolonged release after a residence time in the polymer that protects the peptide against the enzymatic and hydrolytic influences of biological fluids.

Although some deposit formulations are known for administering peptides by parenteral route in a polymer, in the form of microparticles or of an implant, only in very few cases it has been possible to obtain satisfactory profiles of prolonged release of the peptide. Special measures must be taken to ensure a continuous release of the peptide for a therapeutically active drug rate in serum and, if necessary, to avoid excessively high drug concentrations in the serum causing unwanted drug side reactions.

The release profile of the peptide depends on numerous factors, for example on the type of the peptide and, for example, if this is present in its free form or in another form, for example in the form of salt, which can influence the its solubility in water. Another important factor is the choice of the polymer based on the large number of possibilities described in the literature.

Each polymer has its own biodegradation rate. Free carboxy groups can form which influence the pH value in the polymer thus further compromising the water solubility of the peptide and therefore its release profile.

Other factors that can influence the release profile are the concentration of the peptide in the carrier, the way of its partitioning in the polymer, the shape in the case of an implant and its size.

No somatostatin composition has been marketed to date in a sustained release form for parenteral administration, perhaps because it has not been possible to obtain such a composition with satisfactory serum levels.

Polymer formulations of medicaments intended to give a prolonged or delayed release of the medicament are known.

US patent no. No. 3773 919 discloses controlled release formulations of the medicament in which the medicament, for example a water-soluble peptide, is dispersed in a linear polymer of lactic acid or a linear copolymer of lactic acid and glycolic acid, biodegradable and biocompatible. However, no model of release of the active ingredient has been described and no somatostatin has been mentioned. US patent no. 4293 539 discloses antibacterial formulations in the form of microparticles.

US patent no. 4675 189 discloses protracted release formulations of the decapeptide analogue of LHRH, nafarelin, and other analogues of LHRH in copolymers of lactic and glycolic acids. No release of the peptide has been described.

T. Chang describes in J. Bioeng., Vol. 1, pages 25 to 32 (1976) the prolonged release of enzymes and biological vaccines, starting from microparticles.

Polymers and copolymers of lactic acid and compositions containing them for use in surgical applications and for prolonged release by biodegradation, have been reported in U.S. Pat. Nos. 3991 776, 4076 798 and 4118 470.

The European patent application no. 0203 031 discloses a series of somatostatin analogue octapeptides, for example Compound RC-160 of formula

having a bridge between the -Cys- groups.

The possibility of microencapsulating the somatostatins with a coplmer of lactic and glycolic acids has been mentioned in claim 18, but no instructions are found on how to obtain a continuous therapeutic rate in the serum.

US patent no. 4 Oli 312 indicates that it is possible to obtain a continuous release of an antimicrobial drug, for example polymyxin B, starting from a matrix, in the form of an implant, of a copolymer of lactic and glycolic acids with a low molecular weight ( less than 2000) and having a relatively high glycolic acid unit content when the implant is inserted into the breast canal of a cow. The drug is released in a short period of time, thanks to the high content of glycolic acid units and the low molecular weight of the polymer, both of which favor the rapid biodegradation of the polymer and thus a rapid release of the drug. A relatively high drug content additionally contributes to a rapid release of the drug. The paper mentions no somatostatin and no release is described.

The European patent no. 58481 mentions that a continuous release of a water-soluble peptide starting from a polylactic acid implant is favored by lowering the molecular weight of at least a part of the polymer molecules, introducing glycolic acid units into the polymer molecule, increasing the polymer character polymer blocking when a copolymer of lactic and glycolic acids is used, increasing the drug content of the polymer matrix and enlarging the implant surface.

Although somatostatins are mentioned as an example of water-soluble peptides, no release of somatostatin has been described and it has not been indicated how to combine all these parameters to obtain for example a continuous rate of somatostatin in serum for at least one week, for example one month.

the European patent no. 92918 indicates that continuous release of peptides, preferably hydrophilic peptides, over an extended period of time can be achieved when the peptide is incorporated into a conventional hydrophobic polymeric matrix, for example a polylactic acid, made more accessible for water. by introducing a hydrophilic unit into its molecule, for example of polyethylene glycol, polyvinyl alcohol, dextran, polymethacrylamide. The hydrophilic contribution to the amphiphilic polymer is conferred by all ethyleneoxy groups in the case of a polyethylene glycol unit, by free hydroxy groups in the case of a polyvinyl alcohol unit or a dextran unit, and by amide groups in the case of a polyvinyl alcohol unit. polymethacrylamide. Thanks to the presence of the hydrophilic unit in the polymer molecules, the implant will take on hydrogel properties after water absorption. Somatostatin is mentioned as a hydrophilic peptide, however no release has been described and it has not been indicated what type of polymer is preferred for this peptide and what molecular weight and how many hydrophilic groups it must have.

British patent application 2145 422 B indicates that a prolonged supply of medicaments of different types, for example vitamins, enzymes, antibiotics, antigens, can be achieved over an extended period of time when the medicament is incorporated into a matrix, for example under microcapsule or implant form, consisting of a polymer of a polyol, for example glucose or mannitol, having one or more, preferably at least 3 ester groups with a polylactic acid. The remains of the polyaptic acid preferably contain glycolic acid units. No peptides, for example somatostatins, are mentioned as medicaments which can be used in such matrix.

The present invention relates to formulations with prolonged release, for example formulations of microparticles, of a medicament, especially of a somatostatin or of a somatostatin analogue such as octreotide, water-soluble with hormonal activity, which give a satisfactory piasmatic rate of drug. , for example in a biodegradable and biocompatible polymer, for example in a polymer matrix obtained by microencapsulation. The polymer matrix can be a synthetic or natural polymer.

The microparticles of the present invention can be prepared according to any usual method, for example the organic phase separation method, the spray drying method or the triple emulsion method, whereby the polymer is precipitated together with the medicament and the resulting product is then hardened when the phase separation or triple emulsion method is used.

If desired, the extended release formulations can be in the form of an implant.

The Applicant has found an especially useful modification of the phase separation method for the preparation of microparticles of any medicament.

The present invention therefore equally relates to a process for the preparation of microparticles comprising a medicament in a biodegradable and biocompatible carrier polymer, a process according to which

a) the polymer is dissolved in a solvent in which the drug is not soluble,

b) to the solution obtained under a) a solution of the medicament is added and dispersed in an appropriate solvent, for example an alcohol, which is not a solvent for the polymer,

c) a phase inducing agent is added to the dispersion obtained under b), to cause the formation of microparticles,

d) an oil-in-water emulsion is added to the mixture obtained under c), to harden the microparticles, and

e) the microparticles thus obtained are recovered.

