SA90110050B1 - Extended-release water-soluble peptide preparations - Google Patents

Abstract

Abstract: Sustained release of a peptide drug compound, preferably octreotide similar to somatostatin in the form of pamoate salt. The drug compound is in a carrier of a double origin (polymer), preferably a polylactide-co-glycolide (polylactide-co-glycolide), especially polylactide-co-glycolide (glucose). It is preferable that the preparation be in the form of a preparation stored in the form of a single piece of a monolithic microparticle.

Description

B. Extended-release Preparations of Water-Soluble Peptides Full Description BACKGROUND The invention relates to extended-release (depot) preparations of drugs, particularly water-soluble peptides; such as somatostatin or somatostatin analogues such as octreotide; in a biodegradable and biocompatible polymeric carrier Jie biocompatible binder or sale © cover eg. In the form of an implant or preferably a micromolecule (also found in the form of a microcapsule or microball). This invention is also related to those preparations that have satisfactory peptide release Which lasts for a specified period of time.M peptide drugs often have poor bioavailability in the blood, after administration of all or by injection, for example, because of their short biological half-lives due to their metabolic instability.This In addition to its poor resorption from the mucosa in Ala it is given orally or nasally.Hence it is difficult to reach an appropriate drug concentration level in the blood for an extended period of time.Therefore I suggest giving peptide drugs by injection in the form of a buffered formulation In Polymer 0, Mia biodegrades as microparticles or cultures so that it can extend its effect after remaining in the polymer, which protects the peptide from the enzymatic and hydrolytic effects of the biomedia. Although some injectable buffer preparations of peptide-in-polymer drugs are in the form of microparticles or as implants; They are well-known products; The satisfactory release of the peptide was practically found in a very small number of cases. Important parameters must be taken to obtain a sustained release peptide© to reach a therapeutically effective concentration of the drug in the blood. If necessary, very high concentrations of the drug in the blood serum, which may cause undesirable side effects, should be avoided. The mode of release of a peptide drug depends on many factors. such as the type of peptide; For example, is it present in free form or is AT form, such as salt form, which can affect its solubility in water and as an important AT factor is to choose the polymer from the extended list of available polymers mentioned in the references.

.

Each polymer has its own biodegradation rate. It is possible to form Sa carboxyl groups that are responsible for the pH value of the polymer and thus increase the water solubility of the peptide and thus its release.

other factors that can increase the release of the stored preparation; It is the loading of the drug 0 on its polymeric carrier The method of its distribution in the polymer The size of the molecule and the shape of the molecule in the Alla implant; And also the position of the preparation in the affected body. To date, no somatostatin component in an extended-release form has reached the market; Possibly due to the lack of access to a product that has an acceptable ratio in blood serum. Polymer preparations used with drugs designed to give an extended or delayed release of a drug are known preparations in this field.

(se) illustrated US Patent No. 7777919 regulated release preparations in which col gal dispersed a drug form from a water-soluble peptide; In a polylactide-co-glycolide or straight-chain polylactide polymer, it is biodegradable and biocompatible. No drug release methods have been described, nor is there any reference to somatostatin release. chall patent

1 US No. 479720749 Antibacterial preparations in the form of microparticles.

Sel describes US Patent 71781849; Extended-release preparations of LHRH analogues (LHRH) decapeptide nafareline and LHRH analogues in lactide poly-co-glycolide copolymers. The release method was not described. Described by T. mild in the Journal of Bioengineering; fragment 1 p.m. (T.

Chang, J. 59756 7-701 (Bioeng., Voll, pp. 25-32, 1976) v. Continuous release of biomaterials, clad, and particulate vaccines. Cel yy US Patent No. 507797948 and EVVAEY _lactic acid copolymers/copolymers, lactide/glycolide copolymers and related formulations for use in surgical applications and for extended release and biodegradability. Yo European Patent Application No. 1,707,071 described a series of eight peptide analogs of somatostatin; like. Compound 20-160 has the formula: x « D- Phe- Cys- Tyr- D- Trp- Lys- Val- Cys- Trp- NH;

, ¢ It has a communication bridge between Cys molecules (Cys columns ATV). The possibility of encapsulating somatostatins in Air capsules with the poly-MEY polymer-Co-ad Sila was mentioned in Claim No. VA, but it was not List any instructions that describe how to obtain a therapeutically effective and sustained level in blood serum.° US Patent No. 5,011,717 describes that a sustained release of an antimicrobial drug, such as polymyxin B, dissolved in water, can be obtained from a thick binder such as A polylactide-co-glycolide with a small molecular weight (less than 1000) and a high percentage of glycolide content in the form of an implant When the implant is inserted into the nipple duct of a cow The drug is released within a short period of time due to the presence of a high content of A glycolide and a polymer with a small molecular weight of 0 Gilly together catalyze the rapid biodegradation of the polymer and is accompanied by a rapid release of the drug.In addition to the relatively high drug loading content contributing to the rapid release of the drug.However, neither the release methods nor the somatostatin compounds have been described.Bel yy explained EC No. 8441© that the sustained release of a water-soluble peptide from a polylactide culture can be stimulated by decreasing the molecular weight of at least part of the de polymer molecules and introducing glycolide units into the polymer molecule and by increasing the agglomerating property of the polymer block $l polymer character when polylactide-co-glycolide molecules are used; By increasing the drug loading content of the polymeric binder and by increasing the surface area of the implant. However, no somatostatin release methods were described, although somatostatin compounds were mentioned as water-soluble peptides, and no explanation was given on how all these criteria combine to produce a sustained serum somatostatin level for at least one month or one week. sel EP No. 97918 described that a sustained release of peptides can be obtained; hydrophilic peptides are preferred; for an extended period of time when the peptide is introduced into a conventional hydrophobic polymeric binder; such as a polylactide which was made more hydrophilic by inserting an old hydrophilic unit into its molecule; Jia Ethylene glycol amie 001760106817001 Polyvinylalcohol Ye polyvinylalcohol Dextran “dextran polymethacrylamide The contribution is to increase the amphipathic polymer's ability to water (make it water absorbent) by giving it All the ethylene oxide groups in Ala are polyethylene glycol units.

