TWI376241B - Pharmaceutical compositions with enhanced stability - Google Patents

Description

1376241 IX. Description of the Invention: [Technical Field] The present invention provides a controlled release delivery system that is stable as a peak agent. Knife-dissolving polymerizing filaments, there are [previous techniques] In recent years, a large number of various teams have been discovered, such as "peptides, oligopeptides, polymorphisms, and proteins", and are regarded as ——^ ^ The agent is not a variety of peptide agents; the second is easily hydrolyzed or decomposed by the enzyme in the living body, and has a very short cycle = life cycle. Therefore, most of the drugs are administered by injection, usually for each time. However, the pain of injection administration is very expensive and inconvenient. Usually patients are difficult to comply with non-books. A variety of peptide agents, especially & Bellow, require a drug that is delivered at a controlled rate for a long time, so it needs to be controlled. Release delivery system. This system can be obtained by combining a peptide agent with a biocompatible material and a biocompatible polymer matrix. In one method, the polymer is soluble in an organic solvent and then with the peptide agent. Mixing, by removing the organic solvent, the preparation is made into microcapsules, microparticles, or an implantable strip. The peptide agent is packaged in the polymer matrix, and the biodegradable polymer is used as a microparticle and a solid strip. A variety of products in the form of inputs have been successfully developed, such as Lupr〇n, z〇iadex,

Triptorel in and so on. Although this is not effective, the two DPs are clearly effective, but they have shortcomings and limitations, such as a large amount of suspension for microscopic or surgical insertion of solid implants. These products are not comfortable for the patient. Moreover, the manufacturing process for producing sterile regenerative products is cumbersome, resulting in high manufacturing costs. Therefore, it is eagerly desired to make a solution of 1166-8751-PF; Ahddub 5 J^241 and the composition used. • In another method, the biodegradable polymer and the peptide agent are dissolved in a biological .* compatible organic solvent to form a liquid composition. When the liquid composition is injected into the body, the solvent is dissipated in a surrounding water-soluble environment, and the polymer forms a solid or a colloid to release the bioactive agent for a long period of time. The following reference is made to US Pat. No. 6,565,874; 6,528 , 080; RE37, 950; 6, 461, 631; 6, 395, 293; 6, 355, 657; 6, 261, 583; 6, 143, 314; % 5,990, 194; 5, 945, 115; 5,792, 469; 5,780, 044; 5,759,563; 5,744,153; 5,739,1 76; 5,736,152; 5,733,950; 5,702,71 6; 5, 681, 873; 5, 599, 552; 5, 487, 897, 5, 340, 849; 5, 324, 51 9; 5, 278, 202; 5' 278, 201; and 4, 938, 763 are considered representative of the art, which is incorporated herein by reference. Even with a few successes, the above methods do not fully satisfy most peptides, allowing them to be effectively delivered. It is well known in the art that a biofunctional agent containing a base functional group, in combination with a biodegradable polymer, catalyzes (or promotes) decomposition of the polymer to form a conjugate with the polymer and/or its decomposition products. . The interaction between the alkali bioactive agent and the polymer carrier may occur in: when the biologic agent is formulated with the polymer carrier, such as microencapsulation, injection molding, extrusion molding, in organic When the solvent solution is mixed with the polymer solution, etc.; 2) when stored; and 3) when the biodegradation process in the living body and the bioactive agent are released. It is known that the disintegration and reaction of a peptide agent with a biodegradable polymer generally occurs more rapidly in a solution than in a dry, solid environment. The interaction/reaction of a bioactive agent containing a functional group such as an amine with a polymer in the formation of a microparticle U66-8751-PF using a solvent evaporation/extraction method; Ahddub 6 1376241 has been disclosed, wherein the bioactive agent Dissolved/dispersed with a polymer in a non-polar organic solvent [Ten and Flanagan DR., j Control Release. 2000 Nov 3; 69(2): Formation of a significant amount of the guanamine moiety. It is clearly shown in the delivery system. The solvent used in the manufacture of the biodegradable polymer allows rapid reaction between the bioactive agent and the polymer. It has also been reported that organic amines in polar aprotic organic solvents accelerate the disintegration of polymers [Z/Knife Flanagan DR, Linhardt RJ. Pharm Res. 1994 Jul; ll(7): 1030-4}. Since the controlled release delivery system is generally manufactured by the step of dissolving/dispersing the peptide agent in the biodegradable polymer solution in an organic solvent, the stability of all units in the combination of this step exhibits a very significant blending challenge. A method generally used to overcome the manufacturing and storage stability of a peptide agent and a biodegradable polymer in a solution or suspension. n The peptide agent and the polymer solution are stored in two different containers and mixed prior to use. This method assumes that the organic solvent can be rapidly separated by diffusion, extraction or evaporation after the peptide agent is mixed with the polymer solution. As disclosed in U.S. Patent Nos. 6,565,874 and 6,773,714, the disclosure of a commercial product for the treatment of prostate cancer, E1 i(10)8, is a polymeric delivery formulation of leupr〇1 lde acetate, wherein the product is administered as an individual in order to maintain the stability of the formulation. It is provided that the contents of the injection are mixed prior to use. However, because of the viscous properties of the polymer formulation, it is often difficult for the final user to mix the contents of the two injections. Finally, the formula prepared by the user may be significantly different. 'Pollution may also occur, which may significantly affect the quality of treatment. And 1166-8751-PF; Ahddub 1376241 - and this method can not avoid the interaction between the peptide agent and the polymer in the mixing and administration. As disclosed in US20060034923 A1, when octrexide acetate is combined with polylactic acid-glycolic acid copolymer solution in NMP, more than 40% of the octreotide is present in Ethyl acetate within 5 hours. Modification of the peptide can result in significant loss or alteration of the activity of the immunogenicity. At the same time, the molecular weight of the polymer is also significantly reduced. Rapid disintegration of the peptide with the polymer will alter the release profile of the peptide and affect the therapeutic outcome. Therefore, precise control of the manufacturing process and time is critical and this will significantly increase the difficulty for the end user. Moreover, the formation of an implantable polymeric composition implant in a living body is not instantaneous. In general, this solvent dissipative process can occur from hours to days depending on the solvent used. During this time, the presence of an organic solvent also promotes the interaction/use of the peptide agent with the polymer. There is therefore a need to develop pharmaceutical compositions that avoid or minimize the parental interaction/reaction of the peptide agent with the polymer in an organic solution. Further, there is a need to develop a pharmaceutical composition that satisfies a satisfactory storage half-life period in a ready-to-use (t0_use) product structure. SUMMARY OF THE INVENTION It has been found that an injectable biodegradable polymeric composition containing a peptide agent which forms a salt with a strong acid such as hydrochloric acid exhibits a very high degree of stability compared to a polymeric composition which forms a salt with a weak acid. The peptide salt can be formed by neutralization of any peptide base with a strong acid. When the peptide salt formed with a strong acid is formulated as a biodegradable polymeric composition which is oxidizable, the interaction/reaction of the peptide agent with the polymer can be avoided or minimized. The use of peptide 1166-8751-PF formed from a strong acid; Ahddub 8 1376241 probiotic salt allows for the preparation of a stable injectable composition with satisfactory ready-to-use filling in a single syringe Storage stability. The use of a strong acid to form a peptide salt of the present invention to promote the stability of the injectable polymeric composition is not considered in the prior art. Accordingly, the present invention provides a stable injectable biodegradable polyδ composition for the economical, practical and effective controlled release delivery system for forming a peptide agent. The invention also provides methods of making and using same. According to the present invention, the drug delivery system is easy to manufacture and facilitate delivery to an individual, such as a mammal or a human. The composition delivers a therapeutic amount of the peptide agent for an extended period of time, preferably from a few weeks to a year. This composition is biocompatible and biodegradable and disappears harmlessly after delivery of the peptide dose. Salt, avoiding interaction between the peptide agent and the polymer in an organic solution. The composition of the present invention is packaged with a strong acid form.

Shoot. The pharmaceutical composition can be first filled in a ready-to-use product. Body, so you can use a syringe to inject a syringe into the

The peptide agent may also be any peptide, oligopeptide, or any peptide, oligopeptide, polypeptide, or protein disclosed in the literature or its technology, which is stimulating or inhibiting the animal or human. Biological activity in animal or human body or 1166-8751-PF; Ahddub 1376241 According to the invention, suitable release rate modifiers include amphoteric compounds or copolymers, such as alkanoic acids, oleic acid, alkyl alcohols, polar lipids, interfaces Copolymer of living agent, polyethylene glycol and polylactic acid or polylactic acid glycolic acid copolymer Plu polymer (P〇l〇xamers), polyvinylpyrrolidone, polysorbate, etc., single, second, third Carboxylic esters, such as 2_: ethyl ethoxyacetate, diethyl citrate, tributyl citrate, triethyl citrate, glycerol tri-* (n-butyl) hydrazine Diesters, etc.; polyalcohols, such as polyethylene glycol, sorbitol, etc.; fatty acids; triglycerides, such as triglycerides, triglycerides, such as MIGLYGL 810, 812, 818, 829 , 84(), etc. ^ is not limited to this. The release rate mixture can also be used in the polymer system of the present invention. ~ (1) According to the present invention, suitable buffer materials include inorganic and organic salts, such as sulphuric acid, hydrogen peroxide, 'smoked acid, oleic acid, succinic acid, stearic acid, calcium sulphate' Magnesium, oxyhydrin, meat citrate lock 'magnesium oleate, palmitic acid town, stearic acid lock, magnesium phosphate, carbonated words, gas oxidation words, zinc sulphate, zinc oleate, palmitic acid, Zinc stearate, zinc phosphate: and combinations thereof, but are not limited thereto. Suitable antioxidants according to the invention include "± fertility acetate

Ester, brown acid sulphuric acid ester, butyl A „ , butylated hydroxy anthranil (hydroxyanid〇le), butylated hydroxybenzyl hydroxy hydroxy ketone, coumarind, butylated hydroxy Toluene, gallic acid, propyl gallate, octyl gallate, gallic acid, laurel, tetrahydro hydroxybenzoate, trihydroxybutanone, vitamin E, PEG

