MXPA93003118A

MXPA93003118A - Salts of peptides with carboxy-terminated polyesters

Info

Publication number: MXPA93003118A
Application number: MXPA/A/1993/003118A
Authority: MX
Inventors: Gowland Hutchinson Francis
Original assignee: Zeneca Limited
Priority date: 1992-05-28
Filing date: 1993-05-27
Publication date: 2002-03-26

Abstract

This invention relates to novel salts composed of a cation derived from a peptide containing at least one basic group and an anion derived from a carboxy-terminated polyester, processes for the manufacture of such salts, and the use of such salts in the manufacture of extended release pharmaceutical compositions. The salts of the invention possess a variety of properties which are useful in the formulation of extended release pharmaceutical compositions, whether the salts are in pure form or are in admixture with either an excess of the peptide in its free, unbound form or an excess of the free polyester.

Description

PEPTIDE SALTS WITH FINISHED POLYESTERS IN CARBOXI - # OWNER ZENECA LIMITED, a company of British nationality, domiciled at: 9 Millbank, London GB-SW1P 3JF, GREAT BRITAIN INVENTORS FRANCIS GOWLAND HUTCHINSON,] of British nationality, residing at: Alderley Park, Macclesfield, Cheshire, SKIO 4TG,: GREAT BRITAIN.

EXTRACT OF THE INVENTION This invention relates to novel salts composed of a cation derived from a polypeptide containing at least one basic group, and an anion derived from a polyester terminated in carboxy, a process for obtaining such salts, and the use of such salts in obtaining the sustained release pharmaceutical compositions. The salts of the invention have a variety of properties which are useful in the formulation of the sustained release pharmaceutical compositions, whether the salts are in a pure form or are in a mixture with either an excess of the peptide in its form free or without link, or an excess of free polysiter.

This invention relates to novel salts composed of a cation derived from a peptide containing at least one basic group, and an anion derived from a carboxy-terylene polyether, process for obtaining such salts; and to the use of such salts, in obtaining the sustained release pharmaceutical compositions. The salts of the invention have a variety of properties, which are useful in the formulation of the sustained release pharmaceutical compositions, whereby the salts are in pure form or are in admixture with either an excess of the peptide in its free form. , unbound form or an excess of the polyester. Such salts are amphipathic, which comprise in part a peptide, which is hydrophilic or lipophilic, and in part a polyioditer, which is hydrophobic and lipophilic. The term "peptide" is used herein, in a generic sense, to include poly (amino acids), which are generally referred to as peptides, polypeptides or "proteins", t and b basic peptide, is a peptide which is basic in nature, from the presence of an excess of the basic amino acids, for example arginine or lysine, or split the N-terminus of a peptide, or simply a peptide which contains at least one basic group, optionally in the presence of one or more groups of amino acid acids. The term also includes the synthetic analogs of the porpoids,! non-naural amino acids that have a basic functionality, or any other way of introducing the basic character. The word "polié'siter" is then used to mean a polyester terminated in carboxy. European Patent No. 5881 alludes to the possi bility of the specific chemical interactions between the terminal carboxylic acid group: of a polysiter and of a basic group or groups within the peptide. Lawter et al., Proc. Int. Symp. Control Reí Bioact. Mater 14, 19 (1987), and Okada et al., Pharmaceutical Research, 8, 584-587 (1991). it also refers to the possibility, but these publications are speculative with this, in that it does not describe in particular the salt of the peptide-polyester, giving no indication as to how they can be prepared, and they do not indicate anything in relation to any of the beneficial effects of understanding the use of such salts in the preparation of the pharmaceutic compositions. However, according to the present invention there is provided a composition containing or comprising, such as what is initially done, a salt formed from a reactive peptide derived from at least one basic group and a derived anion. of a carboxyl-terminated polyester, which composition is in the form of a solution or a dispersion of the salt in a solvent, this solvent being a solvent for the free polyster, but not a solvent for the free polypeptide, the particle size of the salt in the dispersion is less than 5 um. , and preferably less than 0.2 μm, or in the form of microparticles, or an implant for injection or subdermal implantation. The cation component of the salt can be derived from a basic drug, which is pharmacologically active, or in the form of a basic polypeptide which is pharmacologically inactive. When the basic purpose is pharmacological -ffectively active, the salt of the invention itself can be formulated in a pharmaceutical sustained release formulation. When the basic polypeptide is farachalogically inactive, the salt of the invention can be used as an excipient, in the formulation of sustained release compositions, of other pharmacologically active peptides, which are either acidic in nature (comprising an excess of the acidic amino acids, such as aspartic acid or glutamic acid), or are neutral in nature. In the sustained release formulations of the porptides, an additional requirement, therefore, is that the peptide must be substantially stable in the formulation in the period of the release. By "stable substantial-m menet", means that the drug is not completely insoluble or denatured, with the total loss of pharmacological activity,? during the period of use determined for the # fvormulation. The pharmacologically suitable active peptides have a molecular weight of at least 300 Da, and preferably at least 800 Da. Examples of such peptides, which are sufficiently stable, in sustained lineage formulations, over a long period of release, and which can therefore be used in the compositions of the invention, which are oxytocin, vasopressin , adrenocorticotropic chromium (ACTH), e-pidral growth factor, (EGF), pralactin, lutenization hormone, follicle stimulation hormone, hormone-releasing hormone lutenization of luliberin, (LHRH), insulin, somatostatin, glucagon, interferon, gastrin; tetragastrin,; pentagastrin, urogastrone, secretin, enkephalin calcitonin, endo- fine, kiotorphine, taftsin, thymopoietin, thymosin, thymus stimulin; humoral thymic factor, serum thymic factor, tumor necrosis factor, colony stimulation factors, motilin, dynorphinin bombesin, neurotensin, cerulein, bradykinin; urokinase, kalikrein, analogues of the substance of P ,; and the antagonsites, angiotensin II, nerve growth factor, blood coagulation factor, HIV and IX blood clotting factor, lysozyme chloride, renin, bradykinin ,; tirocidine; gramicidins, growth hormones, demelanocyte stimulation hormone, release thyroid form, thyroid stimulation hormone, parathyroid hormone, panvreoszimine; colecystoquinine,; human placental lactogen, human chorionic gonadotropin, protein stimulation stimulation, gastric inhibitory peptide, vasoactive intestinal polypeptide, growth factor derived from plaquqteas, growth hormone release factor, bone morphogenetic protein, and Synthetic analogs, and modifications and pharmacologically active fragments thereof The preferred peptide components of the compositions of the invention are synotic analogues of LH RH, and particularly, such analogs include, but are not limited to. a buserelin ((D-Ser (Bu +) 6, des-Gly-NH), -LRRH (1-9) NHEt) ° deslorelin ((D-Trp6, des-Gly-NH210) -LHRH (1-9) NH Et), fertireline. ((des-Gly-NH) -LHRH (l-9 (NHEt, goserelin ((D-Ser (Bu ^) 6, A «zgl, y10,) - LHRH)», histreli.na. ((D-His (Bzl,) 6, des-Gly-NH2) -LHRH (1-9), NHEt, leuprerelin, ((D-LeuD, des-Gly-NH210) -LHRH (1-9) NHEt, lutrelin ((D-Trp6.MeLeu7, des-10 fi Gly-NH2) _LHRH (1-9) ° NHEt, naferelin ((D-Nal) 0-LHRH,? trip-torelin,: ((D-Trp) - LHRH), and salt pharmacologically active salts Suitable basic pharmacological porpoids, which can be used in the salts of the invention, are polyarginine, polylysine and poly (arginine-co-lysine) copolymers of neutral amino acids in D? L- and in the form DL-, with the arginine and / or the lysine in the form of D-, L- and in the racomic form;; or the porptides or the colippetids in which the chains of the peptides they are terminated in their complete form or in part by a basic group in the main chain at the N-terminal which comprises the residues of the neutral amino acids.The polyester is thermoformed in carbosi which is used as a source of the anion in the salt. of the invention, it can be a homo-polioscf or a co-polyster. Preferred psyllids with those which degrade or which are worn in an aqueous physiological environment, such as that found in the subcutaneous tissue, for water-soluble low molecular weight fragments. In this environment, the dominant procedure of degradation is a simple hydrolysis as a whole, developing the hydrolytic division, of the oster groups, which lead to the homo- or co-polystyrene fragments of low molecular, and in the end the disappearance of the formulation of its place of administration. However, it is recognized that these injection or of implantation sites, as well as of places in living tissues, that other mechanisms of degradation can be developed, such as those regulated by enzymes. Suitable homo and co-polymers are those derived from hydroxyacids or from the polycondensation of diols and / or polyols, for example (but which are not limited), to polyethylene glycols, polypropylene glycols, alkylene glycols -10C, glycerol, trimethylolpropane, and the polyoxyethylated forms, of the polyfunctional alcohols such as glycerol, trimethylolpropane, and sugars, with dicarboxylic acids, and / or polycarboxylic acids, for example, (but not limits), di-carboxylic acids of 1-10C alkane, particularly malonic, succinic and glutaric acids, phthalic acids, melitic acid, and pyromellitic acids, optionally in the presence of hydroxy-acids, and mono-oles. The preferred methods for the preparation of * shomo and co-polyesters based on hydroxy acids are by opening the polymerization ring, cyclic acid dimers, or by direct polycondensation or co-polycondensation of the hydroxy acids, or of mixtures of hydroxy acids, or lactones derived from such hydroxy acids. These polymerizations, both that of the ring opening type or of the poly condensation type, are preferably carried out, so that they contain the resulting homo or co-polyesters, in whole or in part. , chains of polymers that have the carboxylic acid as the function. Therefore the polycondensation of the ring opening, of the acid dimers, is carried out in the presence of a chain transfer agent of the appropriate polymer, or the co-initiator which regulates both the molecular weight and the structure del - homo or the resulting co-poliotser. Suitable transfer agents are such as water, hydroxycarboxylic acids, dicarboxylic acids and polycarboxylic acids. For polyols prepared by the polycondensation of the co-polycondensation, the polymerization is carried out under conditions such that an excess of the carboxylic acid fume is used; that is, the ratio of (-C00H), to (-0H), is equal to or greater than 1. The structure and molecular weight of the polycondensate are determined by the nature of the alcohols used (such as monools, diols or polyols, or a mixture), the nature of the acids used (they may be mono-di, or polycarboxylic, or a mixture), and the amount of an excess of the carboxylic acid used. The acids that develop in the Krebes cycle are particularly useful. Examples of suitable hydroxyacids, or lactones; which can be used to obtain homo- or co-polyesters in this invention include, for example, beta-propionolactone,: beta-butyrolactone, gamma-butyrolactin, and pivalolactone, and alpha- hydroxybutyric acid, alpha-hydroxyisobutyric acid, alpha-hydroxyvaleric acid, alpha-hydroxyisovaleric acid, alpha-hydroxycaproic acid, alpha-hydroxyisocaproic acid, • alpha-hydroxy-beta-methylvaleric acid, alpha-hydroxyhep- tanoic, hydroxydecanoic acid, alpha-hydroxymyric acid, and alpha-hydroxystearic acid. Preferred are such as homo- and co-polymers with those lactic acid derivatives, in their D-, L- or DL- forms, and glycolic acid, or the corresponding dimers of lactide and glycolide, and a cap on the Preferred optional chain, is lactic acid. Although a macromolecular basic peptide of the drug may exist completely or partly as a polymer-cation, and a polyster may exist together or in part as a polymer-anion, the formation of the salt gives rise to the the acid-base interaction between such polymeric species, using conventional mixing methods, or the use of organic solvents, is extremely difficult or even impossible, for example, the two component mixture is melted, which is unsuitable , since it is well known that the porpoids do not melt normally, but better decompose at elevated temperatures, commonly used in molten polymers. However, even if the peptide does not melt (which is not), it is incompatible, with or insoluble in a homo or co-polyester, for the thermodynamic reasons, as follows: The porpoids are macromolecules, and have most of the typical properties of conventional polymers. These are therefore (in the absence of specific chemical or physical interactions), totally incompatible with, or insoluble, or, in other macromolecules, those which have polymer or chemical major structures, such as free, mixing, energy; of dso types of different polymers, which is highly positive, and therefore does not favor thermodynamics. In the joint state, the porpoids are highly polar and molecularly bound to hydrogen strongly, with the result that the enthalpy of the mixture of the polypeptides, with the homo or co-poliermos (which are relatively non-polar, and in which the hydrogen bond is either absent or weak), is highly positive, this is endothermic and thermally unfriendly is not favored. In addition, macromolecules are by definition, appropriate; and so that they have a low intrinsic entropy, resulting in entropy, of mixing two different macromolecular species, which are very low or even negative, (see, for example, PJ Florey, "Priciples of POlymer Chemistry", Cornell Unoversity, 1953, at 555, L. Bohm., "Polymer Handbook", 2nd edition, J. Wiley, 1975, 111-21 and L. Bonn, Rubber Chemistry and Technology, 1966, 463). Consequently, the mixing of a polypeptide with a polyester at an elevated temperature; in the state of fusion that does not give for mixing on the molecular scale necessary for the formation of the salt to occur. The simple mixture of a porpoise and a polyester, thereof, does not give the formation of the salt. Similar difficulties exist with attempts to form the salts of the polypeptides and polyethers, which use the organic solvents, unless the polypeptide has some solubility or which expands in the solvent. The solubility properties of the polyostides and the peptides are totally different. Solvents that dissolve the peptide, such as water, are not completely solvent for the polyster; and in general good solvents for the polyester, such as dichloromethane, which are not complete solvents for the porptides. These solvents which can dissolve both the polypeptide and the polyester; such as sulfoxide and dimethyl, dimethylformamide, dimethylacetamide, and N-methylpyrrolidine have different problems, because they are relatively non-volatile, have high boiling points, and so are extremely difficult to remove, and also due to the unacceptable toxicity, of some of these solvents. It has been possible to identify certain solvents, for both components, which are more volatile and which are toxicologically acceptable, but such solvents present other difficulties. For example, acetic acid is a solvent, for both the polypeptides and the poliositeres. But the use of a large amount of the acid solvent predisposes the polypeptides to be the same as the acetate salt (due to the effects of the action). of mass), so that the elimination of the acotic acid at room temperature (say 20-25 ° C), or by freeze-drying, results in the phase separation of the polypeptide and the polyether, that the formation of salt tends not to form. It is an object of the present invention, therefore, to provide a process for obtaining a salt; which comprises a cation of a basic peptide, and an anion of a polyiodide terminated in carboxy. The preparation of Isa salts of the polypeptide-polyether; of this invention, may be carried out using a homo- or co-polyether, containing the carboxylic acid groups, and the polypeptides wherein the basic residues occur as the free base or as the salts of a weak acid,] preferably a volatile acid: having an acid dissociation constant of less than 10 or of a pKa (pKa_ = - 'where ka is the acid dissociation constant) of more than 3. A particularly preferred base proteid salt is a salt with acetic acid. However, due to the inherent incompatibility of the two macromolecular species, the particular conditions have to be used in which the salts of the peptide-polyether can be obtained. One means to achieve this is the use of a solvent, which dissolves both the polypeptide and the polyester, to form a solution from which it can be removed directly, leaving either the amfiphatic salt first, or a mixture of the polyster and the polypeptide in a physical state, which is predisposed to form amphipathic salt when processed further. An example of the first investigation is to use solvents such as, but, which do not select dimethoxide, dimethylformamide, dimethylacetamide, and N-methylpyrrolidine,; which are essentially neutral, and which can be solvents for both the polypeptide and the polyester. Under normal circumstances, as indicated above, these solvents are extremely difficult to remove, because of their high boiling points, and that they are relatively non-volatile. When a polypeptide (for example as an acetate salt), and a polyester, dissolve in one of these solvents, the polypeptide tends to exist as the salt with the polyester, such as the lactic or glycolic acid groups most strongly acid in the polyster that displaces the weaker carboxylic acid. The content of the solvent, and the released acetic acid (or other weak but non-volatile carboxylic acid), by vacuum elimination, and the residual solution containing the salt of the polypeptide-polyester is added to the distilled water, to precipitate the insoluble polymer salt. The distilled water is preferably free carbon dioxide, to avoid the formation of the carbonate salts by stripping the anion from the polyester. The residual solvent of the polypeptide-polyester salt is then removed by further washing with water, also by reference to free carbon dioxide. In some circumstances, the polymorphic salt can be isolated by direct precipitation of the water, without any need to remove any amount of the solvent, and this advantage is particularly useful when the polypeptide is used as the base. Therefore, according to one embodiment of this invention, there is provided a process for obtaining a salt comprising a basic polypeptide, and a polyester thermistoring in carboxy, which comprises the dissolution of the basic polypeptide, in the form of a free base , or in the form of a salt with a weak acid, for example acetic acid, and the polyester terminated in carboxy, in a neutral, polar solvent, in which both are soluble, removing the solvent or most of the solvent, and adding the remaining concentrated solution, to an excess of one that is not a solvent, for the salt of the polypeptide-polyester.