The Applicant has likewise found an especially useful modification of the triple emulsion method for the preparation of microparticles of any medicament.

The present invention therefore relates to a process for the preparation of microparticles, a process according to which

(i) a water-in-oil emulsion formed by an aqueous medium and an organic solvent immiscible with water is intimately mixed, containing in one phase the medicament and in the other phase a biodegradable and biocompatible polymer, with an excess of 'an aqueous medium containing an emulsifier or a protective colloid, to form a water-in-oil-in-water emulsion, without adding any substance which retains the drug to the emulsion, or without carrying out any intermediate steps which increase viscosity , (ii) the organic solvent is removed from this mixture, and (iii) the microparticles obtained are isolated and dried.

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

The invention also relates to:

a) a sustained release formulation comprising a peptide in an ester of a polyol with a poly acid (40/60 to 60/40 lactic-co-glycolic), the remainder polyol being selected from alcohols containing a carbon chain in C3 -C6 and 3 to 6 hydroxy groups and the mono- or di-saccharides, and the polyol being esterified with at least 3 poly (lactic-co-glycolic acid chains;

b) a sustained release formulation comprising a peptide which is a calcitonin, the pressin or a somatostatin, in a 40/60 to 60/40 lactic acid and glycolic acid copolymer having linear chains, a molecular weight Mw between 25000 and 100000 and a MW / MW polydispersibility comprised between 1.2 and 2, in a concentration comprised between 0.2 and 10%, preferably between 2 and 10% by weight of the peptide contained in said formulation;

c) a sustained release formulation comprising octreotide or a derivative thereof, or a salt of the compound, in a biodegradable and biocompatible carrier polymer.

The Applicant has found that a new octreotide salt, pamoate, is very stable in such formulations.

The present invention therefore relates to (i) the octreotide pamoate and (ii) a process for the preparation of the octreotide pamoate according to which the octreotide is reacted with pamoic acid (or with a reactive derivative thereof).

The invention also relates to the use of the extended release formulations according to the invention, especially for the treatment of acromegaly or breast cancer.

The medicaments to be used in the processes of the invention are preferably water-soluble medicaments, for example peptides.

The peptides to be used in the processes and formulations of the present invention may be a calcitonin, for example salmon calcitonin, lipressin, and natural somatostatin and its synthetic analogs.

Natural somatostatin is one of the preferred compounds and is a tetradecapeptide of formula

This hormone is produced by the hypothalamus as well as by other organs, for example the gastrointestinal tract. Somatostatin intervenes at the pituitary level to inhibit the secretions of hGH (somatotropic hormone) and TSH (thyrotropic hormone). At the digestive level, it inhibits numerous secretory processes (in the pancreas, stomach, duodenum and small intestine).

The term "somatostatin" includes its analogs or derivatives. By derivatives and analogues we mean linear, bridged or cyclic polypeptides in which one or more amino acid remains have been suppressed and / or replaced with one or more other amino acid remains and / or in which one or more functional groups have been replaced with one or more other functional groups and / or in which one or more groups have been replaced with one or more other isoster groups, in general, the term includes all modified derivatives of a biologically active peptide that exert a qualitatively similar effect to that of unmodified somatostatin.

Agonist analogues of somatostatin are therefore appropriate to replace natural somatostatin in its effect on the regulation of physiological functions. The preferred known somatostatins are:

[See Vale et al., Metabolism, 27, Supp. 1, 139 (1978)].

where in the above formulas there is a bridge between the amino acids marked with a *.

The contents of all these publications including specific compounds are incorporated herein by reference.

The term "derivative" also includes the corresponding derivatives carrying a carbohydrate remainder. When the somatostatins carry a glucid residue, this is preferably coupled to an N-terminal amino group and / or to at least one amino group present in a side chain of the peptide, more preferably to an N-terminal amino group. Such compounds and their preparation are described for example in WO 88/02756.

The term "octreotide derivatives" includes those containing a remainder

The preferred derivatives are N "- [a-glucosyl- (1-4-deoxifructosyl] -DPh-Cys-Phe-DTrp-Lys-Thr-Cys-Thr-ol and N" - [0-deoxyfructosyl- DPhe-Cys-Phe-DTrp-Lys-Thr-Cys-Thr-ol, each having a bridge between the -Cys- groups, preferably in the form of acetate, and are described respectively in examples 2 and 1 of the aforementioned application.

Somatostatins can be present, for example, in free form, in the form of salt or in the form of complexes. The acid addition salts can be formed with, for example, organic acids, polymeric acids and mineral acids and include, for example, the hydrochlorides and acetates. The complexes are formed for example starting from somatostatins by adding mineral substances, for example mineral salts or hydroxides such as calcium and zinc salts, and / or by adding polymeric organic substances.

Acetate is a preferred salt for such formulations, especially for microparticles which lead to reduced initial release of the drug into the plasma. The present invention also includes pamoate which is useful, in particular for implants. The pamoate can be obtained in the usual way, for example by reacting the embonic acid (pamoic acid) with the octreotide, for example in the form of a free base. The reaction can be carried out in a polar solvent, for example at room temperature.

Somatostatins are indicated for use in the treatment of disorders in which long-term application of the medicinal product is considered, for example disorders with an etiology including or associated with excessive secretion of growth hormone, for example in the treatment of acromegaly, for use in the treatment of gastrointestinal disorders, for example in the treatment of peptic ulcer, enterocutaneous and pancreaticocutaneous fistula, irritable bowel syndrome, dumping syndrome, serous diarrhea syndrome, acute pancreatitis and gastroenteropathic endocrine tumors (e.g. vipoma, GRF-secreting tumors, glucagonoma, pancreatic neoplasia, gastrinoma and cancerous tumors) as well as gastrointestinal bleeding, breast cancer and complications due to diabetes.

The carrier polymer can be prepared from biocompatible and biodegradable polymers such as linear polyesters, branched polyesters which are linear chains attached to a polyol group, for example glucose. Other polyesters are polylactic acid, polyglycolic acid, polyhydroxybutyric acid, polycaprolactone, polyalkylene oxalate, esters of a polyalkylene glycol with acids of the Kreb cycle, for example citric acid and the like, and their copolymers.

The preferred polymers of the present invention are linear polyesters and branched chain polyesters. Linear polyesters can be prepared by condensation of α-hydroxy carboxylic acids, for example lactic acid and glycolic acid, or by polymerization of lactone (acid dimers) (see for example U.S. Pat.