Free hydroxyl in the case of a polyvinyl alcohol unit or a dextran unit and with amide groups in the case of a polymethyl acrylamide unit. The implant acquires the characteristics of a hydrogel texture after absorbing water. As a result of the presence of the hydrophobic part in the polymer molecules. Somatostatin is mentioned as a water-absorbing peptide; However, the release method was not described and no clarification was given on the type of polymer suitable for this peptide, its molecular weight and the number of hydrophobic groups it should contain. UK Patent_GB 7,145,477 3 describes that a sustained release over an extended period of time can be obtained for several types of drugs; such as vitamins; enzymes; Antibiotics; blood antigens; when inserting the drug into an implant; for example; It has micro-sized particles made of a polymer of polyhydric alcohols; as glucose, mannitol; It has one -0 group or more and preferably at least Sle gare is a polylactide ester. Polylactide ester groups, for example, should preferably contain glycolide units. No Mie peptides mentioned somatostatin compounds as drugs, and no serum levels of the drug were reported. GENERAL DESCRIPTION OF THE INVENTION This invention relates to extended-release preparations” Ma preparations with microparticles 1 a lsd especially somatostatin sly in Jed celal hormonal or an analogue of somatostatin such as octreotide;. Provide satisfactory drug level in plasma. Slay in a biodegradable and biocompatible polymer such as a polymeric binder as a capsule coating. The polymeric binder may be natural or constructed. : The fine particles of this invention can be prepared by any conventional method such as the organic phase separation method, the spray drying method, or the Cua ctriple emulsion method that precipitates the polymer with the drug; Then hardening (rigidity) of the resulting product, using the media separation method or the triple emulsion method. If necessary, extended-release preparations can be in implant form. We've found a particularly useful modification to the midsection technique; To prepare fine particles for any drug. Yeo This invention also provides a method for producing a micromolecule comprising a drug in a biodegradable, biocompatible carrier.

b) addition and dispersion of a solution of the medicinal compound in a suitable solvent; like; An alcohol that does not dissolve the polymer in the solution obtained from Step A. a c) Adding an inducing agent to the medium to the suspension obtained from step b to induce the formation of fine particles. 0 d) adding an emulsifier (oily substance/water) to the mixture resulting from paragraph c to harden the fine particles; and (a) separation of microparticles.|: We also found a particularly useful modification of the triple emulsion method for preparing microparticles for any drug. Accordingly, this invention presents: 0 a method for producing microparticles; comprising: : 1 Aggressive mixing of an emulsion (water / oily substance) consisting of an aqueous medium and an organic solvent that is not miscible with water containing the drug in one medium and a biodegradable and biocompatible polymer in the other medium with more aqueous media containing an emulsifying substance or a semi-substance A protective colloid to produce a (water/Ve oily)-in-water emulsion without adding a drug-retaining substance to the emulsion (water/oily substance) or without applying any intermediate viscosity step. The organic solvent from these elements () Separation and drying of the formed microparticles. This invention also presents the resulting microparticles according to these methods. This invention also presents: - glycolides of polyhydric alcohols from 1/460 to 150/6; the polyhydric alcohol unit is selected from a group of alcohols containing a chain of *-6 carbon atoms with * to 7 hydroxyl groups and a mono- or disaccharide; A polyalcohol ester having at least ¥ chains of a polylactide-co-glycolide. b)_an extended-release preparation containing octreotide or a salt derived therefrom in a biodegradable, bioacceptable polymeric Bla. :

to

We found the new pamoate salt of octreotide complex to be very stable in such formulations. This invention presents successively (1) pamoate octreotide and (7) a method for producing pamoate octreotide that includes reacting octreotide with ammonic acid or an active derivative thereof. Detailed description:

° It is preferable to use water soluble drugs such as peptides in the manufacturing methods of the preparations of this invention.

It is possible that the peptides used in the manufacturing methods and preparations of this invention

Jia “calcitonin” is salmon calcitonin, clypressin, naturally occurring somatostatin and its synthetic analogues. a

0 Naturally occurring somatostatin is one of the preferred compounds. It is a peptide that includes

It contains fourteen amino acids with the formula:- ' Ala-Gly-Cys-Lys-Asn-Phe-Phe-Trp A A

0 This hormone is produced by the hypothalamus gland in addition to other organs Jia the alimentary canal; Its secretion, in association with J dale (growth hormone releasing hormone) (GRE), stimulates neuronal control of the release of growth hormone from the pituitary gland. Somatostatin is an effective inhibitor of a number of systems; jali central and peripheral nervous system; gastrointestinal tract and vascular smooth muscle; This is in addition to its ability to inhibit

© Release of growth hormone from the pituitary gland. Lady inhibits the release of insulin and glucagon. The term “somatostatin” includes derivatives and analogues of this hormone. Derivatives and analogues show the structure of straight-chain polypeptides containing bridges or cyclic ones in which an amino acid unit or one has been deleted. more and/or substituted by one or more other amino moieties and/or where one or more Aled groups have been substituted by one or more other active groups and/or one or more de gana groups or JSTs with isodistributed molecules are substituted Electronic General; the term includes all

A

Therefore, the analogs that support the effectiveness of somatostatin are useful as alternatives to natural somatostatin in terms of its effect on regulating physiological functions. The preferred known somatostatin compounds are:- * * (D)Phe- Cys-Phe-(D)Trp-Lys -Thr- Cys-Thr-ol (1 0 * * (D)-Phe-Cys-Tyr—(D)Trp—Lys-Val-Cys-ThrNH, b)* * (D)Phe- Cys- Tyr- (D)Trp- Lys- Val- Cys- TrpNH,, c) 0 po * 1 * (D)Trp- Cys- Phe- (D)Trp- Lys- Thr- Cys- ThiNH, d) * * (D)Phe- Cys- Phe- (D)Trp- Lys- Thr- Cys- TheNH, ) * * Ve 3-(2-naphthyl)-(D)Ala- Cys- Tyr- (D) Trp- Lys- Val- Cys- ThrNH, (s* * (D)Phe- Cys- Tyr- (D)Trp- Lys- Val- Cys-B- Nal- NH, (J* * 3-(2-naphthyl) )-Ala-Cys-Tyr-(D)-Trp-Lys-Val-Cys-B-Nal-NH, cc * *(D)Phe-Cys-p-Nal-(D)Trp-Lys-Val-Cys - Thr- NH, i) Where in each compound from (a) to (i) there is a bridge between the amino acids marked * as shown in the following formula. Other preferred somatostatin compounds are:- Yo

ho oo

H-Cys—Phe—Phe~(D)Trp—Lys—Thr—-Phe~ Cys—OH

a . (See published EP No. 1795 and Application No. 445.5 AVA 001: * * MeAla—-Tyr—-(D)Trp—Lys—Val— Phe (See Ferber con Aly Life Sciences 4) pp. 1778-1771 Life (Y3ASR) Mullah Verber et “Sciences, 34, 1371-1378 (1984) and EP_Application No. 87105706.6 0. (Publication urge No. (Vo 71) Lin is known as a cyclocyclic compound, Val Phe. Ala (see RFnet et al.; Klein. and Kinsker (RF.