The second advantage is also used in a solvent which dissolves both the polypeptide and the polyester, leaving the solvent, which is capable of elimination by freezing and conventional freeze drying, or by spray drying. An essential part of this process is the removal of the solvent from the polypeptide-polyester mixture at an extremely fast, almost instantaneous rate, and preferably at a temperature below the transition temperature of the polystyrene and the pptido. In this case, the solvent may be neutral or acid, and the preferred solvent is acetic acid. Such extremely rapid elimination, of a solution, which have some degree of viscous flow or of a visco-elastic state, which results in the phase of disparation of the two incompatible macromolecule types occurring on an extremely small colloidal scale. That is, the resulting peptide-polyester mixture has an extremely high surface area and surface energy. As a consequence, when another different solvent, for the polyster, which is normally one that is not solvent, for the polypeptide, the energy of the surface is added to the mixtures of the polyester-polyether essentially free of the solvent, of this type elevated, it dissipates through the formation of the si ,; and the common nature of the peptide in the polyster is eliminated. Suitable solvents for this second advantage have to be freeze-dried and include, but are not limited to, acetic acid, dioxane / water mixtures, and mixtures of ter- butanol / water, or they have to be spray dried. Therefore, according to a further embodiment of this invention, there is provided a process for obtaining a salt comprising a basic polypeptide and a carboxyl-terminated polyster; which comprises the dissolution of the basic polypeptide, in the form of a free base, or in the form of a salt with a weak acid, for example, acetic acid, and the polyester terminated in carboxy, in a solvent in which are both soluble, and which is capable of being removed by freeze drying, freezing the resulting solution at a high speed, the By drying by freezing the resulting frozen mixture, the dispersion of the resulting mixture in a solvent for the polyester component, and allowing the mixture to dissolve as the salt of the polypeptide-polyester is formed. More particularly, in this process, the solution of the polypeptide and polyacetic acid, or of a copolymer, of the lactic acid or of the glycolic acid, in the acetic acid is added to the liquid nitrogen in a quantity in portions, These results in a freezing more or less instantaneous of the solution of the acotic acid, and more or less the instantaneous generation of a mixture of the polido-polyester essentially free of the solvent. Freeze drying for the removal of the solvent of acotic acid is a product of the polyester-polyester, which is mixed on an extremely fine colloidal scale. For most of the porpoids, the colloidal nature of such material is demonstrated when a solvent for the polyester is added, for example dichloromethane, when an extremely fine colloidal suspension is obtained, and it provides an excess of acid function carboxylic, in the mixture. a clear solution is obtained eventually in the rest, the energy of the surface of the excess, is lost as the salt of the polyester-polyester is formed. Other methods that are more or less instantly frozen from the polyester / polyester / acetic acid can be used in place of the portionwise addition to the liquid nitrogen, for example, in portions of the mixture in a mixture of the carbon-dioxide dioxide and the hexane. Hypothetically, therefore, the totally insoluble compound can be made soluble if it can be reduced to a sufficiently small average particle size. If we have that the particle is a sphere of a radius r, it has an alpha density, and this has a super-Y energy, such as a particle which has a super-energy of 4 >.; l r and associated with it. It also has a mass of 4/3. r, and also a surface energy per unit mass of 3? ' ^,, Consider now two cases of saturated solutions :-( i) when the excess of the solid is extremely sufficient and therefore has a low surface energy, and the saturated solution has a concentration of C, then the free energy of Gibbs, is : G solution = G0 + R lnCs = ^ solid '(ii) when the excess solid is of particles of extremely small size of radius r, the free energy of Gibbs, of the solution which is in equilibrium with the extremely small particles is : 2 G sun, uci .ón = Go + RTlnC but in the case that the solid has a free energy of Gibbs of solid PY 'and 2 1 3 G scnolluurc-iionn = Go + RTlnC = G sol.ido, "' or G ^ 1 sol, i • .d, o = GQ + RTlnC - * / O? Í / I But of ( 1) previous ,; G = G + RTlnC, solid 0 s and therefore Go + RTlnC - 3 G or + RTln Cs, or C = Cs.e ^ / Q. so that r decreases, C (hypothetically) increases. In the usual case, the high rather than normal solubility is due to the particle size that is metastable, and the growth of the particles in their size, for example by dissolution and recrystallization, so that the effect of the energy of the elevated surface is denied. However, with the small particle size polydide-polyester mixtures, salt formation may occur; and this offers a means of alternative, for the reduction of the surface energy of the colloidal particles, allowing the formation of the soluble amfifhatic salt, which as a solution has lower free energy conditions. According to a further embodiment of the invention, there is provided a process for obtaining a salt comprising a basic peptide and a carboxyl-terminated polyster, which comprises the reaction of a basic polypeptide in the form of a salt with an acid strong, such as a chloride or a sulphate, with a polyester in which part or all of the polyester is in the form of a salt of the carboxylic acid, with an alkali metal or alkaline earth metal; for example sodium, potassium, calcium, or the salt of the magnesium carboxylate. For low molecular weight polyols, (having a weight average molecular weight of less than about 10,000), the salts with the alkalis can be dissolved, or very finely dispersed in water. The addition of such a solution or dispersion to an aqueous solution (preferably free of dioxide), of the peptide, results in the precipitate of the water-insoluble amphiphilic polypeptide-polyester salt. In a similar manner, the salts of the chloride or of the sulfate, of the "pegylated" basic polypeptides (polyoxyethylene conjugates of phoptides), are or may be partially compatible with or soluble in the solvents, such as dichloromethane, and the salts of Sodium or potassium polymers, of thermoset polymers in carboxy, and can also be soluble in dichloroethane. Therefore, when two salts of these are mixed in the appropriate proportions, the soluble polyether-ester salt is generally double decomposition, with precipitation of the alkali metal chloride or sulfate. The thermodynamic incompatibility of the different macromolecules referred to above has been found for many years: but it has rarely been considered in any of the characteristics of the previous technique, of the sustained release of the drugs from the polypeptides, from the matrices of the polyster. A necessary consequence of this thermodynamic incompatibility, or insolubility, is that in polyesters of normal circumstances they are typically impervious to the drugs of the porpoids. For the diffusion of Fickian dependent on the division, of a peptide drug through a polyester so that it occurs, the peptide must have more solubility in the polyster. However, for the reasons mentioned above ,; this is not the case, and therefore the polypeptide is transported through the polyester so that Fickian diffusion is impossible depending on the division. Furthermore, if even for the safety of the argumentala the dorga of the polypeptide, or one of its synthetic analogues, has the same solubility in or compatibility with the polyester, it is transported by diffusion through the phase of the polystist that is still impossible. It has been recognized for a long time that the free volume in the polyester, which increases the mobility of the translational and rotational polyester segment, and which allows the passage of the diffusion of the molecules, which is insufficiently long, to accommodate the diffusion of macromolecules that have molecular weights greater than about 500Da or more. (See, for example, RW Baker and HL Lonsdale, "Controlled Release: Mechanims and Rates" in "Controlled Relay of Biologically Active Agents," AC Tanquiary and RE Lacey, Plenum Press, 1974, 15 et seq.) However, even through the transport of a peptide drug, through the polyester through the Fickian diffusion, it is essentially impossible, for the peptide, of more than about 500 Da, or more, the continuous release of the peptide has remained unchanged. , all in all. * European Patent No. 5881, mentions how the continuous release # of a peptide drug of a polyester is obtained by using the very different properties of the two macromolecules, of thepóptidos, which are hydrophilic and soluble in water, and the polystyres that are hydrophobic and insoluble in water. In the formulation described in such patent, the release of the peptide drug is mainly achieved through the aqueous pores, which are initially generated by simple filtration of the polypeptide, the total surface of the formulation, or the total of the Peptide drug which are continuous or contiguous, with the surface of the formulation. This filtration provides for an initial phase of libreation, and subsequently the complete hydrolytic degradation of the polyesters resulting in the generation of additional porosity within the polyster, and thus the release of the polypeptide, driven by degradation and erosion, which it may have. If the porosity occurs from the degradation of the polyester that does not occur rapidly, the initial release of the filtration phase is complete before the porosity-sufficient degradation occurs in the supply system, and the discontinuous libreation of the peptide is obtained. The parameters of the formulations are mentioned in EP 58 581, and are therefore selected so that the hydrographic degradation of the polyester occurs in a long time, in relation to the release phase of the initial filtrate; so as to ensure that the two release phases are conjugated, resulting in the continuous release of the peptide drug. However, where the diffusional Fickian transport of a porpoptide through the piluester phase is impossible in the case of those simple polypeptide-mixture, a different total situation occurs in the case of formulations of the peptide-polyester salts of the present invention, optionally in the presence of the free polymer. In the formulations containing these materials, there is no separate phase consisting of the polyster alone, better, than the continuous phase which regulates the release of the peptide which is complete or in part from the salt of the polypeptide. The free polypeptide has some solubility in this phase, from the salt of the polyester, and thus in the formulations using such materials, due to the diffusion depends Fuckian division, a peotid is impossible. if other requirements are present, such as the effective free volume. Because the peptide-polyester salt contains a highly hydrophilic segment, the polypeptide-salt formulation of the polyester salt has a much more emitted water ingress than that of the polyster alone. In addition, in this formulations the water inlet is further increased, due to the non-ionic nature, of the peptide-polyester interaction, # and the solvationes of the ions or of the ion pairs in the salt of the macromolecule by means of water. This implies, a nature essentially of the hydrogel for the polyester-polyester salt, and to provide an increase in the degree of mobility of the macromecular segments in the polycation-polyanion complex. This is the effective free volume of the matrix material that is increased, and thus the micromolecular peptide is included. The net effect of these properties of the peptide-polyester salt, (optionally in the presence of the free polymer), is to allow diffusion of Fickian from a macromolecular peptide through the salt matrix of the polypeptide or the mixed salt from the free polymer phase. This is a totally different situation from that which occurs with the polyester alone, or with simple mixtures of the peptides and polyesters, and isolates the sustained release matrices or the membranes based on increased permeability. of the peptide-poly-ester salt which are central to the formulations for the sustained release of the peptides described above in this application. The salts of the polyester-polyester of the present invention provide new and unexpected advantages in the form of parenteral drug delivery systems.; based on the solutions or on the dispersions they use # various mixtures of the drugs of the free polypeptides, the salt of the free polyster and the polyether-polyether, in both pharmaceutically acceptable non-aqueous and aqueous injection vehicles, and based on the sub-dermal implants which can be injected intramuscularly, sub-cutanemanete or implanted, for vitur of the novel solubility and inesperdas of the fractions that the polypeptide contains in the lipolitic solvents, In addition, the formulations based on the salts of the polioative popties, particularly those that use the polyesters. Ipofilicos highly, can also be administered by other routes. Of particular importance, is the oral route; in which various combinations of the salt of the polypeptide -polyst and / or the free peptide drug and / or the free polyester can be used for a good effect. In most examples, for oral administration; it is preferred to use a pharmaceutically acceptable carrier, such as a vegetable oil; or a variant thereof, and including the mono-di, and tri-glyceroids, either alone or in combinations thereof, or in mixtures with other oils. Of lesser importance are the routes to topical, rectal or intranasal admission. OTra Patent such as European Patent No. 5881 (1982), refers to the above, Lawter et al., (Loe "ßk cit), and Okada et al., (Loe cit), are the unique prior art. known to the applications referred to herein, for the possibility of obtaining the salts of the peptide-polyether, but both publications are speculative, in that they do not mention how this reaction or interreaction can be carried out or used. Further object of the present invention is to provide the sustained release pharmaceutical formulations, which comprise various combinations of the peptide-polyster salt and / or the drug of the free and / or the free polyster, in various proportions thereby obtaining at least three different profiles of sustained drug release, Thus, according to a further aspect of the invention there is provided a pharmaceutical composition of sustained freedom, comprising a salt of the drug. polyster as mentioned above and / or the drug of the polypeptide -, * s * and / or the free polyster, and optionally another excipient or excipients pharmaceutically. The form of the pharmaceutical compositions of this invention is based on the following considerations. Where a simple peptide drug is normally soluble in water, both its salt with a polyester, and the free polyester itself, are normally insoluble in water completely (although it is recognized that, for very low oligomeric forms, polyesters and of the co-poliesters, while they can by # if they are insoluble in water, but can be soluble in water, when it is a polyester-polyester salt). However, the incubation of a mixture of the peptide drug and a polyester, where all or a part of the peptide is present, such as the salt of the polypeptide in strong physiological fluids, SB results in part of the degradation The polyester. If these degraded products are inso-flp lubles in water, then the degradation of the polyester polypeptide salt remains insoluble. Otherwise, if the polyester is of sufficiently low molecular weight, or, - contains a polymeric component, of equal or similarly low molecular weight, such that the acidic fragments derived from the water-soluble polyster, are produced, then these fragments (like anions), they are co-transportable with the polypeptide cation. It has been shown for the new compositions of the polypeptide-polyether salts of this invention, such that the release of the product is strongly dependent on the molecular weight and the molecular weight distribution of the polyether component. The molecular weight distribution is defined as M W where K ^ (weight average molecular weight) = s! Wi «Mi = ni.M.2 € r ^ .Mt and Mn (but molecular average number) = ^ n -.M ^ s of the polymer having a molecular weight M., and n is the number of the molecules of the polymer having a molecular weight M ^. The molecular weight distribution is frequently referred to as the poly-dispersity, and the various values for wide, and probable, and most likely, normal or reduced distribution; which are well known (see, for example, the POII Manual, 2nd edition, J.Wiley 1975, IV-3), It is generally accepted; that a polydispersity of less than 1.8 is # a reduced distribution, or a low polydispersity; Approximately .8 to 2.2 is a more probable or normal distribution, or a normal polydispersity, and more than about 2.2 is a large or wide distribution of high polydispersity. For the administration of the drugs of the pentaptide by the parenteral route; such as an intramuscular or sub-cutaneous injection, or sub-dermal implantations, of a supply system or deposit, polystyres have a pe¬ The average molecular weight of more than 2000Da, or an inherent viscosity of 1% w / v at 25 ° C, in chloroform, of more than or equal to 0.08dl / g and up to or including 4.0 od / g are preferred. For administration by other routes, such as oral, the preferred range of the number average molecular weight is 500 to 5000Da. It is obvious from the above considerations, the * which have been largely ignored, in the state of the art, that the degradation of polyesters, particularly in the presence of a basic peptide, giving even a small fraction, of the water-soluble derivative fragments, and the time interval for this occurs, it will be regulated by molecular weight and molecular weight distribution. The essentially immediate degradation for water-soluble fragments occurs using both the short and normal distribution of the poly- esters, which have molecular weight weights F of less than about 10,000 Da, and less than about 15,000 Da, respectively (depending on the type of molecular weight distribution), but in general the low polarity of the polyster, the molecular weight of the low weight is required for degradation Immediate water-soluble fragments. For the polyster of the weight average molecular weight of greater than 15,000Da, normal or wide distributions are required. Again it depends in part on the nature and type of the molecular weight distribution, but in general the average molecular weight of the weight, the high level of polydispersity is necessarily needed, to achieve the early degradation of the fragments soluble in water. . For the compositions of the polyester, or copolyester and peptide wherein part or all of the peptide is in the form of a salt of the polypeptide-polyester, optionally containing the free polyster, three different release profiles can be obtained. The first of these is when the degradation of the polyster occurs to give the essentially immediate generation of acidic hydrophilic or water soluble fragments, which result in the immediate release of the polypeptide according to the following mechanism: < - ^ release of the drug. polymer / salt of _ + where P is a fragen where PD drug which is hydrophilic or is a totally insoluble species soluble in soluble water in water - + graded but PD nl water, and P is insoluble in water polymer degrad water insoluble (P = a water-soluble degraded polyster fragment, or a fragment of the water-insoluble hydrophilic water-insoluble polyster, which becomes soluble in water, when present, in the form of a salt with the basic peptide. D = base peptide).

# In this expensive priemr, the composition either may contain all the drug as the salt of the peptide-polyester, or may contain some of the drug without binding or free, in addition to part of the polypeptide-polyester salt , in both cases also optionally in the presence of the free polymer. However, the polymer degrades the water - soluble fragments in the presence of the porpo - tide, almost immediately, with the consequence that almost the continuous liberation continues in - ediata of the beginning of the pe - tide. It is noted that the diffusion of * Free water-soluble peptide, through the composition of the degradation is facilitated mediate the increased permeability of the matrix due to the presence of the polypeptide-polyester salt in the continuous phase of the regulated release. The second of these cases, when all the drugs of the polypeptides, is present as the peotid-polyester salt, (optionally in the presence of the free polyster), # but the polyster does not immediately degrade water-soluble fragments. This results in an initial interval; in which there is no release of the drug from the polypeptide. Even through the salt of the peptide-polyester that occurs on the matrix, the permeability to the free diffusion peptide increases, there is no free drug available for diffusion. All of the polypeptide is in the form of a water-insoluble water-polyester salt, and only after a considerable time is it that the polyester degrades the water-soluble fragments, and gives the drug this free and transportable. This gives the result in a period of sustained induction, during which there is initially no release of the polypeptide, after which the induction period begins to be released. This second case is ideal for a regulated release with measure, soluble vaccines and peptides.