Jing E or vitamin E-TPGS, etc., but is not limited to this. 1166-8751-PF; Ahddub 12 1376241 The present invention still further provides a method of making and using the composition, for example, a method of making the composition, comprising neutralizing an alkali amine group of a peptide agent to form a salt to avoid the alkali amine The interaction/reaction or enthalpy between the group and the polymer is minimized, and the beneficial salt is combined with other compositions and selective combinations or a plurality of excipients. The peptide agent is preferably formed into a salt and then A combination of polymers dissolved in an organic agent. This composition is physiologically stable in the process of controlling the delivery system (such as microparticle formation or other implantable matrix formation). The injectable composition is preferably Manufacture of physiochemically stable 'subsequent administration' in the production of a sustained release implant at the site of administration. + Praise further—~~%%, cut the set of components to form a continuous controlled release storage system The kit comprises a biodegradable polymer dissolved in a pharmaceutically acceptable solvent; having at least one amine group formed by the action of a strong acid dissolved or dispersed in the polymeric carrier a salt, and optionally one or more excipients. The mono-composition of all components is packaged in a container. The container is preferably a syringe. Therefore: Month also provides a method comprising filling the composition in a syringe, shaped A stable product of ready-to-use has been used. The present invention further provides a method for producing an implant, the method of generating an implant, the function of which is a controlled release delivery system of the peptide agent in an individual. Preferably, the sentence is added to the in situ generated implant towel, and the peptide is released in the surrounding tissue fluid and related body tissues or organs. The square is supplied in a liquid manner by any suitable method. Injecting the composition of the invention into the injection composition at the implant 'for example, syringe, needle, cannula, catheter, house force = U66-8751-PF; Ahddub 13

S 1376241 - Method of adding etc. The invention provides a stable, injectable biodegradable polymeric composition that forms an economical, practical, and efficient controlled release delivery system for peptide agents. The invention also provides methods of making and using same. The composition of the present invention comprises a) a salt of a peptide agent formed with a strong acid, which avoids interaction or reaction of the peptide agent with the polymer in an organic solution or minimizes its effect. b) Biodegradable a polymer; q) a pharmaceutically acceptable organic solvent. In the present invention, the pharmaceutical composition may optionally comprise one or more excipients to achieve the desired delivery of the peptide agent. The injectable polymeric composition of the present invention may be a viscous or non-viscous liquid, a gel, or a semi-solid such as a liquid, and thus may be injected by a syringe. Injectable polymeric composition - can be first filled in a syringe to form a ready-to-use structure (ready_t〇_use) product set. The controlled release system of the present invention can be external (7) ". (d) can: : combined with matrix, or in situ. Glue or solid implant. _ «& medicine individual' according to the composition of the implanted person's controlled release of the peptide agent ° maintains & desired time. In addition to the selected biodegradable polymer and other, the sustained release time of the peptide agent can be controlled over several weeks to one year. The phrase "a" or "," is interpreted as "one or more" and "at least _," and "stable" is also stable in the composition of the salty injectable polymeric composition. The monthly improvement must meet the steady state required to develop practical products. The stable, ruthenium, and predominantly polymeric composition of this V" composition of the AI composition such as H66-8751*PF; Ahddub 14 1376241 The polymer and the peptide agent, during the manufacturing process and after long-term storage (eg From month to year 'preferably over 12 months', under appropriate conditions, retain at least 80%, preferably at least 90% of its original molecule 1, structure and/or biological activity. After administration, after a period of desire, for a long time, it is preferably at least several weeks to one year, and the peptide is delivered in the living body.

The peptide agent is generally referred to as poly(amino acid), generally referred to as peptide, oligopeptide, and "polypeptide" or "protein." Also included is a peptide agent analog, derivative, acetylated derivative. , a glycosylated derivative, a derivative, a healing protein D agent" is a natural face peptide derived from an alkali amino acid such as arginine or lysine, "from the nitrogen end of the peptide agent, or contains at least A one-base peptide agent selective for one or more acidic amine sulfhydryl groups. Also included are synthetic analogs of peptides, non-natural amino acids with base functionality, or other forms that introduce basicity. '

c includes any calendaring agent having diagnostic and/or therapeutic properties, including antimetabolite properties, antifungal properties, anti-inflammatory properties, anti-tumor properties, anti-infective properties, avidin f, nutrient properties, agitation properties, and Antagonistic properties, but not limited to this. It is also said that the agent of 纟心明 can be any agent that forms a beneficial salt with a strong acid, in particular, a peptide containing a thiophenanthoquinone, which is known as a nitrogen atom, such as an amine or an imine. Or ring nitrogen. The peptide agent has one or more exposed amine functionalities compared to W. It can be used in this delivery month, and the peptide agent produced by the product, the hormone, the angiotensin, the kidney, the EGF, the platelet-derived growth anti-growth factor, only the u thousand (PDGF), prolactin, and 1166- 875l-PF; Ahddub 15 1370^1 Hormone promotes "Physin-releasing hormone (LHRH), LHRH agonist, LHRH phenomenological growth hormone (including human, pig, and cattle), growth hormone releasing factor,: Tengdaosu' Erythropoi auxin (including all erythrocyte-promoting active substances) growth hormone release inhibitor (soma tos tat i η), glycoside, interleukin (including IL-2, IL-u, IW2, etc.), interferon α:, dry, prime θ, interferon r, stomach hormone, four stomach hormones, five stomach hormones, urea-lowering hormone, small intestinal hormone, calcitonin, enkephalins, camphor endorphins, Vascular contractile hormone, gonadotropin releasing hormone (TRH), tumor necrosis factor (TNF), parathyroid hormone (PTH), nerve growth factor (NGF), granulocyte-colony stimulating factor (G_CSF), Granulocyte-macrophage-stimulating factor (GM-CSF), macrophage-colony stimulating factor M_CSF), heparin-enzyme vascular endothelial growth factor (VEG-F), bone morphogenetic protein (βΜρ), • hANP, glucagon peptide (GLP_1), exenatide, peptide γΥ (ΡΥΥ), Renal enzyme, vasopressin kinase, bacitracin, polymyxin, pheromone, bacillus, gramin, ubiquitin (including synthetic and pharmaceutically active fragments), enzymes, cells Hormones, antibodies, vaccines, avidin, antibodies, glycoproteins, follicle stimulating hormone, kyotophhin, taitsin, thym〇p〇ietin, thymosin, thymus stimulating hormone (thymostimulin), thymus fluid factor, serum thymus factor, colony stimulating factor, motilin, bombardin (b〇mbesin), dinophin, nervous enzyme, cerulein, urinary tract Kinase, kallikrein, substance p analog and antagonist, angiotensin II, blood coagulation factor VII and sputum, chlorfenapyr, melanin stimulating hormone, thyroxine releasing hormone, thyroxine stimulating hormone, 1166-8751 -PF; Ahddub 16 1376241 . Incretin, cholecystokinin, human placental prolactin, human chorionic gonadotropin, protein synthesis stimulating peptide, gastric inhibitory peptide, intestinal vascular, platelet-derived growth factor, and the like And pharmaceutically active fragments are not limited thereto. Preferred peptide agents of this description include those which are nitrogen-terminated non-primary amines. For example, the nitrogen end of the peptide agent is pyroglutamic acid, such as LHRH, LHRH agonists such as leuprorelin, buserelin, gonadorelin 'deslorelin',芙泰瑞林 • (fertirelin) 'histrelin, lutrelin' g'serelin, nafarel in 'triptorel in Wait. Or a nitrogen-terminal amine plus (four) or a brewing, such as cetrorelix, enfuvirtide 'thymosin' α 1, abari 1 iX )Wait. The preferred peptide agent may also include a covalent modification of the nitrogen-terminated primary amine group in the hydrophilic and/or φ lipophilic moiety, such as PEGylation, acetamidine, and the like. The peptide agent further includes covalent modification of the pendant primary amine group in the hydrophilic and/or lipophilic moiety, such as PEGylation, acetamidine, and the like. The preferred peptide agent further comprises a spontaneous covalent modification of the nitrogen-terminated primary amine group to the pendant primary amine group in the hydrophilic and/or lipophilic moiety, such as PEGylation, acetamylation and the like. The hydrophilic moiety 'is any water-soluble linear or branched chain oligomer or polymer, including polyethylene glycol and polypropylene, and similar linear or branched polymer 'but is not limited thereto. The polymer preferably has a molecular weight of from about 500 daltons to about 50,000 dartons. The hydrophilic polymerization 1166-8751-PF used in the present invention; Ahddub 17 1376241 may have a reactive group to link an amine group, a carboxyl group or a sulfur group of the desired peptide agent. This "PEGylation" is a covalent linkage of soluble polyethylene glycol to the peptide agent. Polyethylene glycol can be prepared as standard procedures, with one end fluorenyloxy attached to the crown and the other end forming a bond with the peptide activator. For example, various methods for preparing polyethylene glycol and PEGylation are described first.. Former technology: [eg Roberts MJ, Bentley

MD, Harris JM, Chemistry for peptide and protein PEGylation. Adv Drug Deliv Rev. 2002 Jun 17; 54(4): 459-76. Veronese FM. Peptide and protein PEGylation: a review of problems and solutions. Biomaterials. 2001 Mar; 22(5): 405-17 and US Patents Nos. 6, 1 1 3, 906; 5, 446, 090; 5, 880, 255, incorporated herein by reference. The 'lipophilic moiety' is any molecule which is soluble in water at less than 5 mg/ml at 20 ° C, preferably less than 0 5 mg/ml, more preferably less than 〇l mg/ml. The moiety is preferably selected from the group consisting of C2_39-alkyl 'C2 3g-alkenyl, C2 3?--dilutyl, and sterol residues. The "C2_39-alkyl, C2 39-alkenyl, C2 39-dienyl" includes Linear and branched chains are preferably linear, saturated, monounsaturated and diunsaturated hydrocarbon groups of 2 to 39 carbon atoms. The lipophilic moiety is introduced to covalently with the peptide agent to form a lipophilic modified peptide, which is more natural than a knife. And 5, can improve the therapeutic effect. Generally, it can be achieved by reacting the amine group of the peptide agent with the acid or other reactive groups of the lipophilic molecule, or reaching the peptide agent and lipophilicity via the V-force P-bridge spacer or the linking moiety. Part of the bond, the bond can be biodegradable or bioindegradable. It is disclosed in the prior art such as "p σ Un , . i and υ such as Le.g., Hashimoto, Μ., et al.