Nuttetal,. (1 Gal) 14 (VIAT) Klin.

Wochenschr. (1986) 64 (Suppl.

VII) - * * Cys - His - His - Phe -Phe (D)Trp - Lys - Thr - Phe - Thr - Ser - Cys - OH - 11 (see European patent application 0108748 ). Where X denotes a cationic anchor, in particular * * Ac-hArg(Et,)-Gly- Cys—Phe-© -Trp-Lys—Thr—-Cys— NH, ' 7 (see patent application European No. 17 17584.). Where there is a bridge between the amino acids marked with * mentioned earlier. The term 'derivative' also includes appropriate derivatives bearing a residue of a sugar when somatostatin carries a residue of a sugar preferably combined with an amino group at the N-terminal (last) and/or with at least one amino group present in the pls peptide chain It is more preferable that they bond with a YO amine group at the terminal 17. These compounds and methods for their preparation are described for example in International Patent Application No. 71787 (WO 88/02756) + AA[+

Ve The term 'octreotide derivatives' includes those compounds which contain the *: * fragment bridging between an amino acid residue —D-Phe—~ Cys—Phe-DTrp—Lys—Thr— Cys-

Cys derivatives in particular are:

N*[a-glycosyl(1-4-deoxyfructosyl ]- Dphe-Cys-Phe-DTrp-Lys-Thr-Cys-Thr-ol 0 3

N® -[B-deoxyfructosyl] ]- Dphe-Cys-Phe-DTrp-Lys-Thr-Cys-Thr-ol preferably in the form of an acetate salt (Cys each containing a bridge between the 0 amino acid moieties: Somatostatin compounds can exist, for example, in free form, in the form of salt, or in the form of complex compounds thereof. For example, organic acids, polymeric acids, and inorganic acids. The salts resulting from the addition of Da compounds include acids, for example, hydrochlorides and acetates. Complex compounds1 somatostatin are formed by adding inorganic substances, for example, inorganic salts or hydroxides such as calcium salts and zinc and/or by adding polymeric organic materials. Acetate salt is preferred for such formulations, especially for fine particles, and it leads to a reduction, especially for implants, of the release of the first amount of the drug. Ye Bamoate can be obtained in a conventional way, such as the reaction of ammonic acid (pamoic acid) with an eg octreotide in the form of a free base.The reaction can be carried out in a polar solvent at room temperature.The use of somatostatins is recommended in the treatment of disorders Of Lk ssl ve for use in the treatment of acromegaly disorders, for example in the treatment of ossification of the extremities “GH-harmone”, ulcers of the gastrointestinal tract and their prevention, and intestinal fistula gle in Oa digestive; lal

1 11 enterocutaneous fistula and pancreatic ela pancreaticocutaneous fistula _irritable bowel syndrome irritable bowel syndrome A disease of rapid emptying of the contents of the stomach into the intestines, accompanied by a decrease in the level of glucose in the blood al Jew! ela “dumping syndrome” watery diarrhea inflammation | (uly Sid) Acute pancreatitis and endocrine tumors of the digestive system 0 (such as benign adipose tissue tumors cvipomas Tumors with increased secretion of SU factor (growth hormone dL) GRFomas with excess JA glucagon 0005] ; Tumors accompanied by increased secretion of insulin 03011000028 Tumors accompanied by increased secretion of gastrin cgastrinomas carcinoid tumors in addition to gastrointestinal bleeding 1 gastro-intestinal bleeding breast cancer cbreast cancer and complications 0 | associated with diabetes mellitus can be prepared Polymeric carrier of biocompatible and hydrodegradable polymers such as straight polyesters; Branched polyesters are nl straight chains of a polyhydric alcohol moiety; as glucose other esters of polylactic acid glycolic acid caddie polyhydric butyric acid; polycaprolacthone polyoxalate alkylene; Polyalkylene glycol esters of the kreb's cycle 0 for example; citric acid cycle and its analogues and copolymers thereof. The preferred polymers of the present invention are the esters straight poly and branched chain poly esters. Straight polyesters can be prepared from alpha hydroxy carboxylic acids; For example, lactic acid and glycolic acid; by double lactone condensation; See JE in US Patent No. YVAN To | Preferably the polylactide-co-glycolides used traditionally according to the invention have an Aida weight between veer, ree 75.0055 and a polydispersity degree polydispersibility Mw/Mn between 0.1 and 7, for example. The preferred branched polyesters used according to the invention can be prepared using polyhydric compounds such as polyhydric alcohols such as; glucose or mannitol as a starting material. These vo_esters of polyhydric alcohols are compounds known and described in ely of British invention GBY, 1 £0,£YYB The polyalcohol has at least ¥ hydroxyl groups and has a molecular weight of Yoyo and is at least 1 Preferably at least oF, for example, on average