3 773 919).

The linear copolymers of lactic and glycolic acids, preferably used according to the invention, conveniently have a molecular weight of between 25000 and 100000 and a polydispersibility Mw / Mn for example of between 1.2 and 2.

The branched polyesters preferably used according to the invention can be prepared using polyhydroxylated compounds, for example a polyol, for example glucose or mannitol, as initiator. These polyol esters are known and described in British patent application no. GB 2145 422. The polyol contains at least 3 hydroxy groups and can have a molecular weight of up to 20,000, at least 1, preferably at least 2, for example on average 3 of the hydroxy groups of the polyol being in the form of esters containing acid chains polylactic or a copolymer thereof. Typically 0.2% glucose is used to initiate polymerization. The structure of branched polyesters is a star structure. The preferred polyester chains in the linear and star-structured polymers, preferably used according to the invention, are copolymers of a-carboxylic acids, lactic acid and glycolic acid, or of the dimers (lactone). The molar ratio of lactic acid to glycolic acid is between about 75:25 and 25:75, for example between 60:40 and 40:60, the most preferred ratio being between 55:45 and 45:55, for example between 55:45 and 50; 50. The star-shaped polymers are preferably prepared by reaction of a polyol with a dilactide and preferably also with a diglycolide, at a high temperature and in the presence of a catalyst, which makes polymerization with the opening of the lactone cycle possible.

The Applicant has found that an advantage of the star-like polymer in the formulations of the present invention is the fact that its molecular weight can be relatively high, thus conferring physical stability, for example a certain hardness, to the implants and microparticles. which avoids their agglomeration, although relatively short polylactic acid chains are present, and leading to a controllable polymer biodegration rate of between several weeks and one or two months and a corresponding delayed release of the peptide, so that a formulation deposit prepared with such a polymer is suitable for example for a one-month release.

The star-structured polymers preferably have an average molecular weight comprised between about 10,000 and 200,000, preferably between 25,000 and 100,000, especially between 35,000 and 60,000, and a polydispersibility comprised for example between 1.7 and 3.0, for example between 2.0 and 2.5. The intrinsic viscosities of star-structured polymers of Mw 35000 and 60 000 are respectively 0.36 and 0.51 dl / g in chloroform. A star structure polymer having a of 52000 has a viscosity of 0.475 dl / g in chloroform.

The terms "microsphere", "microcapsule" and "microparticle" are considered to be interchangeable with respect to the invention and denote the microencapsulation of the peptides with the polymer, preferably with the peptide distributed throughout the polymer which then forms a matrix for the peptide . In this case, the terms "microsphere" or more generally "microparticle" are preferably used.

Using the phase separation method of the present invention, the formulations of the invention can be prepared for example by dissolving the polymer carrier in a solvent in which the peptide is insoluble, followed by addition and dispersion of a solution of the peptide in the composition polymer-solvent. A phase inductor, for example a fluid silicone, is then added to induce microencapsulation of the peptide with the polymer.

The piasmatic peak can be significantly reduced by in situ precipitation of ultrafine drug particles by adding a drug solution to the polymer solution prior to phase separation. The state of the art includes the addition of dry particles directly to the polymer solution.

The release duration and the therapeutic activity of the peptide can be increased with a hardening / washing step of the microparticles with a buffer / heptane emulsion. The state of the art process comprises a cure followed by no subsequent washing, or by a separate aqueous wash.

An oil-in-water emulsion can be used to wash and harden the microparticles and remove the unencapsulated peptide, washing facilitates the removal of the unencapsulated peptide from the surface of the microparticles. The elimination of the excess peptide from the microparticles decreases the initial piasmatic peak, characteristic for many formulations obtained by usual microencapsulation. The formulations according to the present invention therefore allow a more consistent drug release over a period of time. The emulsion also facilitates the elimination of the residual solvent of the polymer and of the fluid silicone. The emulsion can be added to the polymer and peptide mixture, or the mixture can be added to the emulsion. It is preferable to add the mixture of polymer and peptide to the emulsion. The oil-in-water emulsion can be prepared using an emulsifier such as sorbitan mono-oleate (Span 80 ICI Corp.) and the like, to form a stable emulsion. The emulsion can be buffered with a buffer which is not harmful to the peptide and the polymer matrix. The buffer substance may have a pH of between 2 and 8, a pH of 4 being preferred. The buffer substance can be prepared from acidic buffering agents such as phosphate, acetate, etc. Water alone can replace the buffer. Heptane, hexane, etc., can be used as the organic phase of the emulsion. The emulsion may contain dispersants such as silicone oil.

A preferred emulsion may contain heptane, a pH 4 phosphate buffer, silicone oil and sorbitan mono-oleate. When a release of the medicament is desired already at the beginning of the application, the hardening / washing step can be replaced with a washing step with an organic solvent such as heptane, hexane, etc.

Other alternatives to the oil-in-water emulsion can be employed to harden the microparticles, i.e .:

Solvent plus emulsifier for hardening of microparticles without washing; and solvent plus emulsifier for curing followed by a separate wash.

The oil-in-water emulsion can be used without the dispersant. However, the dispersant avoids the aggregation of dry microparticles due to static electricity and helps reduce the residual solvent level.

As examples of solvents for the polymer matrix, methylene chloride, chloroform, benzene, ethyl acetate, etc. can be mentioned. The peptide is preferably dissolved in an alcoholic solvent, for example methanol, which is miscible with the solvent of the polymer.

The phase inducers (coacervation agents) are solvents miscible with the polymer-drug mixture and cause the formation of embryonic microparticles before hardening; silicone oils are the preferred phase inductors.

The oil-in-water emulsion can be prepared in the usual manner using heptane, hexane, etc., for the organic phase.

The microparticles of the present invention can also be prepared according to the generally known process of drying by pulverization. According to this method, somatostatin, or a solution of this peptide in an organic solvent, for example methanol, is thoroughly mixed in water or in a buffer substance, for example of a pH between 3 and 8, with a solution of the polymer in an organic solvent, not miscible with the first, for example methylene chloride.

The solution, suspension or emulsion thus formed is then pulverized in a jet of air, preferably a jet of hot air. The generated microparticles are collected, for example with a cyclone, and, if desired, are washed, for example in a buffer solution of for example a pH of between 3.0 and 8.0, preferably of pH 4.0, or in distilled water, and dried under vacuum, for example at a temperature between 20 and 40 ° C. Washing can be done when the particles show an in vivo piasmatic rate and if the plasma rate is not desired to be too important. An acetate buffer can be used as a buffer.