Pharmaceutical j?p〇p〇y/-.u 〇 171 1 n n .

Kesearch, 6: 171-176 (1989), and 1166-875l-PF; Ahddub 18 1376241 • Lindsay, DG, et al., Biochemical J. 121:737-745 (1971), · US Pat. No. 5, 693, 609, WO95/07931, US Pat. No. 5,750,497, and W096/29342. WO98/08871, WO 98/088 7.2, 'and WO 99/43708. These disclosures are incorporated herein by reference to the description of the lipophilic modified peptides and their preparation. The term "strong acid" includes any acid having a pKa value of less than 3, preferably less than 0', more preferably less than 3. The strong acid suitable for the present invention may be selected from the group consisting of hydrochloric acid, hydrobromic acid, nitrous acid, chromic acid, sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid, trimethylacetic acid, di-acetic acid, brominated acetic acid, and vaporized acetic acid. , cyanide acetic acid, 2_propionic acid, 2-ketobutyric acid, 2-chlorobutyric acid, 4-cyanobutyric acid, pam〇ic acid, peroxyacid, acid-filled, moth hydrogenated Etc., but not limited to this. • The "strong acid" of the present invention may comprise any organic sulfuric acid, such as an alkyl, aryl or alkarylsulfate of 1 to 40 carbon atoms, preferably less than 18 carbon atoms, more preferably less than 6 carbons. Atom, an organic sulfonic acid such as an alkyl, aralkyl, aromatic, or alkenyl sulfonic acid having 4 carbon atoms, preferably less than 18 carbon φ atoms, more preferably less than 6 carbon atoms. . The salt of the peptide agent described herein includes any peptide salt formed with a strong acid.

Dry, precipitated, or other prior art well-known: commercially available forms and weak acids (eg, k general ion exchange methods such as cryopreservatives) are replaced by strong acids, such as by lyophilization or lyophilization. For example, 1166-8751-PF; Ahddub 19 1376241 - leuprolide acetate is dissolved in a suitable liquid medium such as water. The peptide solution is mixed with a strong acid aqueous solution such as hydrochloric acid. When the skin acetate and a strong acid such as hydrochloric acid are dissolved in water When the peptide tends to interact with the gas ion, that is, the stronger acid HC1: replaces the weaker acid carboxylic acid. The solvent and the released acetic acid (or other acid but emits (4)) can be removed in the true U. In addition to water and weak acid, it forms a beneficial salt. If the peptide agent is unstable at low pH, the beneficial salt of the peptide agent can be subjected to long-term dialysis to combat very low concentrations of strong acid. The substance may comprise 4.% by weight of the peptide agent. In general, the ideal drug load is determined according to the time and intensity of the peptide agent to be released. Obviously, the low intensity and long-term release of the peptide agent need to be compared. The degree of merging - the apparent biodegradability is the gradual decomposition, dissolution, hydrolysis and/or corrosion of the in situ. As described herein, the biodegradable polymer is generally substantially hydrolyzed and/or enzymatically decomposed. In situ hydrolyzable and/or bioerodible. #This biodegradable polymer" includes any biocompatible and/or biodegradable synthetic and natural polymer that can be used in living organisms, but the polymer To be at least substantially insoluble in the water-soluble vehicle or body fluid. As described herein, the insolubleness of the polymer in the permeate must be sufficient to precipitate the polymer in a water-soluble vehicle or body fluid. Preferably, it is less than 1 liter/6, more preferably less than 〇1% by weight. When the polymer solution is mixed with an aqueous solution in a water-miscible or suspended organic solvent, when the organic solvent disappears, the edge polymer precipitates. Forming a solid or gelatinous matrix. Suitable biodegradable polymers are disclosed in U.S. Patent No. 4,938,763; 1166-8751-PF; Ahddub 20 1376241. The injectable polymeric composition of the present invention may comprise biodegradable The polymer is between 10% and 70% by weight. The viscosity of the injectable polymeric composition of the present invention varies depending on the molecular weight of the polymer used and the organic solvent. Generally, when the same solvent is used, the composition The viscosity is higher when the molecular weight and concentration are higher. The polymer concentration in the composition is preferably less than 7% by weight, more preferably between 30% and 60% by weight. • Poly(lactic acid) and lactic acid and A glycolic acid copolymer (PLGA), including a poly(D,L-lactic acid-glycolic acid) copolymer and a poly(L-lactic acid-glycolic acid) copolymer, is preferably used in the present invention. The thermoplastic polyester) has a lactic acid to glycolic acid monomer ratio of from about 50:50 to about 1 Torr: an average molecular weight of about 2 〇〇〇 _ about 10 0,0 0 0. The biodegradable thermoplastic polyester can be made by methods well known in the art, such as polycondensation and ring opening polymerization (e.g., U.S. Patent No. 4,443,340; 5, 242, 91 0; 5, 31). 0, 865, all of which are hereby incorporated by reference. The terminal group of the poly(D,L-lactic acid-glycolic acid) copolymer may be a hydroxyl group, a thiol group, or an ester' system depending on the polymerization method. Suitable polymers may include φ monofunctional alcohol or polyalcohol residues, and may have no carboxylic acid ends. Monofunctional alcohols such as methanol, ethanol, or dodecanol. The polyalcohol may be a diol, a triol, a tetraol, a pentaol, and a hexaol, and includes ethylene glycol, hydrazine, 6-hexanediol, polyethylene glycol, glycerin, a saccharide, a reducing sugar such as sorbitol, and the like. Many suitable PLGAs are commercially available, and the specific composition of pLGA "T is prepared according to the prior cutting technique. Various monomer ratios and molecular weight PLga can be prepared by B〇ehr inger-Ingel he im (Petersburg, Va, USA) > Lakeshore Biomaterials (Birmingham, AL, USA) > DURECT Corporation (Pelham, AL). 1166-8751-PF; Ahddub 22 1376241 The type, molecular weight, and amount of biodegradable polymer in the present composition affect the length of time that the release release agent releases the peptide agent. The choice of the molecular weight of the biodegradable polymer in this composition, and the number of molecules to achieve the desired controlled release implant properties can be confirmed by simple experimentation. A preferred embodiment of the invention provides a controlled release delivery system for the formulation of leuprolide hydrochloride using a liquid composition. In this embodiment, the biodegradable thermoplastic polyester is preferably a 85/15 poly(3) lactic acid-glycolic acid copolymer, including a base end and a laurel end; about 30% of the composition Weight % - 60% by weight; average molecular weight is about 15 〇〇〇 to about 50, 00 0. Use of Liquid Composition Another preferred embodiment of the present invention is a controlled release delivery system for the formulation of leuprolide hydrochloride. In this embodiment, the biodegradable thermoplastic polyester is preferably a 85/15 poly(D,L-lactic acid-glymouthic acid) copolymer comprising two base ends; it may comprise about 30 weights of the composition. The average molecular weight is about 15, 〇〇〇 _

50, 000. Another preferred embodiment of the invention is the use of a liquid group.......~π Z15C you? And η is used to formulate a controlled release delivery system of leuprolide hydrochloride. ^ Embodiment +, biodegradable thermoplastic polymer is preferably $ 85/15 (D, L-lactic acid-glycolic acid) copolymer, including the acid end; can account for about 30% by weight of the composition - 60% by weight; the average molecular weight is about 15 〇〇〇 to about 5 〇〇〇. [Further embodiment of the present invention is the use of the present composition for the controlled release of eupro 1 ide Delivery system. In this embodiment, the biodegradable thermoplastic polyester is preferably 1 〇〇/〇 poly(d,L-lactic acid _ 1166-875l-PF; Ahddub 23 J/0Z41:?. copolymer, including/not The acid terminal is included; it may comprise about 60% by weight of the composition; the average molecular weight is about 8, about 5 Å, 〇〇〇. The pharmaceutically acceptable organic solvent includes a biocompatible organic solvent, ^The liquid or body fluid is made to be miscible or dispersed. "A" means that the dissolved water is partially soluble or miscible. Preferably, the single solvent or solvent mixture is soluble or miscible in the water. The solubility is greater than 〇·1% by weight. More preferably, the solvent has a solubility or miscibility of more than 3% by weight in water. The solvent preferably has a bathability or miscibility of more than 7% by weight. It should be able to diffuse into the body fluid, thus allowing the liquid composition to coagulate or solidify. The solvent and/or mixture of the solvents can be used alone, and the suitability of the solvent can be confirmed by simple experiments. Pharmaceutically acceptable organic solvents including N-mercapto 2_pyrrolidone, methoxypolyethylene glycol, alkoxy polyethylene glycol, polyethylene glycol vinegar, kelly Glyfofuroi), glycerol 1 f〇rmal, decyl acetate, ethyl acetate, methyl ethyl ketone, dimethylformamide, dimethyl milling, tetrahydrofuran, caprolactone, mercapto dimethyl Sulfone, benzyl benzoate, ethyl benzoate, triacetin, diacetin, tributyrin, triethyl citrate, tributyl citrate , triethyl citrate ethyl ester, tributyl citrate ethyl ester, triethyl glyceryl ester, phosphoric acid bismuth, citric acid diacetic acid, tartaric acid diethyl vinegar, lactic acid ethyl vinegar, propylene carbonate vinegar, ethylene carbonate , butyrolactone, and 1-dodecylazide ring-heptan-2-y, and combinations thereof, but are not limited thereto. Solubility of the biodegradable polymer in various pharmaceutically acceptable organic solvents According to the characteristics of the polymer and its compatibility with different solvents 1166-8751-PF; Ahddub 24