bin ¥ hydroxy groups of a polyhydric alcohol; In the form of esterification groups containing poly-co-lactide chains or poly-lactide chains and glucose 0,7 7 is used as a starting material in the modular polymerization process. The structure of the branched polyesters is in the form of a star. The preferred polyester chains in straight or star-shaped polymer compounds preferred to be used according to 0 of the invention are alpha-carboxylic acid copolymers; lactic acid and glycolic acid; or from a double lactone. The molar ratios between lactide:glycolides range from 5:75 to Ma 0:08£0114 to 10:46 with 45:80 to 00:80Me being the most preferred from §000 to 6 ! Star polymers may be prepared by reacting a polyhydric alcohol with a lactide, preferably also a Z0 glycolide, at an elevated temperature in the presence of a catalyst, in the presence of which facilitates the ring-opening polymerization. We have found that there is an advantage to the presence of the star polymer in the formulations of this invention, which is that it can have a large molecular weight; which gives a natural stability a certain hardness; For implants and microparticles, which prevents their adhesion with the intestine, despite the presence of somewhat short AY chains that lead to a rate of biodegradation of the polymer. which can be controlled to range from a few weeks to a month or two; and as it leads to a sustained and identical release of the peptide for which dang the buffered preparation made from it is appropriate; For example, to launch for a month. Star peptides preferably have a basic molecular weight in the range from 00000 to Yaa: preferably from 19,000 to 0000608 especially from 75,060 to 0.0060 and a degree of Ye | Mia polydispersity from 17 to “ex. From 7 to 1.0 the intrinsic viscosities of the star polymers having a molecular weight of 9.0005100 and a molecular weight of 10.0050 are dlig 1.501 and 177 in chloroform (where dl = 100 mM) respectively . The star polymer with a basic molecular weight of 07.0080 has a viscosity of 1476 01/8 in chloroform. Terminology is a fine ball; Aids capsule and ALE micromolecule are interchangeable and denote the encapsulation of ve peptides in capsules by the polymer preferably with the peptides dispersed in the polymer which is a binder ial In this case it is preferable to use the terms microball or micromolecule iS inclusively .

VY

As in this invention; The “phase separation technique” can prepare preparations of the present invention; eg by dissolving the polymeric support in a solvent; The peptide is then insoluble by the addition and dispersion of a solution of the peptide in the polymer-solvent mixture. A catalyst was added to the medium, such as liquid silicon; Inducing the encapsulation of peptide into capsules by polymer. Sudden release of the drug can be reduced. by local deposition of very fine drug particles; By adding a drug solution © to a polymer solution prior to the medium separation process. The previous method involves adding dry particles directly to the polymer solution. The method [buffering fine particles by emulsion of a buffer solution] comprises the former a hardening step; This is then followed by a subsequent washing step; or followed by a separate aqueous washing step. 0 | water to wash and harden the microspheres to remove non-fu peptides) An emulsion of the encapsulated type can be used. Washing removes the unencapsulated peptide from the surface of the initial drug microspheres. Excess peptide removal reduces microballoons; From the initial surprising effect of the drug, characteristic of many traditional preparations encapsulated in capsules. Therefore, it is possible to reach a burst to a consistent release of the drug within a certain period, for microball preparations ve

Sad The emulsifier also contributes to the removal of residual polymer solvent and silicone liquid. The emulsifier can be added to the polymer and peptide mixture or the mixture can be added to the emulsion. It is preferable to add the polymer and peptide mixture to the emulsion. The oil/water emulsion can be prepared using an emulsifier such as sorbitan mono-oleate Y. and the like to obtain ICT produced by Etihad Span 80 A+ (Span sorbitan mono-oleate 200- a stable emulsion The emulsion can be regulated by a pH buffer solution that is harmless to the peptide and the polymeric bonding material, and it is preferable to use a detrimental buffer solution. pH ;., A to 1” between acetate buffer cphosphate buffer acidic solutions such as Yo buffer phosphate solutions and the like. Water alone can replace the buffer solution.

1¢ heptane can be used; hexane and the like as an organic medium for the buffer solution; The emulsion may contain dispersants such as silicone oil. The preferred emulsion includes heptane; Phosphate buffer solution with pH ef silicone oil and sorbitan mono-oleate if we want to get a first release of the drug; © can be substituted for a solvent-free quenching step; by emulsion hardening. Heptane, hexane, and the like can be used as solvents. Other alternatives to the oil/water emulsion may be used to harden the microcapsules; Such as:- using a solvent plus an emulsifier to harden the microcapsules without washing; solvent addition. . day: into an emulsion for hardening, then a separate washing step. Ve |V oil/water emulsion can be used without a dispersion. prevent dispersant; Dry particles aggregation of microcapsules as a result of electrostatic electricity 81800 and helps reduce residual solvent percentage. Examples of solvents for a polymeric binder include; smethylene chloride, chloroform, benzene, ethyl acetate, and the like. It is preferable to dissolve 0 peptide in an alcoholic solvent eg; Methanol that is miscible with the polymeric solvent. of pall | induced medium (Clyde a(coacervation agents) mixed with the polymer-drug mixture; causing the formation of primitive microcapsules before the hatching process; silicone oils are preferred as media promoters. An oil/water emulsion can be prepared conventionally using (igs hexane and the like) © of the organic medium. Also, the fine particles of this invention can be prepared by the well-known spray-drying method according to this method. The whole of somatostatin or a solution of peptide is mixed in an organic solvent; Da in methanol; in water or in a buffer solution Sle pH 4-7 with a solution of the polymer in an organic solvent immiscible with the first solvent, eg methylene chloride The resulting solution, the suspension or emulsion, is sprayed as a mist in a stream of air; preferably Hot air The resulting fine particles were collected, for example, by means of a cyclone device “070100. And they were washed, for example, in a buffer solution, for example, that has a pH number from 7 to A, and it is preferable that the number be

vo | pH; or sla distilled and dried in a vacuum atmosphere, for example. At a temperature of 10 to 0 C. The washing step can be applied; If a sudden release of drug molecules into the body appears undesirable. A buffer acetate solution can be used as a buffer solution. (Sa) obtaining microparticles accordingly; having an enhanced release of somatostatin into the body. Therefore, the invention relates to microparticles prepared in this way. The invention additionally presents an extended-release preparation prepared by mixing somatostatin or a solution of somatostatin in methanol or in water or in a buffer solution having a pH of 4-7 and a solution_ of polylactide-co-glycolide in methylene chloride; then spraying the solution formed as an emulsion or suspension of 0|somatostatin in the polymer solution in a stream of hot air; then The microspheres were collected and washed in a buffer solution having a pH of 0 to FA in distilled sla and dried in a vacuum at a temperature of 10 to 00 C. Compared to fine particles; prepared according to As for the “phase separation” method, the first one does not contain silicone oil, even if small amounts of it, as no silicone oil was used in the spray drying method. emulsion procedure In the typical method, a peptide such as octreotide is dissolved in a suitable solution such as oll and completely emulsified in a solution of polymer such as 50/50 L-D (lactide-co-glycolide) polyglucose in a solvent; enfin does not dissolve) like methylene chloride. Examples of solvents include: polymer bonding methylene chloride, chloroform; ethyl acetate benzene and the like. Also in addition to Ye | that emulsified; water/Wo Cu emulsion) produced in more water; contains an emulsifier; For example, an anionic or non-anionic igs surfactant, lecithin, or Jie protective colloid, gelatin, dextrin, carboxymethylcellulose, polypyrrolidone. dl JsaS cpolyvinylpyrrolidone polyvinyl chloride; Which provides continuous triple emulsion production (water/oil) YO. Fine particles were formed by natural precipitation of the polymer and hardened by evaporation of the organic solvent. Gelatin contributes to preventing agglomeration of microspheres. The supernatant was decanted (transferred from a container

