JPH07285853A - Preparation of a micro particle - Google Patents

Abstract

PURPOSE: To obtain a microparticle formulation having a continuously sustained release character over a specific time by adding a solution of a peptide medicinal, etc., to a solution of a polymeric base material to effect dispersion followed by addition of a phase inducer and an oil-in-water emulsion. CONSTITUTION: This microparticle formulation is obtained by the following process: (A) a polymeric base material is dissolved in a solvent insoluble for the medicinal compound (pref. a water-soluble peptide), (B) a solution of the medicinal compound prepared by dissolving the compound in a solvent insoluble for the polymer is added to the solution in the process A to effect dispersion, (C) a phase inducer is added to the resultant dispersion to induce the formation of microparticles, (D) an oil-in-water emulsion is added to the above dispersion to effect coagulation of the microparticles, and (E) the microparticles are recovered to obtain the objective microparticle formulation. In an embodiment, for example, an aqueous medium solution of somatostatin at 2.5 g/10 mL and an organic solvent solution of polylactide-co-glycolide at 40 g/100 mL incompatible with the above aqueous medium are vigorously mixed with each other in a weight ratio of e.g. (1:16) and via the above processes C to E, to obtain the microparticles.

Description

Detailed Description of the Invention

The present invention relates to microparticulates of a drug, in particular a water-soluble peptide, for example somatos titanium or a somatos titanium analogue, for example octreotide, in a biodegradable and biocompatible polymer base, for example a matrix or coating. The present invention relates to a method for producing a sustained release (depot) preparation in the form of an agent (also called microcapsule or microsphere).

The present invention further relates to such formulations which exhibit a satisfactory peptide release profile over a certain 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 time.

Parenteral administration of peptide drugs as depot formulations in biodegradable polymers, eg 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 certain residence time in.

Microgranules are known for some parenteral depot formulations of peptide drugs in polymers in the form of implants, but 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. I have to be.

[0006] Peptide drug release patterns depend on many factors, including the type of peptide and the drug in its free form or in other forms, which affects its water solubility.
For example, it depends on whether it is present in salt form. 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,
It therefore additionally influences the water solubility of the peptide and its release pattern.

Other factors that may affect the release pattern of depot formulations may be added in the case of polymer-based drug loading, how the drug is dispersed in the polymer, and in the case of granules and implants. Is its shape. 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 Prior Art Polymeric formulations with drugs designed to give a prolonged, or delayed, release of the drug are known.

US Pat. No. 3,773,919 discloses a controlled drug release formulation in which the drug, eg, a water soluble peptide drug, is biodegradable and biocompatible with linear polylactide or Dispersed in polylactide-coglycolide polymer. However, there is no description of the drug release pattern and no mention of somatostatin. U.S. Pat. No. 4,29
No. 3,539 describes an antibacterial formulation in the form of microgranules.

US Pat. No. 4,675,189 describes a sustained release formulation of the LHRH analog decapetide naphthalene and similar LHRH congeners in polylactide-coglycolide polymers.

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

[0013] US Pat. No. 3,991,776; 4, for action and sustained release and biodegradation of lactic acid polymer / copolymers and lactide / glycolide copolymers and related compositions for surgical administration. 076,798 and 4,118,470.

European Patent Specification No. 0203031 discloses in columns 15-16 a series of somatostatin octapeptide analogs, for example compound RC-1 having the formula:
60 is written. There is a bridge between the -Cys- moieties in the formula.

The possibility of microencapsulating somatostatin with D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH ₂ polylactide-co-glycolide polymer is described in claim 18. However, it does not disclose a method for achieving continuous therapeutically active serum concentrations.

US Pat. No. 4,011,312 discloses an antibacterial agent from a polylactide-co-glycolide matrix having a low molecular weight (up to 2000) and a relatively high glycolide content in the form of implant tablets, eg water-soluble. It states that this can be achieved by inserting a continuous release implant of polymyxin B 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.

European Patent No. 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 molecule, thereby reducing glycolide units in the polymer molecule. By introducing, 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 by broadening the surface of the implant. By
It is disclosed to be stimulated. Although somatostatin is mentioned as a water-soluble peptide, there is no description of the release profile of somatostatin, and in order to obtain a continuous somatostatin serum concentration for at least one week, for example, for one month, all of these factors are required. No instructions are given on how to combine the.

EP 92918 discloses a continuous release of a peptide, preferably a hydrophilic peptide, over a long period of time by incorporating hydrophilic units such as polyethylene glycol, polyvinyl alcohol, dextran, polymethacrylamide in the molecule. It is noted that this can be achieved by increasing the hydrophilicity, for example by introducing the peptide into a conventional hydrophobic polymer matrix of polylactide.
The hydrophilic contribution to the amphiphilic polymer is due to the ethylene oxide group in the case of polyethylene glycol units, the free hydroxyl group in the case of polyvinyl alcohol units or dextran units, and the amide group in the case of polymethacrylamide units. Given by. 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 the hydrophilic peptide, but there is no description about the release profile, and what kind of polymer is suitable for this peptide and how many hydrophilic groups the polymer has. There is no indication as to whether it should have a sexual group.

British Patent GB 2,145,422B discloses that the sustained release of various drugs, eg vitamins, enzymes, antibiotics, antigens, allows the drug to carry, for example, one or more, preferably three polylactide ester groups. , Polyol,
It is noted that this can be achieved when it is included in an implant, for example of the size of microgranules, consisting of polymers of glucose or annitol. The polylactide ester group preferably contains, for example, glycolide units. I haven't listed any peptides as drugs, such as somatostatin,
It does not disclose any serum drug concentration.

SUMMARY OF THE INVENTION The present invention provides a drug, for example, a hormonally active, water-soluble somatostatin or, for example, octreotide, in a biodegradable, biocompatible polymer, such as an encapsulating polymer matrix. The present invention relates to a method for producing sustained release microparticle formulations of somatostatin analogs that provide satisfactory drug serum concentrations.