The third case, is when a formulation, based on the polyester.ter-peptide drug system, which contains drugs of epitope in its free form and in the form of a salt of polymeric polymer, optionally also in the presence of free polyester, and in which the polyesteriter has an average molecular weight of more than about 15,000 Da, (and preferably greater than about 30,000 Da), and which has a narrow or most probable molecular weight distribution, is placed In a physiological environment, such as is found in subcutaneous and intramuscular injection sites, discontinuous release may result. A first phase, of release, due to the presence of the free drug of polypeptide, and its ability to transport it through the salt system of the polyester-peptide. If this first phase, the release of the free drug of polypeptide is complete before the degradation of the polyester in the salt of the polypeptide-polyester, it occurs so that the additional free alcohol can be added; then the release of the drug from the discontinuous polypeptide is achieved. Obviously, if there is no interval in which the peptide drog, free is absent from the composition during its degradation, then continuous release is obtained. This release profile is similar to that mentioned in the European Patent NO. 58,881, but the release mechanism in European Patent No. 5881, and the material used (no porpeptide of the polyester-polyester salt), are quite different from the mechanisms and materials defined in this application. Dependent,; The profile of the release of these mixtures are ideal for the continuous release of peptides, proteins, and soluble vaccines. As mentioned before, the polypeptide polypeptide drug salt systems, their physiochemical characteristics and the mechanism by which the release of the polypeptide is given, which are different from those mentioned in European Patent Nos. 58,481, and 52,510, and all other publications related to the libreation of the peptide of homo- and co-polymers of lactic and glycolic acids, which are known to the inventor thereof. Of these only the European Patent No. 58, 81, Lawter et al. (loe cit), and Okada et al. (loe. cit), make any reference to the formation of the salt that gives the ionic interaction of the carboxylic acid groups of the polyester and of the basic amino acids in the porptides, but the composition is done as described, not containing the drug of the polypeptide / salt of the polyster. This foregoing description, however, is speculative in relation to this, and does not consistently establish that such interaction does not necessarily occur, nor do they demonstrate how such peptide-polyster salts can be prepared and isolated, and then used to effect the release of the optics, with a variety of different preprofiles of libera¬ # tion, by virtue of its unexpected solubility, in lipophilic organic solvents. Among the properties of the mixtures of polypeptides, which delimit the release, and which has been mentioned in the same, are the groups, functional in the polypeptide and the number of the carboxylic groups in the polysiter. The aforementioned publications are also important in relation to the unexpected and remarkable effects, the use of the salts of the polypeptide-polyacter, and the surprisingly high permeability of the systems that contain, in total or in part, the salt of the peptide. -polypsiter, compared to the permeability of polyester alone, or mixtures in which the components, or the two components are simply mixed and which therefore contains no salt of the polypeptide-polyether. This difference in permeability can be demonstrated in the experiments of the cells of diffusion cimple, in which a membrane of the polyester free of failure and continuous, separates the two aqueous compartments, one containing a solution of the aqueous phobic acid. , and the other contoene the aqueous phase alone, will not allow the transport of the polypeptide, before the significant degradation of the membrane of the polyater. In contrast, the membranes contoene, in whole or in part, the salt of the polypeptide-polyester allows the transport of the drug through the membrane that contains the salt, through the division-dependent diffusion, even if the polypeptide has a weight molecualr more than 500 Da. The polystyrene salts of the invention have any other useful and surprising advantageous properties, unknown in any material of the foregoing technology, which are particularly useful in the form and preparation of pharmaceutical delivery systems. One of the most useful properties, is the good solubility, of the polypeptide, in the form of a polyester si, in the organic solvents, in which the peptides are completely and normally insoluble. Rsto offers much greater advantages in pharmaceutical procurement, in that it allows new procedures and procedures, which are used in obtaining drug delivery systems, and particularly facilitates aseptic manufacturing. These methods and the procedures and materials used are totally different from the methods and materials mentioned in the prior art. Therefore, the solutions of a peptide-polyster salt optionally contain the free polymer, and / or the free polypeptide in a selubilized or dispersed form, which is filtered in a sterile manner; therefore, it facilitates the normally associated problems, with the obtaining é &teril of the formulations of the peptides in suspension or solids, A sterile filtered solution of a salt of the polypeptide-peptide can therefore be subjected to a variety of the procedures of pharmaceutical drying, in an aseptic environment. Spray drying, spray freezing, and other drying processes, which generate solid particles, are preferred methods which easily lead themselves to aseptic operation. Particularly useful is the generation of microparticles that have particle sizes in the range of 0.2 μm to 500 μm. , the cyales can be suspended in a pharmaceutically acceptable injection vehicle. Such microparticles can be suspended in a vehicle from the injection of brine before use, or alternatively in a vehicle of an organic injection, which is not a solvent for the material used. For delivery systems based on homo- and co-polymers of lactic and glycolic acids, organic and suitable carriers are highly lipophilic oils, such as (but not limited to), ethyl oleate, isopropyl myristate, vegetable oils, and several glycerides of fatty acids. In certain circumstances, it is preferable to use mixtures of such lipophilic vehicles.

Although such lipophilic vehicles are not dissolvent for the lactic and glycolic acid delivery forms, they are unsuitable for the use of lipophilic polyesters, such as those based on long chains of the hydroxy acids, for example hydroxystearic acids, For such highly lipophilic polyesters, or co-polyesters, hydrophilic organic injection vehicles are preferred, such as (but not limited to), 2. W, propylene glycol, and low molecular weight polyethylene glycol. Obviously, the vehicles of the aqueous injection are also suitable; for delivery systems based on the largest lipophilic polymers. An alternative means for obtaining the microparticles; it uses another advantageous and unexpected property, of the salts of the polypeptide-polyether, of this invention. The salt of the peptide-polyester, mushroom comprised of a hydrophilic peptide, which prefers thermodynamically to exit, or dissolve in an aqueous or polar environment or phase, and a polyester chain which is hydrophobic, and therefore prefers to dissolve thermodynamically. , in a hydrophobic phase. Therefore, the polyester-polyester salt is amphiphic, and has the active surface properties, which are not present in the salts of the simple polypeptide. This surface activity gives as a result in the salt of the polyester-polyester, preferably so that there is an interface of the phase, and due to the general nature of the salt (proportion and length of the hydrophobic chain), most of the stable type thermodynamically, in a long aqueous phase, it is for the salt of the polydrug-polyster, to exist as a dispersion in water (as the critical micellar concentration is very low, and not all the salt can exist as the interphase in any situation.). It has therefore been found that the salt of the peptide-polyester is extremely effective as a dispersant to obtain as well as to maintain itself, and the stability of the aqueous dispersions. In this second method, for the preparation of the microparticulate pharmaceutical formulations, the peptide-polyester solution (saying, for example in dichloromethane, is simply dispersed in an aqueous phase, which may optionally contain a viscosity-increasing polymer, such as (but not limited to) polyvinyl alcohol using the properties of the active surface of the polyester-polyester salt Although some organic solutions containing such polyester-polyester salts can optionally be dispersed as a general rule of some agitation or movement that is required in the preparation of the aqueous dispersion A further preferred aspect of the process, as indicated above, is to carry out the operations that the aqueous dispersion takes away. Effective in the absence of carbon dioxide and in an inert atmosphere, it is also preferred that the organic solutions of the that of the peptide-polyester, is free of carbon dioxide, due to the carbon dioxide carbonization in air and in water under normal conditions, which is sufficiently eroded, in comparison with the polyester concentrations of the acid groups carboxylic, so that it enters the formation of competitive salts, due to the effects of the action of mass according to the equation: - _ + P .D + HCO. H _ - > 3 ^ D "..HpC ^ Ou3" + P where P is the polyester and D is the drug of the polypeptide. The resulting aqueous dispersions can be dried by a variety of techniques, such as the removal of the organic solvent, under vacuum, followed by freeze drying, or by direct removal of both the solvent and water, in a drying operation. by freezing. The resultingproduct can then be used to obtain the pharmaceutical preparations for injection in the manner as described above. A means of additional alternative, the preparation of the microparticulate pharmaceutical ulations, use an essentially dry solution, of the polyethylene salt, containing colloidally dispersed the free peptide, in a solvent or in a suitable organic vehicle. (The term "essentially dry" is used as it is virtually impossible to remove all traces of the peptide agane, and it is also significant, that none of the drugs exist as an aqueous solution, in a separate aqueous phase). In addition to a non-solvent, the polymer, under the condition of vigorous stirring, followed by the addition of the solvent salt-polyster-polypeptide (optionally containing the free polymer and optionally containing the free drug), eun a large volume of a second non-solvent, to further harden and stabilize the precipitate of the microparticles, giving the final phase. Obviously, the appropriate conditions, or in the presence of an appropriate active surface agent, such as (but not limited to) the fatty acid esters of sorbitol the precipitation of the microcircles that can be carried out using a single non-solvent the polyester, example, a paraffin such as hexane. The microparticles are made by several procedures described above, which are totally different in their structure from the microcapsules prepared in accordance with the methods indicated in the European Patent NO. 52,510 (Syntex), and l45,240 (Takeda), wherein the peptide is encapsulated in a single phase of the polyster. The microwells are defined, as one or more nuclei of one or a material within the second continuous phase, so that the continuous coating of the second phase material completely encloses or microencapsulates the nucleus material so that none of these materials They exist on the surface of the microcapulas, and the microcapsule material retains in all respects the thermodynamic and physicochemical properties of the compound or the encapsulated nicloo material. Therefore, in European Patent No. 52,510, a coacervation process of the phase separation is used to coat the droplets of an aqueous diluted solution of the polypeptide such that the polymer only comprises a continuous coating around the aqueous droplets. That is, these are true microcapsules, which have the geometry and shape of the smcirospheres. After the isolation, of the precipitated microcapsules, and of curing and drying, a product is obtained in which the drug of the polypeptide exists as a discrete nucleus or nuclei, inside the polymer shell. Due to the presence of water inside the micro-shell before drying, its elimination during the dehydration process at a temperature which is below the temperature of the transition of the glass, of the polymer that can result in a particle. which is highly foraminous. There is no stage of the process and of the materials, used or written in European Patent No. 52,510, which mentions a salt of the polyester-polyester, does not develop the process that allows the sterile filtration of a solution or suspension of the polypeptide-polyester, in a aseptic procedure, which is required. Also,; This patent, which specifically concerns the polyesters based on the lactic and glycolic acids described in the US Patent. No. 3,773, 919 (Bos well) 0 which is defined inside as being soluble in benz not at 25 ° C. In the present invention, insoluble benzene polyethers, based on lactic acid and glycolic acids, but which are not soluble in chloroform, are preferred for relatively short delivery periods, such as less than two months. In European Patent No. 190,833 (Takeda) 0 the peptide is trapped as a gelled aqueous solution of the drug and the aqueous gelled phase is dispersed in a solution of the polymer. This dispersion in water (gel of the aqueous drug) - in oil (solution of the polymer), then by itself dissolves under agitation in the water, which results in a double dispersion of water in oil - in water. After removal of the organic solvent under vacuum, μ lyophilization, the microcapsules are obtained where the gel / drug agent is encapsulated by the polymer alone. The products of this procedure retain the drug as the simple salt, and not as the salt of the polymer of the peptide. The pharmaceutical formulations; of the present invention therefore have physicochemical characteristics, and structures, and thermodynamic properties; which are totally different to the products described in European Patent Nos. 52,510, 145,240, and 190,833 wherein the microcapsules have the shape and geometry of the microspheres in which a nucleus or nuclei, of the drug is totally enclosed by the polymer alone.

The products of this present application may also have the geometry and shape of (but not limited to) the microspheres, but whether they are not mcirocápsulas, as all those that were effected before, but which are better solutions of the salt of the polypeptide-polyester (which optionally contains the free polymer), or that the microcapsules wherein the drug of the peptide, free is encapsulated within a continuous phase or the coating of the drug-polymer salt, which also optionally contains the polymer free. As indicated above, the permeability properties of such a drug-polymer salt are totally different from those of the polymer alone, so that the products of the present invention # tion release their drug from the driving porptide in a manner which is totally different from those described in the earlier European Patent Nos. 52,510, 145,240, and 190,833. Therefore, a further embodiment of the invention is for the preparation of either the microspheres, which are not microcapsules; using a solution of the polypeptide-polyster salt, optionally containing the free polymer, or the preparation of the microspheres, which are microcapsules, but which comprise the free drug encapsulated by a phase or coating of the salt of the polyster polypeptide , optionally containing the free polymer. Such diverse particles can be obtained by a variety of different processes such as sputtering, coacervation of phase separation, spray drying, and spray freezing. The preferred size ranges of the particles; they range from 0.2 μm to 500 μm, and the particles can be injected as a suspension in a suitable injection vehicle. Particularly effective and useful parenteral pharmaceutical formulations of the peptide drugs can also be prepared in the form of the polyester-drug salt solutions, optionally containing the free polyster and optionally containing the free drug solubilized or dispersed, in a solvent pharmaceutically acceptable organic, which is a solvent for the free polyester, but a non-solvent for the phoptides and the simple salts thereof, such as for example the chlorides and the acetates. Therefore, according to the present invention, however, there exists or is provided a pharmaceutical composition comprising a drug of the polypeptide, and a polyster, for the sustained release of the drug from the polypeptide, ca¬ * Characterized; wherein the composition is in the form of a solution, comprising: (a) a basic drug of the polypeptide, as mentioned above, having a molecular weight of at least 300Da, and preferably less than 800Da, which is in the form of a salt with the polyester, the salt comprising, a cation of the basic polypeptide, and the anion of a polyester by thermo-carboxy, (b) a pharmaceutically acceptable organic solvent which is a solvent for the free polyster but not is solvent for the free polypeptide, (c) an excess of the polyester, and optionally, (d) an excess of the drug of the free polypeptide in a solubilized or colloidal dispersed form. Suitable basic peptides, and carboxy polyesters, are as defined above, and the preferred preferred peptides are those synthetic synthyl LRRH, as mentioned above. For the drug salts of the polyster-polyether, wherein the polyester is based on homo- or copolymers of lactic or glycolic acid, suitable pharmaceutically acceptable solvents include, but are not limited to, benzyl benzoate, alcohol of benzyl, ethyl lactate, glyceryl triacetate, esters of citric acid, and polyethylene glycols of low molecular weight (less than 1000) alkoxy polyethylene glycols, and polyethylene glycol acetates, etc., and of these benzyl benzoate and benzyl alcohol are especially preferred benzyl benzoate. The only requirement for such an organic solvent is that it be pharmaceutically acceptable, and that the salt of the polyster-peptide drug be soluble therein. Whether or not such a single solvent is used, or a mixture of such solvents, the suitability of such solvents can easily be determined by a simple experiment. Homo- and co-polymers, of lactic and glycolic acids, are among the most polar and lipophobic polyethers, and therefore dissolve in such solvents of organic injection, and of ethyl oleate, the oil is vegetables, and ortho lipophilic carriers, but homo and co-polymers based on lipophilic monomers and co-monomers, or of the lipophilic hydroxy acids, such as hydroxystearic acid, are soluble in such lipophilic injection vehicles. The ratio of the drug from the polypeptide to the polyester in the solids, which are dissolved to form the composition of the solution of the invention, will naturally vary according to the potency of the peptide drug, the nature of the polyster used, and the period of the release of the desired peptide drug. The preferred level of incorporation of the drug of the peptide is from 0.1 to 30% w / v. In general, the optimal drug leads to its dependence on the molecular weight of the polyster and its molecular weight distribution, the desired release period, and the potency of the peptide drug. Obviously, for drugs, of relatively low power, high levels of incorporation can be required.

The entry of water through composition is an important factor in regulating the rhythm of the hydrolytic division of the polyster and the proportion of the water intake, which is to some degree determined by the drug that is in the composition. Therefore, in cases where relatively fast drug release is required for a relatively short period, say three months, up to 30% of the drug's charge of the drug may be appropriate.

The composition of the monomer of a co-polyether, for example the ratio of lactic acid to glycolic acid in the polyacters of phthalic acid-co-glyceruror, is also important in the determination of the proportions of the degradation of the polyester and of the release of the drug of the idiot. The duration of the release is also determined in part by the average molecular weight of the polyester weight, but the amount of the drug of the polypeptide, which can be incorporated as the salt of the polyster-drug, is determined by the molecular weight of the average of the number, Esro, is the polydispersity (the proportion of the average weight of the molecular weights of the number average), in an important parameter. Therefore, for the durations of peptide drug release from one to four months, the compositions comprise the average molecular weight polymers but from 4000 to 20,000 with the polydispersity of 1.2 to 2.2 and the peptide drug contains from 0.1 to 30% are preferred. In general, the lower drug leads, the lower molecular weight of the average weight and the higher polydispersity of the polyester are required. For the long release periods ,; At six months, the use of the peptide drug having 0.1 to 20%, and the polyesters having average molecular weight of 8000 to 20000, and the polydispersity of 1.5 to greater than 2.2 is preferred. For release periods longer than 6 months, the peptide of the # drug is 0.1 to 10% are preferred, and poly- strests have an average molecular weight between 20,000 and 500,000, and the polydispersity of > 1.0. The level of the incorporation of the solids of the total peptide-polyesters in the composition of the invention; it will naturally vary, depending on the potency of the component of the peptide, the period of time over which the supply of the peptidose drug is desired, the solubility of the total smells in the solvent is selected, and the volume and viscosity of the composition of the solution which you wish to administer. The viscosity of the composition of the solution of the invention is determined by the molecular weight of the polyester and the loading of the drug of the polypeptide. In general,; the solutions containing above 40% solids w / v, (peptide drug / salt of the polyster, the free drug and the free polyster), and where the polyester has a weight average molecular weight of 80000, are difficult to administered by injection due to its viscosity. Therefore the solutions of - 40% w / v are preferred for these polyesters. For the compositions of the oslutions, which comprise the poly-esters of average molecular weight of the weight of about 8000 to about 20,000, the concentrations of 30 p / v are preferred, and for the compositions comprising the polyps of average molecular weight of the weight approximately 20000a approximately 50000, the cookings of the < 20% p / v, are preferred. In some cases, for example, if it is desired to inject the composition using a small needle, very low viscous solutions may be preferred, and the concentration may be reduced to 2% w / v and even less, but these may be the equilibrium , therefore, between the reduction of the viscosity and the increase the volume is required for the injection. According to a further embodiment of the invention, a method for obtaining a composition of the invention is provided., which comprises: 1. the dissolution of an intimate mixture of the drug of the basic polypeptide and the polyester in a pharmaceutically acceptable solvent, or 2. the addition of a solution of the drug of the ***e in an alkanol of 1- 6C0 for a solution of the polyester in a suitable solvent for injection, after which if the hydroxylic solvent is not pharmaceutically acceptable for injection, it is removed by evaporation, or if the hydroxylic solvent is pharmaceutically acceptable for the injection, its elimination is not necessary. The intimate mixture of the drug of the basic polypeptide and the polyester, using the above procedure 1, is preferably obtained by dissolving the basic peptide and the polyether in a solvent or a mixture of solvents, which is capable of dissolution of both. of the basic peptide and polyster drugs, and is capable of drying by freezing. Suitable examples of such dissolvent or mixtures of solvents are glacial acetic acid and mixtures of dioxane and water, then by freeze drying the solution is obtained. Alternatively, two components can be dissolved, for example, dimethyl sulfoxide, and the solvent is consequently removed. The intimate mixture can also be obtained by dissolving the drug of the polypeptide in a hydroxylic solvent, for example methanol, and the addition of this solution to a solution of the polyester in, for example, dichloromethane, is guided by the elimination of the youthful ones. , for example, by evaporation. Alternatively, an aqueous solution of the pepo drug, such as the chloride salt, may be added to a broth solution or dispersion, of the sodium salt of the polyster, and the mixture is dried by freezing whereby a mixture is obtained. of the peptide / polyester drug and sodium chloride. The latter can be eliminated if desired by mixing the product in an organic solvent and filtering the insoluble sodium chloride. In process 1., the dissolution of the intimate mixture in the pharmaceutically acceptable solvent can be maintained by heating and / or stirring the reaction mixture. In process 2, above, a suitable alkanol solvent, for the peptide is for example, methanol, ethane, or propylene-1,2-diol. A major advantage, of the pharmaceutical drug prodrugs, in the form of a salt solutions of the peptide-polyester drug, optionally contains, the free drug and / or the free polyster, is such that the preparation of an injectable product in sterile form, to be used immediately, without the need of the pre-mixed premix, for administering to a patient, can be obtained using sterile filtration. This is much simpler for the obtaining operation than the sterilization of a suspended product or a solid. An alternative procedure, for obtaining the sterile injectable solutions, is to dissolve a salt of the sterile polypeptide-polyster drug, which optionally contains the free drug and / or the libtre polyester, in the vehicle of the pharmaceutically acceptable orga- nic injection. Although these forms are mainly for those of the parenteral administration routes, the drugs of the polyster salts of the invention can also be used in obtaining the orally administrable formulations. A quite different type of formulation, which must be injected or implanted sub-dermally, is a drug delivery system based on the implants, or the mixture of different types of implants. These can be prepared from the drug salts of the polyester-peptide, of the invention optionally containing the free drug and / or the free polyosther, using the techniques of the conventional polymer melt process, such as, but that are not limited to extrusion, compression, or injection molding, where elevated temperatures (preferably less than 100 ° C) are used for the fusion of the polyester-salt drug to the preparation of the implant. The preparations of such implants can be carried out under aseptic conditions, or alternatively, by thermonal sterilization by irradiation, using but not limited to gamma rays or X-rays. These solid dosage forms can be reduced for microparticulate forms. -das, by dividing or grinding. The sizes of the preferred particles may vary from 1 um to 500 um. , and these microparticle delivery systems (which are either microspheres or microcapsules), can be suspended # in a suitable conventional pharmaceutically acceptable injection vehicle. The procedure of the fusion of the salt of the drug of the polypeptide-polyester amarca emits a more significant difference and an important difference between the physicochemical and thermodynamic properties of the salts of the peptide-polyester drug, of this invention and the free peptides. and the simple salts of them. The salts of the polyester polypeptide of this invention in most examples melts and flows, in contrast to that of the free peptides and their simple salts, such as chlorides and acetates, which do not melt but decompose at elevated temperatures. The degradation of polyesters is partly dependent on their molecular weight and their polydispersity. Obviously, for the deegration to occur mainly through the hydrolytic division of the ester groups. the polyester or a pharmaceutical formulation containing a polyster must be in water. For these systems where the release regulation matrix, or the membrane contains in whole or in part, the salt of the peptide-polyster drug having greater amount of water through the matrix or regulation membrane when compared to the polyster alone. Consequently, the phases of the contoin matrix, or of the membranes containing the salt of the polyster drug, degrade # differentially of these phases of continuous matrices, or of the base membranes on the polyster alone. It will also be understood that the proportion of the diffusion of water to physiological fluids, in such a matrix or membrane of the release-regulating polyester, will control the rate of degradation in part. This diffusion of water, or of physiological fluids, are also regulated by the dimensions and forms of the formulation, and thus of the release of the drug from the compositions containing the polymer salts of the polypeptides and poly-esters, which also depend of these factors. Of particular interest, as the polyester component of the polypeptide-polyester drug salts of this invention, are also based on the homo- or co-polymer of lactic and glycolic acids, wherein the lactic acid it can be any of one or more of its optically active or racemic forms. Polyesters of this type generally have been known for many years, and have been studied in detail in a variety of delivery systems for the sustained release drug (see, for example, "Controlled Relase of Bioactive Agents, from Lactide / Glycolide Polymers "by D HLewis, in" Blodegradable Polymers as Drug delivery Systems ", ed M.CHasin &R. Langer, Marcel Dekker, and references).