'W such as PLGA has a higher solubility for N-mercapto-2-pyrrolidone (NMp) than triaCetin. However, when the solution of PLGA is contacted with an aqueous solution, NMp rapidly disperses to form a solid polymeric matrix because of the high water miscibility. The rapid rate of diffusion of this solvent can quickly cause solid implants to also cause high initial flush release. When pLGA is contacted with aqueous solution in a solution of triacetin, because of the low water miscibility of triacetin (tnacetin), triacetin (4) will be very slow and the slow diffusion rate of the solvent will make the viscosity The liquid takes a long time to turn into a solid matrix. At this point, a balance is formed between the diffusion of the solvent and the coagulation of the polymer, and the skin is wrapped. It is therefore advantageous to combine different solvents to achieve a desired delivery system. Low and high water miscible solvents can be combined to improve the solubility of the polymer, modify the viscosity of the composition, achieve a desired diffusion rate, and reduce the initial flush release. The active/polymeric macromolecules of this month generally comprise a weight percent by weight of an organic solvent. The viscosity of the injectable polymeric composition of the present invention varies depending on the molecular weight of the polymer and the solvent used. The dot material agronomy in the composition is preferably less than 7 G weight%. The polymer concentration in the ruthenium solution is more preferably from 30% by weight to 60% by weight. The term "excipient" as used herein includes any advantageous constituents other than the formulation of the present composition or the biodegradable polymer. Suitable excipients may include release rate modifiers, flush effect mitigating materials, buffers, antioxidants, and the like. According to the present invention, suitable release rate modifiers include amphoteric compounds or copolymers such as alkanoic acid, oleic acid, alkyl alcohol 'polar lipids' interface 1166-8751-PF; Ahddub 25 1376241 agent, polyethylene glycol Copolymer with polylactic acid or polylactic acid glycolic acid copolymer, Plu oxaniers, polyethylene. Bile ketone, polysorbate, etc.; mono-, di-, tricarboxylic acid ester, . 'such as 2 - ethoxy ethyl acetate, citric acid diethylene, B, tributyl citrate, acetonitrile citric acid Triethyl ester, glycerol tris(π butyl) decanoic acid S, specialized in polyalcohols such as polyethylene glycol, mountain 4 sugar alcohol, triglyceride, such as triglyceride, intermediate chain Triglycerides such as MIGLY0L 810, 812, 818, 829, 840, etc., but limited to this polymer system of the invention may also employ a release rate conditioning mixture. The release rate modifier can be present in the injectable polymeric composition in an effective amount to reduce the initial flushing of the polymeric composition to release the peptide agent within the first hour after implantation. The polymeric composition preferably comprises @@重量% of about 50% by weight of a release rate modifier, more preferably about 2 by weight to about 2% by weight. According to the present invention, suitable buffering agents include inorganic and organic, ypic acid calcium, calcium hydroxide, meat glutinous rice, calcium, calcium oleate, calcium palmitate, stearic acid,酸酸约、碳酸录,奇格儿楚^虱magnesium oxide, magnesium citrate, magnesium oleate, palm acid acid town, stearic acid town, acid town, zinc carbonate, oxidized The combination of oleic acid, grazing zinc acid, stearic acid (tetra), zinc-filled acid, and two, but is not limited thereto. The buffer can be effectively placed in the injectable polymeric composition to stabilize the cut enthalpy of the implant during decay. The polymeric composition preferably ranges from about 1% by weight to about 30% by weight of the female, 曰-containing buffering agent' more preferably from about 2% by weight to about 15% by weight. 1166-8751-PF; Ahddub 26

1376241 Suitable antioxidants according to the invention include d_a 纟 酸酸酸

Ester, palmitic acid sulphuric acid ester, A 丞 hydroxy valeric acid ester (hydr〇_id〇le), benzylated benzoic acid, butylated quinone hydroxy coumarin ' • Xylene, gallic acid ethyl vinegar, gallic acid broth, gallic acid vinegar, gallic acid laurel, propyl acetate, three (four) 孑玍 Beijing, PEGylated vitamin Ε or Vitamin e_tpg$, etc., but is not limited to this. The antioxidant can be present in the injectable polymeric composition in an amount effective to capture any free radicals or peroxides produced in the implanted person. The polymeric composition preferably comprises from about i% by weight to about 3% by weight of the antioxidant, more preferably from about 3% by weight to about 15% by weight. In one aspect, the invention provides a stable injectable biodegradable polymeric composition, which forms an economical, practical and effective controlled release delivery system for a peptide agent, comprising a) a beneficial salt of a peptide agent formed with a strong acid, avoiding the peptide And interacting with or reacting the polymer in an organic solution to minimize 〇 biodegradable polymer; e) pharmaceutically acceptable organic solvent; and heart selection) · habitat or eve species Achieve the ideal delivery of t-peptide. Preferably, the injectable polymeric composition is packaged in a set comprising the step of filling the composition into a syringe to form a ready-to-use structure. The composition in the kit is stable over a reasonable period of time and has an appropriate storage half-life under controlled storage conditions, preferably at least one year. Preferably, the composition is injected into the individual to form an implant in situ to release the peptide agent in a therapeutically effective amount for a desired, extended period of time. The stable injectable biodegradable polymeric composition of the present invention may be from 27 1166-8751-PF; Ahddub 1376241, a peptide salt, a bioorganic knife-solving polymer, a pharmaceutically acceptable organic refrigerant, And a selective encapsulation agent ~ μ to make & The composition of the fungus can be conveniently formed in the early position, and P ^ ^ is manufactured by any method known in the prior art. Manufacture of the present invention, & I, the invention of the composition of the invention - a preferred method is to dissolve the raw materials ... ... in the pharmaceutically acceptable organic solvent, first obtain a single type of polymerization ... % D, Liquid/suspension liquid. The peptide agent is then forced into this solution/suspension. This composition is t-formed using any suitable method to obtain a mono-type solution/suspension 1 and then transfer the appropriate amount of the bath/suspension to a note. (7) Sub-τ forms a usable structure.

Cready-to-use) product. The degree of action of the peptide salt of the composition of the present invention with the polymer, depending on the ability of the peptide agent, the desired delivery time, the dissolution of the polymer in the solvent, and the volume and viscosity of the injectable composition to be administered, And there is a difference of 8

In a preferred embodiment of the invention, the injectable biodegradable polymeric composition forms an economical, practical and effective peptide delivery delivery system comprising from about 0.1% to about 40% of the peptide salt. And about 1% to about 7% by weight of the poly(lactic acid-glycolic acid) copolymer. The composition further comprises about _-m of a pharmaceutically acceptable organic solvent. In a preferred embodiment of the invention, the composition further comprises from about U-40% of a suitable excipient, including a release rate modifier as defined above, a knockout effect mitigating material, a buffer material, an antioxidant , tissue transfer agents, etc. According to the invention, the injectable composition is transferred to a sterile container, such as a syringe, suitable for injectable administration. The container is packaged and stored, the composition of 1166-8751-PF; Ahddub 28 1376241 retains at least 80% of the original molecular weight, structure and/or organism during manufacture and storage or prior to administration to an individual such as an animal or human. Activity is preferably ••90%. • According to the invention, the stabilizing composition can be delivered to the individual to be administered by controlled release of the desired peptide agent. As such, the individual, including a warm-blooded animal, is preferably a mammal, and more preferably a human. The term "administering an individual" is to disperse, deliver or provide the composition (e.g., a pharmaceutical formulation) in the desired individual position by the appropriate route of delivery of the composition. Preferably, the compositions of the present invention are administered subcutaneously, intramuscularly, intraperitoneally, or intradermally and/or implanted, and the desired dosage will be provided according to the criteria for the various pharmacological conditions of the peptide agent. - The controlled release delivery is "after the administration, after a period of time - after the rut is good for at least several weeks to one year, the body (//7 of the peptide agent is continuously delivered. The continuous controlled release of the agent can be called For example, for a prolonged therapeutic benefit of the agent (such as LHRH analogues, the sustained delivery of the analog may be referred to as long-term continuous inhibition of testosterone synthesis). Alternatively, continuous delivery of the agent may be referred to as prolonged detection. The presence of the agent in the body. The amount of the injectable composition generally varies depending on the desired properties of the controlled release implant. For example, 'the amount of the injectable composition can affect the 4 peptide agent from the control The length of time during which the release of the implant is released. In a preferred embodiment of the invention, the volume of the injectable polymeric composition of the present invention is 〇.lmL_2 〇mL' is preferably "m, more preferably 0e3fnL- 0.5 in L. The present invention still further provides a method of forming an implant in situ, comprising 1166-8751-PF; Ahddub 29 1J/0Z41 - an injectable composition comprising an individual θ of 1 in an individual, the injectable composition Including • species and strong acid formation Peptide agent salt, avoiding the peptide agent and the polymer • interacting/reacting or minimizing in organic, liquid; b) biodivisible. depolymerization, c) pharmaceutically acceptable organic Solvent; and d) selecting - or - excipients - to achieve the desired delivery of the peptide agent; allowing the solvent to disperse; surrounding water, in a compatible environment, forming a liquid by phase separation The storage may be a viscose, a semi-solid, or a solid substrate. The storage may also be a matte or non-porous material. The storage is used as a delivery system for the peptide agent to be released for an extended period of time. In another preferred embodiment, the injectable composition can be administered to a body cavity to form a storage system. The body cavity includes a cavity formed after surgery, or a natural body cavity, such as a vagina, an anus, etc. The invention provides a stable liquid biodegradable polymeric composition, which forms an economical, practical and effective controlled release delivery system for peptide agents, comprising a) a salt of a peptide agent formed with a strong acid, avoiding the peptide agent and the Polymer in organic solution Interacting/reacting or minimizing it; b) biodegradable polymer; pharmaceutically acceptable organic solvent; and d) optionally one or more excipients to achieve the desired delivery of the peptide agent. The liquid biodegradable polymeric composition can be formed into an implantable polymeric matrix, wherein the liquid biodegradable polymeric composition retains at least 90%, preferably 95%, of the original molecular weight, structure and structure before and during the manufacturing process. / or biological activity. The term "implantable polymer matrix," includes particles, films, troches, cones, disks, microcapsules, microspheres, naphthalene ββ-8751-PF/Ahddub for drug delivery. 30 1376241 Meter spheres, microparticles, wafers and other known polymeric structures. Methods of forming various pharmaceutically acceptable polymeric carriers are well known in the art. For example, U.S. Patent Nos. 6, 41 0, 044; 5, 698, 213; 6, 312, 5, 410, 016; 5.529, 914; 5, 501, 863; and pcT 'public' case w〇93/1 6687; 4.938, 763; 5, 278, 201; 5,278,202; EP 0,058, 481, herein incorporated by reference. According to the present invention, the microsphere-type implantable polymer matrix is formed by encapsulating the peptide salt in the polymer. A wide variety of biocompatible and/or biodegradable polymers having specific properties suitable for delivery to different biological environments or suitable for influencing specific functions can be used to encapsulate the beneficial salts of the peptide agents. Therefore, the dissolution rate and delivery of the peptide agent can be confirmed by specific packaging techniques, polymer composition, polymer crosslinking, polymer viscosity, polymer solubility, volume of bioactive compound/polyanionic polymer, and solubility. The encapsulated peptide salt is dissolved or suspended in a polymer solution in an organic solvent. The polymer solvent concentration must be sufficient to completely encapsulate the beneficial salt after the peptide salt is added to the solution. The weight ratio of the peptide salt to the polymer is from J 〇. 01 to about 50 Å, preferably about 〇·Ab about 3 Å. When the peptide salt is encapsulated in contact with the polymer, it should remain suspended and not agglomerate. Thus, the polymer solution of the peptide salt can be used in a variety of micro-encapsulation techniques including spray drying, spray freezing, emulsifying, and solvent evaporative emulsification. According to one embodiment of the present invention, the benefit salt of the peptide agent is dissolved or suspended in an organic solvent-derived polymer solution. This solution or suspension is placed in a larger volume of aqueous solution with an emulsifier. In this aqueous solution, the organic phase is emulsified and the organic solvent evaporates or diffuses from the polymer. The cured H66-875l-pF; Ahddub 31 polymer encapsulates the peptide salt, forming a hardening phase process which reduces the amount of material in the system if the encapsulated polymer has some additional interface. Polymer matrix. The emulsifier assists in the interaction of the interfacial tension between the phases. Or inherited interface activity, may not be required according to the invention '. The emulsifier used to make the encapsulated peptide agent Yi salt includes poloxamers and polyvinyl alcohol, which can reduce the polymer and solution between the peptide salt and the beneficial salt. Interface tension surfactants and other interface active compounds. The organic solvent used for the production of the microspheres of the present invention, in addition to the above, includes acetic acid, acetone, (tetra)alkane, ethyl acetate, and gas imitation.