The microgranules according to the invention can be prepared by any conventional method, for example by organic phase separation, spray drying or three-phase emulsion methods, in which case phase separation or three-phase emulsion is carried out. If a liquid is used, the polymer is precipitated with the drug and then the product is cured.

If desired, the sustained release formulation may take the form of an implant.

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

In the present invention, the steps: a) dissolving the polymeric base material in a suitable solvent that does not dissolve the drug compound, and b) a suitable solvent that is a non-solvent for the polymer, such as an alcohol, in A solution of the drug compound of step a) is added and dispersed in the solution of step a), c) a phase inducer is added to the dispersion of step b) to induce microgranule formation, and d) step c). Microparticles consisting of the drug in a biodegradable, biocompatible base consisting of adding an oil-in-water emulsion to the mixture of to harden the microgranules and e) recovering the microgranules. A method of manufacturing the agent is also provided.

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

According to the present invention there is provided a method for producing microgranules, which method comprises: (i) forming a drug in one phase and another formed from an aqueous medium and an organic solvent incompatible with water. A water-in-oil emulsion containing a biodegradable, biocompatible polymer in the phase is vigorously mixed with an excess of an aqueous medium containing an emulsifying substance or a protective colloid to form a water-in-oil emulsion. To form a water-in-oil-in-water emulsion without adding any drug-protecting substances or applying any intermediate viscosity-increasing steps, (ii) then removing the organic solvent, and (iii) thus It consists of isolating and drying the resulting microgranules.

The invention further: a) polyol 40 / 60-60 / 40 polylactide - co - consists glycolide peptide drug compounds in the ester, a polyol units having from 3 to 6 hydroxyl groups (C ₃ ~ ₆₎ Carbon chain-containing alcohols and esterified polyols selected from the group of mono- or disaccharides and esterified polyols are sustained release formulations having at least 3 polylactide-co-glycolide chains; b) a molecular weight Mw of 25,000 to 100,000. And 1.2
40 / 60-6 having linear chains with polydispersity Mw / Mn of 2
0.2 in a 0/40 polylactide-glycolide polymer
Sustained release formulation consisting of a peptide drug compound selected from the group of calcitonin, lypressin or somatostatin, preferably in a concentration of 10% by weight of peptide drug compound; c) biodegradable, octreotide in biocompatible polymer base. Alternatively, a salt or derivative thereof is also provided.

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

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

In addition or according to the present invention, a depot formulation as described above is administered parenterally to a patient in need thereof, in particular for the treatment of acromegaly or breast cancer. Methods of administering peptides are provided.

Description of the Preferred Embodiments The drug for use in the method of the invention is preferably a water soluble drug, especially a water soluble peptide.

Peptides for use in the present invention may be, for example, calcitonin, such as salmon calcitonin, lypressin and naturally occurring somatostatin and their synthetic analogs.

Naturally occurring somatostatin is one of the preferred compounds and is a tetradecapeptide having the following structure:

[0034]

[Chemical 1]

This hormone is produced by the hypothalamic glands and other organs, such as the GI tract, and, together 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 containing 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 are omitted and / or substituted by one or more other amino groups and / or
Or a straight chain, a bridge or one or more functional groups substituted by one or more other functional groups and / or one or more groups substituted by one or more other equivalent groups It means a cyclic polypeptide. 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 effect on the regulation of physiological function. Suitable known somatostatins are:

[0038]

[Chemical 2]

Here, in each of the compounds a) to i), as shown by the following formula, a bridge exists between the amino acids marked with *.

Other suitable somatostatins are:

[0041]

[Chemical 3]

(Bale et al., Metabolism, 27, Addendum
1, 139 (1978))

[0043]

[Chemical 4]

(See European Patent Publication No. 1295 and Application No. 78 100994.9)

[0045]

[Chemical 5]

(Barber et al., Life Science, 3
4, 1371-1374 (1984) and European Patent Application No. 82106205.6 (published as 70021)), also known as cyclo (N-Me-Ala-Tyr-D-Trp-Lys-Val-Phe). .

[0047]

[Chemical 6]

(Refer to R. F. Nat et al., Klin Wotsuhienshiyuru (1986) 64 Addendum VII).

[0049]

[Chemical 7]

(See EP-A-200, 188)

[0051]

[Chemical 8]

And X-Cys-Phe- D- Trp-Lys-Thr-Cys-Thr-ol where X is especially a cationic anchor.

[0053]

[Chemical 9]

(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 N-. It is preferably bound to the terminal amino group. Such compounds and their formulations are disclosed, for example, in WO 88/02756.

The term octreotide is a moiety having a bridge between Cys residues:

[0058]

[Chemical 10]

Including those including.

A particularly preferred derivative is N ^α- [α-glycosyl- (1-4-deoxyfructosyl] -DPhe-Cys-P
he-DTrp-Lys-Thr-Cys-Thr-ol and N ^α- [β
-Deoxyfructosyl-DPhe-Cys-Phe-DTrp-Lys
-Thr-Cys-Thr-ol, where -C
It is preferred to have the bridge between the ys-moieties and be in the acetate form, and described in Examples 2 and 1 of the above patent specification, respectively.

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. The acid addition salt is
For example, hydrochloric acid and acetate are included. Complexes are formed, for example, from somatostatin by addition of inorganic substances, for example inorganic salts or hydroxides such as Ca- and Zn salts and / or 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 in a conventional manner, for example by reacting embonic acid (pamonic acid) with, for example, octreotide in the form of the free base. This reaction is carried out in a polar solvent, for example,
It can be performed at room temperature.

