JPH0832624B2 - Sustained-release formulation of water-soluble peptide - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present specification relates to drugs, in particular water-soluble peptides, such as somatostatin or, for example, octreotide,
A biodegradable and biocompatible polymer base of a somatostatin analog, such as in a matrix or coating,
For example, sustained release (depot) formulations in the form of implants or preferably microgranules (also called microcapsules or microspheres) are disclosed.

The present specification further discloses such formulations that exhibit satisfactory peptide release profiles over a specified period of time.

Peptide drugs often exhibit low blood bioavailability after oral or parenteral administration, eg, due to their short half-life caused by metabolic instability. Moreover,
When administered orally or intranasally, they often show only poor absorption through the mucous membranes. It is difficult to maintain therapeutically relevant blood levels over a long period of time.

Parenteral administration of peptide drugs as depot formulations in biodegradable polymers, such as microgranules or implants, protects the peptides from the enzymatic and hydrolytic effects of biological media. It has been suggested to allow sustained release of the drug after a residence time of

Although microgranules are known for some parenteral depot formulations of peptide drugs in polymers in the form of implants, few are practically able to achieve satisfactory peptide release profiles. Special measures are used to achieve continuous peptide release for therapeutically active drug serum concentrations and, if necessary, to avoid too high drug serum concentrations causing undesirable pharmacological side effects. There must be.

Peptide drug release patterns depend on many factors, such as the peptide type and whether the drug exists in its free form, which affects its water solubility, or in other forms, such as salt forms. Depends on. Another important factor is the choice of polymer from the vast list of possibilities described in the literature.

Each type of polymer has its own characteristic biodegradation rate. It is also possible to generate free carboxyl groups, which contribute to the pH value of the polymer and thus additionally affect the water solubility of the peptide and its release pattern.

Other factors that may affect the release pattern of depot formulations are the drug loading of the polymer base, the way the drug is dispersed in the polymer, the granules and, in the case of implants, their shape. Is. Yet another factor is the site in the body where the formulation affects.

To date, somatostatin compositions in sustained release form for parenteral administration have not been marketed, presumably due to failure to obtain compositions exhibiting satisfactory serum concentration profiles.

Description of the Prior Art Polymeric formulations with drugs designed to give a long-term, or delayed, release of the drug are known.

U.S. Pat.No. 3,773,919 discloses a controlled drug release formulation in which the drug, e.g. a water soluble peptide drug, is biodegradable and biocompatible linear polylactide or polylactide-co-glycolide polymer. Disperse in. However, there is no description of the drug release pattern and no mention of somatostatin.

U.S. Pat. No. 4,293,539 describes an antimicrobial formulation in the form of microgranules.

U.S. Pat. No. 4,675,189 describes a sustained release formulation of the LHRH analog decapeptide naphthaleline and similar LHRH congeners in polylactide-co-glycolide polymers.

T. Jiang, Journal of Bioengineering, Vol. 1, pp. 25-32, 1976, describes delayed release of biochemical agents, enzymes and vaccines from microparticles.

U.S. Pat. No. 3,993,311 discloses the action and sustained release and biodegradation of lactic acid polymer / copolymers and lactide / glycolide copolymers and related compositions for surgical administration.
1,776; 4,076,798 and 4,118,470.

European Patent Specification No. 0203031 describes in columns 15-16 a series of somatostatin octapeptide analogs, for example compound RC-160 having the formula: In the formula −
There is a bridge between the Cys-parts.

D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH
_{2 The} possibility of microencapsulating somatostatin with a polylactide-co-glycolide polymer is described in claim 18, but for a method for achieving a continuous therapeutically active serum concentration. Is not disclosed.

U.S. Pat. No. 4,011,312 discloses a continuous release implant of an antibacterial agent, such as water soluble polymyxin B, from a polylactide-co-glycolide matrix with a low molecular weight (up to 2000) and a relatively high glycolide content in the form of implant tablets. It describes what can be achieved by inserting a lock into the bovine mammary gland. The drug is released in a short period of time due to the low molecular weight and high glycolide content of the polymer, which together stimulate the rapid biodegradation of the polymer and the consequent rapid release of the drug. Moreover, the relatively high drug content causes a rapid drug release. There is no mention of somatostatin or of drug release patterns.

EP 854,81 discloses that continuous release of water-soluble peptides from polylactide polymer implants reduces the molecular weight of at least a portion of the polymer molecules,
By introducing glycolide units into the polymer molecule, by increasing the block polymerizability of the polymer when using polylactide-co-glycolide molecules, by increasing the amount of drug in the polymer matrix, and It is disclosed that stimulation is achieved by widening the surface of the implant. Although somatostatin is mentioned as the water-soluble peptide, there is no description of the release profile of somatostatin, for example, for at least 1 week,
There is also no indication as to how to combine all these factors in order to obtain a continuous somatostatin serum concentration, for example over a month.

EP 92918 discloses a continuous release of a peptide, preferably a hydrophilic peptide, over a long period of time, for example polyethylene glycol, polyvinyl alcohol,
Achieved by introducing hydrophilic units such as dextran, polymethacrylamide into the molecule to increase the hydrophilicity, e.g. by introducing the peptide into the usual hydrophobic polymer matrix of polylactide. It states that it can be done. The hydrophilic contribution to the amphiphilic polymer is due to the ethylene oxide groups in the case of polyethylene glycol units, the free hydroxyl groups in the case of polyvinyl alcohol units or dextran units, and in the case of polymethacrylamide units. Provided by an amide group. Due to the presence of hydrophilic units in the polymer molecule, the implant acquires a hydrogel character after absorption of water. Somatostatin is mentioned as a hydrophilic peptide, but there is no description about the release profile, and what kind of polymer is suitable for this peptide, and how many polymers are There is no indication as to whether it should have hydrophilic groups.

British Patent GB 2,145,422B describes various drugs such as
Sustained release of vitamins, enzymes, antibiotics, antigens consists of drugs, eg polymers of polyols, eg glucose or annitol, having one or more, preferably 3 polylactide ester groups, eg in the size of microgranules. It is noted that this can be achieved when included in an implant. Polylactide
The ester group preferably contains, for example, a glycolide unit. It does not mention any peptides as drugs, eg somatostatin, nor discloses serum drug concentrations.

SUMMARY OF THE INVENTION The present specification describes drugs, especially hormonally active water-soluble somatostatin or somatostatin analogs, such as octreotide, in biodegradable, biocompatible polymers, such as in encapsulated polymer matrices. Disclosed are sustained release formulations, such as microparticle formulations, that provide satisfactory drug serum concentrations.

The microgranules described herein can be manufactured by any conventional method, for example by an organic phase separation method, a spray drying method or a three phase emulsion method, where
If phase separation or a three phase emulsion is used, the polymer is precipitated with the drug and then the product is cured.

