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    • 专利摘要:
    A process for producing a sustained-releasecomposition which comprises mixing an aqueous solutioncontaining a physiologically active substance and an acidor base in a molar amount of 1.5 or more times that of thephysiologically active substance with a solution of abiodegradable polymer and then drying the mixture isprovided.
    公开号:EP1532985A1
    申请号:EP03760937
    申请日:2003-06-24
    公开日:2005-05-25
    发明作者:Kazumichi Yamamoto；Kazuhiro Saito；Tetsuo Hoshino
    申请人:Takeda Pharmaceutical Co Ltd；
    IPC主号:A61K-38
    专利说明:
    [0001] The present invention relates to a process forproducing a sustained-release composition comprising aphysiologically active substance and a biodegradablepolymer, a sustained-release composition produced thereby,and the like. Background Art
    [0002] JP-A 57-118512, JP-A 57-150609 and JP-A 6-145046disclose a method of producing a sustained-releasemicrocapsule from a W/O type emulsion using a biodegradablepolymer.
    [0003] A sustained-release biodegradable polymer is useful as,for example, a base material for a physiologically activesubstance-enclosing microcapsule or the like. It is knownthat polylactic acid, a copolymer of lactic acid andglycolic acid or the like is useful as such a biodegradablepolymer (e.g., JP-A 11-269094).
    [0004] JP-A 7-97334 discloses a sustained-release preparationcomprising a physiologically active substance or a saltthereof and a biodegradable polymer having terminalcarboxyl, and a process for producing the sustained-releasepreparation.
    [0005] An object of the present invention is to provide aprocess for producing a sustained-release composition whichallows stable formation of a W/O type emulsion, asustained-release composition produced by said process, andthe like. Disclosure of Invention
    [0006] Under such circumstances, the present inventorsintensively studied in order to develop a process forproducing a sustained-release composition which allowsstable formation of a W/O type emulsion. As a result, theyfound that a W/O type emulsion can be stabilized by usingan aqueous solution containing an excess amount of an acidor base relative to a physiologically active substance.Based on this finding, they further studied and finallycompleted the present invention.
    [0007] That is, the present invention provides: (1) a method for producing a sustained-release composition,which comprises mixing an aqueous solution containing aphysiologically active substance and an acid or base in amolar amount of about 1.5 or more times that of thephysiologically active substance with a solution of abiodegradable polymer, and then drying the mixture; (2) the method according to the above (1), wherein the aqueous solution is obtained using a salt of thephysiologically active substance with the acid or base; (3) the method according to the above (1), wherein theproportion of the physiologically active substance in thesustained-release composition is about 0.001 to about 50%by weight; (4) a method for stabilizing a mixture of an aqueoussolution containing a physiologically active substance anda solution of a biodegradable polymer, which comprisesadding an acid or base in a molar amount of about 1.5 molor more times that of the physiologically active substance; (5) a method for allowing a mixture of an aqueous solutioncontaining a physiologically active substance and asolution of a biodegradable polymer to have a viscosity ofabout 3,000 cp or less, which comprises adding an acid orbase in a molar amount of about 1.5 mol or more times thatof the physiologically active substance; (6) the method according to any one of the above (1), (4)and (5), wherein the physiologically active substance is aphysiologically active peptide; (7) the method according to the above (6), wherein thephysiologically active peptide is an LH-RH derivative; (8) the method according to the above (7), wherein the LH-RHderivative is a compound represented by the generalformula:
    [0008] Fig. 1 is a photograph showing the appearance of W/Otype emulsions prepared in Experimental Example 2. Thenumerical values below the photograph represent the molarratios of acetic acid to a drug.Fig. 2 is a graph showing relationship between thetime of emulsification and the viscosity of a W/O typeemulsion in a case where acetic acid was used in a molar amount of 1.5 or more times that of peptide A inExperimental Example 6.
    [0009] The cases where the molar ratios of acetic acid to adrug are 1.4, 1.6, 1.8, 2.3 and 2.8 are shown from the left.