Somatostatin is used in the treatment of diseases for which long-term administration of drugs is planned, for example of diseases of etiology involving or accompanied by excess GH secretion, eg in the treatment of acromegaly. For the treatment of gastrointestinal diseases, for example, peptic ulcer, intestinal skin and intrapancreatic skin fistula, inflammatory bowel syndrome, dumping syndrome, water laxative syndrome, acute pancreatitis and gastroenteropathic endocrine tumor (eg , Bipomath, GR
F trout, glyca gonorrhoeae, insulinomas, gastrinomas and carcinoid tumors) and gastrointestinal bleeding, breast cancer and complications associated with diabetes are needed for use in the treatment or prevention.

Polymer bases can be made from biocompatible and biodegradable polymers, such as linear moieties, linear polyesters that are linear chains derived from glucose moieties, such as glucose; branched polyesters; etc. The esters of polylactic acid, polyglycolic acid, polyhydroxybutyric acid, polycaprolactone, polyalkylene oxalates, cribs cycle, for example, citric acid cycle, polyalkylene glycol esters of acids, and copolymers thereof.

The preferred polymers of this invention are linear polyesters and branched chain polyesters. Linear polyesters can be prepared from alpha hydroxycarboxylic acids such as lactic acid and glycolic acid by condensation of lactone dimers (see, for example, US Pat. No. 3,773,919).

The linear polylactide-co-glycolide preferably used in the present invention is 25,000-10.
Conveniently, it has a molecular weight of 20,000 and a polydispersity Mw / Mn of, for example, 1.2-2.

Branched polyesters which are preferably used in the present invention can be prepared using polyhydroxy compounds as initiators, for example polyols such as glucose or mannitol. Esters of these polyols are known and are known from British Patent GB2,
145,422B. The polyol has at least 3 hydroxyl groups and has a molecular weight of up to 20,000 and at least 1, preferably at least 2, for example 3 hydroxyl groups of the polyol have a polylactide or copolylactide chain. In the form of an ester group containing. Generally 0.2%
Glucose is used to initiate the polymerization. The structure of branched polyester is star-shaped. Suitable polyester chains in linear and star polymers suitable for use in the present invention include alpha carboxylic acid moieties, lactic acid and glycolic acid,
Alternatively, it is a copolymer of a lactone dimer. The lactide: glycolide molar ratio is about 75:25 to 25:75, such as 60:40 to 40:60, and 55:45 to 4
It is also preferred that it has a ratio of 5:55, for example 55:45 to 50:50.

Star polymers are obtained by reacting a polyol with a lactide and preferably further glycolide at elevated temperature in the presence of a catalyst allowing ring opening polymerization.
It can be manufactured.

The advantage of the star polymers in the formulations according to the invention is that their relatively high molecular weight allows them to provide physical stability, eg some hardness, to implants and microgranules, While preventing mutual sticking, this results in a controllable biodegradation rate of the polymer and a sustained release of the corresponding peptide over a period of weeks to 1 or 2 months due to the presence of relatively short polylactide chains, The depot formulation produced from
It means that it should be suitable for one month release.

Star polymers are about 10,000-200,000.
0, preferably 25,000-100,000, especially 3
It has a main molecular weight Mw in the range of 5,000 to 60,000 and a polydispersity of, for example, 1.7 to 3.0, for example 2.0 to 2.5. The intrinsic viscosities of star polymers with Mw of 35,000 and 60,000 are, respectively, in chloroform:
0.36 and 0.51 dl / g. Mw 52,000
Is a star polymer having 0.475d in chloroform.
It has a viscosity of 1 / g.

The terms microspheres, microcapsules and microgranules should be understood to be interchangeable in the context of the present invention and mean the encapsulation of peptides by polymers, in which case the peptide The peptides are preferably distributed throughout the matrix polymer. 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 can be prepared, for example, by dissolving the polymer base in a solvent that is a non-solvent for the peptide and then dissolving the peptide in a polymer-solvent composition. Can be prepared by adding and dispersing. 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 the microgranules with buffer / heptane emulsion. Conventional methods either 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 reduces the burst of initial drug, which is a characteristic of many conventional encapsulation formulations. 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.

The O / W emulsion can be prepared by using an emulsifier such as sorbitan mono-oleate (Span 80ICI Co.) to form a stable emulsion. The emulsion can be buffered with a buffer that is harmless to the peptide and polymeric material. Buffers can be prepared, for example, 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 contain dispersants such as, for example, silicone oils. A suitable emulsion may consist of heptane, pH 4 phosphate buffer, 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 hardening. Solvent plus emulsifier for and subsequent separate washing steps.

The O / W emulsion can be used without a dispersant. 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 compatible with the polymer solvent,
It is preferably dissolved in an alcohol solvent, for example methanol.

Phase inducers (coacervation agents) are solvents which are miscible with the polymer-drug mixture and give rise to 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 heptane, hexane or the like as an organic phase.

The microgranules of the present invention can also be produced by a generally known spray drying method. According to this method, somatostatin, 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 incompatible with the above solvents, such as methylene chloride, is used. Mix the combined solution thoroughly.

The solution, suspension or emulsion formed is then atomized in a stream of air, preferably in a stream of warm air. The formed microgranules are collected, for example by a cyclone, and washed, if necessary, in a buffer having a pH of 3.0 to 8.0, preferably pH 4.0, or in distilled water, and then the temperature of, for example, 20 to 40 ° C. To dry under reduced pressure.
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.

It is thus possible to obtain microgranules which show an improved in vivo somatostatin releasing profile.