If desired, sustained release formulations can take the form of implants.

We have found a particularly useful modification of the phase separation method for the preparation of drug microgranules.

A microgranule consisting of a drug in a biodegradable, biocompatible polymer base has the steps: a) dissolving the polymer base material in a suitable solvent that does not dissolve the drug compound, and b) the polymer. A solution of the drug compound in a suitable solvent which is a non-solvent for, eg alcohol, is added and dispersed in the solution of step a), and c) a phase inducer is added to the dispersion of step b). Manufactured by a method comprising inducing microgranulation, d) adding an oil-in-water emulsion to the mixture of step c) to harden the microgranulate, and e) recovering the microgranulate To be done.

We have also found a particularly useful modification of the three-phase emulsion method for the manufacture of drug microgranules.

This method comprises (i) a water-in-oil emulsion formed from an aqueous medium and an organic solvent that is incompatible with water, containing a drug in one phase and a biodegradable, biocompatible polymer in the other phase. The suspension is mixed vigorously with an excess of an aqueous medium containing an emulsifying substance or protective colloid to add some drug protectant or apply some intermediate viscosity increasing step to the water-in-oil emulsion. Without further action, forming a water-in-oil-in-water emulsion, (ii) removing the organic solvent from it, and (iii) isolating and drying the resulting microgranules.

Among the disclosures of the present specification, the present invention provides a sustained-release preparation comprising a peptide drug compound or a salt or derivative thereof in a biodegradable, biocompatible polymer base, which comprises the polymer base. Is a 40 / 60-60 / 40 polylactide-co-glycolide ester of a polyol, wherein the polyol unit comprises a ( _C3-6 ) carbon chain-containing alcohol and a mono- or disaccharide group having 3-6 hydroxyl groups. Claim a sustained release formulation, characterized in that the selected and esterified polyol is one having at least 3 polylactide-co-glycolide chains and the peptide drug compound is octreotide or a salt thereof. To do.

We have found that the new salt of octreotide is a pamonate which is extremely stable in such formulations.

Octreotide pamonate can be prepared by reacting octreotide with embonic acid (or a reactive derivative thereof).

Description of the Preferred Embodiments Peptides for use in the methods and formulations described herein can be, for example, calcitonin, lypressin and naturally occurring somatostatins and their synthetic analogs, such as salmon calcitonin. it can.

Naturally occurring somatostatin is one of the preferred compounds and is a tetradecapeptide having the following structure: This hormone is produced by the hypothalamic glands and other organs, such as the GI tract, and, along with GRF, mediates neuromodulation of pituitary growth hormone release. In addition to inhibiting GH release by the pituitary gland, somatostatin is an effective inhibitor of many systems, including central and peripheral nerves, gastrointestinal and vascular smooth muscle.

The term "somatostatin" includes its analogs or derivatives. Derivatives and analogues are those in which one or more amino acid units have been omitted and / or substituted by one or more other amino groups and / or one or more functional groups It means a linear, bridged or cyclic polypeptide which is substituted by other functional groups of and / or one or more groups is substituted by one or more other equivalent groups. In general, this term includes all modified derivatives of biologically active peptides that exhibit a qualitatively similar effect to that of the unmodified somatostatin peptide.

Thus agonist agonist analogs of somatostatin are useful to replace natural somatostatin in its effects on the regulation of physiological function. Suitable known somatostatins are: Here, in each of the compounds a) to i), a bridge exists between the amino acids marked with * as shown in the following formula.

Other suitable somatostatins are: (Bale et al., Metabolism, 27, Addendum 1, 139 (1978).
reference) (European Patent Publication No. 1295 and Application No. 78 1009
(See 94.9) (Barber et al., Life Science, 34, 1371-1374.
(1984) and European Patent Application No. 82106205.6 (No. 70).
No. 021)), also known as cyclo (NM
e-Ala-Tyr-D-Trp-Lys-Val-Phe).

(RF Nat et al., Klin, Wotsuhienshiyuru (1986)
64 See Addendum VII) (See EP-A-200, 188) And X-Cys-Phe- D- Trp-Lys-Thr-Cys-Thr-ol where X is especially a cationic anchor.

(See EP 0363589A2) Here, there is a bridge between the amino acids marked with * in the above listed amino acids.

The term derivative also includes the corresponding derivatives with sugar residues.

If somatostatin has a sugar residue, it has to the N-terminal amino group and / or to at least one amino group present in the peptide side chain, more preferably the N-terminal amino group. Preferably bound to. Such compounds and their formulations are disclosed, for example, in WO 88/02756.

The term octreotide has moieties that have a bridge between Cys residues: Including those including.

Particularly preferred derivatives are N ^α [α-glycosyl- (1-4
-Deoxyfructosyl] -DPhe-Cys-Phe-DTrp-Ly
s-Thr-Cys-Thr-ol and N ^α [β-deoxyfructosyl-DPhe-Cys-Phe-DTrp-Lys-Thr-Cys-Thr
-Ol, each of which has a bridge between -Cys- moieties and is preferably in the acetate form, and
Each is described in Examples 2 and 1 of the above patent specification.

Somatostatin can exist, for example, in free form, in salt form or in the form of complexes thereof. The acid addition salt can be formed using, for example, an organic acid, a polymeric acid and an inorganic acid. Acid addition salts include, for example, hydrochloric acid and acetate. Complexes are formed, for example, from somatostatin by the addition of inorganic substances, for example inorganic salts or hydroxides such as Ca- and Zn salts and / or the addition of polymeric organic substances.

A preferred salt for such formulations, especially for microgranules which results in a reduced initial drug burst, is acetate. The invention further provides a pamonate salt, which is particularly useful for implants and methods for its manufacture.

Pamonates can be obtained by conventional methods, for example by reacting embonic acid (pamonic acid) with, for example, octreotide in the form of the free base. This reaction can be carried out in a polar solvent, for example at room temperature.

Somatostatin is for use in the treatment of diseases for which a long-term administration of a drug is planned, for example, diseases caused by etiology involving or accompanied by excess GH secretion, for example in the treatment of acromegaly, In the treatment of gastrointestinal diseases, for example, peptic ulcer, intestinal skin and pancreatic cutaneous fistula, inflammatory bowel syndrome, dumping syndrome, water laxative syndrome, acute pancreatitis and gastroenteropathic endocrine tumors (eg, Bipomas, GRF trout, glicagonomas, inculinomas, gastrinomas and carcinoid tumors) and its use in the treatment or prevention of gastrointestinal bleeding, breast cancer and complications associated with diabetes.