The solvent is selected according to the nature of the polymer and the properties of the polymer. The solvent that will dissolve the polymer should be chosen as 'non-toxic. According to the present invention, these implantable polymeric matrices are used to maintain the desired release of the peptide agent in the individual's desired release. The implantable polymeric matrix of the present invention is preferably administered subcutaneously, intramuscularly, intra-abdominally, or intradermally and/or implanted to provide the desired agent in various medical conditions for treatment with a peptide agent. Known parameters. All of the books, articles, and patents described herein are incorporated by reference. [Embodiment] The following examples illustrate the composition and method of the present invention. The following examples should not be construed as limiting how to make effective controlled release drug delivery compositions. Example 1 Production of a peptide agent Yi salt and a peptide agent derivative with a strong acid 1166-8751-PF; Ahddub 32 1376241 A peptide agent or a peptide agent derivative containing at least one functional group is dissolved in water. A chemical dose of a strong acid is added to the aqueous solution of the peptide agent t to neutralize the test of the agent. Get asleep with the Shen Dian method, the sputum and/or the cold and dry method. Example 2 Production of leuprol ide hydrochloride Leuprol ide is a luteinizing hormone (LHRH) agonist containing 9 amino acid residues and 2 basic functional groups. (tissue amine and • arginine) ° its nitrogen-terminal amine is blocked by pyro-proline. It has been used in the treatment of prostate cancer and ectopic endometriosis. LeUpr〇lide acetate U-Ac can be obtained from the peptide laboratory (p〇iypeptides Lab〇rat〇ries,

Inc. ) (PPL Lot#PPL-LEUP0401A). Leupr〇lide hydrochloride (LA-HC1) can be obtained by ion exchange and freeze-drying steps to replace acetic acid with HQ. In general, l〇〇〇mg leupr〇Ude acetate is dissolved in 3 mL of water. Add 3.19 mL of 0.5 N. HC1 (HC1:LA~2. 2:1) and mix well. This solution was lyophilized for 72 hours, and acetic acid was removed. The dried powder is then redissolved and lyophilized. φ Example 3 Production of leuprol ide methane sulfonate

343.5 mg of leupr〇Ude acetate (ppL)

Lot#PPL-LEUP0401A) was dissolved in 20 mL of water. Add 32 to L. methanesulfonic acid (leuprol ide acetate to methanesulfonic acid molar ratio ~ 1:2), and mix well. This solution was lyophilized for 72 hours and the acetic acid was removed. The dried powder was redissolved in water and lyophilized. Manufacture of Gospellin η hydrochloride

766 mg of geiselin (g〇sereUn) acetate (ppL)

Lot#0603-21 9) Dissolved in 20 mL of water. 2.12 mL of 〇·5 N HC1 (HC1 1166-8751-PF; Ahddub 33 1376241 vs. Goserel in acetate molar ratio ~2·2:1) was added and mixed well. This solution was lyophilized for 72 hours and the acetic acid was removed. The dry powder is then redissolved in water and lyophilized. • Example 5 Production of palm sputum-octreotide (PAL-OCT) 50 mg of octreotide acetate was dissolved in 1000 uL of '10〇uL, TEA without water. In DMS0. Mg. lmg palmitic acid N-succinyl succinimide (Mw 353.50) was dissolved in 3 mL of anhydrous DMS0 and injected directly into the peptide solution. The reaction was allowed to proceed at room temperature overnight. The mixture was poured into diethyl ether to precipitate palmitate octreotide. The precipitate was washed twice with diethyl ether and dried in vacuo. The obtained acetaminophen was a white powder. Neutralization of residual alkali amine groups with strong acid to form acetaminophen salt. Example 6 Production of furfural-actinotropin octreotide (DCL-〇CT) φ 50 mg of somatostatin peptide (octreotide) Dissolved in ρΗ5, 0.1 M acetic acid

2 mL, 20 mM sodium cyanoborohydride (Mw 62.84, NaCNBH 〇 (2.51 mg) solution in buffer. I3.7 mg of furfural (Mw 156.27) (OCT: DCL = 1:2) was directly injected into the peptide. The reaction was carried out overnight at 4° C. The mixture was centrifuged to freeze the precipitated PAL-0CT. The residual alkali base was neutralized with a strong acid to form the acetaminophen salt. The octreotide is prepared by adding a solution of octreotide acetate (10 mg/mL) in water to a 2 molar equivalent of amber 34 1166-containing 0.1 M phosphate buffer, pH 7.4. 8751-PF; Ahddub 1376241 In a vial of yttrium imidate propionate monomethoxy PEG (SPA-mPEG, MW 2000 Darton). The reaction was carried out overnight at 4 ° C. Using C-18 (YMC ODS., A 4. 6x250mm, 5um, Waters Corporation) reverse phase HPLC (RP-HPLC) · Separation of this reaction. The mobile phase consists of water 〇. 1% TFA (A) and CAN (B) containing 0.1% TFA The mobile phase was moved with a linear gradient of flow rate iml/min, 30-60% eluent B for 20 minutes, and the UV absorbance of the 215 nm eluent was detected. The eluted fractions were collected according to individual peaks and washed with nitrogen. Cold-beam drying. Alternatively, oxy-specific octreotide PEGylation can be obtained. 20 mM sodium cyanoborohydride (NaCNBHO medium octreotide acetate (10 mg/mL) solution, and hydrazine. A 1 M acetic acid buffer, pH 5 solution was added to a vial containing 3 molar equivalents of monomethoxy PEG-propionic acid (ALD-mPEG, MW 2000 Darton) in water. The reaction was allowed to react overnight at 4 °C. This reaction was isolated by reverse phase HPLCaP-HPLC of C-18 (YMc 〇DS-A 4.6X250mm, 5 ι ιη, Waters Corporation). The mobile phase was hydrated from water. 1% TFA (A) and CAN containing 〇. 1% TFA (B) The mobile phase is moved at a flow rate of 1 m 1 /miη, 3〇_6〇% eluent b linear gradient for 2G minutes, and the UV absorbance of the 215 nm eluent is detected. According to the individual peaks, respectively. The eluted fraction was washed with nitrogen and lyophilized. The residual alkali amine group was neutralized with a strong acid to form a pegylated peptide salt. The stability of the peptide agent of Example 8 and the biodegradable polymer in the injectable polymerizable composition. Poly (DL-lactic acid-glycolic acid) having a lauryl ester end group and having a ratio of lactic acid to glycolic acid of 85/15 Copolymer (pLGA) (DLPLG85 / 15, IV: H66-8751-pF; Ahddub 35 1376241 square · 28) was dissolved in N- Yue yl -2- ° ratio "for each one (NMP), into a 50 wt% solution. The PLGA solution in NMP was mixed with the ieupr〇i ide salt to form a single-form injectable composition in the proportions shown in Table 1. • Using a gas tight microtube. (luer-lock tjP) These injectable compositions were filled in a 1.2 mL polypropylene syringe. The pre-filled injections β are then sealed with a gas-tight micro-cap (1) (1" ("1"). These capped syringes are packaged in a vacuum and sealed in a plastic bag. Store at 4 ° C and room temperature (~ 22 ° C) until 18 months. These injectable compositions were sampled at 24 h, 1, 2, 3, 6, 12, -18 months. The purity of the leuprolide in the sample was confirmed by HPLC. The molecular weight of the polymer was confirmed by gel permeation chromatography (GPC) of a polystyrene standard value of known molecular weight. Table 1 Injectable polymer formulation samples tested Liu Yulin (1 eupr ο 1 i de ) salt (mg) DLPLG 8515/NMP (mg) Drug loading (%, .w/w) Blank test 0 1000 r~·~~ LA-Ac 50 890 5.3 LA-MS 54 960 5.3 LA-HC1-1 106 940 Γ〇Τ~ LA-HC1-2 41 730 O' This example unexpectedly found the use of liupulin (丨eupr〇丨i de) hydrochloride and methane sulfonate When the acetate is substituted, it will decrease the leupr〇iide and polymer disintegration of the PLGA solution in NMP over time. Tables 2 and 3 show each at 4 ° C. PLGA in time-lapse P at room temperature The disintegration of leuprol ide with liquid solution. After 18 months at 4 ° C, up to 23% of the leuprolide acetate polymer composition is degraded by leuprolide. In the formulation containing leuprolide hydrochloride and 36 1166-8751-PF; Ahddub 1376241 methane sulfonate, less than 2% leupr〇Hde decays. After 12 months under the dish More than 35% of the formula of leupr〇1 ide acetate is degraded by iuprolide, and in the formula containing leupr〇Hde hydrochloride and broth Only about 11% of leuprolide was degraded, and at room temperature, a color change (from cream to yellow to rust) and phase separation were observed. This phase separation resulted in a heterogeneous formulation and formulation. Heterogeneous degradation of peptides and polymers. Formula heterogeneity may fluctuate for results observed at different time points. _4 C under F^GA/NMP formula of liuupulin (ieupr〇iide) stable Tang time (month) LA - AC LA-HC1-1 LA-MS 0 100.0 100.0 100.0 1 89.3 100.0 100.0 3 100.0 100.0 100.0 6 94.1 100.0 100.0 12 88.2 100.0 98. 9 18 ~~7679 98.5 98.3 Table 3 leuprolide stability time (month) of PLGA/NMP formula at room temperature. LA_AC LA-HC1-1 LA-HC1-2 LA-MS 0 100 100 100 100 1 75 99 100 95 2 78 98 97 97 3 86 100 100 100 6 87 99 100 99 12 65 89 89 89