The invention thus further relates to the microgranules produced by the method of the invention. Thus, the present invention further comprises mixing somatostatin or a solution of somatostatin in methanol or water or a buffer of pH 3-8 with a solution of polylactide-coglycolide in methylene chloride and forming a solution of somatostatin in a polymer solution, The emulsion or suspension is sprayed in a stream of warm air, the microspheres are collected, washed with a buffer solution of pH 3.0-8.0 or distilled water, then at 20-40 ° C.
The sustained release preparation produced by drying under reduced pressure at the temperature of They do not contain any silicone oils since they do not use silicone oils in the spray-drying method 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, the peptide, eg, octreotide, is dissolved in a suitable solvent, eg, water, and the polymer in a solvent that is non-solvent for the peptide, eg, methylene chloride, eg 50/50 poly (D, L). -Lactide-coglycolide) vigorously emulsified in a solution of glucose. Examples of solvents for polymeric matrix materials include methylene chloride, chloroform, benzene, ethyl acetate and the like. Generated water / oil (W /
O) if the emulsion is further emulsified in excess water containing an emulsifying substance such as an anionic or nonionic surfactant or lecithin or a protective colloid such as gelatin, dextrin, carboxymethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol. , Which results in the continuous production 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 works to prevent agglomeration of microspheres. After the sedimentation of the micro-granules, the supernatant is decanted, the micro-granules are washed with water and then with the acetate buffer. The microgranules are then filtered and dried.

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

A three-phase emulsifier method is described in US Pat. No. 4,652,4.
No. 41 is known. According to this patent, in the first step, a drug solution (1) in a solvent, for example somatostatin in water (second column, lines 31-32), is prepared in such a way that the first solvent does not dissolve therein. Water-in-oil (W / O) of the fine drug-containing droplets of (1) in solution (2) by thoroughly mixing with excess polylactide-coglycolide solution (2) in a solvent such as methylene chloride. ) Give emulsion (3). In the solution (1), a so-called drug-retaining agent (column 1, line 31), such as gelatin, albumin,
Also dissolve pectin or agar.

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

In the third stage, excess water was thoroughly mixed with the W / O emulsion (3) (7th column, 52-54).
Row), to form a W / O / W 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. This detachment is carried out by a known method (8th column, lines 3 to 5),
For example, pressure drop while stirring (8th column, 5th-7th columns)
Line) or by bubbling nitrogen gas into the oil layer (eg methylene chloride) (line 19).

The formed microgranules are recovered by centrifugation or filtration (lines 26 to 27) and the components not incorporated in the polymer are removed by washing with water (line 29). If desired, better removal of water and solvent (eg removal of methylene chloride from the walls of the microgranules) can be achieved by heating the microgranules under reduced pressure (30-3).
2 lines).

Although the above methods are also satisfactory for the preparation of the formulations according to the invention, however, the so-called drug-carrying substances mentioned above, eg gelatin, albumin,
Pectin or agar is also encapsulated in the resulting microgranules.

We hereby omit the step for the addition of the drug-carrying 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 it is also possible to obtain satisfactory microgranules when means of adding protective colloids such as emulsifying substances or gelatin are used. Moreover,
The microgranules do not contain any drug-carrying substances and only very small amounts of methylene chloride.

The present invention therefore comprises: a) preferably 0.8 to 4.0 g / 1 to 120 ml, especially 2.5 g in an aqueous medium, preferably water or a buffer.
A solution of the drug, preferably somatostatin, especially octreotide, in a buffer of pH 3 to 8 in a weight / volume ratio of / 10 ml, especially acetate buffer, and b) an organic solvent which is incompatible with the aqueous medium, eg A solution of a polymer as described above, preferably polylactide-coglycolide, in methylene chloride, preferably in a weight / volume ratio of 40 g / 90 to 400 ml, especially 40 g / 100 ml, preferably weight / weight of drug to polymer. The mixture is vigorously mixed to form a ratio of 1/10 to 50, especially 1/16, and a volume / volume ratio of aqueous medium / organic solvent of 1 / 1.5 to 30 and especially 1/10. A) W / O emulsion in b) and c) an emulsifying substance or protective colloid, preferably in a concentration of 0.01 to 15.0% by weight, in particular 0.1 to 3%, in particular 0.1.
An excess of aqueous medium containing 5% concentration of gelatin,
Preferably water or a buffer, preferably pH 3-8, such as acetate or phosphate buffer, is added to 1/10 to 10
At a volume / volume mixing rate ratio of 0, especially ab / c) of 1/40, add some drug-retaining substance or apply some intermediate viscosity increasing step to the water-in-oil emulsion. W / O /
The initial microgranules in the W emulsion are hardened by elimination of organic solvents, preferably methylene chloride, preferably by evaporation, and the microgranules formed are isolated, optionally washed and dried. A method for producing a micro-granule produced by the above is provided.

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 a 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.

Sustained-release preparations may also be prepared by other methods, for example as follows: -when the peptide is sufficiently stable for the manufacture of implants, especially as described above. Thus, a peptide in polylactide-coglycolide, for example a microgranule containing somatostatin or a mixture thereof obtained by mixing the peptide with a polymer, for example 70-1
It is heated at a temperature of 00 ° C. and extruded and cooled to a dense substance, after which 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 are in depot form, eg
It can be used as an injectable microsphere or implant.

They can be processed in the usual way, for example by
For known indications for the drugs contained in it,
It can be administered by subcutaneous or intramuscular injection.

Sustained-release preparations containing octreotide include
For all known indications of octreotide or its derivatives, for example British Patent No. 2,199,829A, 8
It can be administered to those disclosed in pages 9-96 and for 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, or peptide, 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 peptide can be verified by bioavailability testing. The formulation may contain the peptide in an amount of 3.0 to 6% by weight, based on the polymer matrix.

The release time of the peptide from the microgranules is 1
~ 2 weeks to about 1 month.

Sustained release formulations include somatostatin, such as octreotide, in a biodegradable, biocompatible polymer base, which is administered subcutaneously in rats at a dose of 10 mg somatostatin per kg body weight. sometimes,
It is advantageous to exhibit a concentration of somatostatin in serum of at least 0.3 ng / ml and preferably less than 20 ng / ml over a period of 30 days, or conveniently 60 days.

Alternatively, the sustained-release preparation is 5 kg / kg of body weight.
Biodegradable, biocompatible, exhibiting a concentration of at least 0.3 ng / ml and, if appropriate, a maximum of 20 ng / ml over 50 days when administered intramuscularly to rabbits at a dose of mg Conveniently it consists of somatostatin, eg octreotide, in a polymer base.