Polymeric bases can be made from biocompatible and biodegradable polymers, such as linear polyesters, or branched polyesters having radial chains from polyols such as glucose; other esters Are polylactic acid, polyglycolic acid, polyhydroxybutyric acid, polycaprolactone, polyalkylene oxalate, cribs cycle such as citric acid cycle, polyalkylene glycol ester of acid, and copolymers thereof.

Linear polyester is alpha hydroxycarboxylic acid,
For example, it can be prepared from lactic acid and glycolic acid by condensation of a lactone dimer (see, for example, US Pat. No. 3,773,919).

Linear polylactide-co-glycolide is 25,000-100,00
Conveniently, it has a molecular weight of 0 and a polydispersity Mw / Mn of, for example, 1.2 to 2.

Branched polyesters can be prepared using polyhydroxy compounds such as polyols as initiators such as glucose or mannitol. Esters of these polyols are known and are known from British Patent GB2,
145,422B. At least 3 polyols
An ester having at least 1, preferably at least 2, for example on average 3 hydroxyl groups of a polyol having a hydroxyl group of up to 20,000 and containing a polylactide or copolylactide chain. It is in the form of a base. Generally 0.2% of glucose is used to initiate the polymerization. The structure of branched polyester is star-shaped. In the present invention, a star polymer is used as the polymer base. The preferred polyester chains in the star polymer are copolymers of alfacarboxylic acid moieties, lactic acid and glycolic acid, or lactone dimers. The lactide: glycolide molar ratio is about 75:25 to 25:75, such as 60:40 to 40:60, 55:45 to 45:55, such as 55: 4.
5 to 50:50 is also preferable.

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

The advantage of the star polymers in the formulations of the present invention is that their relatively high molecular weight allows them to provide physical stability, eg some hardness, to implants and microgranules, thereby making them mutually compatible. While the stickiness of the polymer can be prevented, it results in a controllable biodegradation rate of the polymer and a sustained release of the corresponding peptide over a period of several weeks to one or two months due to the presence of relatively short polylactide chains, from which it is produced. That is, the depot formulation is suitable for a one month release, for example.

Star polymers are about 10,000-200,000, preferably 25,000.
Main molecular weight Mw in the range of up to 100,000, especially 35,000 to 60,000
And has a polydispersity of, for example, 1.7 to 3.0, for example 2.0 to 2.5. The intrinsic viscosities of Mw 35,000 and 60,000 star polymers are 0.36 and 0.15 respectively in chloroform.
dl / g. The star polymer with Mw 52,000 has a viscosity of 0.475 dl / g in chloroform.

The terms microspheres, microcapsules and microgranules should be understood to be interchangeable in the context of the present invention and mean the encapsulation of the peptides by the polymer, in which case the matrix which is the matrix for the peptides. It is preferred that the peptides are distributed throughout the coalescence. In that case it is preferred to use the term microspheres or, more generally, microgranules.

By using the phase separation method of the present invention, the formulation of the present invention,
For example, it can be prepared by dissolving a polymer base in a solvent that is a non-solvent for the peptide, and then adding and dispersing a solution of the peptide in the polymer-solvent composition. At that time, a phase inducer, for example silicone oil, is added to induce the encapsulation of the peptide by the polymer.

The drug burst effect can be significantly reduced by in situ precipitation of ultrafine drug particles by adding the drug solution to the polymer solution prior to phase separation. Conventional methods involve adding dry particles directly to the polymer solution.

The therapeutic duration of peptide release can be increased by hardening / washing with microgranulate buffer / heptane emulsion. Conventional methods do not perform a wash after the curing step, or include a separate water wash step.

An oil-in-water (= O / W) emulsion can be used to wash and harden the microspheres and to remove unencapsulated peptide. Washing facilitates the removal of unencapsulated peptide from the surface of the microspheres. Removal of excess peptide from the surface of microspheres is a characteristic of many conventional encapsulation formulations. Reduces initial drug burst. Thus, more consistent drug release over time is possible.

The emulsion also helps remove residual polymer solvent and silicone oil. The emulsion may be added to the polymer peptide mixture, or the mixture may be added to the emulsion. It is preferred to add the polymer peptide mixture to the emulsion.

O / W emulsions can be prepared, for example, with emulsifiers such as sorbitan mono-oleate (Span 80ICI) to form stable emulsions. The emulsion can be buffered with a buffer that is harmless to the peptide and polymeric material. The buffer solution is, for example,
It can be prepared from acidic buffers such as phosphate buffers, acetate buffers and the like. It is also possible to use only water instead of the buffer solution.

As the organic phase of the buffer solution, heptane, hexane or the like can be used.

The emulsion may, for example, contain a dispersant such as silicone oil.

A preferred emulsion is heptane, pH 4 phosphate buffer,
It can consist of silicone oil and sorbitan mono-oleate. If initial drug release is desired, a single non-solvent cure step can be used instead of emulsion cure. As the solvent, heptane, hexane or the like can be used.

As an alternative to the O / W emulsion, the following can be used for the hardening of the microcapsules: solvent plus emulsifier for hardening the microcapsules without washing; and for hardening Solvent plus emulsifier followed by a separate wash step.

O / W emulsions can be used without dispersants. However, the dispersant avoids agglomeration of dry particles of the microcapsules by static electricity and helps reduce the concentration of residual solvent.

Examples of solvents for polymeric matrix materials include methylene chloride, chloroform, benzene, ethyl acetate and the like. The peptide is preferably soluble in an alcohol solvent, eg methanol, which is compatible with the polymer solvent.

Phase inducers (coacervation agents) are solvents that are miscible with the polymer-drug mixture and cause the formation of nascent microcapsules before curing; silicone oils are the preferred phase inducers.

The O / W emulsion can be prepared by a conventional method using an organic phase such as heptane and hexane.

The microgranules of the present invention can also be produced by a generally known spray drying method. According to this method, octreotide, or an organic solvent such as methanol, water, or a solution of the peptide in, for example, a buffer of pH 3-8 and an organic solvent that is incompatible with the above solvents, such as methylene chloride, is used. Mix the combined solution thoroughly.

The resulting solution, suspension or emulsion is then atomized in a stream of air, preferably in a stream of warm air. The resulting microgranules are collected, for example by a cyclone, and optionally washed, for example, in a buffer of pH 3.0 to 8.0, preferably pH 4.0 or in distilled water, and then decompressed, for example at a temperature of 20 to 40 ° C. Dry down. If the granules exhibit a drug burst in vivo and the extent of the drug burst is undesirable, a wash step can be applied. An acetate buffer can be used as the buffer.

Thus, it is possible to obtain a microgranule exhibiting improved octreotide release profile in vivo.