For example, in U.S. Patent No. 3,773,919, it indicates in general terms, that pharmaceutical sustained release, regulated formulations of lactic polyesters and lactic co-polyesters, contain the antimicrobial poly- peptides can also be prepared. However, the developed antimicrobial peptides are unsatisfactory for the generation of a salt of the polyster, due to their occurrence as sulfates, or to other forms which inhibit or prevent the formation of the drug salt of the polyster-polypeptide. Unnecessarily, when the examples shown in this patent are followed, the mixing of the peptide of the drug, irrespective of its nature, with a polymer at a high temperature mentioned, results in the catastrophic decomposition of the drug of the peptide. Similarly, an antimicrobial polypeptide, colistin, is mentioned in European Patent No. 25,698, as one of the majority of a list of compounds, which can be formulated, with polylactide, but again, this compound has a structural mode which avoids the formation of the salt with the terminal carboxylic acid groups of the polyster. Colistin is used pharmaceutically as a colistin sulfate or sodium colistin sulphomethate, -either in the forms that allow obtaining the salts -amifiates with the polyesters according to the present invention. Another prior art, which develops the use of polypeptides with biodegradable polymers based on homo- or co-polymers of lactic and glycolic acids, are European Patent Nos. 52,510, 58,481, 145,240, and 190, 833, previously reported. . Although the co-polymers of lactic and glycolic acids have been known for many years, the complexity of their structure correlates with the distribution of the co-nomer units and their subsequent sequence length (after the same units of the individual co-monomer the copolymer, which are random others), and the effect of such structural variations, when used as the drug release matrices, have long been ignored, in the prior art. These co-polymers by their structure determine in part, both the solubility and the dispersibility of the polymer in the solvents such as benzene, as well as the rate of degradation. This correlation is first noted by Hutchinson (European Patent No. 58 581), but has been extended and refined in the present invention. To illustrate this point, the US Patent. No. 3,773, 919, mentions certain formulations of the regulated libreation drug that uses 50/50 of the copoly- sters of lactic acid and glycolic acid which are soluble in benzene, and this is unnec- essary, the US patent specifically limits this (Conversion to lactic / glycolic copolymers), to which they are soluble in benzene. The utility of these benzene co-polyesters have also been reinforced by their specific use of European Patent No. 52,510. However, in the E.UA patent. above, No. 2,70 316 (which is commonly with US Patent No. 3,773,919), mentions the 50/50 copolyethers of lactide / glycol, which are insoluble in benzene. Because these Patents are commonly in the name of (DuPOnt), it should be assumed that the invention protected in the latter of these patents, the insoluble copolymers in bebcene are lower in relation to as compared to those which are soluble in benzene. This point of view is reinforced by the European Patent No. 52,510, which uses only the co-polymers solubles in benzene of the US Patent. DO NOT. 3,773,919. The prior art, with the exception of our patent application NO. 58, 81, has elucidated the effect in which the structure of the co-polyesters of lactic acid and glycolic acid have their own solubility and degradability. We have shown that polyesters of similar molecular weight and molecular weight distribution, the following general relationship; it is applied, in the majority of the cases for the polyesters which are soluble in chloroform at 25 ° C, mainly the polyesters insoluble in benzene are degraded after the poly-esters which are dispersible but not dissolved in benzene, and such polyesters dis persibie s in benzene degrade more rapidly than those polyesters which are freely soluble in benzene, when the degradation experiments are carried out in the physiological fluids, or in a regulating solution with unpH of 7.4 to 37 ° C. Consequently, it is particularly useful; the use of polyesters, which are insoluble in benzene, to provide the continuous release of the porpoids from the parenteral formulations over a short period of time, say from one week to two months. Therefore, for the compositions which contain 0.1% w / v, from the poptide up to 75% w / v of the polypeptide, the following holds with relation to the composition of the polyester, and its relationships to the structure, viscosity, and poly - dispersibility. For obtaining the drug salts of the polypeptide-polyester, which can be formulated according to this invention, to give a continuous release of the drug, in a period of time from one week to two months, the molar composition of such benzene-insoluble polyesters, which preferably contain a broad polydispersity, preferably in the ranges of 60% glycolic acid (or glycolide / 40% lactic acid (or lactide), to about 25% glycolic acid) (or glycolide / 75% of the lactic acid (or lactide), and polyester ethers preferably have an inherent viscosity of 1% w / v in chloroform at 25 ° C, which varies from 0.08 to 4 dl / g. By appropriate selection of the parameters of the polyester, including the distribution of the molecular weights and the pesomolecular weight, it is also possible to achieve the continuous freedom of the polypeptides in a period of time from one week to two months, starting from of the formulations according to this invention, using the homopolymer of the polylactic acid or the co-polyethers having a molar composition varying from 35% of the glycolic acid (or glycolide) / 65% of the lactic acid (or lactide), 10% of glycolic acid (or glycolide) / 90% lactic acid (or lactide), which are soluble in benzene, which have an inherent viscosity of 1% in chloroform at 25 ° C, from 0.08 to 0.5dl / g., and that have a plidispersibility from small to broad. Continuous release of the peptide over a longer period, say 2 to 6 months, of the formulations according to this invention can be achieved using a homopolymer of the polyacetic acid, or of the co-polyesters having molar composition varying from 35% of glycolic acid (or glycolide / 65% lactic acid (or lactide), 0% glycolic acid (or glycolide), / 100% lactic acid (lactide), which They are soluble in benzene having an inherent viscosity of 1% pvc in chloroform at 25 ° C, from 0.08 to 0.8 dl / g, and having a polydispersity from small to broad.The continuous release of the peptides in one period of long time, i.e. of up to 2 years, the formulations according to this invention can be achieved by using the polyacetic acid homopolymer or the co-polyeste-three having a molar composition varying from 25% of the glycolic acid (or the glycolide) / 75% of the acid or lacitco (lactu-tro), at 0 ° glycolic acid (or glycolide) / 100% lactic acid, (or lactide), which are soluble in benzene, which have a viscosity inherent to 1% w / v in chloroform at 25 ° C, at 4.0 dl / g, and a polydispersity from normal to high. Time or pulsed release (with a period of induction prior to release) continuous release (where there is an initial phase of release followed by a period of no release or i-nefective release, followed by a second release phase) in a second release phase), in a relatively short period of time, up to 2 months, can be achieved with the formulations according to this invention, using the benzene-insoluble poly-mers, which have a molecular weight distribution of small to most probable, and an inherent viscosity of 1% w / v in chloroform at 25 ° C, from 0.3 to 4.0 dl / g. Still another embodiment of the present invention, which is novel or distinguishes this invention from the others described above; the release systems of the controlled release drug, based on the polyesters or the copolyesters, and which further regulate the release rate, is the level of the incorporation of the peptide into the salt of the polyester (optionally in the presence of a free drug and / or free polymer). This also regulates; the nodalities are completely different from those parameters, which result in the increased release regimes in the more conventional delivery systems, based on the polyostres, which are directly directed to the supply of the highly lipophilic drugs, which have the solubility relatively low water, such as steroids. In these cases, such as the level of incorporation of the drug aumeta, an increased rate of release is generally seen, even through the entry of such water into the system. # subjects that are reduced, due to the volume of the increased phase, of the lipophilic drug. In fact, such increased proportions, from the release of drugs like steroids, are independent, from the drug that is retained in its thermodynamic identity, and over Fickian's unsimple of kinetic diffusion, (see Baker and Lonsdale loe, it). This is for drugs such as steroids, as drugs that increase their burden, and - * provide the lipophilic drug that has the same solubility in the lipophilic polymer, the simple Fickian diffusion regimes are increased. A completely different situation exiet, with the products of the present invention. It is now recognized that a greater component in a part of the degradation of the polyethers and co-polystyres hydrolyzes the oster groups and the regime in which it occurs depends on the water input • (see Pitt ans Zhog. = Wei Gu, J. Controlled Reléase 4, 283-292 (1987), Hutchinson and Furr ibid, 13, 279-294 (1990) .Popidids are hydrophilic, and their formation of salt with The polystyrene gives rise to a phase that contains the salt of the polyester drug, which has a higher water input than that of the polyester alone.This is the polyester chain in the salt can degrade faster than the polyester. polyester li-bre alone, which has a similar composition a molecular weight and a dispersibility A release of the strong peptide dependent on the degradation, then the release s regulates in part by both of the levels of the incorporation of the salt of the polyster-polypeptide drug, in the composition, and the proportion of the polypeptide in the salt.For the poly-esters, or the co-polyesters of the same composition and structure, the increase of one or both of these parameters gives as result, in the incremental regimes of the lib eration, and by implication can be reduced, in certain circumstances ,; the periods of time, over which the release may occur. The levels of the drug's incorporation of the peptide either as the salt of the drug-polyester, or as the salt of the drug-polyester in combination with the free polypeptide, preferably in the range that varies from 0.1% p / pa 75% p / p in the drug-polyster label. The loading of the drug of the polypeptide in the composition of the invention and its variciaon with the molecular weight of the polyester and of the polydispersity, is as follows. For the continuous release, of a peptide over long periods of time, say 2 years, low levels of drug incorporation, vary from 1.0% to 20% w / w, which are preferred, using poly- thomas that have molecular weights - averages of the preferred weight of 20,000Da, or more and a polydis- # Persistence of more than 2.2 and preferably of more than 3.5 These parameters, for a long time also depend in part on other modalities, be the formulation of the drug, such as the composition in relation to the content of the co-monomer, the structure, the solubilide / insolubility in benzene, and the geometry and dimensions of the dosage form. A polyester with a weight of approximately 20000 weight has an inherent viscosity of about 0.2,, dependent $ of such factors as its structure, composition and dispersibility. For the continuous release over relatively long periods of time, say, up to 6 that are preferred levels of the incorporation range of the drug from 0.5% to 35% w / v, using the polyesters and the co-polyesters, which have weights Molecular values preferably of up to 10,000 Da or more, and a polydispatibility greater than 1.8 and of preference greater than 2.2, depending on other parameters such as composition, structure, solubility / insolubility in benzene, and the geometry and dimensions of the dosage forms. For continuous release in relatively short periods of time, say 2 months, the preferred levels of the peptide drug for its incorporation vary from 0.1% to 75% w / w, using the poly- esters having high molecular weight. - average lecuals of preferred weight, of 2,000Da or more, and polydispersities of more than 1.2, depending on other parameters, such as the composition, structure, solubility insolubility in benzene, and the geometry and dimensions of the dosage forms. An additional parameter with which the release of the drug from the polypeptide of the formulations according to the invention, and which are absent from the prior art types, of the homo and co-polymeric delivery systems of the lactic acid and glycolic acid, is the functionality of the optic; do, in relation to the number of basic groups such as arginine, and the residues of lysine, in the molecule of the drog of the polypeptide, and the functionality of the polyster or copolipester in relation to the average number of carboxyl groups it contains by the average polymer or the copolymer, of the chain, In general, for the continuous release, of the drug of the polypeptide, the greatest level of such polyfunctionability interaction, in the polypeptide-polyester electrolyte complex, is required of the greatest polydispersity. In contrast, for discontinuous or pulsed release, the polydispersity is less than 2.2. faith which is the preferred one. One of the relatively rare occurrences, mutual compatibility and solubility of two different types of polymers in their chemical structures, is represented by the mixtures of the poly- esters, based on homo- or copolymers, of the acids lactic or glycolic, with low molecular weight poly oxyethylene, and in particular low molecular weight polyethylene glycols. This compatibility has been pointed out, for the purposes of good effects on the salts of the drug of the polypeptide-polyester, and its preparation, in the foregoing inevitability in a novel and unexpected manner. Therefore, it is known that certain pharmacological peptides, the pegylated ones can be mentioned that is conjugated with a glycol or an alkoxy-polyethylene glycol, in such a way that the pharmacological activity of the peptide is retained. The presence in the molecule of the pegylated peptide, of the conjugated polyoxyethylene chains, therefore gives the pegylated peptide partially compatible with the polyester or with the co-polyester. Therefore, the ratio of the residues of the remaining lysine and arginine in the pegylated peptide occur as the weak acid salts, this compatibility facilitates the preparation of the salt of the poly-ester-peptide drug, as well as the addition of an additional element of the release control. Pharmacologically active conjugates of the peptides with other water-soluble polymers, such as polysaccharides, synthetic polypeptides, and polyvinyl pyrrolidone, are also useful, but are less preferred as none of these water-soluble polymers that are they mention the latter, which is soluble in either the polyster or the co-polyester. This invention is preferably applied to drugs containing pharmacologically active compounds, which have a basic functionality. However, it can also be applied to peptides which are pharmacologically active and which are either neutral or which tend to have high polyanions (the polypeptides having excess of the functionality of the carboxylic acid). In the first of these examples, (a pharmacologically active neutral polypeptide, which contains either an acid or basic residue), a salt of a synthetic polypeptide which contains the basic function, and which inactive pharma cologicamnete, and use polyester Such pharmacologically synthetic inactive synthetic polypeptide salt and the polyester or co-polymer is also amphiphic, and can act as a dispersing agent for the solubilization or colloidal dispersion of a pharmacologically active, but neutral peptide in an organic phase.