Other suitable properties of the somatostatins obtained, eg octreotide-containing depot formulations, are, depending on the manufacturing method used, the following: phase separation method rabbit : somatostatin 5 mg / kg, intramuscular delay (0 ~ 42 days) 76% Mean serum concentration (Cp. Ideal) (0-42 days) 4ng / ml AUC (0-42 days) 170ng / ml x day Spray drying method Rat : somatostatin 10mg / kg, subcutaneous delay (0 ~ 42 days)> 75% Mean serum concentration (Cp. Ideal) (0-42 days) 4-6 ng / ml AUC (0-42 days) 170-210 ng / ml
× day Rabbit : Somatostatin 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 to 240ng / ml
× day three-phase emulsion method rat: somatostatin 10 mg / kg, sc delay (0-42 days)> 75% Mean serum concentration (. Cp ideally) (0-42 days) 4~6.5ng / ml AUC (0~ 42 days) 170-230ng / ml
× day Rabbit : Somatostatin 5 mg / kg, intramuscular delay (0 to 42/43 days)> 74% Mean serum concentration (Cp. Ideal) (0 to 42/43 days) 3.5 to 6.5 ng / m
l AUC (0-42 / 43 days) 160-270ng / m
The present invention thus also provides somatostatin, preferably octreotide and octreotide analogue compositions having the following properties: at least 70 over a period of 1.0 to 42 or 43 days.
%, Preferably at least 74%, eg at least 75%, 80%, 88% or at least 89% delay,
And / or 2. When subcutaneously administering 10 mg of somatostatin in rats, the mean serum concentration of 2.5-6.5, preferably 4-6.5 ng / ml over 0-42 days and / or 5 mg of somatostatin in rabbit. When administered intramuscularly for 3.5 to 6 over 0 to 42 or 43 days.
5, for example, an average serum concentration of 4 to 6.5 ng / ml, and / or at least 160 over 0 to 42 days for rats subcutaneously administered 3.10 mg of somatostatin,
Preferably 170-230 ng / ml x AUC and / or 5 mg somatostatin intramuscularly for at least 160, preferably 180-275, e.g. 2 over 0-42 or 43 days for a rabbit.
AUC of 00-275 ng / ml x day.

For the quantitative properties of the above sustained release formulations, see F. Nimmerfall and J. Rosentara, Internal Journal of Pharmacy. 32 , 1-6 (1986), the area deviation (AD) method is used.

Briefly, the AD method is based on the ideal profile of constant mean serum concentration (= Cp, ideal) resulting from the conversion of the area under the experimental serum concentration-time curve (AUC) to an equal area rectangle. Calculate the area deviation of the experimental serum profile from the experimental serum profile from. The% delay is calculated from the percentage area deviation (denoted as AUC) as follows:% delay = 100 × (1−AD / AUC) This method calculates the whole serum profile measured over a preselected time as a single mathematical expression. Characterized by a positive index.

Proceeding of National Academy of Science, USA 85 (1988) 56
82 to 5692, the serum concentration profile in the rat of the octapeptide analog of somatostatin of the formula below is shown in FIG.

[0114]

[Chemical 11]

However, the above definite comparison with the serum concentration data of the composition of the present invention in the rat is based on a different administration method (intramuscular injection), and more importantly, the serum concentration profile described. In particular, the loading level of microcapsules (2-6%) and dosage (at least 45%)
Quantitative over 20 days, but 20-50
A definite comparison cannot be made because the mg microcapsule portion is not indicated exactly (for 30 days). Moreover, the type of poly (Dl-lactide-coglycolide) 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 1 g of poly (D, L-lactide-coglycolide) (molar ratio 50/50, Mw = 45,000; polydispersity about 1.
7) was dissolved in 15 ml of methylene chloride using a magnetic stirrer and then dissolved in 0.5 ml of methanol 7
5 mg of octreotide acetate was added. 1
5 ml silicone oil (Dow 360 medical silicone oil,
1000 cs) was added to the polymer peptide mixture. The mixture thus obtained is mixed with 400 ml of n-heptane, 100
ml pH 4 phosphate buffer, 40 ml Dow 360 medical silicone oil, 350 cs and 2 ml span 80
(Emulsifier) was added to the stirred emulsion. 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 is about 90% of micro granules in the particle size range of 10-40 microns.
Met.

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) glucose (Mw = 45,000, polydispersity about 1.7 molar ratio 5
5/45, according to the method of British Patent No. 2,145,422B, prepared from 0.2% glucose) was dissolved in 25 ml ethyl acetate using a magnetic stirrer and then 3 m
75 mg octreotide dissolved in 1 of methanol was added. 15 ml of silicone oil (Dow 360 brand medical silicone oil, per polymer-peptide mixture,
1000 cs) was added. 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 collected 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 to be 0.5 over 21 days.
A serum concentration of ~ 2ng / ml was exhibited.

Example 3 A solution of 1.5 g of octreotide acetate in 20 ml of methanol was stirred and stirred with 18.5 g of poly (D, L-lactide-co-glycolide) glucose (molar ratio 50) in 500 ml of methylene chloride. / 50, Mw = 45,000
0). 500 for peptide-polymer suspension
8 ml with Dow 360 Medical Silicone Oil (1000cs)
Phase separation was achieved by adding 00 ml of Dow 360 Medical Silicone Oil (350 cs). 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 filtration.

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 was added to 1 ml of span 80
Washed by stirring with 1000 ml of ethanol containing. 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, collect the micro-granules by vacuum filtration, 3
Dry overnight in a vacuum oven at 7 ° C. The residual methylene chloride concentration of the microgranules washed in this way fell from 1.2 to 0.12%.

The combined yield of product was 18.2 g (91%) microgranules containing 5.6% octreotide with an average diameter of 24 microns and 1.5% residual heptane.