The invention further comprises mixing octreotide or a solution of octreotide in methanol or water or a buffer of pH 3-8 with a solution of the polymer base in methylene chloride and forming a solution of octreotide in a polymer solution, an emulsion. Spray the liquid or suspension in a stream of warm air, collect the microspheres, wash it in a buffer solution of pH 3.0 to 8.0 or distilled water, and then dry it under reduced pressure at a temperature of 20 to 40 ° C. There is provided a sustained release preparation produced by. While using silicone oils in the spray-drying method, they do not contain any silicone oil compared to the microgranules prepared by the phase separation method.

The formulations of the present invention can also be manufactured using the three-phase emulsifier method. In a typical method, octreotide is dissolved in a suitable solvent, such as water, and is a solvent that is a nonsolvent for octreotide, such as a polymer in methylene chloride, such as 50/50 poly (D, L-lactide- Vigorous emulsification in a solution of co-glycolide) glycose. Examples of solvents for polymeric matrix materials are methylene chloride,
Includes chloroform, benzene, ethyl acetate and the like.
The resulting water / oil (W / O) emulsion further contains an emulsifying substance such as anionic or nonionic surfactant or lecithin or protective colloid such as gelatin, dextrin, carboxymethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol. Emulsification in excess water that results in the continuous formation of a three-phase (W / O / W) emulsion. The spontaneous precipitation of the polymer produces microgranules, which harden by evaporation of the organic solvent. Gelatin acts to prevent aggregation of microspheres. The supernatant liquid after the sedimentation of the micro granules is decanted, and the micro granules are washed with water and then with an acetate buffer solution. The microgranules are then filtered and dried.

It is also possible to disperse octreotide directly in the polymer solution and then to mix the resulting suspension with the gelatin-containing aqueous phase.

The three-phase emulsifier method is known from US Pat. No. 4,652,441. According to this patent, in the first step, a drug solution (1) in a solvent, for example somatostatin in water (2nd column, lines 31-32), is prepared in such a way that the first solvent does not dissolve therein. Water-in-oil (W) of fine drug-containing droplets of (1) in solution (2) by thoroughly mixing with excess polylactide-co-glycolide solution (2) in a solvent such as methylene chloride. / O) Give an emulsion (3). In the solution (1), a so-called drug retaining agent (column 1, line 31), such as gelatin, albumin, pectin or agar, is additionally dissolved.

In the second stage, heating the viscosity of the inner phase (1),
It is increased by any suitable means such as cooling, pH changes, addition of metal ions or crosslinking of gelatin with aldehydes.

In the third stage, excess water is thoroughly mixed with the W / O emulsion (3) (7th column, lines 52-54) to form a W / O / W type three-phase emulsion. . If desired, an excess of water may be present, for example an anionic or nonionic surfactant, or a so-called emulsifier, for example selected from the group of polyvinylpyrrolidone, polyvinyl alcohol or gelatin (7th column). , Line 56).

In the fourth stage, the W / O / W emulsion was not "water dried" (line 52). This means that the organic solvent in the oil layer is desorbed to generate a micro granule. Desorption is carried out in a known manner (8th column, lines 3-5), for example by pressure drop with stirring (8th column, lines 5-7) or nitrogen gas into the oil layer (eg methylene chloride). It is achieved by the insufflation (line 19).

The produced micro-granule is recovered by centrifugation or filtration (lines 26 to 27), and components not incorporated in the polymer are removed by washing with water (line 29). Better removal of water and solvent, if necessary, by heating the microgranules under reduced pressure (eg removal of methylene chloride from the walls of the microgranules).
Can be achieved (lines 30-32).

The above method is also satisfactory for the preparation of the formulations according to the invention, however, the so-called drug-carrying substances mentioned above, such as gelatin, albumin, pectin or agar, are also encapsulated in the microgranules which also form.

We hereby omit the steps for the addition of the drug-retaining substance (= in solution (1)) and the viscosity increase of the inner phase and in the excess water of the three-phase W / O / W emulsion, It has been found that when using means to add substances or protective colloids such as gelatine one can also obtain satisfactory microgranules. Moreover, the microgranules do not contain any drug-carrying substances and only very small amounts of methylene chloride.

The invention therefore comprises: a) an aqueous medium, preferably water or a buffer, preferably at a weight / volume ratio of 0.8-4.0 g / 1-120 ml, especially 2.5 g / 10 ml, and a pH of 3-8. A solution of octreotide in a buffer, especially an acetate buffer, and b) an organic solvent which is incompatible with the aqueous medium, for example methylene chloride, preferably at a weight / volume ratio of 40 g / 90 to 400 ml, especially 40 g / 100 ml. , A solution of the polymer base as described above, preferably with a weight / weight ratio of drug to polymer of 1 /
A) in b) which is 10 to 50, in particular 1/16, and which is vigorously mixed and produced so that the volume / volume ratio of the aqueous medium / organic solvent is 1 / 1.5 to 30, especially 1/10. A) W / O emulsion of c) and c) an emulsifying substance or protective colloid, preferably in a concentration of 0.01 to 15.0% by weight, especially gelatin in a concentration of 0.1 to 3%, in particular 0.5%, in excess of aqueous solution. A medium, preferably water or a buffer, preferably pH 3-8, such as acetate or phosphate buffer, at a ratio of 1/10 to 100, in particular 1/40 ab) /
At the volume / volume mixing rate ratio of c), the water-in-oil emulsion was vigorously mixed and produced without the addition of any drug-retaining substance or the application of any intermediate viscosity increasing step. The initial microgranules in the W / O / W emulsion are hardened by elimination of the organic solvent, preferably methylene chloride, preferably by evaporation, and the formed microgranules are isolated and optionally washed. The present invention provides a method for producing a microgranule produced by drying and drying.

The present invention further provides a modified method, which comprises dispersing the drug directly in the polymer solution and then mixing the resulting dispersion with the gelatin-containing aqueous phase.

The present invention also provides microgranulates produced by these methods. Like the microgranules produced by the spray-drying method, they do not contain silicone oil. Unlike the microgranules prepared according to the known three-phase emulsion method, they contain no protective colloids.

The sustained-release preparation can also be produced, for example, by another method as described below. That is, the microgranules containing octreotide in the polymer base or a mixture thereof obtained by mixing octreotide and the polymer base, for example, heated at a temperature of 70 to 100 ° C. and extruded and dense. The material is cooled to material and then the extrudate is cut and optionally washed and dried.

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

The formulations according to the invention can be used in depot form, for example as injectable microspheres or implants.

They can be administered by the usual methods, for example by subcutaneous or intramuscular injection for the indications known for the drugs contained therein.

Sustained-release preparations containing octreotide, for all known indications of octreotide or its derivatives,
It can be administered, for example, to those disclosed in British Patent No. 2,199,829A, pp. 89-96, as well as acromegaly and breast cancer.