Tables 4 and 5 show the molecular weight changes of the polymers in the different formulations. Compared with the blank test, the 1 euprol i de acetate formulation was reduced by more than 10% at 4 ° C after 6 months ‘more than 90% reduction at room temperature. However, the PLGA molecular weight in the formulation containing leuprolide hydrochloride and decane sulfonate was the same as in the blank control group even after 12 months. However, after 12 months of 1166-8751-PF/Ahddub 37 1376241, the blank control group and the formulation containing leuprolide hydrochloride and bismuth citrate had more than 90% polymer degradation. The results indicated that the leuprol ide salt formed by strong acids such as HC1 and • acetonic acid was used to avoid interaction/reaction between the peptide and PLGA in the solution. However, if it is a weak acid such as acetic acid, the serious interaction between the peptide and PLGA in the DMS0 solution cannot be avoided. Thus, the use of a peptide salt formed with a strong acid improves the stability of the formulation, and enables the manufacture of ready-to-use injectable compositions having satisfactory storage stability for at least one year. • Table 4 PLGA Formula Molecular Weight of Different Formulations at 4°C, Time (Month) Blank Test LA-AC LA-HC1-1 LA-MS 0 24655 23842 24369 24556 1 25214 24282 25203 24574 3 24567 22775 24833 24833 6 23935 21957 24661 24034 12 23905 18906 23837 23393 18 22178 16107 22802 22227 Table 5 PLGA formulation with different formulations at room temperature Molecular weight time (months) Blank test LA-AC LA-HC1-1 LA-HC1-2 LA-MS 0 465 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 Stability with a polymer in an injectable polymeric composition will have a lauryl ester end group and a poly(DL-lactic acid-glycolic acid) copolymer (PLGA) having a ratio of lactate to glycolic acid of 85/15 ( DLPLG85/15, IV: 0. 28) Dissolved in dimercaptopurine (DMS0) to a 50% by weight solution. Compared with 1166-8751-PF; Ahddub 38 1376241 in DMS0, the pLGA molecular weight of the leUpr〇iide acetate formulation was reduced by about 40% at 4 C after 16 months. The PLGA molecular weight of leuprol ide hydrochloride and willow leuprolide methane sulfonate formulation was similar to the blank test group at 4 C after 16 months. The results indicate that the leUpr〇lide salt formed by hc 1 and 烧 calcined acid-specific acid almost completely avoids the interaction/reaction between peptide and PLGA in DMS0 solution. In the case of a weak acid such as • acetic acid, a severe interaction/reaction between the peptide and PLGA in the DMS0 solution cannot be avoided. ® Example 10 Bio-release (//? f/po) Liupulin (ieupr〇iide) from injectable polymeric composition Three polymer carrier solutions were prepared as follows: 'PLG 85" with lauryl end groups 5 (0_28 IV), 50% by weight and 55% by weight in NMP; ' and RG503 having a carboxylic acid end group, soluble in NMP at 50% by weight. Each of the appropriate amounts of leuprolide hydrochloride (LAHC1) and leuprolide methanesulfonate was mixed with the polymer solution in an amount of 6 φ% by weight. A fully mixed formula gives a single type of formula. A portion (aliqu〇t) of the formulation suspension (about 100 mg) was injected into 37 C, pH 7.4, a 3 mL aqueous solution of physiological saline solution having 〇·ι% sodium azide. The resulting liquid was replaced with fresh buffer solution at the selected time point, and the removed buffer solution was diluted twice with pH 7 4 phosphate buffer, and the concentration of the agent was analyzed by HpLc. Calculate the amount of release at each time point. Figure 3 shows the cumulative release of leupr〇lide over time. As shown in Figure 3, there was no significant difference in the release of leupr〇lide between LAHC1 and LAMS. However, the type and concentration of PLGA seem to significantly affect the release of 1166-8751-PF; Ahddub 40 ^/6241 leuprolide. The RG503 formulation has a much faster release rate than the PLG85m5 formulation. Therefore, the RG5〇3 formulation may be suitable for short-range delivery of leupr〇l ide, and the PLG85/15 formulation is suitable for long-range delivery of the peptide. The release rate of the peptide can be further modified by changing the PLGA concentration. When the concentration of PLG85/15 was increased from 50% to 55%, the initial release rate of eupro 1 i de was significantly reduced. Therefore, the specific formulation parameters that allow the peptide to reach the desired release state can be easily obtained by simple experiments. Example 11 Effect of excipients on the release of eupro 1 ide in vitro

A polymer carrier solution with and without excipients was prepared as follows: Prepare PLA 10 000 DLPL (0.26 IV, Lakeshore, AL) with laurel end groups dissolved in NMP according to the appropriate amount of Table 7, and Vitamin E TPGS . The appropriate amount of leuprolide hydrochloride (LAHC1) was mixed with the polymer solution to give 15% by weight. A fully mixed formula gives a single type of formula. Effect of ginseng 7__ ¥ shape agent on the release of leuprolide in vitro ___ —#本PLA 100DLPL(%) NMP(8)~~Vitamin E TPGS(8)~~LAHCK%') Formula-1 47 38 〇—~ Ϊ5 -Formula __36J_12_ 15 A portion of the formulation suspension (about 1 〇〇 mg) was injected into 37 C, pH 7.4, 3 mL of phosphate buffered saline solution with 〇·1% sodium azide. This liquid was replaced with fresh buffer solution at the selected time point. The removed buffer solution was diluted 10-fold with pH 7.4 PBS, and the concentration of the drug was analyzed by HPLC. Calculate the amount of release at each time point. Figure 4 shows the cumulative release of Liu Pulin (1 eUpr〇 1 i de) over time. 41 1166-8751-PF; Ahddub ^/6241 _ Figure 4 shows that the addition of vitamin E TPGS does not affect the release of sputum, but it seems to reduce Liu Bolin (I(9) pr〇Hde) at a later stage. Release rate. Therefore, vitamin ETPGS can be used to extend the delivery of the peptide and also as an antioxidant. Effect of the excipient of Example 12 on the release of leuprolide in vitro

A polymer carrier solution with and without excipients was prepared as follows: Prepare pLA 100D040 (0.44 IV, Durect, CA) with laurel end groups dissolved in NMp according to the appropriate amount of Table 8, and a medium-chain triglyceride ester