The microgranules were suspended in a vehicle and injected intramuscularly into white rabbits at a dose of 5 mg / kg octreotide. Blood samples are taken regularly for RI
Measured by A, 0.3-7. Over 49 days.
A serum concentration of 7 mg / ml was shown.

Example 4 1 g of poly (D, L-lactide-co-glycolide) glucose (Mw = 46,000, polydispersity about 1.7; according to the method of GB 2,145,422 B). Gauze, prepared from 0.2% glucose in a molar ratio of 50/50) was dissolved in 10 ml of methylene chloride using a magnetic stirrer, then 75 mg dissolved in 0.133 ml of methanol.
Octreotide was added. The mixture is, for example,
A suspension of very small crystals of octreotide in the polymer solution was produced by vigorous mixing at 20,000 rpm for 1 minute using an Ultra-Trax.

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 microgranules. 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. After 72 hours, the final product was obtained by sieving the micro-granules (sieve size 0.125 mm).

The microgranules were suspended in an excipient and 5 mg / kg to white rabbits (chinchilla-bustard).
Was administered intramuscularly at a dose of octreotide and subcutaneously at a dose of 10 mg / kg to male rats. Blood samples were taken at regular intervals and measured by radioimmunoassay (RIA) analysis for 0.3 to 10.0 ng / ml (dose 5 mg) in rabbits and 0.5 to 7.0 ng / ml in rats over 42 days. The serum concentration of

Example 5 Microgranules by spray drying similar to the method described in Example 4 except the only difference is that octreotide is directly suspended in the polymer solution without the use of methanol. Was manufactured.

The microgranules were suspended in a vehicle and administered subcutaneously to male rats at a dose of 10 mg / kg octreotide. Blood samples were taken at regular intervals and showed serum concentrations of 0.5-10.0 ng / ml over 42 days as determined by radioimmunoassay (RIA) analysis.

Example 6 1 g of poly (D, L-lactide-co-glycolide) glucose (Mw = 46,000, polydispersity about 1.7; molar ratio 50/50; British Patent No. 2,145,422). No. B, produced with 0.2% glucose) according to No. B)
After dissolving in 1 methylene chloride, 75 mg octreotide dissolved in 0.125 ml deionized water was added. The mixture was vigorously mixed using, for example, an Ultra-Trux at 20,000 rpm for 1 minute (inner W /
O phase).

1 g of gelatin A was dissolved in 200 ml of deionized water at 50 ° C. and the solution was cooled to 20 ° C. (outer W phase). The W / O phase and the W phase were vigorously mixed. This separated the inner W / O phase into small droplets, which were evenly dispersed 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 microgranules, the supernatant was removed by suction, the microgranules were collected by vacuum filtration, 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 a vehicle and administered intramuscularly at a dose of 5 mg / kg octreotide for white rabbits (chinchilla-bustard) and 10 mg for male rats.
/ Kg was administered subcutaneously. Blood samples are taken at regular intervals and measured by radioimmunoassay (RIA) analysis at 0.3 to 0.3 in rabbits for 42 days.
A serum concentration of 15.0 ng / ml (5 mg dose) and 0.5-8.0 ng / ml in the rat 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. 0.12 for the preparation of the inner W / O phase
Instead of 5 ml of water, 0.25 ml of 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. A second wash of microgranules was omitted.

Example 8 The procedure was repeated, except that 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 for Example 7.

Example 9 Similar to that described in Example 6, except that the drug compound is directly dispersed in the polymer solution, and then the resulting dispersion is mixed with the gelatin-containing aqueous phase. Micro granules were prepared.

Example 10 Octreotide Pamoate 10.19 g of octreotide free base (10 mM) and 3.88 g of embonic acid (10 mM) were dissolved in 1 l of water / dioxane (1: 1). The reaction mixture was filtered, lyophilized to a yellow powder of octreotide pamonate hydrate.
[α] ²⁰ D = + 7.5 ° (c = 0.35 in DMF) was obtained. 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 1 g of poly (D, L-lactide-co-glycolide) in 20 ml of methylene chloride (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 silicone oil (Dow 360 medical silicone oil, 1
000 cs) was added for phase separation. The mixture thus obtained was mixed with 100 ml of pH 4 phosphate buffer, 4 ml.
00 ml n-heptane, 4 ml span 80 and 40
ml silicone oil (Dow 360 medical silicone oil, 1
000 cs) to a stirred emulsion. After stirring for 10 minutes, collect the microgranules by vacuum filtration and
Dry overnight in a vacuum oven at 7 ° C. A yield of 1.1 g of microgranules containing 5.9% calcitonin was obtained.

Example 12 9.9 g of poly [D, L- in 140 ml of methylene chloride
Lactide-co-glycolide] (molar ratio 50/50, Mw
= 44,300) was added to 100 mg of lypressin.
After magnetically stirring this dispersion for 1 hour, 140 ml of silicone oil (Dow 360 medical silicone oil, 1000c
s) and 2.5 ml of Span 80 was added. 2 of that mixture
It was added to 000 ml of 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 for 10 minutes by stirring in water; 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 main features and aspects of the present invention are as follows.

1. a) dissolving the polymer-based material in a suitable solvent that does not dissolve the drug compound, and b) adding a solution of the drug compound in a suitable solvent that is a non-solvent for the polymer in step a) and By dispersing, c) inducing the formation of microgranules by adding a phase inducer to the dispersion of step b), and d) adding an oil-in-water emulsion to the mixture of step c). A method for producing a microgranule that includes a drug in a biodegradable, biocompatible polymer base, which comprises the steps of curing the microgranule and e) recovering the microgranule.

2. A micro granule obtained by the method described in the above item 1.

3. (i) Water-in-oil milk 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. Add any drug-retaining agent to the water-in-oil emulsion or apply any intermediate viscosity-increasing step by vigorously mixing the suspension with an excess of aqueous medium containing the emulsifying substance or protective colloid Biodegradable, biocompatible, which consists of forming an oil-in-water emulsion without any action, ii) desorbing the organic solvent therefrom, and iii) isolating and drying the resulting microgranules. A method for producing a microgranule containing a drug in a base material.