In the second case, (where the polypeptide contains the residual carboxylic acid function and is pharmacologically active), a salt of a synthetic polypeptide, which has at least two basic groups, in the synthetic polypeptide chain, and which faramcolopically inactive, and a polyester or a co-polyester is used. In this second case, in the salt of the synthetic polypeptide and the polyester, the cocnentration of the basic functional groups, in the salt is? Jfl? greater than the concentration of the carboxylic acid groups, in the pharmacologically active peptide active, This excess of basic functionality, in the salt can then be reacted by the formation of the additional salt, with the carboxylic acid groups of the pharmacologically active peptide active . The complexes of the resulting salts can be solubilized or dispersed in an organic solvent or phase, which is not a total non-solvent, for the polypeptide in question, but the solvents for the polyester or the co-polyester, the manner dectite before, for the other salts of the polyester-peptide. Because the salts of the peptides contain a basic functionality, with polyesters and co-polyesters it contains the functionality of the carboxylic acid, are amphipathic, their properties of the active surface, can be used to facilitate the dispersion of other hydrophilic beads, or aqueous suspensions, of such drugs, in a solvent or organic phase containing the salt of the polyester-peptide. The use of such salts in the thiatic, the peotides, the polyesters or the co-polyesters is how the dispersing or solubilizing agents form a further embodiment of the invention. The invention is illustrated, but not limited by the following examples. The measurement of the viscosities and their relation to the various average molecular weights are mentioned in Sorensen and Campbell "Preparative Methods of Polymer Chemistry", 2a. edition, 1668, Interscience Division of John Wiley 43-50 In the examples described above, a viscosity of Ubblohde gives a flow time for chloroform solod for about 100 seconds. Chlorofortm is used as the solvent as this is undisovente for benzene-soluble polymers and insolubles in benzene, it is mentioned over the range of the composition. The molecular weights and the distributions of the molecular weights, of the poly-esters described in this application, of higher molecular weights, than those of approximately 2000 Da, are determined by size exclusion chromatography, in relation to the polystyrene standards, which are used dee 3 x 30 cm., the size of the columns of PL gel, the mixed columns B of 10 um, (ex Polymer Laboratorie Chruch Stretton, fíhoropshire, United Kingdom), in relation in the series and are fixed with a guard column of 10 um. The tetrahydrofuran used as the solvent at 40 ° C, with a nominal flow rate, of 1 ml. , by minutes. The molecular weight characteristics are calculated using a Perkin-Elmer 7700 Computer - Professional from Emapque Data Analysis, with the GPC technique. For the measurement of molecular weights of less than 2000Da, size-exclusion chromatography is not the preferred method of molecular weight discrimination, and instead of the potentiometric-non-aqueous, titration method. it can be used, to give it the molecular weight, or the equivalent weight, of polyester, by directly measuring the content of the carboxylic aido of polyester or co-polyester. Non-cured potentiometer titrations are generally carried out using a known weight of the polyester or co-polyester, which is dissolved in acetone containing 10% v / v of water. The titrations are carried out using the diluted sodium hydroxide solutions and using the equipment supplied by the Radiometer (Copenhagen, Denmark). These consist of a titrator (TTT80), and a autoburette (ABU 80), a pH meter (PHM 83), and a CMAWK Russell electrode. The titration is carried out on a Servoimpressor (REC 80), and the molecular weight of the polymers is: W x 100 xf * vxn where w is but of the polymer used, f is the average number of carboxylic acid groups on the polymer chain, v is the volume of sodium hydroxide used, n is the normality of sodium hydroxide using Example 1 Goserelin acetate (100.6 mg, equivalent to about 86 mg, of the polypeptide as the free base), and 50/50 mol% of D, L-lactide / glycolide co-polymer (300.3 mg containing a group of terminal carboxylic acid, by the polymer chain and having an average molecular weight of 4300 Da and an inherent viscosity of 1% w / v in chloroform at 25 °., of 0.08dl / g., and which is insoluble in benzene, are dissolved in glacial acetic acid free of anhydride (3 ml.) The solution of acetic acid, of the drug and of the polymer is added in portions to liquid nitrogen, and the frozen drops, They dry by congenation for 24 hours under conditions at high vacuum. elation, gives a mixture of the polyester drug containing approximately 25% w / w of goserelin acetate (equivalent to approximately 22.3%, p / p of the polypeptide as the free base. The mixture of the dry polyster drug (400 mg) is added to dichloromethane, and up to 4 ml. Initially, a cloudy colloidal mixture is obtained, but within 1 hour, it becomes clear to form a clear solution. This solution is like a film, and it is left to dry at the ambient temperature, for 6 hours, then for 20 hours, at 50 ° C, under high vacuum. A clear, transparent film contains the salt of the polyster drug and is obtained in this way. (i) The transparent clear film (100mg) is thus obtained, melted and molded in compression at 80 ° C. , whereby the transparent film, 0.02 cm thick, is obtained. Upon immersion in water at 37 ° C, for 24 hours, the weight of the drug / polymer film increases to 225 mg. In contrast, the polyster alone (100mg) is treated similarly by increasing the weight to only 126mg., And a film comprises a simple mixture of goserelin acetate (25mg.) And the polymer (75mg.), ( addition of the drug to a solution of the polymer in dichloromethane, the elimination of the solvent and the compression molding of the resulting material with which a film of approximately 0.02 cm thickness is obtained.). weighing only 136 mg., after immersion in water for 24 hours at 37 ° C. It is evident from experience that the composition of the salt of the drug polyster is considerably more hydrophilic, and has an entry into the water elevadam whether the polystyrene is alone or mixtures -11- of the drug and polyester. * In a simple mixture of the drug and the polymer in dichloroethane, the drug shows no sign of dissolution even after 1 month, and when it is dried and compressed by molding, the simple mixture gives an opaque film. However, it is an additional experiment; the transparent clear film, which has been obtained before (lOOmg.), is dissolved in dichloromethane (lml.), whereby a JK solution of the clear transparent polyester drug is obtained. To this solution trifluoroacetic acid (50ul) is added, and the mixture is stirred vigorously. An immediate precipitate is obtained from goserelin as the trifluoroacetate salt. These two experiments show the clear, transparent film containing the salt of the drug-polyester obtained as mentioned above, capable of being processed to a delivery system in the manner that the fabrication techniques of fusion use of conventional polymer. Also this product contains virtually, no amount of acetic acid or acetate anion, and thus the drug can exist in the form of the salt of the polyster. The salt of the polyester drug due to the terminal lactic acid and the glycolic acid groups on the co-polymer are much stronger than the acetic acid, and thus the more weak acetic acid,; it moves through the polymer. The ~ jF & carboxylic acid of the polymer, in the salt of the polyester drug soluble in dichloromethane. it can in turn be displaced by a much stronger carboxylic acid, such as trifluoroacetic acid. When this occurs, the salt of the trifluroacetate, of the peptide formed, and as it is not soluble in dichloromethane, is precipitated. (ii) The transparent clear film, obtained as described above (50 mg), containing the salt of the polyester fl oc drug, is molded to give the film at approximately 0.02 cm. , of thickness. The film is incubated in the phosphate buffer saline; (containing 0.02% sodium azide), at pH 7.4 and 36 ° C, and the buffer is periodically tested by UV to determine the amount of goserelin released. This molded product releases goserelin continuously for approximately 2 weeks, and for 3 weeks, has virtually completely degraded, and disappears from the incubation medium. This experiment demonstrates the utility of the very low molecular weight, the insoluble polymers in benzene, for supplying the drug in a short time. Similar molded formulations can be obtained by using instead of goserelin acetate, whether the gonadotropin releasing hormones, or other potent analogues are present (agonists, or antagonists, of the gonadotropin release of the hormone, such as triptorelin, leuprorelin, buserelin, and nafareline, preferably as salts of the acetate or salts with other weak acids, or of any other polypeptide hormones, which regulate the secretion of intact gonadotropin, or either of the subunits of the troponin gonado Example 2 flßt The product of the clear transparent film, obtained in the Example, before, (lOOmg.), and a molar ratio of 50/50 of D , L-lactide / glycolide copolymer (1.05g) having a weight average molecular weight of 121,000Da, and an inherent viscosity at 1% w / v in chloroform at 25 ° C, of 0.84 dl / g, and which is insoluble in benzene, dissolve in dic loroemtano (lOOml.). The solution is stirred vigorously at 1000 revolutions per minute, and the silicone oil (50 ml.), Is added in one hour, in order to precipitate both the salt of the polyester drug and the free polyester. After 1 hour, the partially precipitated mixture of the polyster drug salt, the free polyester, the silicone oil and the dichloromethane is added to the vigorously stirred hexane (2 liters), to harden the microparticles of the salt of to the drug of the polyester and of the polyester, er free, This mixture is stirred for 2 hours, and then it is allowed to settle, and the layer is discharged from the hexane. The microparticles (containing approximately 1.95% w / w of goserelin as the free base), are washed three times with fresh hexane (500 ml.) And finally isolated by filtration and dried at 35, C, p 24 hours, under high vacuum. The average size of the approximately thus obtained spherical microparticles, which comprises a solution of the polyester-drug salt, in the free polymer, is about 30 μm. A portion of this product (250mg.), Is incubated in the regulation phosphate solution (containing 0.02% of the sodium azude), at pH 7.4 at 37 ° C, and the regulatory solution is periodically mediated by UV for the determination of the amount of goserelin released. The drug releases the microparticles in about 5 weeks, and after 7 weeks they have to virtually disappear from the incubation month. The composition of the polymer used in this experiment is a mixture of two co-polymers of the same lactide / glycolide composition, but having widely different molecular parameters, and which as a mixture, as described above, is insoluble in benzene, it has an average molecular weight of 108,000Da, a polydispersity of 5.1, and an inherent viscosity of 1% w / v in chloroform at 25 ° C. of 0.72 dl / g.

These experiments show the usefulness of benzene-insoluble polyesters, which have a high molecular weight, and a high polydispersity, for the release of goserelin in relation to short periods of time of 5-7 weeks. Formulations of similar microparticles can be obtained by using, instead of acetate: goserelin, whether it is naturally analogues of the gonadotropin releasing hormones, or other # Highly potent synthetic agonists (agonists and antagonists) of the gonadotropin releasing hormone such as triptorelin, leuprolein, buserelin or nafarelin, preferably as the salts of acetates, or weak acid salts, or any other of other hormones of poly-order, which regulates or modulates the secretion of gonadotropins or of the subunits of gonadotropin in¬ # dividual. Example 3 Goserelin acetate (101 mg., Equivalent to about 86 mg., Of goserelin as the free base), and 100 mole% of poly (D, L-lactic acid), (299.7 mg. .), which is soluble in benzene, has a weight average molecular weight of about 5400Da, an inherent viscosity, at 1% w / v in chloroform at 25 ° C, of 0.08 dl / g, and a polydispersity of 1.8, it is dissolved in glacial acetic acid free of the anhydride (4 ml.). This solution ^^ of acetic acid, goserelin and polyester are added in portions to the liquid nitrogen, and the frozen drops are isolated; they are dried by freezing under vacuum for 24 hours, and then they are dried at 55 ° C, for 24 hours under high vacuum. (i) The resulting dry product is added to the dichloroethane (4 ml.), thereby obtaining a tur¬ F bia initially, which dissolves quickly with which a clear solution is obtained, which is filtered through a 0.2 um nylon sterilization filter. This experiment shows that the solutions, of the salt of the polyster, of the goserelin, can be filtered sterile, in contrast to the mixtures, of the dispersions of the salts of the simple drug, in an organic solution of the polyester. I (ii) The trifluoroacetic acid (50ul) is added to the clear dichloromethane solution of (l), before (lml.), With vigorous stirring. There is an immediate precipitation, of goserelin as its trilfuroacetate salt, showing that goserelin is present in the dichloromethane solution, like the salt with the carboxy-terminated polyster. Formulations of the similar sterile solution can be obtained by using, instead of gose reline acetate, either hormones that release the gonad ¬ * naturally occurring tropine, or other highly potent synthetic analogues (agonists or antagonists), of the gonadotropin releasing hormone, such as triptorelin, leuporelin, buserelin or nafarelin, preferably as acetate salts, or salts, with other weak acids, or any of the other hormones of the polypeptides, which regulate or modulate the secretion of the intact gonadotropins, or either of the subunits of the # individual gonadotropin. EXAMPLE 4 The dichloromethane solution of the goserelin polyester obtained in Example 3 (2 ml.) Is diluted with dichloroethane and made at 10 ml. This solution is sprayed in vigorously stirred hexabole (1 liter), whereupon It has more microparticles; which after isolation and drying under vacuum at 45, C, for 2 4 hours, it was in a size of approximately 2 um to approximately 30 um, with average sizes of approximately 10 um. The goserelin content of these microparticles are equivalent to about 22% as the free base. These microparticles are incubated in a cone-1 buffer phosphate at pH 7.4 at 37 ° C, and the supernatant is periodically tested by UV for goserelin. The jtf goserelin is continuously released, the release is essentially complete, at approximately 8 weeks, and by 11 weeks the microparticles have complete and complete degradation of the incubation medium. This experiment shows that the utility of polyesters soluble in benzene of very low molecular weight, the release of the continuous peptide is provided for about 2 months. If goserelin acetate in the above experiments is replaced by thetrifluoroacetate salt, then a clear solution is not obtained, but instead the solution of the polyster, in dichloromethane, contains essentially a dispelion of the trifluoroacetate of goserelin. . This mixture will not pass through a 0.2 μm filter, and because of this it is not able to filter in a sterile way; and such dispersion of trifluroacetate and goserelin in the polyester solution when sprayed in the stirred hexane produces a flocculated and frozen mass, better than the microparticles. Therefore, the salt of the polyster-goserelin has properties, which make it much easier to formulate in a form of the microparticle, than the mixture of the simple salt, in a solution of the polymer of very low molecular weight. Formulations of similar microparticles can be obtained through the use of goserelin acetate, whether natural gonadotropin occurs or not. * of release hormones or other highly potent synthetic analogues (agonists or antagonists), of the gonadotropin releasing hormone, such as triptorelin, leuprolein, buserelin or nafarelin, preferably as the salts of the acetate or the salts with the weak acids, or any of the other hormones of the polypeptides which regulate or modulate the secretion of the intact gonadotropins; or either of the sub-units of the gona¬ # individual dotropina. Example 5 Goserelin acetate (304 mg, equivalent to approximately 248 mg, goserelin as the free base) and 100% polymolar (D, L-lactate), (102 mg), which has a weight average molecular weight of about 5400, an inherent viscosity of 1% w / v of chloroform at 25 ° C, of 0.08 dl / g, and a polydispersity of 1.8, dissolves, in free glacial acetic acid of the anhydride (2 ml.) . The solution of acetic acid, gosererlin and polyester is added in portions, to liquid nitrogen and frozen drops, are isolated, dried by freezing, under high vacuum for 24 hours, and then dried by vacuum at 55 ° C, 24 hours. The resulting product is added to dichloromethane, (2 ml.), Whereby a colloidal mixture is obtained. 'cloudy, which does not clarify completely at this time. This dichloroethane mixture essentially comprises a dispersion of goserelin acetate in the salt of the goserelin polyster. This dispersion of the goserelin acetate, in methylene chloride, ensolution, of the salt of the polyster of goserelin, which is formulated in a microparticulate form containing approximately one equivalent of goserelin. # te 72% p / p as the free base, where the free goserelin acetate, is dispersed through a continuous phase of the polyster salt of goserelin, by spray-drying, dew freeze, precipitation simple, or, by co-acervation of the separation of the phase. Formulations of similar microparticles can be obtained by use, instead of acetate # of goserelin, whether naturally occurring gonadotropin-releasing hormones, or other highly potent synthetic agonists (agonists or antagonists) or gonadotropin releasing hormones, such as triptorelin, leuroprorelin, buserelin, or nafarelin, preferably the salts of acetate or salts, with weak acids, or any other hormone of the peptide, the cyal regulates or modulates the secretion of intact goandotropins or of their individual subunits. • Example 6 A co-polyester of D, L-lactic acid, and glycolic acid, which has a molar composition of 78% of D, L-lactic acid, and 22% glycolic acid, is prepared by the co-polyester. -polycondensation of the two hydroxy acids. After purification of the copolymer by addition of a solution of the co-polyester in acetone to metyanol; To precipitate the co-polyester, and the separation and drying of the precipitated material, the co-polyester has a weight average molecular weight of about 11, 000 Da, an average molecular weight of the number (as determined by non-aqueous potentiometric titration). , and assumes that each of the chains of the co-polyester has only one of the terminal carboxylic acid groups of 6100Da, and therefore, a polydispersity of 1.6 and an inherent viscosity of 1% w / v in chloroform at 25 ° C, of 0.15 dl / g. Goserelin acetate (228.9 mg, equivalent to about 200 mg, goserelin as the free base), and the co-polyester described above (1.8 g.), Are dissolved in glacial acetic acid free of anhydride ( 10 ml.) The polyester solution of goserelin thus obtained is added in portions to the liquid nitrogen, and the droplets freeze > Jß ladas are isolated,] they are frozen to dry for 24 hours, and then they are finally dried at 50 ° C, for 24 hours under vacuum. The mixture of polyster-goserelin is added to dichloromethane (10 ml.), To give initially a cloudy colloidal mixture, but after 24 hours, this has changed to a clear solution, which is filtered through a 0.2 um nylon sterilization filter. When trifluoroacetic acid is added to a small aliquot of this solution, there is an immediate precipitate of goserelin, such as the trifluroacetic salt, which shows, in the clear, clear dichloromethane solution, goserelin in the mixture of polyester of goserelin, is present mainly or completely as the salt of polyester. The dichloromethane solution of the polyester-goserelin salt is evaporated to dryness, and the resulting solid is dried at room temperature, for 6 hours, and then at 55 ° C, for 20 hours, under vacuum, to give a solution , from " " . of polyester from gasere lina containing the pelleting of clear casting. The dry goserelin polyester mixture is prepared as described above (lg.), Which is dissolved in 8 ml. of dichloromethane. The resulting solution is colored in a 250ml flat bottom, multibock, and with an inlet for a stream of nitrogen, for the elimination of all of the air, and to generate a free atmosphere of the carbon dioxide. Water (90 ml.), Which has been previously degassed, to remove carbon dioxide, and then stored under nitrogen free of dioxide, is introduced into a flask, and the mixture is stirred vigorously, at approximately 500 rpm, under a atmosphere, which is essentially free of carbon dioxide. The dichloromethane solution of the lagoserelin polyester salt is rapidly dispersed, whereby an etable oil (dichloromethane solution of the drug-polymer salt) is obtained in the dispersion in water. While the stirring is maintained at about 200 rpm, a vaccine is applied gradaully, and the dichloromethane set evaporates under vacuum, whereby a dispersion of the salt of the goserelin polyster in water is obtained. Freeze drying of this dispersion produces the microparticles, in which goserelin, is present as the goserelin-polyester salt having an average particle size of about 20 μm, which is shown for the release of goserelin by approximately 6 weeks, when incubated in saline, it is regulated with a phosphate at pH 7.4 at 37 ° C, and the supernatant is periodically tested by UV for goserelin. Similar microparticles can also be obtained by incorporating agents in the aqueous phase which are known to improve the stability of the polypeptide such as mannitol. Although it is preferred to carry out the above procedure, in a carbon dioxide free atmosphere, it is possible to achieve satisfactory results, in the presence of traces of carbon dioxide, depending on the molecular weight of the polyester, and the loading of the drug. . The similar sterile solution, the cast film and the formulations of the microparticles, can be obtained in a similar way that are used, instead of the acetate of goserelin, either the natural aanlogos of the hormones of the liberation of the gonadotropin or of other highly potent synthetic analogs (agonists or antagonists), such as triptorelin, leuproline, buserelin or nafarelin, preferably as acetate salts or salts, with other weak acids, or of any other polypeptide lasts which can regulate or modulate the secretion of the intact glands, or tropics, or in their subunits. EXAMPLE 7 The procedure described in Example 7 is repeated, whereby a clear transparent film is obtained and this film (lg) is dissolved in dichloromethane (4 ml.), And the solution is heated to approximately 35 ° C., and then a solution at approximately 40 ° C, of the purified gelatin (15 mg, 0, in water (100 ul), is added to the dichloromethane solution of the goserelin-polyester salt and the mixture is stirred vigorously at approximately 35 ° C., whereby an extremely fine dispersion of the aqueous gelatin solution in the dichloromethane solution is obtained from the polyester-goseraline solution. The experiment shows that the salt of polyester goserelin has active surface properties and can be used for stable dispersions in an oil phase, italicum dichloromethane, of aqueous solutions of other water-soluble agents, such as gelatin, polysaccharide, and other hydrophilic polymers, or vice versa The procedure described in Example 6 is repeated, using the dispersion of the aqueous gelatin in the solution. ion of the dichloromethane, of the salt described before the goserelin polyester described above,] whereby a product of the microcapsule which contains both the gelatin salt and the goseralin polyester is obtained. Other compounds of low molecular weight can be incorporated into the aqueous polymer phase. In particular, it is useful to include compounds such as mannitol, which are known to increase the stability of the peptides. Alternatively, these stabilizing agents can be incorporated in both aqueous phases of the water-in-oil-in-water dispersion complex comprising the dispersed aqueous gelatin in the dichloromethane solution of the goserelin polyester, and the resulting water dispersion. in oil, in turn that disperses in water. Similar suspension and formulations of microparticles can be obtained similarly by using, in place of goserelin acetate, other highly potent aanlogos (agonists or antagonists), from the gonadotropin of the libration hormone, such as triptorelin, buse ,! or naferelin, preferably as salts of the acetate or salts with other weak acids, or of any other polypeptide hrommer, which can regulate or modulate the secretion of the intact gonadotropins or their subunits. Example 8 Goserelin acetate (771 mg., Equivalent of about 670 mg, of goserelian as the free base 95/5 molr of D, L-lactide / glycolide copolymer (1.8g.) ° having a weight average molecular weight of about 3600 Da, and of an inherent viscosity at 1% w / v in chloroform at 25 ° C. ° C, 0.08 dl / g., And 95/5 of the D, L-lactuous molar / glycolide of the copolymer having an average molecular weight of about 15,000 Da, and an inherent viscosity of 1% p / v in chloroform at 25 ° C, 0.17 dl / g (4.2 g), are dissolved in glacial acetic acid free of anhydride (70 ml.), The combined polymers have a weight average molecular weight of approximately 12,300 Da and a polidis-oersibilidad of approximately 2.6. The gase-polyester resin solution is added in portions to the liquid nitrogen and the frozen drops are isolated under freeze-drying under high vacuum, for approximately 18 hours. The product of the drug polymer emulsion is finally dried at 55 ° C, for 24 hotras under high vacuum. The mixture of the dry polymer-drug (6 g.) Is added to dichloromethane (60 ml.), Whereby a turbid colloidal mixture is initially obtained which, over the course of 1 hour, gradually becomes clear, thereby obtains a caira solution, from the salt of goserelin-polyester in dichloromethane. This solution is spray-dried using a Buchi spray drier, using an inlet temperature of 60 ° C, and an outlet temperature of 35 ° C, whereby approximately approximately 1 μm spherical microparticles are produced approximately 10 um in diameter. In these microparticles the drug is present as the salt of goserelin-polyester completely, as the content of acetic acid, such as free acid or anion that is 0.06% or less, instead of 0.6 to 0. 7% which? it is required if gosereline are present as its acetate salt.