The microgranules of the present invention may have a particle size range of about 1-250 microns, preferably 10-200, especially 10-130, for example 10-90 microns. The implant can be sized, for example, about 1-10 cubic mm. The amount of drug, octreotide, present in the formulation depends on the desired daily release dose and thus the rate of biodegradation of the matrix polymer. The exact amount of octreotide can be verified by bioavailability testing. The formulation may contain octreotide in an amount of 0.2 to 10%, preferably 3.0 to 6% by weight, based on the polymer matrix.

Release time of octreotide from micro granules is 1-2
It can be from a week to about two months.

Sustained release formulations include octreotide in a biodegradable, biocompatible polymer base, which is
When administered subcutaneously in rats at a dose of 10 mg octreotide over a period of 30 days, or if convenient
It is convenient to show a concentration of octreotide in serum of at least 0.3 ng / ml and preferably less than 20 ng / ml over 60 days.

Alternatively, the sustained release formulation is at a concentration of at least 0.3 ng / ml over 50 days when administered intramuscularly to a rabbit at a dose of 5 mg / kg body weight and a maximum concentration of 20 ng / ml if well. Conveniently, it comprises octreotide in a biodegradable, biocompatible polymer base.

Other suitable properties of the obtained octreotide-containing depot formulation are the following, depending on the manufacturing method used: Phase separation method Rabbit: Octreotide 5 mg / kg, intramuscular delay (0-42 days) 76% Average serum concentration (Cp. Ideal) (0-42 days) 4ng / ml AUC (0-42 days) 170ng / ml ×
Daily Spray-drying method Rat: Octreotide 10 mg / kg, subcutaneous delay (0 to 42 days)> 75% Mean serum concentration (Cp. Ideal) (0 to 42 days) 4 to 6 ng / ml AUC (0 to 42 days) 170 ~ 210ng
/ ml × day Rabbit : Octreotide 5 mg / kg, intramuscular delay (0 to 43 days)> 75% Mean serum concentration (Cp. ideal) (0 to 43 days) 4 to 6 ng / ml AUC (0 to 43 days) 200-240ng
/ ml × day Three-phase emulsion rat: Octreotide 10 mg / kg, subcutaneous delay (0 to 42 days)> 75% Mean serum concentration (Cp. ideal) (0 to 42 days) 4 to 6.5 ng /
ml AUC (0-42 days) 170-230ng
/ ml × day Rabbit: Octreotide 5 mg / kg, intramuscular delay (0 to 42/43 days)> 74% Mean serum concentration (Cp. ideal) (0 to 42/43 days) 3.5 to 6.
5ng / ml AUC (0-42 / 43 days) 160-27
The invention thus also provides octreotide and octreotide analogue compositions having the following properties: at least 70%, preferably at least 74%, for example at least 75% over a period of 1.0 to 42 or 43 days. , 80
%, 88% or at least 89% delay, and / or 2. 2.5 to 6.5, preferably 4 to 6, over a period of 0 to 42 days when 10 mg octreotide is administered subcutaneously in the rat.
A mean serum concentration of 5 ng / ml and / or a mean serum concentration of 3.5-6.5, for example 4-6.5 ng / ml over 0-42 or 43 days, when 5 mg octreotide is administered intramuscularly in a rabbit, and / or Or 3.10 mg octreotide subcutaneously administered to rats for at least 160, preferably 170-230 ng / ml x day AUC for 0-42 days, and / or 5 mg octreotide intramuscularly administered rabbits 0-42. Or 43
At least 160, preferably 180-27 over the day
5, eg AUC of 200-275 ng / ml x day.

For the quantitative properties of the sustained release formulation above, here
F. Nimmer Forall and J. Rosentaller, Internals of the Year of Pharmacy. 32,1
6 (1986), the area deviation (AD) method is used.

Briefly, the AD method is an experiment from an ideal profile that is a constant mean serum concentration (= Cp, ideal) resulting from the conversion of an area under the experimental serum concentration-time curve (AUC) into an equal area rectangle. Calculate the area deviation of the experimental serum profile from the serum profile. Area deviation percentage (AUC
%) Is calculated as follows:% delay = 100 × (1−AD / AUC) By this method, the whole serum profile measured over a preselected time period is characterized by a single mathematical index.

Proceeding of National Academy of Sciences, USA 85 (1985) 5682-5692 shows in FIG. 4 the serum concentration profile of the octapeptide analog of somatostatin in the rat rat.

However, the above clear comparison with the serum concentration data of the composition of the present invention in the rat is that the serum concentration profile described is based on another administration method (intramuscular injection), and more importantly, A clear comparison of microcapsule loading level (2-6%) and dosage (20-50 mg portion of microcapsules for 30 days, although quantified for at least 45 days) is not accurately indicated Can not do. Moreover, the type of poly (Dl-lactide-co-glycolide) used is not stated exactly.

Thus, the disclosed values in the literature are too low to be acknowledged as known literature which hinders the present invention.

 The invention is illustrated by the following examples.

The Mw of the polymer is the average molecular weight as measured by GLPC using polystyrene as a standard.

Example 1 (Reference Example) 1 g of poly (D, L-lactide-co-glycolide) (molar ratio 50/50, Mw = 45,000; polydispersity of about 1.7) was added to 15 ml of methylene chloride using a magnetic stirrer. Dissolved and then added was 75 mg of the acetic ester of octreotide dissolved in 0.5 ml of methanol. 15 ml of silicone oil (Dow 360 medical silicone oil, 1000 cs) was added to the polymer peptide mixture. The mixture thus obtained was mixed with 400 ml of n-heptane, 100
It was added to a stirred emulsion containing 1 ml pH of phosphate buffer, 40 ml of Dow 360 medical silicone oil, 350 cs and 2 ml of Span 80 (emulsifier). Stirring was continued for a minimum of 10 minutes. The microgranules thus obtained were collected by vacuum filtration and dried overnight in a vacuum oven. The yield was about 90% microgranulate in the particle size range of 10-40 microns.

Microgranules were suspended in a vehicle and administered to New Zealand white rabbits at an intramuscular dose of 4 mg octreotide. Blood samples were taken at regular intervals and showed serum concentrations of 0.5-1.0 ng / ml over 30 days as measured by radioimmunoassay (RIA) analysis.

Example 2 1 g of poly (D, L-lactide-co-glycolide) glycose (Mw = 45,000, polydispersity about 1.7 molar ratio 55/45, according to the method of British Patent No. 2,145,422B, 0.2% glycose. Was dissolved in 25 ml of ethyl acetate using a magnetic stirrer, then 75 mg in 3 ml of methanol.
Octreotide was added. To the polymer-peptide mixture was added 15 ml silicone oil (Dow 360 brand medical silicone oil, 1000 cs). The resulting mixture was added to the emulsion described in Example 1. Stirring was continued for a minimum of 10 minutes. The microgranules thus obtained were recovered by vacuum filtration and dried in a vacuum oven overnight. Yields in excess of 80% of micron granules in the 10-40 micron particle size range were obtained.