4. i) vigorous mixing of the drug compound suspension consisting of the drug compound and a water-insoluble organic solvent containing the biodegradable, biocompatible polymer with an excess of an aqueous medium containing the 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) and then adding an organic solvent. A method of producing a microgranule containing a drug compound in a biodegradable, biocompatible polymer, which comprises desorbing, iii) 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, and the resulting water-in-oil emulsion in b) in a) is formed. C) vigorous mixing with an excess of aqueous medium containing protective colloid, without the addition of any drug protectant or application of any intermediate viscosity increasing step to the water-in-oil emulsion. A method for producing a micro-granules, which comprises curing the initial micro-granules in the water-in-oil-in-water emulsion produced by desorption and isolating the micro-granules produced.

6. The drug is somatostatin No. 5 above
Method described in section.

7. The fifth drug, wherein the drug is octreotide
Method described in section.

8. The method according to claim 5, wherein the drug is an octreotide pamoate salt.

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 claim 5, wherein the aqueous medium is a buffer having a pH of 3 to 8.

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

13. a) 0.8-4.0 g / 1-120 ml
A solution of somatostatin in water or a buffer at a weight / volume ratio of b) and b) a solution of polylactide-coglycolide in an organic solvent that is incompatible with the aqueous medium, the weight / weight ratio of drug to polymer being 1/10. To 50 and the volume / volume ratio of the aqueous medium / organic solvent is 1 / 1.5 to 30 and mixed vigorously to produce a water-in-oil emulsion of a) in b). c) with excess water or buffer containing a protective colloid,
No addition of any drug protectant or application of any intermediate viscosity increasing step to the water-in-oil emulsion at volume / volume mixing rates of ab) / c) of 1 / 10-100. A method for producing a micro-granules, which comprises vigorously mixing, curing the initial micro-granules in the resulting water-in-oil-in-water emulsion by evaporation of an organic solvent and isolating the formed micro-granules .

14. 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) a solution of polylactide-coglycolide in an organic solvent which is incompatible with the aqueous medium at a weight / volume ratio of 40 g / 100 ml. Weight / weight ratio of drug to polymer is 1 /
16 and produced by vigorous mixing such that the volume / volume ratio of the aqueous medium / organic solvent is 1/10.
a) a) water-in-oil emulsion in b) and c) an excess of aqueous medium containing protective colloid at a concentration of 0.01-15.0% of 1/4 ab) / c). In the oil-in-water produced by vigorous mixing at volume / volume mixing rate ratio, without adding any drug-protecting substance or applying any intermediate viscosity increasing step to the water-in-oil emulsion. A process for the preparation of micro-granules, which comprises curing the initial micro-granules in an aqueous emulsion by evaporation of an organic solvent and isolating the formed micro-granules.

16. a) 2.5 g / in buffer of pH 3-8
A solution of octreotide in a weight / volume ratio of 10 ml and b) a solution of polyacrydo-coglycolide in methylene chloride in a weight / volume ratio of 40 g / 100 ml resulted in a weight / weight ratio of drug to polymer of 1/16 and an aqueous solution. The mixture was vigorously mixed such that the volume / volume ratio of the medium / organic solvent was 1/10, and the water-in-oil emulsion of a) in c) and c) concentration of 0.5% by weight in the produced b). PH3 containing gelatin at
~ 8 excess of buffer added to the water-in-oil emulsion at any ab) / c) volume / volume mixing rate ratio of 1/40 with any drug protectant or any intermediate. Without applying a viscosity increasing step, vigorous mixing was used to cure the initial microgranules in the water-in-oil-in-water emulsion formed by evaporation of the organic solvent and to isolate and wash the formed microgranules. A method for producing a microgranule, which comprises drying and drying.

17. Micro granules 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. The polymer is poly- (DL-lactide-
19. The sustained-release preparation according to item 18, which is co-glycolide) glucose.

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

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

22. Octreotide concentration by weight is 2.
20. The sustained-release preparation according to item 18, which is 0 to 10%.

Sustained release dosage form according to claim 18 in the form of microgranules having a diameter of 23.1 to 250 microns.

24. 40/60 to 60/4 of polyol
0 polylactide - co - encompass peptide drug compound in glycolide ester, polyol units selected from (C ₃ ~ ₆₎ groups of the carbon chain-containing alcohols and monosaccharides or disaccharides having a 3-6 hydroxyl groups, and The esterified polyol has at least 3 polylactide-co-
A sustained-release preparation having a glycolide chain.

In a linear 40 / 60-60 / 40 polylactide-co-glycolide polymer having a molecular weight of 25.25,000-100,000 and a molecular chain of polydispersity Mw / Mn of 1.2-2. Sustained-release formulation comprising a 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.

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

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. 3 when administered subcutaneously to rats at a dose of 10 mg of drug compound per kg of body weight
20 ng / at least 0.3 ng / ml over 0 days
26. The sustained-release preparation according to the above 18, 24 or 25, which represents the concentration of the drug compound in serum less than ml.

30. 5 when administered intramuscularly to a rabbit at a dose of 5 mg of drug compound per kg of body weight
26. A sustained release formulation according to claim 18, 24 or 25 which exhibits a drug compound concentration in serum of at least 0.3 ng / ml and at most 20 ng / ml over a period of 0 days.

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

32. 0 when administered subcutaneously to rats at a dose of 10 mg of drug compound per kg of body weight
26. The sustained release formulation according to above 18, 24 or 25 which exhibits a mean serum concentration (Cp ideal) of 2.5 to 6.5 ng / ml over 42 days.

33. Nos. 18, 24 or 25 above, which exhibit a mean serum concentration (Cp ideal) of 3.5 to 6.5 ng / ml when administered intramuscularly to rabbits at a dose of 5 mg of drug compound per kg of body weight. The sustained-release preparation according to the above item.