It is therefore possible to obtain microparticles which show an improved release of somatostatin in vivo.

The invention therefore equally relates to the microparticles prepared according to this process. The invention also relates to a prolonged release formulation prepared by mixing a somatostatin or a solution of a somatostatin in methanol or water or a buffer substance of pH between 3 and 8 and a solution of the lactic acid copolymer and the 'glycolic acid in methylene chloride and pulverizing in a jet of hot air the solution, emulsion or suspension formed of somatostatin in the polymer solution, collecting the microparticles and washing them in a buffer solution with a pH between 3, 0 and 8.0 or in distilled water and drying them under vacuum at a temperature between 20 and 40 ° C. In comparison to microparticles prepared according to the phase separation method, they do not contain silicone oil, even in trace amounts, since silicone oil is not used in the spray drying method.

The formulations of the invention can likewise be prepared using a triple emulsion process. According to a typical method, the peptide, for example the octreotide, is dissolved in an appropriate solvent, for example water, and is emulsified in the polymer solution, for example the poly (D, L-lactic-co-glycolic acid) glucose. 50/50, in a solvent in which the peptide is not soluble, for example methylene chloride. As examples of suitable solvents for the polymer matrix, methylene chloride, chloroform, benzene, ethyl acetate, etc. can be mentioned. The resulting water-in-oil emulsion is emulsified in an excess of water containing an emulsifying substance, for example an anionic or non-ionic surfactant or lecithin, or a protective colloid, for example gelatin, dextrin, carboxymethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, which allows a continuous generation of the triple emulsion (water / oil / water). The microparticles are formed by spontaneous precipitation of the polymer and are hardened by evaporation of the organic solvent. Gelatin is used to avoid agglomeration of microparticles. After sedimentation of the microparticles, the supernatant is decanted and the microparticles are washed with water and then with an acetate buffer. The microparticles are then filtered and dried.

The peptide can also be dispersed directly into the polymer solution, after which the suspension obtained is mixed with the aqueous phase containing gelatin. The triple emulsion process is known from U.S. Pat. 4652 441. According to this patent, a solution of active ingredient (1) in a solvent, for example somatostatin in water (column 2, lines 31-32), is thoroughly mixed in a first stage with an excess of a solution of poly (lactic acid-co-glycolic acid) (2) in another solvent, in which the first solvent is not soluble, for example 11 methylene chloride, which gives a water-like emulsion in oil (3) of fine droplets of solution (1) in solution (2). In solution (1), a so-called active substance retaining substance (column 1, row 31) is dissolved in addition, for example gelatin, albumin, pectin, or agar. In a second step, the viscosity of the inner phase (1) is increased by appropriate means, for example by heating, cooling, changing the pH, adding metal ions or crosslinking, for example, gelatin with an aldehyde, in a third stage, an excess of water is thoroughly mixed with the water-in-oil emulsion (3), (column 7, lines 52-54), which gives a triple emulsion of the water / -oil / water type. If desired, a so-called emulsifier (column 7, row 56) may be present in the excess water, selected from the group comprising, for example, an anionic or non-ionic surfactant or, for example, polyvinylpyrrolidone, polyvinyl alcohol or jelly. In a fourth step, the emulsion of the water / oil / water type is subjected to a "drying in water" (line 52). this means that the organic solvent in the oil layer is desorbed to generate microparticles, the desorption is carried out in a per se known manner (column 8, rows 3-5), for example by decreasing the pressure under stirring (column 8, lines 5-7) or for example by blowing nitrogen through the oil layer (for example methylene chloride) (line 19). The formed microparticles are recovered by centrifugation or filtration (lines 26-27) and the components which are not incorporated into 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 solvent (e.g. methylene chloride from the microparticle wall, lines

30-32). However, although the aforementioned process is satisfactory for the preparation of formulations according to the invention, the so-called active substance retaining substance mentioned above, for example gelatin, albumin, pectin or agar, is still included in the microparticles. resulting.

The Applicant has now found that by omitting the addition in solution (1) of the substance which retains the active principle and the step for increasing the viscosity of the internal phase and maintaining the addition of an emulsifying substance or a protective colloid in the excess water of the triple water / oil / water emulsion, satisfactory microparticles can also be obtained. Furthermore, the microparticles do not contain any substance that retains the active ingredient and contain only a very small amount of methylene chloride.

The invention therefore relates to a process for the preparation of microparticles according to which the following are intimately mixed:

a) a solution of an active ingredient, preferably a somatostatin, especially the octreotide, in an aqueous medium, preferably water or a buffering agent, preferably in a weight / volume ratio of 0.8 to 4.0 g / 1 to 120 ml, especially 2.5 / 10 and in a buffering agent of pH 3-8, especially an acetate buffering agent, and

b) a solution of a polymer, preferably a poly (lactic acid-co-glycolic acid) as mentioned above, in an organic solvent, not miscible with the aqueous medium, for example methylene chloride, preferably in a weight / volume ratio 40 g / 90 to 400ml, especially 40/100, preferably in such a way that the weight ratio of the active ingredient to the polymer is 1/10 to 50, especially 1/16 and the volume / volume ratio of the aqueous medium to organic solvent is 1 / 1.5 to 30, especially 1/10, and the water emulsion in the oil of a) and b) is intimately mixed together with

c) an excess of an aqueous medium, preferably water or a buffering agent, for example an acetate or phosphate buffer, preferably of a pH of 3-8, containing an emulsifying substance or a protective colloid, preferably in a concentration of between 0.01 and 15.0%, in particular gelatin, especially in a concentration of between 0.1 and 3%, in particular of 0.5% by weight, preferably at a rate mixing volume / volume of ab) / c) between 1/10 and 100, especially 1/40,

without adding to the emulsion water in the oil any substance that retains the active principle or without applying any intermediate stage to increase the viscosity, the embryonic microparticles in the water / oil / water emulsion formed are hardened by dissorption, preferably by evaporation of the solvent organic, preferably methylene chloride, e

the generated microparticles are isolated, possibly washed and dried.

The invention also relates to the variant of the process according to which the active principle is dispersed directly in the polymer solution and the dispersion obtained is subsequently mixed with the aqueous phase containing gelatin. The invention also relates to the microparticles prepared according to these processes. Like the microparticles prepared according to the spray drying method, they do not contain silicone oil. In comparison to the microparticles prepared according to the known triple emulsion process, they do not contain any protective colloids

The extended release formulations can also be prepared according to other methods known per se, for example, if the peptide is stable enough for the preparation of an implant, by heating the microparticles containing the peptide, for example a somatostatin, in a poly (lactic acid-co-glycolic acid), especially as described above, or a mixture obtained by mixing the peptide and the polymer, at a temperature ranging for example between 70 and 100 ° C and subjecting the compact mass to extrusion and cooling, after which the extruded product is cut and possibly washed and dried.