Miglyol 812. An appropriate amount of leupr〇1 ide hydrochloride (LAHC1) was mixed with the polymer bath to give 15% by weight. A fully mixed formula yields a single type formulation. Table 8 Samples of the exogenous release of leuDr〇lide in vitro. PLA l (J0D040 (9〇NMPC%) Miglyol 812 (%) LAHC1C%) ~~4^5-〇- 15 with θ 4^5—~~381-4~2- 15 The part (aliqu〇t) of the ό海 formula suspension (about 1〇〇mg) was injected into 37 C, ρΗ7·4, with 〇. 1% sodium azide. 3 mL of phosphate buffer solution of physiological saline solution. This liquid was replaced with fresh buffer solution at the selected time point. The removed buffer solution was diluted 10-fold with PH7.4 PBS, and the concentration of the drug was analyzed by HPLC. The amount of release at each time point is again calculated as a standard curve. Figure 5 shows the cumulative release of Liu eulin (1 eUpr〇 Hde) over time. As shown in Figure 5, the addition of Miglyol 812 significantly reduced the release of leuprolide and maintained the willow 1166-8751-PF at a later stage; Ahddub 42 1376241 - leuprolide Release rate. Therefore, Miglyol 812 can be used as a result of prolonging the delivery of the peptide compared to the example, and the amount of the polymer also significantly affects the release of eupro 1 ide. . · - It seems that the smaller the PLA molecular weight 'Liu Bolin (1 eUpr〇i丨7); the smaller the release amount. Example 13 (i/? ρ/κσ) release of 1 euprol ide' will have a lauryl ester end group and have a ratio of lactate to glycolic acid of 85/15 (DL- The lactic acid-glycolic acid) copolymer (PLGA) (DLPLG85/15, iV: ® 0.28) was dissolved in N-mercapto-2-pyrrolidone (NMP) to a 55% by weight solution. Mixing the PLGA solution in the sputum with the sulphate (ieupr〇i sulphate) salt, ie leuprolide hydrochloride and decane sulfonate, forming a single type of injectable composition with a drug loading of about 12%. </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; Each formulation was then subcutaneously injected into the rats by about 100//L. Serum samples were collected 3 hours, 1, 3, 7, 14, 28, 42, φ 56, 70 days after injection. Serum samples were analyzed for serum concentrations of Liu Pulin (1 eUpr 〇 1丨de) using a set of EL ISA from Peninsula Laboratories Inc. The residual lycopene (1euprolide) in the implant was analyzed by HPLC at different times. Fig. 6 shows the release state of the two formulas of Liupulin (]_eupr〇iide). Both formulations showed that leupr〇lide was initially rushed out and released. The formulation containing LAHC1 reached CDax 661.6 ng/mL in 3 hours, and the formulation containing LAMS reached Cnax 370. 6 ng/mL in 3 hours. Both formulations showed a prolonged sustained release of leuprolide compared to the formulation containing LAHC1 containing 1166-8751-PF; the Ahddub 43 1376241 LAMS formulation showed a more sustained serum concentration of iupup〇i ide. The release of leuprolide in the body of Example 14 (//7 f/叩) will have a 1,6-hexanediol moiety and a poly(lactic acid) ratio of 85/15 to glycolic acid ( DL-lactic acid-glycolic acid) copolymer (DLPLG 85/15, IV: 0.27) was dissolved in N-methyl-2-pyrrolidone (NMP) to a 50% by weight solution. The PLGA solution in NMP was mixed with the ieupr〇iide salt, leuprolide hydrochloride and methanesulfonate, to form a single type injectable composition of about 12% drug loading. These injectable compositions were filled in a 丨.2m 1 polypropylene syringe attached to a 19-thick thin-walled needle using a gas tight microtube (luer-l0Ck t i p). Each formulation was then subcutaneously injected into rats approximately 1 000 #L. Serum samples were collected 3 hours, 1, 3, 7, 14, 28, 42, 56, 70, 91, 112, 133, 154, 175, and 206 days after each injection. The concentration of leupr〇lide in serum samples was analyzed by ELISA from a laboratory of Peninsula Laboratories Inc., and the concentration of testosterone was analyzed by LC/MS/MS. The residual leuprolide in the implant was analyzed by HPLC at different times. Use other LHRH analogues such as bus erel in, deslorelin 'fertirelin', histrelin' lutrelin, gerselilin (goserelin) 'nafarelin' triptorelin, cetrorel ix, abarei ix; and other peptides such as GLP-1 , PYY, etc., as well as other polymers and solutions, designed similar experiments. Example 1 Use of a stable injectable polymeric composition 1166-8751-PF; Ahddub 44 1376241 Administration of a stable, subcutaneous or intramuscular injection of a bio-injectable implant, such as a transdermal cream With the patient. There are a variety of methods for the polymeric composition. Knife-polymerized composition, in situ formation' can also be produced by rectal or vaginal embolization of Example 16 containing LAHC1 polymer microspheres. Poly (lactic acid-glycol) is produced using an oil-in-water (ο/w) single emulsion technique. Acid) Copolymer (PL(4) microspheres. Dissolve pLGA in methylamine (DCM). The reagent is mixed with PLGA solution in DCM for wrapping LAHC1'. Emulsify the mixed solution or suspension in a freezer at 4 °C. Cold 5 〇〇 mL, 〇 5_1% (w/v) PVA (PVA, 88% hydrolyzed, average molecular weight 31 〇〇〇 5 〇〇〇〇, Signm-Aldrich). The emulsion was continuously stirred at RT. The hardened microspheres were collected, washed 3 times with deionized water, and then lyophilized. Example 17 Stable injectable polymeric composition for the manufacture of an implantable polymer matrix from lactic acid to glycolic acid 50:50- A 100:0 poly(lactic-glycolic acid) co-φ polymer composed of a biodegradable polymer, such as RG503H (Boehringer Ingelheim Chemicals, lnc. USA), dissolved in a volatile organic solvent such as ethyl acetate or gas. Methane. Take the appropriate amount of salt as defined above, such as goserelin (goserelin) The terpene-based acid salt (%% by weight of this polymer) is dissolved/dispersed in the polymerization solution. The solution is completely mixed to obtain a single type solution or suspension. After the mixture is completely evaporated The solvent is removed. A small single-type particle is formed for injection by a spray drying process. An implant can also be formed in the mold. The resulting polymer matrix can also be ground into a powder to prepare an injectable suspension. 45 H66 -8751-PF; Ahddub 1376241 Therefore, the obtained solid dosage form can be injected subcutaneously or intramuscularly, or can be implanted under the skin to implant a human-planted person's or a p-peptide delivery part of the oral delivery system. It can be made into a suspension or a non-aqueous solution, or it can be delivered by a pulmonary agent. (4) A patient who takes a drug can make the microparticle (4) float in the oil or saliva or vaginal plug. The agent is administered to the patient. [Simplified illustration] Figure 1 The stability of LA in the formula after 16 months. Figure 2 shows the molecular weight of pLGA in the formula after 16 months at 4C. Figure 3 shows the release of PLGA from the type and concentration of PLGA (8)-) influences. Figure 4 is the effect of vitamin E on the release of u from injectable compositions. Figure 5 is a graph showing the effect of Mygly〇i on LA release in injectable compositions in injectable compositions. ’ The β-graph is for the rat’s $c vote, can, and * rainbow take people z

Only Jun Jun has released the LA release state of the polymer composition. [Main component symbol description] None 0 46 U66-8751-PF; Ahddub

Claims (1)