Micron granules were suspended in vehicle and administered intramuscularly to New Zealand white rabbits at a dose of 4 mg octreotide. Blood samples were taken periodically and measured by RIA, showing serum concentrations of 0.5-2 ng / ml over 21 days.

Example 3 18.5 g in 500 ml methylene chloride with stirring of a solution of 1.5 g octreotide acetate in 20 ml methanol.
Of poly (D, L-lactide-co-glycolide) glycose (molar ratio 50/50, Mw = 45,000). 500ml Dow 360 Medical Silicone Oil (1000cs) and 800ml Dow 360 Medical Silicone Oil (350c) for peptide-polymer suspension
Phase separation was achieved by adding s). The mixture thus obtained was added to a stirred emulsion consisting of 1800 ml of n-heptane, 2000 ml of sterile water and 40 ml of span 80. After stirring for 10 minutes, the microspheres were collected by vacuum depressurization.

Half of the product was dried in a vacuum oven at 37 ° C overnight. The residual methylene chloride concentration was 1.2%.

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

The combined yield of product was 1% of the average diameter of 24 microns containing 1.5% octreotide and 1.5% residual heptane.
It was 8.2 g (91%) of microgranules.

The microgranules were suspended in a vehicle and injected intramuscularly into white rabbits at a dose of 5 mg / kg octreotide. Blood samples were taken periodically and measured by RIA to show serum concentrations of 0.3-7.7 mg / ml over 49 days.

Example 4 1 g of poly (D, L-lactide-co-glycolide) glycose (Mw = 46,000, polydispersity about 1.7; British Patent No. 2,145,42)
2B was prepared from 0.2% of glucose in a 50/50 molar ratio) was dissolved in 10 ml of methylene chloride using a magnetic stirrer, followed by 75 mg of dissolved in 0.133 ml of methanol. Octreotide was added. The mixture was vigorously mixed using, for example, an Ultra-Trux at 20,000 rpm for 1 minute to form a suspension of very small crystals of octreotide in the polymer solution.

The suspension was atomized using a high speed turbine (nitro atomizer) and the small droplets were dried in a stream of warm air to give a microgranulate. The microgranules were collected by "dicron" and dried in a vacuum oven at room temperature overnight.

The microgranules were washed with 1/15 molar acetate buffer pH 4.0 for 5 minutes and dried again in a vacuum oven at room temperature. Sieve micro granules after 72 hours (sieve size 0.12
5 mm) to obtain the final product.

The microgranules were suspended in a vehicle and administered intramuscularly at a dose of 5 mg / kg octreotide for white rabbits (chinchilla-bustard) and subcutaneously at a dose of 10 mg / kg for male rats. Was administered. Blood samples were taken periodically and measured by radioimmunoassay (RIA) analysis to range from 03-10.0 ng / ml (dose 5 mg) in rabbits over 42 days,
Rats showed serum concentrations of 0.5-7.0 ng / ml.

Example 5 A microgranulate was prepared by spray drying similar to the method described in Example 4, with the only difference that octreotide was directly suspended in the polymer solution without the use of methanol. .

The microgranules were suspended in the vehicle and administered subcutaneously to male rats at a dose of 10 mg / kg octreotide. Blood samples should be taken regularly for radioimmunoassay (RI
A) 0.5-1 over 42 days as measured by analysis
A serum concentration of 0.0ng / ml was shown.

Example 6 1 g of poly (D, L-lactide-co-glycolide) glycose (Mw = 46,000, polydispersity about 1.7; molar ratio 50/50; according to GB 2,145,422 B 0.2% Glucose) was dissolved in 2.5 ml methylene chloride, followed by the addition of 75 mg octreotide dissolved in 0.125 ml deionized water. The mixture was vigorously mixed for 1 minute at 20,000 rpm using, for example, Ultra-Trux (inner W / O phase).

1 g of gelatin A was dissolved in 200 ml of 50 ° C. deionized water and the solution was cooled to 20 ° C. (outer W phase). The W / O phase and the W phase were vigorously mixed. This separated the inner W / O phase into small droplets, which were evenly distributed in the outer W phase. The three-phase emulsion thus obtained was slowly stirred for 1 hour. This caused the methylene chloride to evaporate and the microgranules hardened from the inner phase droplets. After sedimentation of the micro-granules, the supernatant was removed by suction, the micro-granules were recovered by vacuum depressurization, and the gelatin was removed by washing with water. The microgranules were dried, sieved, washed and second dried as described for Example 4. The microgranules were suspended in the excipient, and 5 mg / white rabbit (chinchilla-bustard) was added.
It was administered intramuscularly at a dose of octreotide of kg and subcutaneously at a dose of 10 mg / kg to male rats. Blood samples are taken regularly and measured in rabbits over 42 days in rabbits as measured by radioimmunoassay (RIA) analysis.
0.3-15.0ng / ml (5mg dose) and 0.5-at rat
A serum concentration of 8.0 ng / ml was shown.

Example 7 A microgranule was produced by the three-phase emulsion method in the same manner as described in Example 6 except that the following three points were changed.

1. 0.25ml instead of 0.125ml water for inner W / O phase preparation
PH 4.0 acetate buffer was used.

2. Post-collection washes of the microgranules were performed using 1/45 molar pH 4.0 acetate buffer instead of water.

3. Omitting a second wash of microgranules.

Example 8 For Example 7 except that only the inner W / O phase was prepared with water containing 0.7% (w / v) sodium chloride instead of acetate buffer. Microgranules were prepared by the three-phase emulsion method in the same manner as described.

Example 9 Microgranulate as described in Example 6, with the only difference that the drug compound is directly dispersed in the polymer solution and then the resulting dispersion is mixed with the gelatin-containing aqueous phase. Was prepared.

Example 10 (Reference Example) Octreotide Pamoate 10.19 g of octreotide free base (0 mM) and 3.88 g of embonic acid (10 mM) were dissolved in 1 water / dioxane (1: 1). The reaction mixture was passed through, freeze-dried and octreotide pamoate hydrate yellow powder [α] ²⁰ D = + 7.5
Was obtained (c = 0.35 in DMF). Coefficient = 1.4, where coefficient = weight of lyophilizate / weight of octreotide contained therein.

Pamonates can be used in place of the octreotide acetic acid present in the microgranules of Examples 1-9 and have excellent stability.