    [0010] A physiologically active substance to be used in thepresent invention is not particularly limited as long as itis pharmaceutically useful, and may be a non-peptidecompound or a peptide compound. Examples of the non-peptidecompound include an agonist, an antagonist, and acompound having enzyme inhibiting activity. The peptidecompound may be an agonist or an antagonist and may be, forexample, preferably a physiologically active peptide,suitably a physiologically active peptide having amolecular weight of about 300 to about 40,000, preferablyabout 400 to about 30,000, more preferably about 500 toabout 20,000.
    [0011] The proportion of a physiologically active substancein the composition of the present invention variesdepending on the kind of a physiologically active substanceto be used, the desired pharmacological effect, duration ofthe effect and the like and not particularly limited. Forexample, it is about 0.001 to about 50% by weight,preferably about 0.02 to about 40% by weight, morepreferably about 0.1 to about 30% by weight, even more preferably about 0.1 to about 24% by weight, mostpreferably about 5 to about 24% by weight of the totalweight of the composition.
    [0012] Examples of the physiologically active substanceinclude, but not limited to, physiologically activepeptides, antitumor agents, antibiotics, antipyretic agents,analgesics, anti-inflammatory agents, antitussiveexpectorants, sedatives, muscle relaxants, antiepilepticagents, antiulcer agents, antidepressants, anti-allergicagents, cardiotonics, antiarrhythmic agents, vasodilators,hypotensive diuretics, antidiabetics, anticoagulants,hemostatics, antitubercular agents, hormone agents,narcotic antagonists, bone resorption suppressors, andangiogenesis inhibitors.
    [0013] Examples of the physiologically active peptide includeluteinizing hormone-releasing hormone (LH-RH), insulin,somatostatin, growth hormones, growth hormone-releasinghormone (GH-RH), prolactin, erythropoietin, adrenocorticalhormone, melanocyte-stimulating hormone, thyroid hormone-releasinghormone (TRH), thyroid-stimulating hormone,luteinizing hormone, follicle-stimulating hormone,vasopressin, oxytocin, calcitonin, gastrin, secretin,pancreozymin, cholecystokinin, angiotensin, human placentallactogen, human chorionic gonadotropin, enkephalin,endorphin, kyotorphin, tuftsin, thymopoietin, thymosin, thymostimulin, thymic humoral factor, blood thymic factor,tumor necrosis factor, colony-stimulating factors, motilin,dynorphin, bombesin, neurotensin, caerulein, bradykinin,atrial natriuretic factor, nerve growth factor, cell growthfactor, neurotrophic factor, peptides having endothelinantagonism and derivatives thereof, and fragments thereofand derivatives of such fragments.
    [0014] The physiologically active peptide may be also an LH-RHantagonist (see U.S. Patent Nos. 4,086,219, 4,124,577,4,253,997, and 4,317,815).