The formulations according to the invention are conveniently prepared under aseptic conditions.

The formulations according to the invention can be used in the deposit form, for example in the form of injectable microparticles or implants.

They can be administered in the usual way, for example by subcutaneous or intramuscular injection, for example for the known indications for the active ingredient contained in the formulations.

The extended release formulations containing octreotide can be administered for all known indications for octreotide or its derivatives, for example those described in British patent application 2199 829, pages 89-96, as well as for the treatment of acromegaly and carcinoma mammary.

The microparticles of the present invention can have a diameter comprised between about 1 and 250 μ, preferably between 10 and 200, especially between 10 and 130, for example between 10 and 90 μ. The implants can have a volume, for example, between about 1 and 10 mm3. The quantity of active principle, i.e. of peptide present in the formulation depends on the desired daily dose to be released and therefore on the biodegradation rate of the encapsulating polymer. The exact amount of peptide can be determined by bioavailability tests. The formulations can contain the peptide in an amount of at least 0.2, preferably between 0.5 and 20% by weight with respect to the polymer matrix, preferably between 2.0 and 10, especially between 3.0 and 6% by weight.

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

The extended release formulations conveniently comprise a somatostatin, for example the octreotide, in a biodegradable and biocompatible carrier polymer, which, administered subcutaneously to a rat at a dose of 10 mg of somatostatin per kg of body weight of the animal, have a piasmatic concentration of somatostatin of at least 0.3 ng / ml and preferably less than 20 ng / ml over a period of 30 days, or conveniently a period of 60 days.

Alternatively, the prolonged release formulations conveniently comprise a somatostatin, for example the octreotide, in a biodegradable and biocompatible polymer carrier, which, administered to a rabbit intramuscularly at a dose of 5 mg per kg of body weight of the animal, they have a plastmatic concentration of somatostatin of at least 0.3 ng / ml over a period of 50 days and conveniently a concentration of at most 20 ng / ml.

Other preferred properties of the obtained prolonged release formulations containing a somatostatin, for example the octreotide, depend on the preparation processes used.

Phase separation method

Rabbit 5 mg of somatostatin / kg, intramuscularly

Spray drying method

Rat 10 mg of somatostatin / kg, subcutaneously

Rabbit 5 mg of somatostatin / kg, intramuscularly

Triple emulsion method

Rat 10 mg of somatostatin / kg, subcutaneously

Rabbit 5 mg of somatostatin / kg, intramuscularly

The invention therefore equally relates to compositions containing somatostatin, preferably the octreotide and the analogues of the octreotide, having the following properties: 1) a delay of at least 70%, preferably of at least 74%, for example of at least 75 %, 80%, 88% or at least 89% over a period of 0 to 42 or 43 days and / or

2) a mean piasmatic rate (cp, ideal) of 2.5-6.5, preferably 4-6.5 ng / ml over a period of 0 to 42 days, in rats, when subcutaneously administered 10 mg of somatostatin, and / or a mean piasmatic rate of 3.5-6.5, for example 4-6.5 ng / ml over a period of 0 to 42 or 43 days, in rabbits, when given intramuscularly 5 mg of somatostatin and / or

3) an ASC over a period of 0 to 42 days of at least 160, preferably between 170 and 230 ng / ml x days, for the rat, when subcutaneously administered 10 mg of somatostatin, and / or an ASC on a period of 0 to 42 or 43 days of at least 160, preferably between 180 and 275, for example between 200 and 275 ng / ml x days, for the rabbit, when intramuscularly administered 5 mg of somatostatin.

For the quantitative characterization of the protracted release formulations described above, the Applicant used the surface deviation method (AD = area deviation) published by F. Nimmerfall and J. Rosenthaler; intern. J. Phacmaceut. 32, 1-6 (1986). Briefly, the AD method is used to calculate the surface deviations of the experimental piasmatic profile in comparison to the ideal profile which is a constant mean piasmatic rate (cp, ideal) obtained by converting the area under the experimental curve into a rectangle with equal surface. piasmatic rate as a function of time (ASC). The delay in% is calculated as follows:

delay in% - 100 x (1 - AD / ASC).

According to this method, the entire piasmatic profile, measured over a preselected period of time, is characterized by means of a single numerical index.

In Proc. Born. Acad. Sci. USA (55 (1988), 5688-5692, a piasmatic profile of the octapeptide analogue of somatostatin of formula

in the rat.

However, a clear comparison cannot be made with the aforementioned plasma rates of the compositions of the invention in the rat, since the piasmatic profile described is based on another method of administration (intramuscular injection) and, more importantly, the concentration of the active ingredient in the microcapsules (between 2 and 6%) and the dose to be administered (from 25 to 50 mg of microcapsules for 30 days, although determinations have been made for at least 45 days) have not been indicated exactly. furthermore, the type of poly ((D) -lactic-co-glycolic acid) employed has not been exactly described. Taking into account the insufficiency of data, this document can therefore in no way be considered as giving any teaching, in particular on the well-defined formulations of the invention having the advantages already mentioned, especially the plasma rates as reported above. The following examples illustrate the present invention without limiting its scope in any way. Mw means the average molecular weight of the polymers determined for GLPC using polystyrene as the reference substance.

EXAMPLE 1

1 g of poly (D, L-lactic-co-glycolic acid) (50/50 molar, Mw - 45000; polydispersibility about 1.7) is dissolved in 15 ml of methylene chloride under magnetic stirring and then added 75 mg of octreotide acetate in solution in 0.5 ml of methanol. To the mixture of the polymer and the peptide, 15 ml of silicone oil (brand Dow 360 Medicai Fluid 1000 cs) (silicone fluid) is added. The mixture obtained is added to an emulsion under stirring containing 400 ml of n-heptane, 100 ml of phosphate buffering agent of pH 4, 40 ml of Dow 360 Medicai Fluid, 350 cs and 2 ml of Span 80 (emulsifier). The stirring is continued for at least 10 minutes. The microparticles are recovered by filtration under reduced pressure and dried overnight in an oven under reduced pressure. The yield is about 90% of microparticles having a size between 10 and 40 μ.