Example 11 (Reference Example) 1 g of poly (D, L-lactide) in 20 ml of methylene chloride.
A solution of co-glycolide) (molar ratio 50:50, molecular weight = 36,100) was added with stirring to a solution of 100 mg calcitonin in 1.5 ml methanol. 20 ml of silicone oil (Dow 360
Phase separation was performed by the addition of medical silicone oil, 1000cs). The mixture thus obtained was added to a stirred emulsion consisting of 100 ml of pH 4 phosphate buffer, 400 ml of n-heptane, 4 ml of span 80 and 40 ml of silicone oil (Dow 360 medical silicone oil, 1000cs). . After stirring for 10 minutes,
The microgranules were collected by vacuum vacuum and dried in a vacuum oven at 37 ° C overnight. Contains 5.9% calcitonin
A yield of 1.1 g of microgranules was obtained.

Example 12 (Reference Example) 9.9 g of poly [(D, L-lactide-co-glycolide) (molar ratio 50/50, Mw = 44,300) in 140 ml of methylene chloride was added to 1 part.
Added to 00 mg of Ripressin. After magnetically stirring the dispersion for 1 hour, 140 ml of silicone oil (Dow 360 medical silicone oil, 1000 cs) and 2.5 ml of Span 80 were added. The mixture was added to 200 ml heptane and stirred for 10 minutes. The microcapsules thus obtained were collected by vacuum filtration, washed 3 times with heptane and then dried under suction for 10 minutes. Half of the sample was stirred by stirring in water for 10 minutes; the other half was left unwashed. Both samples were dried overnight in a vacuum oven at 30 ° C. The total yield was 10.65 g of microcapsules.
Analysis of the washed sample showed 0.5% lypressin and 0.5% lypressin for the unwashed sample.

 The description of the present invention is summarized as follows.

1. a) dissolving the polymer base material in a suitable solvent that does not dissolve the drug compound, and b) adding to the solution of step a) a solution of the drug compound in a suitable solvent that is a non-solvent for the polymer. And disperse, c) induce the formation of microgranules by adding a phase inducing agent to the dispersion of step b), and d) add an oil-in-water emulsion to the mixture of step c). A method of producing a microgranule comprising a drug in a biodegradable, biocompatible polymer base, comprising the steps of: curing the microgranulate, and e) recovering the microgranule.

2. Micro granules obtained by the method described in the above item 1.

3. (i) A water-in-oil emulsion consisting of an aqueous medium containing a drug in one phase and a biodegradable biocompatible polymer in the other phase and an organic solvent incompatible with water. No addition of any drug maintenance substance or application of any intermediate viscosity increasing step to the water-in-oil emulsion by vigorous mixing with an excess of aqueous medium containing the emulsifying substance or protective colloid Forming a water-in-oil-in-water emulsion, ii) desorbing the organic solvent therefrom, and iii) isolating and drying the resulting microgranules, a biodegradable, biocompatible group. A method for producing a microgranule containing a drug in a drug.

4.i) Vigorous mixing of a solvent compound suspension consisting of a water-incompatible organic solvent containing a drug compound and a biodegradable biocompatible polymer with an excess of an aqueous medium containing an emulsifying substance or protective colloid. By forming an oil-in-water emulsion in which the drug compound is dispersed in the oil component, without adding any drug protectant or applying any intermediate viscosity increasing step, ii) Then, the organic solvent is removed, and iii) a method for producing a microgranule containing a drug compound in a biodegradable biocompatible polymer, which comprises isolating and drying the microgranule thus produced.

5. a) A solution of the drug in an aqueous medium, and b) a solution of the polymer in an organic solvent that is incompatible with the aqueous medium are vigorously mixed to form a water-in-oil emulsion of b) in a) produced. The liquid is vigorously mixed with excess aqueous medium containing protective colloids, c) without adding any drug protectants or applying any intermediate viscosity increasing steps to the water-in-oil emulsion. A method for producing a micro-granules, which comprises mixing, curing the initial micro-granules in the produced water-in-oil-in-water emulsion by desorption, and isolating the produced micro-granules.

6. The method according to the above item 5, wherein the drug is somatostatin.

7. The method according to the above item 5, wherein the drug is octreotide.

8. The drug is octreotide pamoate salt
The method described in the section.

9. The method of claim 5 wherein the polymer is polylactide-co-glycolide.

10. The method according to claim 5, wherein the aqueous medium is water or a buffer solution.

11. The method according to the above item 5, wherein the aqueous medium is a buffer having a pH of 3 to 8.

12. The method according to the above item 5, wherein the organic solvent is methylene chloride.

13.a) a solution of somatostatin in water or buffer at a weight / volume ratio of 0.8-4.0 g / 1-120 ml and b) a solution of polylactide-co-glycolide in an organic solvent which is incompatible with the aqueous medium, In the b) produced by vigorous mixing such that the weight / weight ratio of the drug to the polymer is 1/10 to 50 and the volume / volume ratio of the aqueous medium / organic solvent is 1 / 1.5 to 30. a) a water-in-oil emulsion and c) excess water or buffer containing a protective colloid,
At volume / volume mixing rates of ab) / c) of 1 / 10-100 without adding any drug protectant or applying any intermediate viscosity increasing step to the water-in-oil emulsion A method for producing a micro-granules, which comprises vigorously mixing, hardening the initial micro-granules in the water-in-oil-in-water emulsion formed by evaporation of the organic solvent and isolating the formed micro-granules .

14. The method according to the above item 13, wherein the protective colloid is gelatin.

15.a) a solution of somatostatin in an aqueous medium at a weight / volume ratio of 2.5 g / 10 ml and b) of polylactide-co-glycolide in an organic solvent which is incompatible with the aqueous medium at a weight / volume ratio of 40 g / 100 ml. The solution was vigorously mixed in such a manner that the weight / volume ratio of the drug to the polymer was 1/16 and the volume / volume ratio of the aqueous medium / organic solvent was 1/10, and a) in b) formed. Of the water-in-oil emulsion of c) and c) an excess of aqueous medium containing protective colloid at a concentration of 0.01-15.0% at a volume ratio of 1/4 ab) / c) in oil. The initial micron in a water-in-oil-in-water emulsion produced by vigorous mixing without adding any drug protectants to the water-based emulsion or applying any intermediate viscosity increasing steps. Harden granules by evaporation of organic solvent and isolate the formed microgranules A method for producing a microgranule comprising the following.

16.a) a solution of octreotide in a weight / volume ratio of 2.5 g / 10 ml in a buffer of pH 3-8 and b) a solution of polyacrydo-co-glycolide in methylene chloride in a weight / volume ratio of 40 g / 100 ml. In the oil of a) in b) produced by vigorous mixing such that the weight / weight ratio to the polymer of 1 is 1/16 and the volume / volume ratio of the aqueous medium / organic solvent is 1/10. Aqueous emulsion and c) gelatin at a concentration of 0.5% by weight, pH 3-8
Excess buffer of 1/40 ab) / c) at a volume / volume mixing rate ratio of water-in-oil emulsion to which some drug protectant was added or some intermediate viscosity increase Without applying steps, mix vigorously to harden the initial microgranules in the resulting water-in-oil-in-water emulsion by evaporation of the organic solvent and isolate, wash and A method for producing a microgranule, which comprises drying.