    [0015] Further examples of the physiologically active peptideinclude insulin, somatostatin, somatostatin derivatives(see U.S. Patent Nos. 4,087,390, 4,093,574, 4,100,117, and4,253,998), growth hormone, prolactin, adrenocorticotropichormone (ACTH), melanocyte-stimulating hormone (MSH),thyroid hormone-releasing hormone [represented by thestructural formula: (Pyr)Glu-His-ProNH2, hereinafter alsoreferred to as TRH] and salts and derivatives thereof (seeJP-A 50-121273 and JP-A 52-116465), thyroid-stimulatinghormone (TSH), luteinizing hormone (LH), follicle-stimulatinghormone (FSH), vasopressin, vasopressinderivatives [desmopressin, see ENDOCRINE JOURNAL, Vol. 54,No. 5, pp. 676-691 (1978)], oxytocin, calcitonin,parathyroid hormone, glucagon, gastrin, secretin,pancreozymin, cholecystokinin, angiotensin, human placental lactogen, human chorionic gonadotropin (HCG), enkephalin,enkephalin derivatives (see U.S. Patent No. 4,277,394 andEuropean Patent Publication No. 31567), endorphin,kyotorphin, interferons (e.g., α-, β-, and γ-interferons),interleukins (e.g., I, II, and III), tuftsin, thymopoietin,thymosin, thymostimulin, thymic humoral factor (THF), bloodthymic factor (FTS) and a derivative thereof (see U.S.Patent No. 4,229,438), other thymic factors [Igaku no AyumiVol. 125, No. 10, pp. 835-843 (1983)], tumor necrosisfactor (TNF), colony-stimulating factor (CSF), motilin,dynorphin, bombesin, neurotensin, cerulein, bradykinin,urokinase, asparaginase, kallikrein, substance P, nervegrowth factor, cell growth factor, neurotrophic factor,blood coagulation factors VIII and IX, lysozyme chloride,polymyxin B, colistin, gramicidin, bacitracin,erythropoietin (EPO), and endothelin-antagonistic peptides(see European Patent Publication Nos. 436189, 457195, and496452 and JP-A 3-94692 and JP-A 3-130299).
    [0016] Examples of the antitumor agent include bleomycin,methotrexate, actinomycin D, mitomycin C, binblastinsulfate, bincrystin sulfate, daunorubicin, adriamycin,neocartinostatin, cytosine arabinoside, fluorouracil,tetrahydrofuryl-5-fluorouracil, krestin, picibanil,lentinan, levamisole, bestatin, azimexon, glycyrrhizin,polyI:C, polyA:U, and polyICLC.
    [0017] Examples of the antibiotic include gentamicin,dibekacin, kanendomycin, lividomycin, tobramycin, amikacin,fradiomycin, sisomycin, tetracycline hydrochloride,oxytetracycline hydrochloride, rolitetracycline,doxycycline hydrochloride, ampicillin, piperacillin,ticarcillin, cefalothin, cefaloridine, cefotiam, cefsulodin,cefmenoxime, cefmetazole, cefazolin, cefotaxime,cefoperazon, ceftizoxime, moxalactam, thienamycin,sulfazecin, and aztreonam.
    [0018] Examples of the antipyretic agent, analgesic and anti-inflammatoryagent include salicylic acid, sulpyrine,flufenamic acid, diclofenac, indomethacin, morphine,pethidine hydrochloride, levorphanol tartrate, andoxymorphone.
    [0019] Examples of the antitussive expectorant includeephedrine hydrochloride, methylephedrine hydrochloride,noscapine hydrochloride, codeine phosphate, dihydrocodeinephosphate, alloclamide hydrochloride, clofedanolhydrochloride, picoperidamine hydrochloride, chloperastine,protokylol hydrochloride, isoproterenol hydrochloride,sulbutamol sulfate, and terbutaline sulfate.
    [0020] Examples of the sedative include chlorpromazine,prochlorperazine, trifluoperazine, atropine sulfate, andmethylscopolamine bromide.
    [0021] Examples of the muscle relaxant include pridinol methanesulfonate, tubocurarine chloride and pancuroniumbromide.
    [0022] Examples of the antiepileptic agent include phenytoin,ethosuximide, acetazolamide sodium, and chlordiazepoxide.
    [0023] Examples of the antiulcer agent include metoclopramideand histidine hydrochloride.
    [0024] Examples of the antidepressant include imipramine,clomipramine, noxiptiline, and phenelzine sulfate.
    [0025] Examples of the anti-allergic agent includediphenhydramine hydrochloride, chlorpheniramine maleate,tripelennamine hydrochloride, methdilazine hydrochloride,clemizole hydrochloride, diphenylpyraline hydrochloride,and methoxyphenamine hydrochloride.
    [0026] Examples of the cardiotonic include trans-n-oxocamphor,theophyllol, aminophylline, and etilefrine hydrochloride.
    [0027] Examples of the antiarrhythmic agent includepropranolol, alprenolol, bufetolol, and oxprenolol.