The microparticles are suspended in a vehicle and administered intramuscularly to white rabbits (New Zealand) at a dose of 4 mg of octreotide. Blood samples are taken periodically; plasma rates, determined by radioimmunoassay, range from 0.5 to 1.0 ng / ml for 30 days.

EXAMPLE 2

1 g of poly (acid D, L-lactic-co-glycolic acid) glucose (Mw - 45000, 55/45 molar prepared according to the procedure of GB 2145 422 B; polydispersibility about 1.7; prepared starting from 0 , 2% glucose) in 25 ml of ethyl acetate under magnetic stirring and then 75 mg of octreotide in solution in 3 ml of methanol are added. To the mixture of the polymer and the peptide, 25 ml of silicone oil (brand Dow 360 Medicai Fluid, 1000 cs) is added. The mixture obtained is added to the emulsion described in example 1. The stirring is continued for at least 10 minutes. The microparticles obtained by filtration under reduced pressure are recovered and dried overnight in an oven under reduced pressure. The yield is greater than 80% of microparticles having a size between 10 and 40 μ.

The microparticles are suspended in a vehicle and administered intramuscularly to white rabbits (New Zealand) at a dose of 4 mg of octreotide. Blood samples are taken periodically; plasma rates, determined by radioimmunoassay, range from 0.5 to 2.0 ng / ml for 21 days.

EXAMPLE 3

A solution of 1 , 5 g of octreotide acetate in 20 ml of methanol. Phase separation is carried out by adding 500 ml of Dow 360 Medicai Fluid (1000 cs) and 800 ml of Dow 360 Medicai Fluid (350 cs) to the suspension of the peptide and polymer. The mixture obtained is added to an emulsion under stirring consisting of 1800 ml of n-heptane, 2000 ml of sterile water and 40 ml of Span 80. After stirring for 10 minutes, the microparticles are collected by filtration under reduced pressure .

Half of the product is dried overnight in an oven under reduced pressure at 37 ° C. The residual methylene chloride content is 1.2%.

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

The combined yield of the product is 18.2 g (91%) of microparticles containing 5.6% of octreotide; average diameter - 24 μ; residual heptane - 1.5%.

The microparticles are suspended in a vehicle and injected intramuscularly into white rabbits at a dose of 5 mg / kg of octreotide. Blood samples are taken periodically; plasma rates, determined by radioimmunoassay, range from 0.3 to 7.7 ng / ml for 49 days.

EXAMPLE 4

1 g of poly (acid D, L-lactic-co-glycolic acid) glucose (Mw - 46000; 50/50 molar prepared according to the procedure of GB 2145 422 B, polydispersibility about 1.7, prepared starting from 0 , 2% glucose) in 10 ml of methylene chloride under magnetic stirring and then 75 mg of octreotide in solution in 0.133 ml of methanol are added. The mixture is mixed intimately, for example with the aid of an Ultra-Turax apparatus, for 1 minute at 20,000 rpm, which gives a suspension of very small octreotide crystals in the polymer solution. The suspension is pulverized by means of a high-speed turbine (Niro Atomizer) and the droplets are dried in a jet of hot air that generates microparticles. The microparticles are collected by means of a "cyclone" and dried overnight at room temperature in an oven under reduced pressure. The microparticles are washed for 5 minutes with a 1/15 molar acetate buffering agent of pH 4.0 and dried again at room temperature in an oven under reduced pressure. After 72 hours the microparticles are sieved (mesh size - 0.125 mm) to obtain the final product.

The microparticles are suspended in a vehicle and administered intramuscularly to white rabbits (mongrel chinchillas) at a dose of 5 mg / kg of octreotide and subcutaneously to male rats at a dose of 10 mg. / kg of octreotide. Blood samples are taken periodically; plasma rates, determined by radioimmunoassay, are between 0.3 and 10.0 ng / ml (5 mg dose) in rabbits and between 0.5 and 7.0 ng / ml in rats for 42 days.

EXAMPLE 5

Proceeding as described in Example 4, microparticles are prepared according to the method of drying by pulverization, with the only exception that the octreotide is suspended directly in the polymer solution, without using methanol.

The microparticles are suspended in a vehicle and administered subcutaneously to male rats at a dose of 10 mg / kg of octreotide. Blood samples are taken periodically; the plaematic rates, determined by radioimmunoassay, are between 0.5 and 10.0 ng / ml in rats for 42 days.

EXAMPLE 6

1 g of poly (acid D, L-lactic-co-glycolic acid) glucose (M „- 46000, 50/50 molar prepared according to the procedure of GB 2145 422 B, polydispersibility about 1.7, prepared starting from 0.2% glucose) in 2.5 ml of methylene chloride and then 75 mg of octreotide in solution in 0.125 ml of deionized water are added. The mixture is mixed intimately, for example with the aid of an Ultra-Turax device, for 1 minute at 20,000 rpm (water phase in the internal oil).

1 g of Gelatin A is dissolved in 200 ml of deionized water at 50 ° C and the solution is cooled to 20 ° C (external aqueous phase). The water in the oil and aqueous phases are intimately mixed, thus separating the water phase in the internal oil into droplets which are homogeneously suspended in the external aqueous phase. The triple emulsion obtained is stirred slowly for one hour, thus evaporating the methylene chloride and hardening the microcapsules starting from the droplets of the internal phase. After sedimentation of the microparticles, the supernatant is removed by aspiration and the microparticles are recovered by filtration under reduced pressure and rinsed with water to remove the gelatin. The microparticles are dried, sieved, washed and dried a second time as described in Example 4.

The microparticles are suspended in a vehicle and administered intramuscularly to white rabbits (mongrel chinchillas) at a dose of 5 mg / kg of octreotide and subcutaneously to male rats at a dose of 10 mg. / kg of octreotide. Blood samples are taken periodically; plasma rates, determined by radioimmunoassay, are between 0.3 and 15.0 ng / ml (5 mg dose) in rabbits and between 0.5 and 8.0 ng / ml in rats for 42 days.

EXAMPLE 7

Microparticles are prepared according to the triple emulsion method proceeding as described in Example 6, with the following three exceptions:

1) to prepare the water phase in the internal oil, 0.25 ml of acetate buffering agent of pH 4.0 are used, instead of 0.125 ml of water;

2) 1/45 molar of a buffer agent of pH 4.0 is used for rinsing the collected microparticles, instead of water;

3) the further washing of the microparticles is omitted.