These microcapsules when processed further, by compression molding at 80 ° C, give a film bright and transparent and clear. This experiment demonstrates the utility of the salts of the peptide, with the polyols soluble in benzene, the polymers of low molecular weight, and optionally of the high polydispersity. The similar solution, the microparticles, and the molded formulations, can be obtained by using, instead of goserelin acetate, it is already produced naturally from the gonadotropin releasing hormones, or from other highly potent synthetic analogues (agonists or anatomists). of the hormone of libreaciónd ela goandotropina, such as the tr torelina,] euprorelina, buserelin or nafahrelin, preferably like the acetate salts, or the salts, with other weak acids, or any other hormones of the polipet'ido, which regulate the secretion of the gonadotropins or either of the subunits of the gonadotropin. EXAMPLE 9 Goserealin acetate and other highly potent, gonadotropin releasing hormone-like agonists are selective chemical elimination agents which are used in the treatment of hormone-dependent cancers, such as cancer. prostate in men and premenopausal breast cancer in women. These drugs are also used to treat non-malignant gynecological conditions in women, and work by suppressing the secretions of the goandotropins through the pituitary; which leads to a supersession of sex hormones, such as strigence in women and testosterone in men. Consequently, the sustained sustained release of such drugs can be evaluated in vivo in normal female rats, which have regular estrogen cycles, in this animal; the estrogen cycle is about 4 days, and the occurrence of estrus is shown by the presence of only the cornified cells, in the ducts of the vagina, taking on the day of estrus. If the animal is chemically castrated, by means of a drug such as goserelin, then estrus does not occur, leading to the absence of cornified cells from the vagina ducts. The animals in a prolonged period of right-handed, induced by chemical castration, and the dioestrus are maintained for a long as well as effective amounts of the drugs that are being released. (i) The microparticles obtained in Example 8 (450 mg), are dispersed in water containing 2% w / v sodium carboxymethyl cellulose and 0.2% w / v polysorbate 80, and are made with 3 ml. , of water. 0.2 ml. (equivalent to about 3 mg., of goserelin as the free base), is injected subcutaneously into 10 normal adult female rats, which shows regular cyclicity, and the effect of the effect on the cycle of the estrus, is determined by microscopic examination of the vaginal ducts Animals enter a continuous phase, of the right-handed, that is the chemical castration, of 95 - 3 days. This experiment shows that the formulation of the aqueous suspension of the polyster-goserelin salt, based on low molecular weight benzene soluble polyester, provides, for a relatively long period, the release regulated for approximately three months of a peptide drug to which it has a metabolic half life of only 4-6 hours (ii) The microparticles are obtained in Example 8, (450 mg.), dispersed in ethyl oleate, and made up to 3 ml. , OTR once 0.2 ml. Formulation is administered to 6 female rats that show regular cyclicity, by subcutaneous injection. The animals enter to a phase with continuous of the right-handed that lasts 81 3 days. This experiment shows that a formulation of the salt solution of the polypeptide of the goshrelin, in an organic injection vehicle, which is not solvent, for the polyester alone, which provides a relatively large period, of the release of the peptide drug. regulated. Example 10 Leuprorelin acetate (50.3 mg.), And copolyester comprising 78 mol% of D, L-lactic acid and 22 mol% of the glycolic acid described in Example 6, above (453.2 mg. .), is dissolved in glacial acetic acid free of anhydride, (5ml.) The resulting solution is added in steps to liquid nitrogen, and the frozen drops are dried by freezing under high vacuum for 22 hours, and further dried at 55 ° C. , for 24 hours, under high vacuum. The resulting product (500 mg.) Is dissolved in a freshly collected liquid (10 ml.), In a round-bottom container of 100 ml., Which results in a turbid colloidal mixture initially, which gradually becomes clear to a The acetone is evaporated under vacuum and the transparent clear film is dried at 55 ° C for 4 hours under high vacuum.This film of the leu-prolephine-polyether salt is redissolved in acetone (10 ml). ml.), and the solution is degassed and then purged with nitrogen.The freshly distilled water (200ml.), is stirred vigorously under nitrogen, and the acetone solution, of the leuprorelin-polyester salt is sprayed on the surface When all the acetone solution has been sprayed, stirring is continued for an additional hour, and then the mixture is allowed to stand, the microparticles of the salt of the polyester leuprorelin are settling, and the aqueous supernatant is added. d The microparticles are re-suspended in an additional portion of the dioxide free water carbon (200 ml.), and the suspension is stirred under nitrogen for an additional hour. The microparticles are separated,] by initially leaving the mixture to settle, decanting the aqueous layer, and then filtering the residue to separate the microparticles from the excess water. The microparticles are dried at 30 ° C, for 24 hours under high vacuum, whereby a product is obtained, which has an average particle size of approximately 15 u This formulation of the microparticles, of the # salt of leuroprorelin polyester, incised in saline is regulated with the gossato at pH 7.4 to 37 ° C, and the supernatant is tested periodically by UV for leuprorelin. Leuprorelin is released continuously for approximately 5 weeks; by this time the formulation has been totally degraded. Formulations of similar microparticles can be obtained similarly, in place of leuprorelin, either naturally occurring gonadotropin releasing hormones or other highly potent synthetic agonists, (agonists or antagonists), of the hormone releasing hormone. goandotropina. The triptorelin, goserelin, buserelin, or nafarelin, preferably as salts of acetate or other salts, with weak acids, or any of the other hormones of the polypeptide, which control the secretion of intact gonadotropins, or s of the subunits of gonadotropin. * Example 11 i) The goserelin acetater (2.28 g., Equivalents of approximately 2.00 g., Of goserelin as the free base), is dissolved in free glacial acetic acid of the anhydride (60 ml.), A mixture of two copolymers of 95/5 mole of the poly (D, L-lactic acid) polyglycolic acid), (12.6 g., of a copolymer with a weight average molecular weight of 15,846, and a polydispersity of 1.38, and 5.4 g., of a copolymer with an average weight weight of 3,896 and a polydispersity of 1.78), and therefore provide an excess of the carboxylic acid of the copolymer of the final groups in relation to the basic drug, is dissolved with agitation in glacial acetic acid free of anhydride (150ml.), which gives a clear salt. The solution of the drug is added to the solution of the copolymer, and it is mixed vigorously. This mixture is added in portions to the liquid nitrogen to freeze as in small balls; and the solid material is dried by freezing for two days using a freeze drier at high Edwards vacuum. The dried material is also dried at 50-55 ° C, in a vacuum oven for 24 hours. The dry product (lOOmg.) Is added to the dichloroethane (lml.) ° and it is found that it dissolves completely within 2 hours, with which a clear solution is obtained.

• It is shown by this Example, that the formation of the goseraline-polyester salt confers good solubility until such a drug can be dissolved in a non-polar solvent, ii) Goserelin acetate (2.28g., Equivalent to about 2.00) g., of the goserelin as the free base), was dissolved in free glacial acetic acid of the anhydride (60 ml.). A mixture of two 100% molar polymers (of the poly 9-acid D, L-lactide), (12.6 g of a polymer with a mean weight average weight of 15.178 m and a polydispersity of 1.27 and 5.4 g. polymer with a weight average molecular weight of 4.204, and a polydispersity of 1.84) and therefore proprocioanr joins the end groups of carboxylic acid of the polymer in relation to the base drug, dissolves with agitation in free acetic acid galcial of the anhydride (150 ml.), with which a clear solution is obtained. The solution of the drug is added to the solution of the polymer and mixed vigorously, t this mixture is added in steps to the liquid nitrogen for the freezing of the small beds. The solid material is freeze-dried for two days using the Edwards high vacuum freeze dryer. and then the dried material is further dried at 50-55 ° C, in a vacuum oven for 24 hours. This dry product (lOOmg.), Is added to dichloromethane (lml.), And it is found that it dissolves completely within 2 hours, with which a clear solution is obtained. It is shown by this example, that the formation of the polyester-goserelin salt confers good solubility until the drug, such that it can be dissolved in a non-polar solvent. iii) Goserelin acetate (22.8g., equivalents of about .2.00g., of goserelin as the free base), dissolves in the glacial acetic acid free of the anhydride (60ml.) A mixture of 80/20 of the molar copolymer of the poly (acid D, L- ~ ^ ^ lactic / polyglycolic acid), (12.6 g., of the copolymer with the average molecular weight of the weight of 106,510, and a polydispersity of 2.2), and 95% / 5 mol% of the copolymer of the poly (D, L-lactic acid / acid polyglycolic), (5.4g., of a copolymer with an average molecular weight of 3,896, and a polydispersity of 1.78), and by lotantproprovide an excess of the carboxylic acid end groups of the copolymer in relation to the basic drug, dissolves with agitation in the free glacial acxetic acid of the anhydride (150ml.), which gives a clear solution.The drug solution is added to the solution of the copolymer, and it is vigorously mixed.This mixture is then added to the liquid nitrogen for freezing in small balls as the solid material is dried by congelaciaón for two days using a vacuum freeze dryer t Edwards high dry material is further dried at 50-55 ° C in a vacuum oven for 24 hours.

This dry product (100mg) is added to the dichloroethane (lml.), And it is found that it dissolves completely within 2 hours, which results in a cairo solution. It is shown by this Example that the formation of the salt of the polyster goserelin confers good health until the drug as such can be dlled in a non-polar solvent. iv) Goshrelin acetate (2.17 g., equivalent to about 1.90 g., of goserelin as the free base), is dissolved in the free acid acetic acid (60 ml.). A mixture of two copolymers of 67/37% mol of the poly (D, L-lactic acid / polyglycolic acid), (12. Og., D a copolymer with a weight average molecular weight of 35, 833, and a polydrsity of 1.83, and 5.15g., Of a polymer with an average molecular weight of 4,116, and a plidsibilidad of 1.86, and therefore provide an excess of the final carboxylic acid groups of the polymer in relation to the basic drug. , it dissolves with agitation in free glacial acetic acid of the anhydride (150ml), which gives a clear solution. The solution of the drug is added to the solution of the copolymer and it is vigorously added. Nitrogen liquid to freeze it as small balls The solid material is dried by freezing for two days using a high vacuum freezer, and the dried material * also dry at 50-55 ° C, in a vacuum oven for 24 hours. This dry product (lOOmg.), Is added to dichloromethane (lml.), And it is dissolved completely within 10 minutes with which a clear solution is obtained. It is shown by this example, that the salt from the polyester-goseraline salt provides good solubility after the drug, such that it can be dissolved in a non-polar dissolvent. Comparative Example The acetate of gposeraline (2.28 equivalents to about 2.00 g., Of goseraline as the free base), is dissolved in anhydride-free glacial acetic acid. A 50 // 50 mol% copolymer of poly (D, L-lactic acid and polyglycolic acid) 0 (18. Og., Of the polymer with a weight of weight of 22.307, and a polydrsity of 2.06) m -SSs and therefore provides a stoichiometric equivalent of approximately the final groups of the carboxylic acid of the copolymer, in relation to the basic drug, which is dissolved, with stirring in glacial acetic acid free of the anhydride (150ml.), Thereby You get a clear solution. The solution of the drug is added to the copolymer solution and mixed vigorously. This mixture is then added in potions to the liquid nitrogen to freeze as small pellets. The solid material is dried by freezing for two days using a freeze drier at high Edwards vacuum, and the dried material is further dried at 50-55, C, in a vacuum oven for 24 hours. This dry proctuct (lOOmg.), Is added to dichloromethane (lml.), And it is believed that it does not dissolve completely after 4 hours, but it dissolves to fortify a clear solution after 4 days. It shows by this Example, that the froamción of the salt of polióstergoseralina, has good so¬ * lubilidad, until the drug can dissolve in a non-polar solvent, occurring more easily, when the end groups of the carboxylic acid of the copolymer are present in excess in relation to the basic drug. The i-iv dry products are dissolved in dichloromethane and spray-dried using a Buchi laboratory-scale spray dryer of 190, according to the following table: Product% Tempera Ratio. of Product temperature at dientrada ° C. output solvent% i 10 48 32 ii 10 58 38 iii 2 58 44 iv 10 55 35 Spray drying of the i-iv products gives small particles,] with a diameter of approximately 1-10 um in size as it is determined by the scanning electron microscope. The final particles are tested for the content of cetic acid, using a gas chromatography assay, with a detection limit of approximately 0.03%. Acetic acid is not found, in these formulations using assay, and these show that the drug is present as the salt of the polyester, and not the acetate salt, because acetic acid levels are approximately 0.5% what is expected for the salt of acetate. The particles of spray drying (50mg.), I-iv above were dissolved in dichloromethane (0.5ml.), With which a clear solubility was obtained. A drop of trifluoroacetic acid is added to each, and in each case this results in the formation of a white precipitate. The samples are centrifuged to collect the precipitate, which is washed with dichloromethane. The HPLC analysis shows the precipitated material to be goserelin. These examples show that the drug can be replaced by the salt of the polyster-it is drunk into the solution in a non-polar solvent by the addition of a strong acid, and that this results in the properties of the solubilide of the drug in a non-solvent solvent. -polar to return as expected from the acid salt, from the peptide drug (for example it is not soluble). Example 12 The particles dried by dew i-iv in Axis 11; is dispersed (18% w / v), in an aqueous vehicle suitable for the injection (of sodium carboxymethylcellulose to 2 (Fluka, viscosity medium), 0.2% of polysorbate 80 (Tween (trademark of Fluka). Spray-dried particles, of Example 11, is dispersed in the injection vehicle as mentioned above, injected into 10 rats derived from Wistar hem bras.Samples of blood taken from the tails of 5 rats in days 7,14, and 28, t these samples are tested, for goserelin using a radioimmunoassay with the known specificity for the drug and to avoid the loss of the metabolites' reactivity.The results of these experiments show that these fo- it is possible to measure the blood levels of the blood glucose for at least 4 weeks Example 13 F The dry product by sprue ii of Example 11 is dispersed in the following aqueous vehicles for injection into sodium carboxymethyl cellulose (viscosity grade). medium density, Fluka), 1.0% and polysorbate 80 (Tween), 0.75 b methyl cellulose (15mPa. s. Fluka), 0.75% and polysorbate 80 (tween) 0.75%. These formulations disperse well in these vehicles, and are suitable for parenteral administration. EXAMPLE 14 The spray-dried product ii of Example 11 (400 mg) is dissolved in dichloromethane (4 ml.). This is added, using a syringe, to a solution of 0.25% polyvinyl alcohol, (PVAOme water (Aldrich, 75% hydrolyzate, molecular weight of 2000), which is stirred at 2500 rpm After 2 minutes, the stirring rate is reduced to 800 rpm, the stirring is continued for an additional 30 minutes.The stirring is then stopped and the particles formed are allowed to settle, the PVA solution is decanted and the particles then they are washed twice with ice-cold water and recovered by centrifugation.The particles are finally dried, by freeze drying and the final product is a fine particulate material containing goserelin Example 15 The spray-dried formulation iv of Example 11, is extruded at 82 ° C, with which an extruded cylindrical one millimeter in diameter is obtained, This extrudate is cut, so that the weights of the lengths are approximately 36mg., And contains approximately 3.6 mg. , of goserelin. This extrudate is made completely clear to the lus better than being of a white appearance, the last appearance is typical of a simple mixture of the drug and the polymer produced without the formation of the peptide salt, with the polyester, (as in the Example for which this commercially available, Zoladex-Zoladex, is a registered trademark) The clarity of this extrudate indicates that the goserelin peptide is compatible with the polyester phase, rather than being in a separate phase, which It results in the division of light, and "a white appearance." This compatibility, m can only occur, if the peptide is in the same phase, as the polymer, for example, is present as the salt of polyester. of the deposits are implanted in rats derived from Wistar 21, under anesthesia.The groups of the subsequent time points, of the three animals are sacrificed, and the deposits are recovered. They are dissolved in glacial acetic acid in a volumetric vessel, and the polymer is precipitated by the addition of an excess of water. This is filtered immediately (Mi llex 0.5 um), and the fiktrados is tested for the content of the drug by HPLC. The profile of the libreation of the deposits are calculated by reference to the content of the drug in the deposits, which have not been impacted, and which are included in the same trial. These deposits, of the polyester-drug salt gives the sustained liberty of gosereline in vivo for a period of at least 4 weeks.