    [0028] Examples of the vasodilator include oxyfedrinehydrochloride, diltiazem, tolazoline hydrochloride,hexobendine, and bamethan sulfate.
    [0029] Examples of the hypotensive diuretic includehexamethonium bromide, pentolinium, mecamylaminehydrochloride, ecarazine hydrochloride, and clonidine.
    [0030] Examples of the antidiabetic include glymidine sodium,glipizide, phenformin hydrochloride, buformin hydrochloride, and metformin.
    [0031] Examples of the anticoagulant include heparin sodiumand sodium citrate.
    [0032] Examples of the hemostatic include thromboplastin,thrombin, menadione sodium hydrogen sulfite,acetomenaphthone, ε-aminocaproic acid, tranexamic acid,carbazochrome sodium sulfonate, and adrenochromemonoaminoguanidine methanesulfonate.
    [0033] Examples of the antitubercular agent include isoniazid,ethambutol and para-aminosalicylic acid.
    [0034] Examples of the hormone agent include predonisolone,predonisolone sodium phosphate, dexamethasone sodiumsulfate, betamethasone sodium phosphate, hexestrolphosphate, hexestrol acetate, and methimazole.
    [0035] Examples of the narcotic antagonist includelevallorphan tartrate, nalorphine hydrochloride andnaloxone hydrochloride.
    [0036] Examples of the bone resorption suppressor include(sulfur-containing alkyl)aminomethylenebisphosphonic acid.
    [0037] Examples of the angiogenesis inhibitor includeangiogenesis-inhibiting steroids [see Science, Vol. 221, p.719 (1983)], fumagillin (see European Patent ApplicationLaid-Open No. 325199), and fumagillol derivatives (seeEuropean Patent Application Laid-Open Nos. 357061, 359036,386667 and 415294).
    [0038] Preferred examples of the physiologically activepeptide include LH-RH derivatives effective againsthormone-dependent diseases, especially sex hormone-dependentcancer (such as prostatic cancer, uterus cancer,breast cancer, and pituitary tumor) or sex hormone-dependentdiseases such as prostatic hypertrophy,endometriosis, hysteromyoma, precocious puberty,dysmenorrhea, amenorrhea, premenstrual syndrome andmultilocular ovarian syndrome; LH-RH derivatives effectivefor contraception (or infertility, if a rebound effect isused after the drug holiday); LH-RH derivatives effectivein preventing recurrence of breast cancer after anoperation for premenopausal breast cancer; and LH-RHderivatives effective against Alzheimer's disease orimmunodeficiency disease; or salts thereof. Additionalexamples include LH-RH derivatives effective against benignor malignant tumor that is not sex hormone-dependent butsensitive to LH-RH.
    [0039] Specific examples of the LH-RH derivatives includepeptides as disclosed in "Treatment with GnRH analogs:Controversies and perspectives" published by The ParthenonPublishing Group Ltd., 1996, JP-A 3-503165, JP-A 3-101695,JP-A 7-97334 and JP-A 8-259460.
    [0040] The LH-RH derivative may be an LH-RH agonist or LH-RH antagonist. Examples of an LH-RH antagonist includepeptides represented by the general formula [I]:X-D2Nal-D4ClPhe-D3Pa1-Ser-A-B-Leu-C-Pro-DAlaNH2wherein X represents N(4H2-furoyl)Gly or NAc, A representsa residue selected from NMeTyr, Tyr, Aph(Atz) andNMeAph(Atz), B represents a residue selected from DLys(Nic),DCit, DLys(AzaglyNic), DLys(AzaglyFur), DhArg(Et2),DAph(Atz) and DhCi, and C represents Lys(Nisp), Arg orhArg(Et2); abarelix, degarelix, antarelix, iturelix,orntide, cetrorelix, or ganirelix, or a salt thereof.