1376241 • No. 096110525 X. Patent application scope: 101 years 9 repairing replacement page body · S曰_ Supplement j 1. An injectable polymerizable composition comprising: a) a peptide salt formed with a strong acid, The strong acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, chromic acid, methanesulfonic acid, trifluoromethanesulfonic acid, trichloroacetic acid, di-acetic acid, bromoacetic acid, gaseous acetic acid, cyanic acid, and 2-air-propylene. Acid, 2-ketobutyric acid, 2-gas butyric acid, 4-cyanobutyric acid, peroxyacid and phosphoric acid; b) - water-insoluble biodegradable polymer; c) a pharmaceutically acceptable organic solvent, soluble a biodegradable polymer 'and miscible or dispersible in an aqueous or biological fluid; and d) optionally one or more pharmaceutically acceptable excipients; wherein 'the peptide agent has a nitrogen end of a non-primary amine, and The peptide agent contains at least one base. ' 2 Injectable polymeric composition as claimed in claim 1 which may be in the form of a solution, suspension, colloid or semi-solid. 3. The injectable polymeric composition of claim 1, wherein the peptide agent comprises at least one alkali amine group. 4. The injectable polymeric composition of claim 1, wherein the peptide agent is selected from the group consisting of oxytocin, angiotensin, adrenocortical hormone (ACTH), epithelial growth factor (EGF), and platelet-derived growth factor (pDGF). , prolactin, luteinizing hormone, luteinizing hormone releasing hormone (LHRH), LHRH agonist, LHRH antagonist, growth hormone, growth hormone releasing factor, insulin 'erythropoietin, somatostatin, somatostatin, liter Glucosin, interleukin, interferon alpha, interferon, interferon, gastric hormone, four stomach hormones, five stomach hormones, urinary gastrin, small 47 1166-8751-PF3 1376241 revised on September 5, 101 Replacement page, No. 096U 0525 Enterotriene, blood-lowering hormone, brain _ β too (enkepha 1 ins), intracerebral _, cytokinin, gonadotropin releasing hormone (TRH), tumor necrosis factor (TNF), S·] thyroxine (PTH), nerve growth factor (NGF), granulocyte-colony stimulating factor (G-CSF), granulocyte-macrophage-bacterial stimulating factor (GM-CSF), giant嗟 cell-colony stimulating factor (M_CS) F), heparinase, blood's official endothelial growth factor (VEG-F), bone morphogenetic protein (BMP), hANP, glucagon peptide (GLP-1), exenatide, peptide Γγ(ργγ), renal enzyme, vasopressin kinase, bacitracin, polymyxin, pheromone, bacillus tyrosin, chlorfenapyr, cyclosporin, cytokines, antibodies, epidemics, antibiotics , antibody glycoprotein, follicle stimulating hormone, kyotorphin, taftsin, thymopoletin, thymus hormone thymostimul in, thymus fluid factor, serum thymus Factor, colony stimulating factor, motilin, omourous peptide (bombesiη), dinorphi η, angiotensin, cerulein, urokinase, kallikrein, substance ρ Analogs and antagonists, angiotensin 11, blood coagulation factors v 11 and IX, chlorfenapyr, melanin-stimulating hormone, scorpion stimulating hormone, scorpion stimulating hormone, incretin, contraction Cholecystokinin, human placental prolactin, human chorionic Hormones, protein synthesis stimulating peptide, gastric inhibitory peptide, a half pipe intestinal peptide, platelet derived growth factor, and synthetic analogues and pharmaceutically active fragments of these. 5. The injectable polymeric composition of claim 3, wherein the peptide agent has a nitrogen end of a non-primary amine. 6. Injectable polymeric composition as claimed in claim 5, wherein 1166-8751-PF3 48 September 5, revised amendment page 1372241 _ 该 该 The peptide agent is selected from luteinizing hormone releasing hormone (LHRH) , LHRH analogs, antagonists, and agonists. 7. The injectable polymeric composition of claim 5, wherein the peptide agent is selected from the group consisting of leuprorelin, buserelin, gonadorelin, and teslorin (deslorelin), fertirelin, histlin, 'lutrelin', goserelin, nafarelin, triptorelin ), cetrorel ix, enfuvirtide, thymosin ab and abarelix. 8. The injectable polymeric composition of claim 1, wherein the peptide agent has a nitrogen-terminal primary amine group and/or a side chain primary amine covalently modified with a hydrophilic moiety. The injectable polymeric composition of claim 8, wherein the hydrophilic portion comprises any water-soluble linear or branched chain polymer or polymer having a molecular weight of about 5 〇〇 Darton (dalt〇n) to about 5 0,0 0 0 Darden. 10. The injectable polymeric composition of claim 8 wherein the hydrophilic moiety is polyethylene glycol and/or a derivative thereof. 11. The injectable polymeric composition of claim 3, wherein the peptide agent has a phenolic moiety covalently modified (iv) a nitrogen-terminal primary amine group and/or a side chain primary amine. 12. The lipophilic moiety is selected from the group consisting of C2-39-alkyl, a/polymeric polymeric composition, Cm-alkenyl, c2-39-dienyl, 49 1166- 8751-PF3 1376241 Revised replacement page, September 5, 101. No. 096110525 and sterol residues. 01重量重量至约40重量百分比。 The composition of the composition of the composition of the present invention, wherein the composition is about 0.01% by weight to about 40% by weight. 14. The injectable polymeric composition of claim 1, wherein the biodegradable polymer is selected from the group consisting of polylactone, polyglycolic acid, poly(lactic acid-glycolic acid) copolymer, polycaprolactone , polydixanone (polydifluorene), polycarbonate, polybutylene acrylate, polyalkylene oxalate, polyanhydride, polyester decylamine, _polyurethane, polyacetal, poly O-carbonate, polyphosphazenes, polyvalerate, polyalkylene succinate, poly-o-ester, and copolymers, block copolymers, branched copolymers, terpolymers, and the like Combinations and mixtures. 15. The injectable polymeric composition of claim 1, wherein - the biodegradable polymer has a ratio of lactic acid to glycolic acid monomer of from about 50:50 to about 1 :?, and A poly(lactic-glycolic acid) copolymer having an average molecular weight of about 2 Å to about 1 Å. The injectable polymeric composition of claim 15, wherein the poly(lactic-glycolic acid) copolymer comprises a hydroxyl end group, a carboxyl end group, or an ester end group. 17. The injectable polymeric composition of claim 15 wherein the poly(lactic-glycolic acid) copolymer comprises a monofunctional alcohol residue or a polyol residue but no carboxylic acid end. The polymeric composition is present in % by weight to 70% by weight. a polymeric composition, wherein the injectable biodegradable polymer according to claim 1 is about 3 〇 1 9 - injectable 1166-8751-PF3 50 as claimed in claim 1 13/5241 K) September 5, 1 revision replacement page No. 096110525 The drug is dry and organic solvent is selected from N_methyl_2_pyrrolidone, dimercaptosulfone, glycerol f〇rmal ' 克 寇 寇 罗 罗 gi gi gi gi gi gi gi gi gi gi gi gi gi gi gi gi gi gi gi gi gi gi gi gi gi gi gi gi gi gi gi gi gi gi gi gi gi gi gi gi gi Triacetin, diacetin, triethyl citrate, triethyl citrate, and mixtures thereof. 20. The injectable polymeric composition of claim 1 wherein the pharmaceutically acceptable organic solvent is from about 30% to about 80% by weight of the composition. 21. The injectable polymeric composition of claim 1 further comprising one or more release rate modifiers. 2 2. The injectable polymeric composition according to claim 21, wherein the release rate adjusting agent is selected from the group consisting of an alkanoic acid, an oleic acid, an alkyl alcohol, a polar lipid, a surfactant, a polyethylene glycol Copolymer of alcohol and polylactic acid or polylactic acid glycolic acid copolymer, Pluol polymer (P〇l〇xamers), polyethylene benzophenone, I sorbitol, 2-ethoxyacetic acid ethyl vinegar, three Triacetin, citric acid, triacetic acid, tributyl citrate, triethyl citrate, glycerol, glycerol, glycerol, poly Ethylene glycol, sorbitol, triglycerides, intermediate chain triglycerides, and mixtures thereof. 23. The injectable polymeric composition of claim 1 further comprising one or more buffering agents. 24. The injectable polymeric composition of claim 23, wherein the buffering agent is selected from the group consisting of carbonic acid fishing, barium hydroxide, barium merate, oleic acid momate, calcium palmitate, calcium stearate, calcium phosphate , magnesium carbonate, magnesium hydroxide, magnesium phosphate, meat stem magnesium citrate, magnesium oleate, magnesium palmitate, magnesium stearate, zinc carbonate, 1166-8751-PF3 51 1376241 September 5, 2011 revised replacement page No. 096110525, zinc hydroxide, zinc oleate, zinc oleate, brown-zinc, stearic acid, and the combination thereof. 25. The injectable polymeric composition of claim i, further comprising one or more antioxidants. 26. The injectable polymeric composition of claim 25, wherein the antioxidant is selected from the group consisting of d-alpha erythroic acid, septic acid brown vinegar, and hydroxyanid 〇le), butylated hydroxyanisole, butylated hydroxyquinone, hydroxycoumarin, butylated hydroxymethyl I, ethyl gallate, propyl gallate, gallic acid g|, lauryl gallate, propyl benzoic acid, benzoquinone, vitamin E, pEG vitamin E and vitamin E-TPGS. 2 7. An injectable polymeric composition comprising: a) a hydrochloride or methanesulfonate of an LHRH antagonist or agonist; b) a poly(lactic-glycolic acid) copolymer, wherein the copolymer Lactic acid: a glycolic acid ratio of 50:50 to about 1 〇〇: 〇; c) N-methyl-2-vallopone (nmp); and d) triglyceride and/or vitamin E. 28. The injectable polymeric composition of claim 27, wherein the LHRH antagonist or agonist is selected from the group consisting of leuprorelin 'bererelin, gonadorelin, Deslo Relin, fertirelin 'histreHn, lutrelin' goserelin, nafarelin 'Cuipu Tourtlin (tript〇relin), Cyrus Ricky 1166-8751-PF3 52 September 5, 2003 Correction replacement page 1372241 __ (cetrorelix), infuvirtide, thymosin ( Thymosin) αΐ, or abarelix aba29. A method of making an injectable polymeric composition to form a sustained controlled release system that delivers a therapeutic amount of a peptide agent, including the following steps: a· Dissolving a water-insoluble biodegradable polymer in a pharmaceutically acceptable organic solvent; b. combining and mixing the peptide salt formed with the strong acid with the polymer solution of step a) to form an injectable composition; The strong acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, and hydroiodic acid. Sulfuric acid, nitric acid, chromic acid, methanesulfonic acid, trifluoromethanesulfonic acid, trichloroacetic acid, dichloroacetic acid, bromoacetic acid, gaseous acetic acid, cyanoacetic acid, 2-chloropropionic acid, 2-ketobutyric acid, 2-air butyl • Acid, 4-cyanobutyric acid, peroxyacid, and acid breaker, wherein 'the peptide agent has a nitrogen end of a non-primary amine, and the peptide agent contains at least one base. 30. The method of claim 29, wherein the biodegradable polymer is dissolved in a pharmaceutically acceptable organic solvent with one or more pharmaceutically acceptable excipients. 31. A method of manufacture as a polymeric composition of a sustained controlled release system for delivering a therapeutic amount of an individual peptide agent comprising: a. dissolving a water insoluble biodegradable polymer in an organic solvent b. forming a strong acid The peptide salt is dissolved or suspended in the step of the polymer solution to form a single type formulation; and A c. open &gt; into microparticles or nanoparticles, including the biological U66-containing the peptide agent 8751-PF3 53 1376241 v No. 096110525, September 5, 101, revised replacement page decomposable polymer; wherein the strong acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, hydrogen acid decomposing, sulfuric acid, nitric acid, chromic acid, methanesulfonic acid, Trifluoromethanesulfonic acid, tri-gas acetic acid, di-gas acetic acid, • bromoacetic acid, chloroacetic acid, cyanoacetic acid, 2-propionic acid, 2-ketobutyric acid 2- 2-butyric acid, 4-cyanobutyric acid, Gas acid and phosphoric acid, wherein the peptide agent has a nitrogen terminal of a non-primary amine 'and the peptide agent contains at least one thiol group. 3 2. A method for the manufacture of a polymeric composition of a controlled release system to deliver a therapeutic amount of an individual peptide agent, comprising: a. dissolving a water-insoluble biodegradable polymer in an organic solvent; Dissolving or suspending a peptide salt formed with a strong acid in the polymerization solution of step a) to form a single type formulation; and c. forming a solid polymer matrix comprising the water-insoluble organism encapsulating the peptide agent a decomposable polymer; φ wherein the strong acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, chromic acid, methyl benzoic acid, trifluoromethyl acid, trigastric acid, dichloroacetic acid, bromine Acetic acid, gaseous acetic acid, cyanoacetic acid, 2-chloropropionic acid, 2-ketobutyric acid 2- 2-butyric acid, 4-cyanobutyric acid, peroxyacid and phosphoric acid, wherein 'the peptide agent has a nitrogen terminal of a non-primary amine And, the peptide agent contains at least one base. 33. The method of claim 32, wherein the solid polymer matrix is microparticles, nanoparticles, rods, films, abrasive particles, cylinders, or wafer types. </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; Subcutaneous or intramuscular injection or insertion; or inhalation. 1166-8751-PF3 55 1376241 096:10525 r &gt; c G ο o O QJ (o 4 2&lt;ivl&gt;l-r-=v_l 4〇: 300 *200 150G 2000 2400 Figure 3 &lt;%h-!arp!lsQ.nal)4::c:§fsi/g: —一0—I Ti ο 3