Example 16 (i) the lactide / glycolyte copolymer (95/5), with the terminal carboxylic acid group alone) (8.87g Mw-570v'3, - A polydispersity = 1.5 molecular weight by the final group of the titration = 2516 g / mol, inherent viscosity at 1% w / v in chloroform, = 0.10 dl / g) is dissolved in dichloromethane (50 ml.), With stirring. To this is added 1.13g. d goseraline acetate, a cloudy suspenation is formed, methanol (5 ml.) is added thereto, with stirring, and after 30 ml. * nutos, the mixture is completely clear. The solvent is then removed from the solution by means of a rotary evaporator, to leave a solid cairo. This solid is redissolved in dichloroethane (50 ml.) And the solvent is removed again by rotary evaporation. The redissolution stage and the solvent elimination stage are repeated twice, but leave a very viscous fluid, the It dries under high vacuum with which it obtains a white foam. The foam is broken and dried under heat for an additional 24 hours at room temperature, whereby a fine amorphous substance is obtained. (ii) The procedure described in Example i) above is repeated, using a lactide / glycol copolymer (75/25), with a single carboxylic terminal acid (8.87g Mw = 10900, the polydispersity = 1.85, of molecular weight? by titration of the final group - 3210 g / mo, viscosity ^ Inherent to 1% of w / v in chlorofromo = 0.14 dl / g) WITH WHICH the fine amorphous solid is obtained. Formulation 1 The lactide-gpserelin polymer / glycolide polymer salt of (i) above (lg.), Is added to the benzyl benzoate (99% 0, ex janssen,; 2 mil), and this is heated using a hand-held air gun while the mixture is stirred until the solids re-dissolves. 110 ul of this solution of the formulation containing 3.6 mg. Of goserelin. Formulation 2 As in Formulation 1, except that the solvent is a mixture of (1.7 ml.), Of benzyl benzoate 67% (99%, ex Janssen), and 33% of benzyl alcohol (9% of the anhydrous ex Aldrich), 100 ul of this formulation of the solution contains 3.6 mg. , of goserelin. Formulation 3 Like formulation 1, except that the solvent is benzyl alcohol (1.7 ml., Of the anhydrous, 99% ex Aldrich), 100 ul of this formulation of the solution contains 3.6 mg. Of goserelin. Formulation 4 As Formulation 1 ,; except that lacturo-goserelin / glycolide polymer as the salt of (ii) above (lg), and 3 ml. of benzoate and methyl are used. 150 ul of this description of the solution containing 3.6 mg. , of goserelin. Formulation 5 Like formulation 4, except that the solvent mixture of the formulation 2 s eusa. 100 ul of this formulation of the solution containing 3.6 mg. Of goserelin. Formulation 6 As formulation 4, except that the solvent of formulation 3, is used, 100 ul of this formulation of the solution containing 3.6 mg., Of goserelin. Biological Evaluation The release of goserelin from the above formulations 1 to 6, in vivo, is determined by the daily study of the svaginal ducts of female dosed rats. The normal cilo estreo (estreo, distreo, met-estreo, or prodigal), can be followed by the proportions of the various types of cells; (leukocytes, epithelial and cornified) in the duct. If the release of the drug from the formulations is continuous, the cycle of normal constipation is interrupted and the rats remain as long as the release of continuous goserelin remains. Formulations 1 -6 are dosed to groups of (n = 6) of female rats of regular cycles at a dose of 3.6 mg. , of goserelin per rat. A syringe is fixed with a needle of 20, patra the dosage of the subcutaneously injections. Unit undosed, 5 rats are used as the control group. The vaginal ducts are taken daily from the rats, and examined to determine the oestree stage of the animals and the results obtained are as follows: Number of the formulation Average duration of the day (day 3 69 ± 5.9 + 4 59 1.2 + 5 61 - 3.7 6 53 - 3.7 From these results, it can be seen that the 6 items give the periods of the release of the gosere¬ • lina in excess of 6 weeks and that forms 1 and 2 release goserelin for a period of three months or more. It can further be seen from these examples that formulations of the goserelin-polyester salt can be provided with solutions, which are administered parenterally using a small needle, and that such formulations are suitable for the treatment of tumors. Dependents of hormones in man.

Example 17 * Formulation 1 As the formulation edl Example 16. Formulation 2 The procedure described in Example 16 (i) is epite, using a polyamide copolymer with a single terminal carboxylic acid (Mw = 5092, polydispersity = 1.44, molecular weight by the titration of the 2 extreme group = 2270 g / mol ,: and the goserelin acetate (0. 46g.), The content of the acetic acid, of this amorphous solid is determined by gas chromatography, and it is found to be 0.14% This salt of the polymer of goserelin-lactide (lg.) Is added to benzyl benzoate (99%, ex Jansse 2 ml.), And this is heated, using a hand-held air gun while stirring, until solido dissolves. "110 ul, of this formulation of the solution contains 3.6 mg., goserelin Formualcióp 3 A copolymer of lactide / glycolide (95/5), with a terminal carboxylic acid (7.86g., NW = 5750, polydispersibility = 1.50 molecular weight mediant e the titration of the final group = 2516 g / mol. and the goserelin acetate (0.98 g.), dissolved in acetic acid (100 ml.). This solution is frozen by the addition in portions of liquid nitrogen, followed by freeze drying for 2 days. The solid residue is then dried for an additional 24 hours at 40 ° C. The acetic acid content of this freeze-dried solid is determined by gas chromatography and is found to be 0.17%. This mixture of lactide dee goserelin / glycolide copolymer (lg.), Is added to benzyl benzoate (2 ml., 99% Janssen), and this is heated using a manual air gun while stirring the mixture you have until the solid dissolves. 110 ul, of this formulation of the solution, containing 3.6 mg., Of goserelin. It has therefore been found that goserelin formulations such as the salt of polyester confer good solubility until the drug, such that it can be dissolved in lipophilic solvents, such as benzyl benzoate, # in which goserelin acetate itself is not soluble. Biological Evaluation the formulations 1-3 are dosed to groups of (n = 10) m, of the female regular cycle rats, at a dose of 3.6 mg, of the goshrelin per rat, as described in Example 16 After the dosage, the animals meet! that enter a period of continuous dis- appearance that indicates the continued release of goserelin. The average pro-i duration of the period of the period for each of the groups, of the rats, is given in the following table. From this table, it can be seen, that all three forms give periods of the release of goserelin, in excess of 14 weeks. Formulation No. Average duration of the distribution (days), (- se) 1 104 (t 5.4 2 99 (- 3.9) + 3 101 (- 2.8) SE you can see in addition to these examples that the particulars of the salt of the polyester of goserelin can be provided as the solution which can be easily administered parenterally with a small needle, and such formulations are suitable for the treatment of hormone-dependent tumors in man Example 18 Formulation 1 Lactide copolymer / glycolide (95/5), with a thermominal carboxylic acid (4.5g., Mw-6806, polydispersity = 1.55, molecular weight by titration of the final group of = 3027 g / mol,] the inherent viscosity at 1% p / v in chloroform = 0.108 di, / g) is dissolved in glacial acetic acid,; (50ml.) To this solution is added goserelin acetate (0.56g., Equivalent to 0.5g., Goserelin) and the mixture is stirred for 10 minutes, which gives a clear colorless solution. . This is frozen by the addition in portions to liquid nitrogen, followed by freeze drying for 2 days. The resulting solid is then dried for an additional 24 hours at 40 ° C. The acetic acid content of this freeze-dried solid is by gas chromatography and the mixture of the goshrelin-lactide / glycolide (L.) G. Copolymer mixture is added to the methyl benzoate (2.0 ml. ., 99%, ex Janssen), and it dissolves with warming and with agitation. The final solution contains 3.67 mg. of goserelin, in 110 ul, and the goserelin content of the dinal product is 10.0% w / w Formulation 2 The procedure described above for formulation 1, is repeated; using a lactide / glycolide copolymer (955 *), with a single terminal carboxylic acid dosus (4.0g., Mw = 6011, polydispersity = 1.56, molecular weight by extreme group titration = 2700 g / mol, the inherent viscosity at 1% w / v in chlorofromine = 0.099 dl / g and 1.12 goserelin acetatrum (equivalent to 1.0 g., ls goserelin) The acetic acid content of this solid is detrminated by chromatography and it is found that it is 0.83% and the content of the gfoserelin of the final product is 19.46% w / w This mixture of the lactyl copolymer of goshrelin / glycolide (0.54 g), is added the benzyl bemzoate (246mg., Ex janse), (and dissolves with heating and t with atgitation The final solution containing 3.50 mg of goserelin is 110 ul. Formulation 3 The procedure described in phoomulation 2, is repeated, using 2.1 g., of the copolymer of lactide / glycol luiro, and 1.0 g., of goserelin acetate (equivalent The content of acetic acid in this freeze-dried solid is determined by gas chromatography and it is 1.14% of the goserelin content of the final product which is 28.91% p / g. p This mixture of the gellrelin / glycolide alactide copolymer (0.36 g) is added to the benzyl benzoate (2.64 ml. ex Janssen), and dissolves with heating and with stirring. The final solution contains 3.47 mg. , of godserelin in 110 ul. Formulation 4 The procedure described above for Formulation 1 ,; be epite, using the copolymer of lactino / gli-coliuro (95/5), with a single terminal carboxylic acid, (8.66g., mw = 5604, polydispersity = 1.71, molecular weight by titration of the final group = 1960 g / mol, viscosity inherent to 1% w / v in chlorofrome 0.04 dl / g and 1.08 goserelin acetate (equivalent to 0.96 g., goserelin) The content of acetic acid, of this solid freeze dried deterrmian by gas chromatography and it is found to be 0.08% and the goserelin content of the final product is .9.90% w / w. Esite mixture of the lactide copolymer of gosere-linaglycolide (l.Og.), is added benzoate debencyl (2.0 ml, 99% 0, ex Janssen), and is dissolved with heating and with shaking.The final solution contains 3.67 mg of goserelin in 110 ul Biological Evaluation Formulations 1-4 are digested, to the rugs (n = 9 or 10), of the female rats of the regu-laresa cycles with a dose of 3.6 mg., d and goserelin per rat, as described in Example 16. Following dosing, the animals are found to enter a continuous period of the dieter indicating the continued release of goserelin. The average duration of the distro period for each of the groups of rats is given in the following table From this table, it can be seen that all three formulations give periods of goserelin release for a period of approximately 3 months or more. Formulation No. Average duration of the period (days), (± s.e.) 1 114 - 1.8 2 94 _ 4.6 3 97 - 5.3 4 83 - 4.3 It can also be seen, from these examples, that the sources of polyester alters of the drug can be provided as solutions, which are easily administered by a paraphernalia using a small, and that such formulations are suitable for the treatment of hormone-dependent tumors in man. Example 19 The salt of goserelin-polyester (ii), of Example 16 (3.75g.), Is dissolved in dichloromethane (50ml.) Which have been previously filtered, through the 0.45um filter. This solution is filtered through a Teflon filter membrane of 0.5 μm (Whatman WTP_.) In a container that has been sterilized using an autoclave.The solution is removed using a rotary evaporator, thereby obtaining a liquid. viscous, and the air is then admitted to the rotary evaporator through a 0.5 μm filter.The viscous liquid is heated and dried in vacuum, where a white foam is obtained.The foam that is obtained is weighed in containers that they are in a utoclave, in a laminar flow cabinet, and fresh distillation solvents are added, thereby obtaining formulations of the salt solution of goserelin-polyester, which are essentially free of particles. Formulation 1. lg., Of the solid is added to the benzyl benzoate (distilled, p.de e 106 ° C), to 0.3 mb, 3 ml), and heated using a hot air gun, until it dissolves, 145 ul of this formualization of the s olution contains 3.6 mg. , of goserelin. F Formulation 2 1 g., The solid is added to the benzyl alcohol (distilled from p.E. 44.C, at 0.3 mb, 1.7 ml.), And heated using a hot air gun, until design 100 ul of this formulation of the solution contains 3.6 mg; of goserelin. Biological Evaluation Two groups of 10 female rats are dosed subcutaneously, sucking a No. 20 guava with formula 1 and 2, at a dose of 3.6 mg.; per rat.The terminal blood samples are taken from the rats at the following times (1 week (n = 4), 4 weeks, by means of the radioimmunoassay.The levels of the blood samples of goserelin are enceuntrream with both formulations, indicating, that the sources of the solutions are the release of the sustained drug for the several weeks, the profile of the level ^ "" J "blood of Formulation 1 is found to have a peak at about four weeks, where with Formulation 2, the peak ocutre in a week, and then the blood levels, enuntram that declinen progressively, with time. The blood level profile of formulation 1 ,: is considered to be more desirable than formulation 2, due to the more constant blood levels, which is obtained when benzyl benzoate is used as the solvent, for the formulation of The solution It is also possible to see, from these examples, that the formulations of the polyester salt of the drug can be provided as the solutions, which are easily administered parenterally using a small needle, and that such formulations are suitable for the treatment of hormone-dependent tumors in man.

Example 20 A copolymer of lactide / glycolide (95/5) with the single terminal carboxylic acid (9.0g., Mw = 6011, polydispersity = 1.56, molecular weight by titration of the end groups = 2700 g / mol, Viscosity inherent to 1% w / v in chloroform = 0.099 dl / g) ° DISSOLVE IN DICHLOROMETAMIN (100 ml.). To this is added the goserelin acetate 124 g., Equivalent to 1 g., Goserelin d). with stirring, followed by the addition of methanol (10 ml.) the cloudy suspension is obtained with stirring at ambient temperature for one hour until the clear solution has been obtained. The solvent is liminated using a gibleatory evaporator, in chloroethane, whereby a clear viscous liquid is obtained. Then it dissolves to dissolve end Ichloroethane and it is dried again as before. This stage is repeated twice more; and the viscous liquid is finally obtained dried under vacuum to produce # a white foam, which dries in addition to the vacuum during the nocvhe. The foam is broken into a fine powder, which is dried for one day at room temperature per day. To this powder is added benzyl benzoate (20 ml., 99% ex Jassen), and the resulting mixture is heated softmnet, with agitation, which results in a solution. Biological Evaluation This formulation of the goserelin solution is dosed subcutaneously using a needle of 20, in each of the 45 female rats (220 ul, equivalent to 7.3 mg. goserelin) 0 The groups of the 5 rats; are finished and the blood samples are taken on days 1 to 4, and weeks 1,; 3.5, 7.9, 11, and 13. In addition to the blood samples, they are taken from the vein of the tail of the groups of the five rats in the weeks 2,4,6,8, 10 and 12. The samples are analyzed, for the goserelin by means of the radioimmunoassay and the results are shown such that the liquid deviations; of the salt of the polyster-goserelin gives the measurable blood levels of the drug approximately 11 weeks after dosing and shows that the formulations give the sustained release of goserelin in vivo. It can also be seen that, from these examples, that the formulations of the polyester salt of the drug can be provided as solutions which can be easily administered parenterally using a small needle, and that such formulations will be convenient for the patient. treatment of hormone-dependent tumors in man. Example 21 The peptide known as substance P, in the form of its acetate salt,: (ex Sigma, 2 mg.) Is added to dichloromethane (3 ml.), And is vigorously stirred, The peptide shows no indication of dissolution in the solvent, and remains as a cloudy suspension. A copolymer of the lactide / copolymer of the glycolide (703 * 0), with the only terminal carboxylic acid (225 mg, = 9755, the polydispersity = 1.62, the molecular weight by the titula- tion of the final group = 1800), is added to it. to the dichloromethane (25 ml.), This is stirred for 15 minutes, whereby a solution of the substance P (25 mg.) is obtained in methanol (0.5 ml.). The resulting cloudy suspension is stirred ^ BL for 1 hour, by the time in which; The clear solution is completely formed. The solvent is removed by rotary evaporation: and the solid in clear crystals is obtained when they are redissolved in dichloromethane (5 ml.), And evaporated again. This is repeated twice. The final solid is dissolved in dichloromethane (3 ml.), And the solution is slowly stopped in a closed container of PTFE, allowing the solvent to evaporate, to form a thin film of a solid of colorless crystals. clear, (peptide content 9.21% w / w), These films (96.8 g.), are placed in a small vial, and a regulated phosphate solution (2 ml, pH 7.4), is added a regulatory solution (which is previously filtered through an O2 filter and which contains 0.02% of the sodium azide, as a preservative, the dry vial, oca in a 37 ° C incubator, and the regulator is removed and rced periodically. The regulatory solute is eliminated by the analysis for the release of the substance P, using an ultraviolet specytrophotometer (Hewlett Packard 8452 AO, at 210 nm, against the normal solutions, of the P substrance, the results show that the susbtancy P s epude dissolve in diclo roemtane, when formed as a salt of a carboxy-terminated carboxyl / glycolide. and it can be processed, in this solvent, whereby a thin film, which continuously lives off, of the peptide is obtained for a period of about 4 weeks. Example 22 An aqueous solution of the leuprolide acetater (otherwise known as leuprolia acetate) (300 mg / ml, of the solution), is added under the conditions # aes of agitation to 20 ml. , of a 10% w / w solution of the poly (hydroxystearic) aido, having a number average molecular weight of about 2000, in Mygliol 812 (Triglicerisod of the medium chain sarurated fatty acids including linolenic acid; ex Dynamit Nobel Reí no Unido), to form the salt of the leurpolida polymer, partly at the oil / aqueous interface, whereby the resulting colloidal suspension of water in oil is stabilized.