    [0041] Examples of a non-peptidic LH-RH antagonist includenon-peptidic LH-RH antagonists described in WO 95/28405(JP-A 8-295693), WO 97/14697 (JP-A 9-169767), WO 97/14682(JP-A 9-169735) or WO 96/24597 (JP-A 9-169768),thienopyridine compounds (e.g., 3-(N-Benzyl-N-methylaminomethyl)4,7-dihydro-5-isobutyryl-7-(2,6-difluorobenzyl)-2-[4-[(1-hydroxycyclopropyl)carbonylamino]phenyl]-4-oxothieno[2,3-b]pyridinedescribed in WO 00/00493), thienopyrimidinecompounds (e.g., 5-(N-benzyl-N-methylaminomethyl)-1-(2,6-difluorobenzyl)-6-[4-(3-methoxyureido)phenyl]-3-phenylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dionedescribed inWO 00/56739), and 5-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenyl)methyl]-N-(2,4,6-trimethoxyphenyl)-2-furamide(American Association for Cancer Research (AACR), 2002. 4.6-10).
    [0042] Examples of an LH-RH agonist include physiologicallyactive peptides represented by the general formula [II]:5-oxo-Pro-His-Trp-Ser-Tyr-Y-Leu-Arg-Pro-Zwherein Y represents a residue selected from DLeu, DAla,DTrp, DSer(tBu), D2Nal and DHis(ImBzl) and Z represents NH-C2H5or Gly-NH2, and so on. Particularly preferred is apeptide wherein Y is DLeu and Z is NH-C2H5 (that is,peptide A represented by the formula: 5-oxo-Pro-His-Trp-Ser-Tyr-DLeu-Leu-Arg-Pro-NH-C2H5)or a salt, in particularacetate thereof (leuprorelin acetate).
    [0043] Preferred specific examples of an LH-RH agonist otherthan leuprorelin mentioned above include: (1) Buserelin
    [0044] The abbreviations used in this specification aredefined as follows: Abbreviations Names N(4H2-furoyl)Gly N-tetrahydrofuroylglycine residue NAc N-acetyl group D2Nal D-3-(2-naphthyl)alanine residue D4ClPhe D-3-(4-chloro)phenylalanine residue D3Pal D-3-(3-pyridyl)alanine residue NMeTyr N-methylthyrosine residue Aph(Atz) N-[5'-(3'-amino-1'H-1',2',4'-triazolyl)]phenylalanine residue NMeAph(Atz) N-methyl-[5'-(3'-amino-1'H-1',2',4'-triazolyl)]phenylalanine residue DLys(Nic) D-(e-N-nicotinoyl)lysine residue Dcit D-citrulline residue DLys(AzaglyNic) D-(azaglycylnicotinoyl)lysine residue DLys(AzaglyFur) D-(azaglycylfuranyl)lysine residue DhArg(Et2) D-(N,N'-diethyl)homoarginine residue DAph(Atz) D-N-[5'-(3'-amino-1'H-1',2',4'-triazolyl)]phenylalanine residue DhCi D-homocitrulline residue Lys(Nisp) (e-N-isopropyl)lysine residue hArg(Et2) (N,N'-diethyl)homoarginine residue
    [0045] Abbreviations for other amino acids are according tothose defined by the IUPAC-IUB Commission on Biochemical Nomenclature or defined in European Journal of BiochemistryVol. 138, pp. 9-37, 1984 or according to conventionalabbreviations in the field. Although amino acids may haveoptical isomers, they are represented in L-configurationunless otherwise specified.
    [0046] The "acid or base" of "an aqueous solution containinga physiologically active substance and an acid or base in amolar amount of about 1.5 or more times that of thephysiologically active substance" and "an acid or base inan amount of about 0.1 to about 20% by weight of saidaqueous solution", when used in the present invention, maybe any acid or base generally used for production and maybe an inorganic acid, an organic acid, an inorganic base,an organic base, an acidic or basic amino acid, or the like.The "acid or base" is preferably an acid, more preferablyan organic acid.