17. A micro granule obtained by the method described in the above item 3.

18. A sustained-release preparation comprising octreotide or a salt or derivative thereof in a biodegradable, biocompatible polymer base.

19. Polymer is poly- (DL-lactide-co-glycolide)
19. The sustained-release preparation according to item 18, which is a glucose.

20. The sustained-release preparation according to item 18, which is in the form of micro-granules in which substantially no drug compound is present on the surface.

21. Drug mixture or its solution in methanol or water or buffer at pH 3-8 and polylactide in methylene chloride
A solution of co-glycolide is mixed and a suspension or emulsion of the drug compound in the resulting polymer solution is atomized in a stream of warm air to collect microspheres and bring it to a pH of 3.0-8.0.
19. The sustained release preparation according to the above item 18, which is produced by washing in a buffer solution or distilled water of 1 above and then immersing it in a vacuum at a temperature of 20 to 40 ° C.

22. The sustained-release preparation according to item 18, wherein the octreotide concentration is 2.0 to 10% by weight.

The sustained release formulation according to claim 18, in the form of microgranules having a diameter of 23.1 to 250 microns.

24. Including a peptide drug compound in a 40/60 to 60/40 polylactide-co-glycolide ester of a polyol, the polyol unit having 3 to 6 hydroxyl groups (C
_3-6 ) A sustained-release preparation selected from the group _{consisting of} carbon chain-containing alcohols and monosaccharides or disaccharides, and wherein the esterified polyol has at least 3 polylactide-co-glycolide chains.

25.25,000-100,000 molecular weight Mw and 1.2-2 polydispersity Mw /
Peptide drug compound selected from the group of calcitonin, lypressin or somatostatin at a concentration of 0.2-10% by weight of the peptide drug compound in a linear 40 / 60-60 / 40 polylactide-co-glycolide polymer having a molecular chain of Mn The sustained-release formulation containing.

Main molecular weight Mw of 26.10,000-200,000 and polydispersity of 1.7-3.0
25. The sustained-release preparation according to the above item 24, which has Mw / Mn.

27. The sustained release preparation according to the above-mentioned item 24, wherein Mw is 35,000 to 60,000.

28. The sustained-release preparation according to the above-mentioned item 24, wherein Mw / Mn is 2.0 to 2.5.

29. The above 18, which represents a concentration of a drug compound in serum of less than 20 ng / ml at least 0.3 ng / ml for 30 days when administered subcutaneously to a rat at a dose of 10 mg drug compound / kg body weight, The sustained-release preparation according to item 24 or 25.

30. Representing a drug compound concentration in serum of at least 0.3 ng / ml and at most 20 ng / ml over 50 days when administered intramuscularly to a rabbit at a dose of 5 mg of drug compound per kg of body weight above 18 The sustained release preparation according to 24, 25 or 25.

31. The above 18, 24 or which exhibits an inhibition of at least 70% over a period of 0 to 42 or 43 days when administered intramuscularly to a rabbit at a dose of 5 mg of drug compound per kg of body weight
The sustained-release preparation according to item 25.

32. 2.5 mg over 0 to 42 days when administered subcutaneously to rats at a dose of 10 mg drug compound per kg body weight
1 above representing an average serum concentration of ~ 6.5ng / ml (Cp ideal)
The sustained-release preparation according to item 8, 24 or 25.

33. The above 18, 24 or 25 item which represents an average serum concentration (Cp ideal) of 3.5 to 6.5 ng / ml when intramuscularly administered to a rabbit at a dose of 5 mg of drug compound per kg of body weight. Sustained-release preparation.

34. The above 18, 24 or 25 items which represent an AUC of 160 to 230 ng / ml × day for 0 to 42 or 43 days when subcutaneously administered to a rat at a dose of 10 mg of the drug compound per kg of body weight. Sustained-release preparation.

35. The above 18, 24 or 25 which exhibits an AUC of 160-275 ng / ml × day for 0-42 or 43 days when administered intramuscularly to a rabbit at a dose of 5 mg of drug compound per kg of body weight
The sustained-release preparation according to the above item.

30. The sustained-release preparation according to the above-mentioned item 18, for use in the treatment or prevention of acromegaly or breast cancer.

37. A method for the administration of a peptide drug to a patient, which comprises parenterally administering to the patient in need thereof the depot formulation of paragraph 18 above.

38. The method according to paragraph 37 above for the treatment of acromegaly or breast cancer.

39. Octreotide-pamonate.

40. A method for producing octreotide-pamonate by reacting octreotide with embonic acid or a reactive derivative thereof.

41. In a biodegradable, biocompatible polymer matrix,
A sustained release formulation comprising a peptide drug compound selected from the group of calcitonin and lypressin and their pharmaceutically acceptable salts.

42. The sustained release preparation according to the above item 25, which comprises a peptide drug compound selected from the group consisting of calcitonin and lipresin.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical indication location A61K 38/04 38/23 47/34 C A61K 37/43 (72) Inventor Hawkins Variant Mall Deing USA New Jersey 07945 Mendam Koreirain 2 (72) Inventor Oskar Naguele Swiss Seeh-4450 Jisatsuha Oberami Yules Tetstenbeek 28 (72) Inventor Jane Edna Pearson United States New Jersey 07439 Ojendendsburg・ Main Street 13 (56) Reference JP-A-57-150609 (JP, A) JP-A-61-236729 (JP, A) JP-A-60-76531 (JP, A)

Claims (3)

[Claims] 1. A sustained-release preparation comprising a peptide drug compound or a salt or derivative thereof in a biodegradable, biocompatible polymer base, wherein the polymer base is 40 / 60-60 / 40 polylactide-co-glycolide ester selected from the group of ( _C3-6 ) carbon chain containing alcohols and mono- or disaccharides in which the polyol unit has 3-6 hydroxyl groups and esterification The sustained-release preparation, wherein the polyol has at least 3 polylactide-co-glycolide chains, and the peptide drug compound is octreotide or a salt thereof. 2. A polylactide-co-glycolide ester is
The sustained-release preparation according to claim 1, which has an Mw of 35,000 to 60,000 and an Mw / Mn of 2.0 to 2.5. 3. A peptide drug compound in a polymer base is 0.2
Claim 1 contained in a concentration of up to 10% by weight
The sustained-release preparation according to item 2 or item 2.