The water is removed at 50 ° C, by stirring it under high heat, until the mixture gives more bubbles, with which a composition in oil is obtained, with which it has a very bad damage, and which is adequate for the oral administration. Example 23 o The salt of Lus acetate (2 mg., Ex Sigma), is added to dichloromethane (3 ml.), And stirred. The peptide shows no indication of the solution in the solvent and remains as a cloudy suspension. A copolymer of lactide / glycolite (703 * 0), with carboxylic acid alone (225 mg, Mw - 9755), polydispersity = 1.52, molecular weight by titration of the final group - 1800), is added to dichloromeyabo (5 ml .) This mixture is stirred for 15 minutes, whereby a clear colorless solution is obtained. To this the glass is added # 8 Presma Lis (25 mg., Ex Sigma), and methanol (0.5 ml.). The resulting turbid suspension is quenched for 1 hour, whereby the completely clear solution is formed. The solvent is removed by means of a rotary evaporator, and the solid in clear crystal form is obtained and redissolved in dichloroethane (5 ml.), And re-evaporated. This is repeated twice. The final solid is dissolved in dichloromethane 93ml.), And the solution is slowly stopped in a PTFE-coated cloth, allowing the solvent to evaporate to form. a thin film of an odor in clear, colorless crystals (content of vasopresma Lus 10% w / w), this film (97.31 mg.), is placed in a small vial, and the phosphate saline solution (2 ml. pH 7.4) is added (a buffer solution has previously been filtered through a 0.2 μm filter and contains 0.02% sodium azide, as a preservative) The vial is placed in an incubator at 37 ° C, and the regulatory solution is eliminated guladora is analyzed for the treatment of the vasopressin na-Lis t using an ultra violet spectrophotometer, (HewlettPackard 8452 A), at 210 nm against the standard solutions, of the vasopressin-t 8 L, s, The results of this test are shown in the following table, The experiment shows that L-vasopressin, can be dissolved in dichloromethane, when it is formed as the salt of a carboxyl-terminated lactide / glycolide and that the resulting mixture gives the continuous libreation of the peptide po r a period of at least four weeks. p Release of vasopressin -Lis in vitro Time (days). Liberacigón of the film of vasopr 8 sina de Lis (%) 1 4.11 4 5.45 7 5.55 14 5.75 28 47.27. Example 24 Two formulations of ZENECA ZD 6003 (Met 'Ar9, 17.27, 60.65.,., Ser) / human G-CSF (granulocyte colony stimulation factor), modified with polyethylene glycol 5000 , as described with reference of the E-jemp, so 4 or 7, of the publication of the European Patent No, 0 473, 268), in the copolymer of the lactide / glycolide is prepared as follows: (i) It is added dichloromethane (4 ml.), to a freeze-dried preparation of ZD 6003 (39.72 mg.), This rests in an opaque dispersion of the drug in the solvent A lactide / glycolide copolymer (75/25), with a only terminal carboxylic acid (363 mg., Mw-9963), polydispersity = 2.19, molecular weight by titration of the final group = 2815), it is added; and a clear solution is formed. this solution is added to a solution (400 ml) m of methyl cellulose (0.25%), p / m of metocel,: 15 mPa.s. ex Fluka), in shaking water (2150 RPM, Heidol ph RZR 50, agitator model). After gating at this rate for 3 minutes, the speed of agitation is reduced to 800 rpm. The resulting particules are then sedimented,: under gravity for 30 minutes. While keeping the cold solution on the ice. The supernatant is then described and the particles are washed and suspended in distilled water with ice (50 ml.), And centrifuged at 1000 rpm. This is repeated four times and then particles are finally dried by freezing. the particles are made in this way to have a good quality, being spherical; and with an average size of 32 um as determined by the analysis of the image of the optical microscope. The content of the drug of the particles is determined by extraction followed by HPLC analysis, and it is found that they are 9.45%, which represents an efficiency in the incorporation of 96% of the drug used to form the microparticles. (ii) Dichloromethane (4 ml.) is added to a freeze dried prearaciaon of ZD 6003 (44.18mg). This results in a dispersion of the drug in a solvent. A lactide / glycolide copolymer (752 * 5, 364.5 ex Boehtinger Ingeiheim) is added. An aid for the determination of the molecular weight of the polynomer by means of the titration of the final group is carried out, but it is not possible due to the fact that I varied at low levels of the titratable fractions, and consequently, this polymer does not have a carboxylic and terminal acid. The mixture of the drug solution and the polymer does not begin to be clear from the addition of the lime and the mixture that remains as a turbid dispersion, indicating as expected, in the absence of the end groups of the acid in the polymer, the salt of the peotide-polyester can not be formed. This mixture is added to a solution (400 ml.) of methyl cellulose (0.25%, w / v of methocel, 15 mPa.s, Fluka), in water under stirring (2150 RPM0 in a Heidolph RZR50 stirrer). ). After stirring at this rate for three minutes, the speed of the gating is reduced to 800 rpm. The resulting particles are then allowed to settle for 30 minutes, while keeping the solution cooled with ice. The supernatant is discharged and the particles are washed and resuspended in distilled water (50 ml.), And the centrifugation at 1000 rpm. This is repeated four times and the particles are then finally frozen.

The particles are made in this way endpnde the inferior quality, compared with that obtained in (l) anteriro), with some irregular shape and an average size of 40 um as determined by the image analysis of the iptico microscope. The drug content of these particles is determined by extraction followed by HPLC analysis, and it is found to be 2.05%. that represents, an efficiency of incorporation of 19% of the drug that suse to form the macropoarticles. The previous example; shows that ZD6003, can be dissolved, in dichlorommethane when in the presence of the polymer with a single terminal carboxylic acid, dichloromethane is removed by itself in a non-solvent, for the drug. In addition, such a solution can be used to form the microparticles of the drug and the polymer with a very high proportion of the incorporation of the drug. In contrast, the above example also shows that ZD6003 can not be dissolved in dichloromethane in the presence of a polymer when such a polymer does not have a terminal carboxylic acid and forms only a bad dispersion. Also,; such poor dispersions of ZD 6003, in a polymer solution, without any carboxylic terminal acid results in poor incorporation of the drug when it is pre-formed to form the microparticles. Example 25 (i) Goserelin acetate (22.47 mg.), Equivalent to 19.99 mg. Goserelin), is added to benzoate benzyl (2.21 g., 99% ex Janssen). This mixture is placed in an incubator at 40 ° C, and the agitation is continued for 9 days, using a magnetic stirrer. After day 2 and 9, the aliquots are taken and crushed for 15 minutes at 13.00 RPM ° for the pellet of the undissolved drug. The aliquots of the supernatant (approximately 100 mg) are safely weighed in 50 ml volumetric containers. To each one add acetic acid glial (2ml.), Followed by a volume with an aqueous solution of trifluoroacetic acid, (0.5 v / v), A poricón of this solution is placed in a tube of the centrifuge, and centrifuge at 13.00 rpm., for 15 minutes to separate the overburden material. The supernatant is assayed for the content of goserelin, using HPLC. There is no goserelin in any of the samples. The limit of the detection of goshrelin in this HPLC assay is 0.2 mg / ml and the limit of quantification is 0.5 ug / ml. Therefore, the solubility of the equilibrium (at 40 ° C.) ° of goserelin in benzyl benzoate can be estimated from the above as less than 0.02 μg. (ii) A lactide / galactide copolymer (85/5), with a single terminal carboxylic acid (29119 mg., Me - 6742), the polydispersity - = 1.61, the molecular weight by titration of the final group = 2565 g / molm the inherent viscosity at 1% w / v chloroform = 0.103 dl / g, is added to the benzyl benzoate (3.38 g, 99%, ex janssen), to form a solution. To this is added goserelin acetate, (22.52 mg, equivalent to 20.03 mg, of goserelin). This mezcal is incubated and shown as described in (i) above. Goserelin was not detected in benzylic benzoate in the 2 years, but on day 9, a level of approximately 0.2 ug, of geserolin per mg of benzyl benaoate is detected. The goserelin detection limit in this HPLC assay is indicated in (1) above. From this it can be shown that the solubility of the equilibrium (at 40 ° C) of goshrelin in benzoate benzoate, when present as a simple mixing with a lactide / glycolide copolymer, can be estimated as 0.2-0.5 ug / mg. (iii) A lactide / galactide copolymer (95/5), with only one terminal carboxylic acid (9.0g., Mw = 60 11, polydispersity = 1.56, molecular weight by titration of the termianl group = 2700 g / mol viscosity inherent to 1% of p / v in the chlorofromo = 0.099 di / g dissolves in the dichloromethane (100ml.), To this is added the acetate of goserelin (1.124 g.,; equivalent to 1 g. of the gosperiline) with stirring, except for the addition of methanol (10 ml.). The cloudy suspension is obtained by stirring at room temperature for about 1 hour, until the clear solution is obtained. The solvent is removed by adding a rotary evaporator, whereby a clear viscous liquid is obtained. This is then redissolved in dichloromethane and dried again as before. This stage then repeats two more vases and the viscous kiquido is finally obtained which is dried under high vacuum, to produce a white foam, which is dried under high vacuum, to produce a white foam, which is also dried by vacuum during the night. The foam is broken into a fine powder, which is dried in vacuum, for 1 day at room temperature. To this powder is added benzyl benzoate, (20 ml., 99% ex Janssen), and the resulting mixture is gently heated, with stirring, whereby a solution is obtained. The solution is stirred and mixed vigorously and lml. of the sample is placed in a centrifuge and moves at 14.00 rpm., for 30 minutes. An aliquot of the supernatant is carefully removed and weighed in a 50 ml volumetric vessel. The sample is tested, for the content of goserelin, as described in (i). The goserelin content of this solution is 24.6 ug / mg benzyl benzoate. this example, shows that benzyl benzoate is a very poor solvent, for goserelin acetate In addition, the addition of lactide / glycolide polymer to form a simple mixture with goserelin acetate in benzoate methyl ester does not lead to the aumneto marked on the equilibrium of the solubility of goserelin acetate in benzyl benzoate. However, the salt of goserelin / polystyrene can be dissolved in the benzyl alcohol to form a solution containing goserelin at a concentration

Claims

much higher than the solubility of the estimated equilibrium, d free goserelin in this solvent. NOVELTY OF THE INVENTION having desfrito the invention consider as a novelty and therefore we claim as our property contained in the following clauses: l.-A composition containing or comprising as it is initially done, a salt that is formed of a cation derived from a peptide containing at least one basic group and an anion derived from a thermogenic polyester in carboxy, the - cmposition is in the form of a solution or dispersion of the al in a solvent, for the free polystyrene but not a solvent for the free peptide, the particle size of the salt in the dispersion being less than 5 um, and preferably less than 0.2 um. or in the form of microparticles or an implant, for injection or sub-dermal implantation.
2. A composition as mentioned in Clau- sul al, where the pe- dia is pharmacologically active, and is selected from oxytocin, vasopressin, adrenocorticotrophic hormone (ACTH), epidermal growth factor. (EGF), prolactin, lutenization hormone, the hormone that facilitates the stimulation of the follicle, the luberine or the hormone of the libreation of the hormone the lutenizaciaón (LHRH) or the insulin, the somatostatin, the glucagom interferon, gastrin, tetragastrin, pentagastrin, uroagstrone, secretin, calcitonin, enkephalins, ebdorfins, quitorfin, taft without,] thymopoetin, thymosim timostimulin, thymic humoral factor, serum thymic factor, necoris factor of the tumor, stimulation factors of the colony, motilin, bombesin, dynorphin; neurotesin, cerulin, bradykinin, urokinase, calikréna, substnce 0 and its analosogosm and antagonists, angiotensin II, nerve growth factor, blood coagulation factor, VII and IX, lysozyme chloride, renin brádi u: i.nina 'itirocidina , gramicidin, growth hormones, stimulation hormones, melanocytes, hormones of thyroid hormone release, thyroid stimulation hormone, parathyroid hormone, pancreozyme, colé cystokinin, human placental lactogen, human chorionic gonadotropin , due to stimulation of protein synthesis; Gastric Inhibitory Peptide, Protein Synthesis Stimulation Peptide, Gastric Inhibitory Peptide, Vasoactive Intestinal Peptide, Plaqgeta Rivate Growth Factor, Hormone Release Factor, Omo Morphogenic Protein, and Analogs or Modifications synthetic ,; and of the pharmacologically active fragments thereof.
3.- A composition as mentioned in the clause to ,; wherein the polypeptide is pharmacologically inactive, and is selected from polyarginine, polylysine, and poly (arginine-co-lysine), copolymers of the neutral amino acids, in the forms, D-, L- or DL-, with the arginian and / or lysine in the D =, L- or racomic forms, or peptides or co-polypeptides, in which the chains of the peptides are partially or completely terminated by a basic group, in the N-terminus, and the Central part is comprised of the residues of neutral amino acids.
4.- A composition according to clause 1 ,; wherein the polyester is selected from those derivatives of the hydroxy acids and derivatives of the polycondensation of the diols * and / or of the polyols with the dicarboxylic acids and / or the polycarboxylic acids.
5. A process for obtaining a solution or a dispersion of a salt as mentioned in clause 1 ,? which comprises: (a) the dissolution of a porphyrid containing at least one amino acid in the free base form, or in the form of a salt, with a weak acid and the finished carboxy polyester is a polar neutral solvent, in which: both are soluble, the removal of the solvent, or of most of the solvent, and the addition of the remaining concentrated solution, to an excess of the non-solvent for the peptide-polyester salt, or (b) the dissolution of the peptide containing at least one basic amino acid, in the form of the free base, of a salt with a weak acid,; and the polyester thermic in carboxy, in a solvent in which both are soluble, and which is able to be removed by freeze drying, freezing the resulting solution at a high speed, freeze drying the mixture resulting frozen, the dispersion of the resulting mixture, in a solvent for the polyester component, and allow the mixture to dissolve as the polypeptide-polyester salt is formed, or (c) the reaction of the polypeptide, which contains at least one basic amino acid, in the form of a salt with a strong acid, with a polyester where part or the total of the polyester is in the form of a salt of the carboxylic acid, with a suitable alkali metal, or alkaline earth metal
6.- A composition as mentioned in clause l ,? comprising a pharmacologically active peptide and polyester, for sustained release, of the peptide drug, characterized in that the composition is in the form of microparticles from 0.2 μm to 500 μm in diamter, suspended in a pharmaceutically acceptable injection vehicle .
7. A composition according to clause 6, wherein the vehicle of the injection is aqueous or is an organic vehicle which is not solvent, for the materials used, or, for highly lipophilic polyesters, it is a vehicle for organic hydrophilic injection. .
8.- Uan composition according to claosula 1 ,; comprising a pharmacologically active peptide, and a polyster, for sustained release, of the peptide drug, characterized in that the composition is in the form of a pharmaceutically acceptable solution, comprising: (a) a peptide drug, which contains at least one basic amino acid, as mentioned above, having a molecular weight of at least 300Da, which is in the form of a salt with the polyester, the salt comprising a cation of the basic peptide, and an anion, of a polyester finished in carboxy! (b) a solvent which is a solvent for the libtre polyester, but not a solvent for the free polypeptide, (c) an excess of the polyether, and optionally (d) part of the peptide is solubilized or colloidally dispersed in the free form.
9. A composition according to clause 8, where the drug of the basic polypeptide is a synthetic ananol, of the hormone of liberation of the hormone of luteinisation, selectivity and buserelin, ((D-Ser ( Bu), des-Gly-NH2 °) -LHRH- (1-9) NHEt), deslorelin ((D-Trp, des-Gly-NH210) _LHRH (1-9), NHEt, fertireline ((des-Gly-NH2) -LHRH (1-9) -NHEt.-goserelin ((D-SER (Bu) 6, Azgly) -LHRH) ° histrelin ((D-His (Bzl), des-Gly-NH210) _LHRH (1_g) NHEt, leuprorelin ((D-Leu, des-Gly-NH 10) LHRH (1 -9) NHEt, lutrelin ((D-Trp, Meleu, des-gly-NH 10) _ LHRH,. ' naferilna ((D-Nal) -LHRH, í trip.toreline ((D-trp) -LHRH,; and the pharmacologically active salts thereof.
10. - A composition as mentioned in the clause * sula 8, wherein the solvent is selected from benzyl benzoate, benzyl alcohol, ethyl lactate, glyceryl triacetate, citric acid esters, and polyethylene glycols of low molecular weight (1000), alkoxy polyethylene glycols, and ethyl acetate. polyethylene glycols.
11. A composition according to clause 8, wherein the proportion of the salt of the drug polypeptide from the basic peptide to the free polyster is from 1: 0 to 0.1; 10.
12.- A composition according to clause 8, wherein the proportion of the total solids to the solvent is 2% ^ p / v to 40% p / v.
13. A process for obtaining a pharmaceutical composition, as mentioned in clause 8 which comprises: (a) the dissolution of an intimate mixture of the peptide drug, and the polyester, in a pharmaceutically acceptable disodvent , or (b) the slow addition of a solution of the peptide drug in a 1-6C alkanol, to a solution of the polyester in a solvent suitable for injection, after which, if the solvent in the solution of the starting peptide: it is not pharmaceutically acceptable for injection. Under protest to tell the truth, I manifest that the best method