to another to filter) after the sedimentation of the fine particles, and the fine particles were washed with water and then with an acetate buffer solution. Fine particles were filtered and then dried. The peptide can be directly dispersed into the polymer solution and then the resulting suspension is mixed with the gelatin-containing aqueous medium. ° The triple emulsion method was known by Bell, US Patent No. 4707187. According to this patent in an initial step fully mix the drug solution (1) in a solvent; such as somatostatin in the slo (oF) column lines (PYF) with a further polylactide-co-glycolide solution (7) in the aT solvent It does not dissolve in the first solvent such as methylene chloride to produce an emulsion (1) of the type water/oil W/o consisting of very small droplets containing the drug from (1) in a solution of (AY) to "1" In addition to that, I dissolved in the solution (1) what is called a drug-retaining substance, substance (0 line column (¥) “oils Jia” albumin pectin 00h06 or –agar Jal In the Ali step, the viscosity of the inner medium (1) was increased by appropriate methods such as heating, cooling, changing the pH, adding metal ions, or by cross-linking, for example, gelatin with an aldehyde. In the cE step, more water was mixed completely with water/oil emulsion (7) (column 0Y vo) to produce a three-layer water/oil/water emulsion. It is possible if necessary to have a so-called emulsifier in more water (column 7; line 0 (“Selected from the group containing anionic or non-ionic surfactants; Ma polyvinyl pyrrolidone polyvinyl alcohol or gelatin. In step Aad the water/oil/water emulsion is subjected to “drying-in-water” (oF haw) This means mixing the organic solvent into the oil bed to produce the fine particles. The desorption process was carried out in a way known by itself (column A (lines of (0=F)), for example. By reducing the pressure during stirring (column A (lines of Y=0) or Wa by pumping nitrogen gas through the oil layer (eg methylene chloride) (line ?1). The formed fine particles were recovered by centrifugation or filtration (lines YY=Y1 vo) and non-polymer constituents were removed by washing with water (line YS). If necessary Bs microparticles under reduced pressure to achieve dual dehydration (Jie) cuddly removal of methylene chloride from the microparticle wall) (AFF lines

L While the foregoing method is considered acceptable for the production of Wy preparations of this invention; However, the so-called drug-preserving substance mentioned above is gelatin; albumen; Pectin or agar is still present in the resulting fine particles. We have now found that when avoiding the addition of drug residue (= in solution 1) and the step of increasing the viscosity of the inner medium; and in the presence of more water for a water/oil/water emulsion and maintaining the procedure for adding emulsifier or colloidal preservative Jie Gelatin; WHY UE obtains acceptable fine particles.In addition, the fine particles do not contain any col pall residue and contain only a small amount of methylene chloride.Therefore, the invention presents a method for producing fine particles prepared by the complete mixing of follows:- 0 | a) _ a solution of a medicine; Somatostatin, especially octreotide, is preferred in aqueous media; Water or buffer solution is preferred; Preferably a ratio (weight/volume) of 18 to ;g/1 to AMAT especially V0 fY,0 and in a buffer solution having a pH of AY especially an acetate buffer solution; and b)_ a solution of a polymer; Preferably poly-lactide-co-glycolides; As previously mentioned in an organic solvent that is immiscible with the aqueous medium; Bia methylene chloride; It is preferable to have a ratio (weight / volume) of 0 mg / 0 to 0 milliliter, especially 001/560. VU) and the ratio (volume/volume) of the aqueous medium/organic solvent from (1.00) to (Fe) and especially 1/01 completely mixes the emulsion: water/oil from () in (b) with a | “c) _more aqueous medium; Water or a buffer solution such as an acetate or phosphate buffer solution is preferred; Preferably a pH of AY containing an emulsifier or colloidal preservative preferably at a concentration of 1.01 to 775 in particular gelatin; Especially at a concentration of 1.1 to TY and in particular 70.5 by weight; It is preferable at a volume/volume ratio of de pd to mix a b (/ =) from 1 01 to 001 especially oY yo without adding any drug residue to the water/oil emulsion or applying any intermediate step To increase the viscosity, it is possible to harden the primitive microparticles in a water/oil/water emulsion

Ya

preferably by evaporating the organic solvent; methylene chloride is preferred; and by separation; optionally by washing with and drying the resulting microparticles directly in the polymer solution; After of gall this invention also presents a different method; In it, the dispersed was mixed by mixing the dispersed solution with the aqueous medium containing gelatin. The fine particles produced by these methods. Like the prepared microparticles Lad presents the invention > they do not contain silicone oil; In comparison with spray drying according to the spray drying method, fine particles prepared according to the triple emulsion method; It does not contain any amount of the substance: the preservative colloid. Extended-release preparations can also be manufactured by other methods known by themselves, for example, in the event that the peptide is sufficiently stable to produce an implant; By heating peptide-containing microparticles such as 0-somatostatin in polylactide-co-glycolides. especially as previously described or a mixture thereof yielded to 100m by extraction and then 71m by addition of peptide and polymer; At a temperature for example. Who. compact block cooling; Then the formed block is cut by extraction and optionally washed and dried. These preparations are produced according to this invention in a sterile atmosphere. Long-acting preparations containing octreotide can be given to all cases that require