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

35. 0 when administered intramuscularly to rabbits at a dose of 5 mg of drug compound per kg of body weight
160-275 ng / ml over ~ 42 or 43 days
26. The sustained-release preparation according to the above 18, 24 or 25, which represents the AUC of x days.

36. The sustained release formulation according to claim 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 the depot formulation according to claim 18 to a patient in need thereof.

38. 38. The method according to clause 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. A sustained release formulation comprising a peptide drug compound selected from the group of calcitonin and lipresin and their pharmaceutically acceptable salts in a biodegradable, biocompatible polymer matrix.

42. The second comprising a peptide drug compound selected from the group of calcitonin and lipresin
The sustained-release preparation according to item 5.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location C07K 7/06 8318-4H 7/08 8318-4H (72) Inventor Thomas Kysel Day of the Federal Republic of Germany −7813 Shiyu Tauwen Im Siyutainer 9 (72) Inventor Hawkins Variant Molding 07945 Mendege Koreyrain 2 (72) Inventor Oscar Nagele Swiss Republic 4450 Jisach Oberami Yure Tetsutenbake 28 ( 72) Inventor Jane Edna Pearson 07439 New Endysburg, U.S.A.

Claims (7)

[Claims] 1. A) a polymeric base material is dissolved in a suitable solvent that does not dissolve the drug compound, and b) a drug compound in a suitable solvent that is a non-solvent for the polymer in the solution of step a). Add and disperse the solution, c) induce the formation of microgranules by adding a phase inducing agent to the dispersion of step b), and d) oil-in-water emulsion to the mixture of step c). A method for producing a microgranule containing a drug in a biodegradable, biocompatible polymer base, which comprises the steps of: curing the microgranule by adding a) and e) recovering the microgranule. 2. A water-in-oil milk comprising (i) 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. Add any drug-retaining agent to the water-in-oil emulsion or apply any intermediate viscosity-increasing step by vigorously mixing the suspension with an excess of aqueous medium containing the emulsifying substance or protective colloid Biodegradable, biocompatible, which consists of forming an oil-in-water emulsion without any action, ii) elimination of the organic solvent from it, and iii) isolation and drying of the microgranules thus formed. A method for producing a microgranule containing a drug in a base material. 3. A drug compound suspension consisting of i) a water-insoluble organic solvent containing a drug compound and a biodegradable biocompatible polymer, and an excess of an aqueous medium containing an emulsifying substance or a protective colloid. By vigorous mixing to form 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 steps. Ii) a method for producing a microgranule containing a drug compound in a biodegradable, biocompatible polymer, which comprises removing an organic solvent therefrom, and iii) isolating and drying the thus formed microgranule. . 4. A water in oil of b) in a) produced by vigorously mixing a) a solution of a drug in an aqueous medium and b) a solution of a polymer in an organic solvent that is incompatible with the aqueous medium. The emulsion in the form of a c) water-in-oil emulsion without the addition of any drug-protecting substance or any intermediate viscosity-increasing step, is added to the excess aqueous solution containing the protective colloid. A process for the preparation of microgranules, which comprises vigorously mixing with a medium, curing the initial microgranules in the water-in-oil-in-water emulsion formed by desorption and isolating the formed microgranules. 5. A solution of somatostatin in water or a buffer in a weight / volume ratio of 0.8 to 4.0 g / 1 to 120 ml and b) polylactide-cor in an organic solvent which is incompatible with the aqueous medium. The glycolide solution is vigorously mixed in such a manner 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 of a) in b) and c) excess water or buffer containing a protective colloid,
No addition of any drug protectant or application of any intermediate viscosity increasing step to the water-in-oil emulsion at volume / volume mixing rates of ab) / c) of 1 / 10-100. A method for producing a micro-granules, which comprises vigorously mixing, curing the initial micro-granules in the resulting water-in-oil-in-water emulsion by evaporation of an organic solvent and isolating the formed micro-granules . 6. A solution of somatostatin in an aqueous medium at a weight / volume ratio of 2.5 g / 10 ml and b) a polylactide in an organic solvent which is incompatible with the aqueous medium at a weight / volume ratio of 40 g / 100 ml. The solution of coglycolide was added to the drug polymer at a weight / weight ratio of 1 /
16 and produced by vigorous mixing such that the volume / volume ratio of the aqueous medium / organic solvent is 1/10.
a) a) water-in-oil emulsion in b) and c) an excess of aqueous medium containing protective colloid at a concentration of 0.01-15.0% of 1/40 ab / c). capacity/
The water-in-oil-in-water form produced by vigorous mixing without adding any drug-protective substances or applying any intermediate viscosity-increasing step to the water-in-oil emulsion at volume mixing rate ratio. A process for the preparation of micro-granules, which comprises curing the initial micro-granules in an emulsion by evaporation of an organic solvent and isolating the micro-granules formed. 7. A) 2.5 g / 10 in a buffer of pH 3-8.
A solution of octreotide at a weight / volume ratio of ml and b) a solution of polyactide-coglycolide in methylene chloride at a weight / volume ratio of 40 g / 100 ml resulted in a weight / weight ratio of drug to polymer of 1/16 and an aqueous solution. The mixture was vigorously mixed such that the volume / volume ratio of the medium / organic solvent was 1/10, and the water-in-oil emulsion of a) in c) and c) concentration of 0.5% by weight in the produced b). PH3 containing gelatin at
~ 8 excess of buffer added to the water-in-oil emulsion at any ab) / c) volume / volume mixing rate ratio of 1/40 with any drug protectant or any intermediate. Without applying a viscosity increasing step, vigorous mixing was used to cure the initial microgranules in the water-in-oil-in-water emulsion formed by evaporation of the organic solvent and to isolate and wash the formed microgranules. A method for producing a microgranule, which comprises drying and drying.