    [0047] Preferred examples of an inorganic acid includehydrochloric acid, hydrobromic acid, nitric acid, sulfuricacid and phosphoric acid. Preferred examples of an organicacid include sulfonic acids such as methanesulfonic acid,benzenesulfonic acid and p-toluenesulfonic acid; fattyacids such as formic acid, acetic acid and propionic acid;aliphatic dicarboxylic acids such as oxalic acid, malonicacid and succinic acid; unsaturated fatty acids such as acrylic acid, fumaric acid and maleic acid; carbocycliccarboxylic acids such as phthalic acid, isophthalic acidand terephthalic acid; and substituted carboxylic acidssuch as trifluoroacetic acid, tartaric acid, citric acid,malic acid, lactic acid and glycolic acid. Among them,fatty acids, lactic acid and glycolic acid are morepreferably used, and acetic acid is particularly preferablyused. Preferred examples of an acidic amino acid includeaspartic acid and glutamic acid. Preferred examples of abasic amino acid include arginine, lysine and ornithine.Preferred examples of an inorganic base include alkalimetals such as sodium and potassium; alkaline earth metalssuch as calcium and magnesium; alkali metal hydrides suchas lithium hydride, potassium hydride and sodium hydride;inorganic hydroxides such as lithium oxide, potassiumhydroxide, sodium hydroxide and calcium hydroxide;carbonates such as sodium carbonate, potassium carbonateand sodium acid carbonate; aluminum, and ammonium.Preferred examples of an organic base include metalalkoxides having 1 to 6 carbon atoms, such as lithiumethoxide, lithium-tert-butoxide, sodium methoxide, sodiumethoxide and potassium-tert-butoxide; metal phenoxides suchas potassium phenoxide and sodium phenoxide; acetates suchas sodium acetate and potassium acetate; organic lithiumsalts such as n-butyl lithium, t-butyl lithium and diethylamino lithium; hydrazines such as phenylhydrazineand p-tolylhydrazine; amidines; quaternary ammoniumhydroxides; sulfonium bases; and amines such astrimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine,ethanolamine, diethanolamine, triethanolamine,cyclohexylamine, dicyclohexylamine and N,N'-dibenzylethylenediamine.
    [0048] When the "acid" is an organic acid, its pKa is notparticularly limited and it is, for example, preferably inthe range of about 0.1 to about 6.0, more preferably in therange of about 1.0 to about 6.0, even more preferably inthe range of about 3.5 to about 6.0.
    [0049] In the present invention, the aqueous solution maycontain the "acid or base" independently of aphysiologically active substance or in the form of a saltwith a physiologically active substance. Alternatively,the aqueous solution may contain both a salt of aphysiologically active substance with the "acid or base"and the "acid or base" independent of a physiologicallyactive substance.
    [0050] As described above, a physiologically active substancemay be used as it is or as a pharmacologically acceptablesalt thereof in the present invention.
    [0051] Such a salt includes, when the physiologically active substance has a basic group such as an amino group, saltswith inorganic acids (also referred to as inorganic freeacids) (e.g., carbonic acid, bicarbonic acid, hydrochloricacid, sulfuric acid, nitric acid, boric acid, etc.) andsalts with organic acids (also referred to as organic freeacids) (e.g., succinic acid, acetic acid, propionic acid,trifluoroacetic acid, etc.). When the physiologicallyactive substance is an LH-RH derivative, such a salt ispreferably acetate. For example, leuprorelin acetate orthe like is preferred.
    [0052] Such a salt includes, when the physiologically activesubstance has an acidic group such as a carboxyl group,salts with inorganic bases (also referred to as inorganicfree bases) (e.g., alkali metals such as sodium andpotassium; alkaline earth metals such as calcium andmagnesium, etc.) and salts with organic bases (alsoreferred to as organic free bases) (e.g., organic aminessuch as triethylamine, basic amino acids such as arginine,etc.). The physiologically active peptide may also form ametal complex compound (e.g., a copper complex, a zinccomplex, etc.).