EXAMPLE 8

Microparticles are prepared according to the triple emulsion method proceeding as described in Example 7, with the only exception that the water phase in the internal oil is prepared using water containing 0.7% (weight / volume) of chloride of sodium instead of an acetate buffering agent. EXAMPLE 9

Microparticles are prepared by proceeding as described in example 6, with the only difference that the active principle is dispersed directly in the polymer solution and the dispersion obtained is then mixed with the aqueous phase containing gelatin.

EXAMPLE 10

Pamoate of octreotide

10.19 g of octreotide in the form of free base (10 millimoles) and 3.88 g of embonic acid (10 millimoles) are dissolved in 1 liter of water / dioxane (1: 1). The reaction mixture is filtered and lyophilized, which gives the hydrated octreotide pamoate in the form of a yellow powder; [a] <20> D - 7.5 ° (c = 0.35 in the dimethylformamide). Factor - 1.4 where the factor - weight of lyophilisate / weight of the ttreotide contained in it.

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

EXAMPLE 11

To a solution of 100 mg of calcitonin in 1.5 ml of methanol, a solution of 1 g of poly (acid D, L-lactic-co-glycolic acid) (50:50 molar, Mw - 36100) is added under stirring in 20 ml of methylene chloride. Phase separation is carried out by adding 20 ml of fluid silicone (Dow 360 Medicai Fluid, 1000 cs). The mixture obtained is added to an emulsion under stirring consisting of 100 ml of a pH 4 phosphate buffering agent, 400 ml of n-heptane, 4 ml of Span 80 and 40 ml of fluid silicone (Dow 360 Medicai Fluid, 1000 cs). After stirring for 10 minutes, the microparticles are collected by filtration under reduced pressure and dried overnight in an oven under reduced pressure at 37 ° C. A yield of 1.1 g of microparticles containing 5.9% of calcitonin is obtained.

EXAMPLE 12

To 100 mg of lipressin, a solution of 9.9 g of poly (D, L-lactic-co-glycolic acid) (50/50 molar, Mw = 44300) in 140 ml of methylene chloride is added. The dispersion is subjected to magnetic stirring for one hour before adding 140 ml of fluid silicone (Dow 360 Medicai Fluid, 1000 cs) and 2.5 ml of Span 80. The mixture is added to 2000 ml of heptane and stirred. for 10 minutes. The microparticles obtained are collected by filtration under reduced pressure, washed three times with heptane and dried for 10 minutes under suction. Half of the sample is washed under stirring in water for 10 minutes; the other half was not washed. Both samples are dried overnight in an oven under reduced pressure at 30 ° C. The total yield is 10.65 g of microparticles. The analysis gave a lipressin content of 0.5% for the washed sample and 0.6% for the unwashed sample.

Claims (1)