ATA p. 03719948745 A Use of octreotide or its derivatives; Such as those described in 0 - breast cancer, as well as cases of ossification of the limbs and breast cancer, to 1. The diameter of the fine particles can range accordingly. The invention is from approx. Norchem 010 to 01 from JAY to 01 especially from Feo to 01 and preferably from Norchem 100 to 10cm. The amount of medicine in the formula depends on the dose 1 be The size of the cultures, for example, to be released throughout the day and the rate of biodegradation of the polymer contained in the capsule shell. Yo The amount of peptide can be accurately determined using bioavailability tests. It may contain

Preparations on a peptide in an amount of at least oY preferably v0 to 7710 by weight for the polymeric binder; * to 01 and especially IY 77 by weight are preferred. The release times for the peptide from the micromolecule range from 1 or 2 weeks to approx

° when the extended-release preparation containing somatostatin is administered, for example, octreotide, in a biodegradable and biocompatible polymeric support; appropriately into a mouse by subcutaneous injection at a dose of somatostatin 10 mg per kg of animal weight; The concentration of somatostatin in the blood plasma is at least “.

ve | In another appropriate alternative manner, when administering an extended-release preparation containing:

somatostatin; eg octreotide in a biodegradable, biocompatible polymeric carrier to rabbit by intramuscular injection at a dose of *mg per kg of animal weight; The somatostatin concentration is at least 0.7 ng/mL over a period of 00 days and appropriately 0*ng/mL at most. :

vo also depends on the preferred traits of the resulting somatostatin; for example, buffered preparations containing octreotide; On the manufacturing methods used: - Phase separation technique Jaws of rabbit: #mg of somatostatin / kg,؛ Intramuscular slowed release (0-7; day) 771

Y | Mean drug concentration in plasma (0-??day) ? nanograms/milliliter

(compared to control) AUC (0-??; day) fal ja gE Ve milliliters x days Spray drying technique Rat: 10 mg somatostatin/cpa by subcutaneous injection

Ives (ag) slowed release (0-7; ve ng/mL 1-4 ng) Mean drug in plasma (0-7; (compared to typical) 7 ng/mL » days 1171-01 The area under the curve (zero-??; day).

Xo Rabbit: *mg somatostatin/kg; Intramuscular injection

Ives slowed release (0-?; day) −1 ng/milliliter days (ag £7 iia) Mean drug in plasma (as compared to control) in milliliters * days fal pa SY 50-701 (ag) The area under the curve (0-; 0

Triple emulsion technique Subcutaneous injection pas Rabbit: 10 mg somatostatin/: Ives (as slowed-release (0-'7); -1.5 ng/mL (ag) Mean percentage of drug in plasma (0-7; : (compared with control case) 0 milliliters” days / Marjonan 771-1171 (ag EY ia) curve 2a area 0” by intramuscular injection cpa Rabbit: *mg of Somatostatin/

IVES (as slowed-down release (0-47/μL fo) ja gili1,0-¥,0 (ass Mean drug in plasma (0-47/μL) (as compared to the control case) 0 milliliters” days / Marjonan 770-101 (ag AUC (zero-47/); thus, the invention also provides somatostatin preparations preferably octreotide and octreotide analogues; it has the following properties:

IAs drug delay at least 7976 preferably at least 7974 eg at least 275 or dus —) within 0 to 47 or 57 days and/or AA or at least TAA or Y. -4 Mean ratio of drug in plasma (compared to typical condition) of 1.0-7.0 preferably .-" when administered Jl ng/mL within zero to day in 2 parenteral somatostatin Subcutaneous and/or the average ratio of the drug in the plasma of #,?-0 mg per day in BY SEY, for example, -;-9 ng/mL over a period ranging from zero to 5: The rabbit when given mg of Somatostatin Intramuscularly and/or Yo

OTe *-_The area under the curve for a period ranging from zero to 47 days has a value of at least days; For the mouse. When given 10 mg of x alle fala gl 790-1170 of Jia 47 somatostatin by subcutaneous injection and/or the area under the curve for a period ranging from zero to

: YA to 001 to 975 for example. from VAL preferably from Te or; day, the value of which is at least 7 nanograms / milliliter days for the rabbit. When administering mg of somatostatin by continuous injection described previously, a deviation method (BDU) is used for the quantitative description of preparations.

FY Publisher F. Nimmervall and Jay Rosetthaler; In the International Journal of Pharmaceutics Part A.D. Area 0 (F. Nimmerfall and J. Rosenthaler; Intern. J. Pharmaceut. 32, 1-6 (YaAT) 2-1 - (1986) for drug ratios tested in area deviations This method calculates, in short, the deviations of the plasma area from the typical ratios, which are a fixed average of the plasma ratios (- in comparison with the case A__typical) resulting from converting the tested area under the test of the relationship between the ratio of the drug in the plasma - 0 10 to a rectangle having The same area, the ratio of 7 deceleration of launch, AUC time, can be calculated as follows:- The drug is in. Plasma and measured in a previously selected time period by means of a single numerical indication. natl. Acad. Sci. USA 85 (1988) 5688-5692) 7 Percentage content in plasma of the mouse eight-peptide isotype of somatostatin having the formula: * %i 3 10-18- Cys-Tyr-D-Trp—- Lys—Val-Cys-Trp—NH, in mouse. 0 and each; It is not possible to make a clear comparison using the previously mentioned data of the drug in the blood because the indicated ratio of the drug in the plasma lal for the preparations of this invention in is based on another method of giving the drug (intramuscular injection) and - and most importantly - the loading ratio to 00 mg portions of YO microcapsules) and the dose administered (475 Y microcapsules (between day and calculations can be made up to at least £0 day) is not clearly stated. This is Ye Bad YO Lactaid-Co - Polyglycolides have not been accurately described. LD in addition to the type of LD