R i v e n d i c a z i o n i 1) A process for the preparation of microparticles comprising a medicament in a biodegradable and biocompatible carrier polymer, characterized in that a) the polymer is dissolved in an appropriate solvent in which the medicament is not soluble, b) to the solution obtained under a) a solution of the medicament is added and dispersed in an appropriate solvent, which is not a solvent for the polymer, c) a phase inducing agent is added to the dispersion obtained under b), to cause the formation of microparticles, d) an oil-in-water emulsion is added to the mixture obtained under c), to harden the microparticles, and e) the microparticles thus obtained are recovered. The microparticles obtained according to the process specified in claim 1. 3) A process for the preparation of microparticles comprising a medicament in a biodegradable and biocompatible vehicle, characterized in that (i) a water-in-oil emulsion formed by an aqueous medium and an organic solvent immiscible with water is intimately mixed, containing in one phase the medicament and in the other phase a biodegradable and biocompatible polymer, with an excess of 'an aqueous medium containing an emulsifier or a protective colloid, to form a water-in-oil-in-water emulsion, without adding any substance that retains the drug to the emulsion, or without carrying out any intermediate steps which increase viscosity , (ii) the organic solvent is removed from this mixture, and (iii) the microparticles obtained are isolated and dried. A process for the preparation of microparticles comprising a medicament in a biodegradable and biocompatible polymer, characterized in that (i) a suspension of medicament consisting of a medicament and an organic solvent immiscible with water, containing a biodegradable and biocompatible polymer, is intimately mixed with an excess of an aqueous medium containing an emulsifier or a protective colloid, to forming an oil-in-water emulsion, the medicament being dispersed in the oil, without adding any substance which the medicament retains or carrying out any intermediate step which increases the viscosity, (ii) the organic solvent is removed from this mixture, and (iii) the microparticles obtained are isolated and dried. A process for the preparation of microparticles, characterized in that a) a solution of an active principle in an aqueous medium and b) a solution of a polymer in an organic solvent, not miscible with the aqueous medium, are intimately mixed, and intimately mix the water emulsion in the oil of a) and b) together with c) an excess of an aqueous medium containing a protective colloid, without adding to the emulsion water in the oil any substance which retains the active principle or without applying any intermediate step to increase viscosity, the embryonic microparticles are hardened in the water / oil / water emulsion formed, by dissorption, and the generated microparticles are isolated. A process according to claim 5, characterized in that the active principle is a somatostatin. 7 A process according to claim 6, characterized in that the active principle is the octreotide. A process according to claim 7, characterized in that the active principle is octreotide pamoate. 9 A process according to any one of the claims; - 5 to 8, characterized in that the polymer is a poly (lactic acid-co-glycolic acid). A process according to claim 5, characterized in that the aqueous medium is water or a buffer. 11) A process according to claim 10, characterized in that the medium is a buffer of pH 3 to 8. 12) A process according to claim 5, characterized in that the organic solvent is methylene chloride. 13) A process for the preparation of microparticles, characterized in that they are intimately mixed a) a solution of a somatostatin in water or in a buffering agent in a weight / volume ratio of 0.8 to 4.0 g / 1 to 120 ml e b) a solution of a poly (lactic acid-co-glycolic acid) in an organic solvent, immiscible with the aqueous medium, in a weight / volume ratio of 40 g / 90 to 400 ml so that the weight ratio of the active ingredient to the polymer is 1/10 to 50 and the volume / volume ratio of the aqueous medium to the organic solvent is 1 / 1.5 to 30, and the water emulsion in the oil of a) and b) is intimately mixed together with c) an excess of water or a buffering agent containing a protective colloid at a volume / volume mixing rate of ab) / c) between 1/10 and 100, without adding water in the oil to the emulsion any substance that retains the active principle or without applying any intermediate stage to increase viscosity, the embryonic microparticles in the water / oil / water emulsion formed by evaporation of the organic solvent harden and isolate themselves the microparticles generated. 14) a process according to claim 13, characterized in that the protective colloid is gelatin A process for the preparation of microparticles, characterized in that they are intimately mixed a) a solution of a somatostatin in an aqueous medium in a weight / volume ratio of 2.5 g / 10 ml and b) a solution of a poly (lactic acid-co-glycolic acid) in an organic solvent, not miscible with the aqueous medium, in a weight / volume ratio of 40 g / 100 ml so that the weight ratio of the principle active to the polymer is 1/16 and the volume / volume ratio of the aqueous medium to the organic solvent is 1/10, and the water emulsion in the oil of a) in b) is intimately mixed together with c) an excess of an aqueous medium containing a protective colloid in a concentration of between 0.01 and 15.0% at a volume / volume mixing rate of ab) / c) of 1/40, without adding water in the oil to the emulsion any substance that retains the active principle or without applying any intermediate stage to increase viscosity, the embryonic microparticles in the water / oil / water emulsion formed by evaporation of the organic solvent harden and isolate themselves the microparticles generated. A process for the preparation of microparticles, characterized in that they are intimately mixed a) a solution of octreotide in a weight / volume ratio of 2.5 g / 10 ml in a buffering agent of pH 3 to 8 and b) a solution of a lactic polyacid-co-glycolic acid) in methylene chloride in a weight / volume ratio of 40 g / 100 ml so that the 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, the water emulsion in the oil of a) in b) is intimately mixed together with c) an excess of a buffering agent of pH 3 to 8, containing gelatin in a concentration of 0.5% by weight at a volume / volume mixing rate of ab) / c) of 1/40, without adding to the water emulsion in oil any substance that retains the active principle or without applying any intermediate stage to increase viscosity, the embryonic microparticles in the water / oil / water emulsion formed by evaporation of methylene chloride are hardened and they are isolated, washed and the generated microparticles are dried. The microparticles obtained according to the process specified in claim 3. A sustained release formulation, characterized in that it comprises the octreotide or a derivative thereof, or a salt of the compound, in a biodegradable and biocompatible carrier polymer. A sustained release formulation according to claim 18, characterized in that the polymer is poly (D, L-lactic-co-glycolic acid) glucose. A formulation according to claim 18 in the form of microparticles, characterized in that the surface of the microparticles is substantially free of active ingredient. A sustained release formulation according to claim 18, characterized in that it has been prepared by mixing the active ingredient or a solution of the active ingredient in methanol or water or in a buffering agent of pH 3 to 8 with a solution of the copolymer of the lactic acid and glycolic acid in methylene chloride and pulverizing the suspension, solution or emulsion formed of the active ingredient in the polymer solution in a jet of hot air, collecting the microparticles and washing them in a buffer solution of a pH between 3.0 and 8.0 or in distilled water and drying them under vacuum at a temperature between 20 and 40 ° C. 22) a formulation with prolonged release according to claim 18, characterized in that the concentration of the ttreotide is comprised between 2.0 and 10% by weight. A formulation with prolonged release according to claim 18, characterized in that it is in the form of microparticles having a diameter between 1 and 250 μ. 24) A formulation with prolonged release, characterized in that it comprises a peptide in an ester of a polyol with a poly acid (40/60 to 60/40 lactic-co-glycolic), the remainder polyol being selected from the alcohols containing a carbon chain in C3 -C6 and from 3 to 6 hydroxy groups and the mono- or di-saccharides, and the polyol being esterified with at least 3 poly (lactic-co-glycolic) acid chains. A formulation with prolonged release, characterized in that it comprises a peptide selected from a calcitonin, lipressin or a somatostatin, in a 40/60 to 60/40 copolymer of lactic acid and glycolic acid having linear chains, a molecular weight Mw included between 25000 and 100 000 and a polydispersibility Mw / Mn between 1.2 and 2, in a concentration between 0.2 and 10% by weight of the peptide contained in said formulation. 26) A formulation with prolonged release according to claim 24, characterized in that it has an average molecular weight Mw between 10000 and 200000 and a polydispersibility Mw / Mn between 1.7 and 3.0. 27) A formulation with prolonged release according to claim 24, characterized in that it has a molecular weight Mw comprised between 35000 and 60000. A formulation with prolonged release according to claim 24, characterized in that it has a polydispersibility Mw / Mn comprised between 2.0 and 2.5. 29) A formulation with prolonged release according to any one of claims 18, 24 and 25, characterized in that, administered subcutaneously to a rat at a dose of 10 mg per kg of body weight of the animal, it has a piasmatic concentration of active ingredient of at least 0.3 ng / ml and less than 20 ng / ml over a period of 30 days. 30) A formulation with prolonged release according to any one of claims 18, 24 and 25, characterized in that, administered to a rabbit intramuscularly at a dose of 5 mg per kg of body weight of the animal, it has a piasmatic concentration of active ingredient of at least 0.3 ng / ml and a maximum of 20 ng / ml over a period of 50 days. A prolonged release formulation according to any one of claims 18, 24 and 25, characterized in that, when administered intramuscularly to a rabbit at a dose of 5 mg per kg of body weight of the animal, it exhibits a delay of at least 70 % over a period of 0 to 42 or 43 days. 32) A formulation with prolonged release according to any one of claims 18, 24 and 25, characterized in that, administered subcutaneously to a rat at a dose of 10 mg per kg of body weight of the animal, it has an average piasmatic rate (ideal cp) between 2.5 and 6.5 ng / ml over a period of 0 to 42 days. A prolonged release formulation according to any one of claims 18, 24 and 25, characterized in that, when administered intramuscularly to a rabbit at a dose of 5 mg per kg of body weight of the animal, it has an average piasmatic rate (cp ideal) between 3.5 and 6.5 ng / ml. 4) A prolonged release formulation according to any one of claims 18, 24 and 25, characterized in that, when administered subcutaneously to a rat at a dose of 10 mg per kg of body weight of the animal, it has an ASC of 160-230 ng / mL x days over a period of 0 to 42 or 43 days. A sustained release formulation according to any one of claims 18, 24 and 25, characterized in that when administered intramuscularly to a rabbit at a dose of 5 mg per kg body weight of the animal, it has an ASC of 160- 275 ng / mL x days over a period of 0 to 42 or 43 days. 36) A sustained release formulation according to claim 18, for use in the treatment or prevention of acromegaly or breast cancer. The octreotide pamoate. A formulation with prolonged release, characterized in that it comprises a peptide selected from a calcitonin and lipressin and their pharmaceutically acceptable salts, in a biodegradable and biocompatible polymer matrix A sustained release formulation according to claim 25, characterized in that it comprises a peptide selected from a calcitonin and lipressin.