: YY Therefore, the value of revealing this invention by publishing it is very small in relation to the result expected before: scavenging which contradicts this invention. The following examples illustrate this invention. The average molecular weight determined by 061.00 using stearine dad of the polymer It is M, as standard. polystyrene H0:1 Je. = M, lactide-co-glycolide) poly)00/00 mol; 0, 0 0 dissolved in 0.0 milliliters of methatol. Octreotide acetate then add 0/mg of octreotide acetate (RTLLM 0001 Medical 701 “Dow Silicone) of liquid type Cay Add fifteen milliliters of 0 0 contains lie (liquid silicone) to the polymer-peptide mixture The resulting mixture was added to an emulsion © 6 pH-regulated heptane-normal cling 100ml of let solution (Span 80 A+) fas medical;*0 “milliliter and ?milliliter of 700 Dow Liquid 0 emulsified”). Stirring continued for at least 10 minutes; fine particles were separated by filtration in Particle 7905 in vacuum. of air; and dried overnight in a vacuum oven. Result of approximately 1 µm. 0 to 10 min. average sizes of paat (dissolve in it) was given by intramuscular injection at a dose of dala suspended fine particles. In fluid from octreotide to New Zealand white rabbits Blood samples taken periodically showed a ratio of 71 ng / milliliter for 1 day as measured by 0.5 to 1 day of drug in plasma ranging from - Radioimmunoassay (RIA) Radioindustrial Analysis 0 46/56 45.0 lactide-co-glycolide (MALA-1, D) 1 gram polyglucose dissolved (GB YV£0£YY B mole yield According to the method described in the British patent yield of glucose (60.7 7) in ?5 mL of ethyl acetate by VY polydispersion degree of about methylol. Add five SLY magnetic stir, then add 1 mg of octreotide dissolved in Natural Yo (1000 milliliters) to mixture 700-00 and twenty milliliters of silicone oil (liquid type: keep stirring on 1.) to emulsify. Described in the example of atl polymer-peptide.The mixture was added

YY

At least for 10 minutes. The fine particles formed were separated by filtration in a vacuum atmosphere and dried overnight in a vacuum oven. He found more than 780 microparticles produced. It has 0 to 10 micron average sizes of fine particles suspended in a carrier fluid and administered intramuscularly at a dose of 0 mg octreotide to New Zealand white rabbits. Blood samples taken periodically showed levels of the drug 0

RIA a day as measured by 71 in plasma ranges from 4.0 to ng/mL for a period of time. Example ©: A solution of 0.0g* of octreotide acetate in 0?mL of methanol was added and stirred to lactide-Co(0) glycolide) (M 00100;-1.“D) from polyglucose pal AC solution of:

Ore of methylene chloride. operation done; Separate the medium by adding lll 0001 in) 45,0060 14.0 Medical 1” Dow Medical (1000 mL) and 1800 mL of 100 mL of Dow Liquid to the peptide-polymer suspension. The resulting mixture was added To a stirred emulsion consisting of (Lillo) Av collected 1 milliliter of sterile water, 56 milliliters of Span, 0001 milliliter of normal heptane; Half of the product was dried overnight in a vacuum oven at 01 ve.

JY The remaining methylene is milliliters of ethanol containing 1 milliliter of 0001. The other half of the product was washed by stirring with ethanol after stirring for one hour, and the resulting fine particles were stirred with Ae span The fine particles were collected Ar of ordinary heptane containing 1 mL of Span Rtyllum 0001 Y by vacuum filtration; After stirring for one hour and dried overnight in a vacuum oven at 7"C. The percentage of residual methylene chloride in the microparticles washed with this reduced from microparticles containing (791) pl AY. The aggregate yield was TY method The fine particles were suspended in a carrier fluid and injected intramuscularly with a dose of octreotide ©mg/kg Yo in albino rabbits. She explained Blood samples taken periodically, levels of the drug in the plasma range from what

The 59-day RIA as measured by ALL ng/VY is between “0,000 to

Ye One gram of polyglucose (©; .1-lactide-co-glycolide) molecular weight cud

B mole produced according to the method described in the UK patent (2 5 yield of glucose 70.7) in 10 mL of OY; The degree of dispersion is about GB 71077 8 magnetic and then by adding #lamgm_ of octreotide dissolved in methylene chloride by 0 for Ultra-Turax milliliters of methanol. The mixture was vigorously mixed, for example, by a centrifuge for 1,077 minutes at 70.005 revolutions per minute to form a suspension of very small crystals of octreotide in the polymer solution. The small droplets were dried in a Niro Atomizer at speed Jo, then sprayed Suspended by turbines a stream of hot air to produce fine particles. Fine particles were collected by 271008 and dried overnight at room temperature in a vacuum oven. within 0 minutes and dry again at room temperature in a vacuum oven. And after a size of 17.0 cm) to get the final product. Subcutaneously, chinchilla-bastard octreotide was administered to white rabbits (chinchilla bastard species) at a dose of 10 mg/kg to male rats. Periodic blood samples showed levels of the drug at 159 to 10 ng/mL (dose *mg). In rabbits and between 01.7 plasma ranges between

RIA ng/mL in the prothrombin for 7 days; day as measured by radioimmunoassay V © dv £ Fine particles were prepared by spray-drying in the same way as described in an example with only one change being to suspend octreotide directly in the polymer solution; Without the use of methanol. The microparticles were suspended in a carrier fluid and administered parenterally by irritating the skin at a dose of 10 mg/kg of octreotide in male rats. Blood samples taken periodically showed levels of the drug in plasma to 10 ng/mL in the two 7-year proboscis; day as measured by analysis 1.5 ranging from Yo

RIA immunofluorescence

Ye: 1 as 27,000 lactide-co-glycolides); Molecular weight LD) one gram of polyglucose dl British invention Bel of the described method_ in Wy product alga sgn 00:04) yield of glucose 750,7) in ©,? milliliters of chloride VY A polydispersion of about 77 GB of octreotide dissolved in 71.0 milliliters of de-ionized water. paaVO methylene then added 0 for one minute and at Ultra-Turax the mixture was vigorously mixed, for example by means of the Ultra-Turax device. cycles per minute (internal water/oil medium). 5 0 of de-ionized water at 0°C and cool the solution ALLY one gram of Gelatin A at 17°C (intermediate - external). Mix the medium water/oil and the medium water vigorously. So the midsection! Photograph of small droplets which dispersed homogeneously in the medium water bi BI water/oil_0 the resulting triple emulsion for one hour. Thus, methylene chloride evaporated and the outer play was reversed by the hardening of the fine particles from the droplets of the inner medium. After sedimentation of the fine particles, the supernatant part was absorbed and the resulting fine particles were separated by filtration in a vacuum atmosphere and rinsed with water to remove gelatin. 4. Drying, sieving, washing and secondary drying were done as described in the example vo. In a pregnant fluid, it was given by intramuscular injection at a dose of #mg/kg of octreotide to white rabbits (Chinchilla Bastard) and by subcutaneous injection at a dose of 10mg/kg to males of gestation. Blood samples taken periodically showed percentages of the drug in plasma ranging between ng/mL A to 1.5 mL (dose #*mg) in rabbits and between folate to

RIA a day as measured by radioimmunoassay £Y in a rat for a period of © | Example no: z Fine particles were prepared by the triple-emulsion method in the same manner as described in the example with three changes: + mL 1,976 instead of fag jue I use ©7.1 milliliters of acetate buffer solution No. 1 - to prepare the medium water/inner oil. coll from Yo Fine particles were rinsed after collection with acetate buffer solution 1 /©;

-# The step of washing fine particles was omitted again. Like A, the fine particles were prepared by triple emulsion method in the same way as described in Example V with only one change, which is to prepare the inner water/oil medium using water containing 0 Lo (w/v) of NaCl instead of a buffered acetate solution. Example 4: The particles were prepared as described in Example + with only one change, CE, to the drug compound directly in the polymer solution; Then, the resulting dispersion solution was mixed with an aqueous medium of octreotide pamoate (pad eV) of free octreotide base (10 mmol) and 2, embonoic acid (10 mmol) in 1 liter of water/dioxane. (1:1) Filter mixture (Jeli lyophilized to yield a yellow powder 0*[”] = aV,0+ (©- 0.305 in dimethylformamide 1 as solvent) from octreotide pamoate hydrate; agent- < 01.4 where factor< is the weight of the lyophilized product/the weight of the octreotide it contains Bamoate can substitute for octreotide acetate in the fine particles in Examples 1-9 and has excellent stability.

Claims (1)

Claims 1-1 A sustained release formulation comprising octreotide, its salts, or one of its Y derivatives in Jala polymeric AD, biodegradable 1 and biocompatible 1. 7?- Formula according to claim No. (1) where octreotide is octreotide acetate .octreotide acetate Y 1 7- Formula according to claim No. (1) where octreotide is octreotide pamoate .octreotide pamoate Y 1: ;- Formula of claim (0) or (7) or (¥) where the polymeric carrier is polyester x | -polyester ¥ | 01 0— release form Sustained release of claim No. (1) where the polymer is poly-(DL-lactide-co-glycolide) glucose Y-1.1 A formulation according to Claim No. (£) in the form of a small molecule where the surface is virtually free of ¥ drug compound. Methanol, water, or a buffer solution with a pH of A=Y and a solution of: 7 for polylactide-co-glycolide polymer 4 methylene chloride 4 spraying the formed suspension solution or emulsion of drug compounds in a solution of adsl stream a 0 air ill collect the small balls and wash them in a buffer solution having a pH of 1 |> ranging from AY or distilled water and dry them in a vacuum at a temperature of 00 to fr v celsius. 1 +- sustained release formula under which of the above claims is the octreotide concentration ¥ of ? to 701 by weight. 1 4- A sustained release formula according to any of the previous claims in the form of small particles having a Y diameter ranging from 1 to 0 * 0 microns. 48/00 to 50/70 polylactide-co-glycolide ester of polyol YA carbon atoms which TY select the polyol unit from the carbon chain group of , contain an alcohol with 7 to 7 hydroxyl groups and a mono or disaccharide; The mastered polyol contains at least ¥ polylactide-co-glycolide chains 1°. polylactide-co-glycolide 1 has a major molecular weight ranging from (01) sustained release formulation according to Claim No. 11-1 MM, 1 to 0117 ranging from polydispersity and a polydispersion of 000.000 to 00 y : 1?1- sustained release formulation according to Claim No. (VY) where the molecular weight ranges from een ¥ to , da -1” 1 | continuous release formula according to claims (01) A or (11) or (VY) where the range MM, Y | between 7 to Xoo : —VE 1 sustained release formula according to Claims (1) or (Ve) which when injected into the mouse vo subcutaneously at a dose of 10 mg of the drug compound per kg of weight, this shows a concentration r of the drug compound in blood plasma of at least 1.7 ng / milliliter and less than 01 ng / 1 milliliter during a period of 71 days. =V0 1 sustained-release formulation according to Claims No. (1) or (01) which when injected into rabbit Y intramuscularly at a dose of © mg of the drug compound per kg of weight, it shows a concentration of v The drug compound has a percentage of at least oY nanograms/milliliter and a maximum of 10 nanograms/milliliter during a period of 00 days. Which when injected into the rabbit intramuscularly at a dose of 1 mg of the drug compound per kg of weight, it shows (Ble) retardation 1 of at least 770 in a period ranging from zero to 47 days. 17-1 A continuous release formulation according to Claims No. (1) or (01), which when injected into rat Y subcutaneously at a dose of 10 mg of the drug compound per kg of weight, shows that the average v The ideal plasma Cp level) is from *.7 to 0 ng/mL over a period of 0 ¢ to Lag £Y Ye -108*1 sustained-release formulation according to Claims No. (1) or (01), which when injected into rabbit Y intramuscularly at a dose of mg of the drug compound per kg of weight, shows that the average level of ¥ The ideal plasma Cp is from 2.8 to *, ng/mL. 11-1 A continuous release formulation according to Claims No. (1) or (01) which when injected into a rat | 0 under the skin at a dose of 10 mg of the drug compound per kg of weight, this shows that the area v induces the curve AUC ranging from 001 to 7700 ng / milliliter for a period ranging from zero to £Y or 7 days . -00 1 sustained release formulation according to Claims No. (1) or (01) which when injected into the rabbit Y | intramuscularly at a dose of 1 mg of the compound of the drug per kg of bodyweight, this shows that the area: r under the curve AUC ranged from 061 to 770 ng/mL for a period ranging from zero to Vf 7 days. 71 1 sustained-release formula according to any of the above elements includes octreotide for use in the treatment or prevention of acromegaly or breast cancer. 1 ??- octreotide-pamoate. Octreotide- pamoate 1 7 ?- Process for the preparation of octreotide-pamoate Cua octreotide-pamoate Octreotide Y is reacted with embonic acid or one of its reactive derivatives.