    [0053] These compounds or salts thereof can be producedaccording to methods described in the above-mentionedliteratures or patent gazettes or methods similar to them.
    [0054] The amount used of the "acid or base" is about 1.5 molor more, preferably about 1.5 mol to about 5 mol, morepreferably about 1.65 mol to about 3 mol per 1 mol of the"physiologically active substance".
    [0055] In the present invention, the proportion (% by weight)of the "acid or base" in the "aqueous solution" is notparticularly limited as long as an effect of the presentinvention is exerted and is preferably about 0.1 to about20% by weight, more preferably about 1 to about 15% byweight, even more preferably about 3 to about 10% by weight.
    [0056] As described above, the "acid or base" may be addedindependently or in the form of a salt with aphysiologically active substance to the aqueous solution.Alternatively, adding the "acid or base" independently andadding a salt of a physiologically active substance withthe "acid or base" may be combined.
    [0057] A biodegradable polymer to be used in the presentinvention is preferably a biodegradable polymer. Examplesof such a biodegradable polymer include aliphaticpolyesters [such as homopolymers (e.g., lactic acidpolymer) or copolymers (e.g., lactic acid/glycolic acidcopolymer and 2-hydroxybutyric acid/glycolic acidcopolymer) of two or more of α-hydroxy acids (e.g.,glycolic acid, lactic acid, 2-hydroxybutyric acid, 2-hydroxyvaleric acid, 2-hydroxy-3-methylbutyric acid, 2-hydroxycaproicacid, 2-hydroxyisocaproic acid, 2-hydroxycaprylicacid, etc.), cyclic dimers of α-hydroxyacid (e.g., glycolide, lactide, etc.), hydroxydicarboxylicacids (e.g., malic acid) and hydroxytricarboxylic acid(e.g., citric acid), or mixtures of the homopolymers and/orthe copolymers (e.g., a mixture of a lactic acid polymerand a 2-hydroxybutyric acid/glycolic acid copolymer,etc.)]; poly-α-cyanoacrylate ester, polyamino acid (e.g.,poly-γ-benzyl-L-glutamic acid, poly-L-alanine, poly-γ-methyl-L-glutamicacid, etc.), and maleic anhydridecopolymers (e.g., a styrene/ maleic acid copolymer, etc.).Preferred are aliphatic polyesters and poly-α-cyanoacrylateesters. Aliphatic polyesters are particularly preferred.Among aliphatic polyesters, preferred are polymers orcopolymers having free terminal carboxyl which aresynthesized from one or more of α-hydroxycarboxylic acidssuch as α-hydroxymonocarboxylic acids (e.g., glycolic acid,lactic acid, etc.), α-hydroxydicarboxylic acids (e.g.,malic acid) and α-hydroxytricarboxylic acids (e.g., citricacid), or mixtures of these polymers and/or copolymers;poly(α-cyanoacrylic acid esters); polyamino acids (e.g.,poly(γ-benzyl-L-glutamic acid), etc.); and maleicanhydride-based copolymers (e.g., a styrene-maleic acidcopolymer).
    [0058] The polymerization type of monomers may be any ofrandom, block and graft types. When the above-mentioned α-hydroxymonocarboxylicacids, α-hydroxydicarboxylic acids,and α-hydroxytricarboxylic acids have an optically activecenter in their molecular structures, they may be in any ofD-, L-, and DL-form. Among them, preferred are lacticacid-glycolic acid polymers [hereinafter, also referred toas poly(lactide-co-glycolide), poly(lactic acid-co-glycolicacid), or lactic acid-glycolic acid copolymer; genericallyreferring to a lactic acid homopolymer, a glycolic acidhomopolymer, and a lactic acid-glycolic acid copolymer,unless indicated specifically; or a lactic acid homopolymeris also referred to as a lactic acid polymer, polylacticacid or polylactide, and a glycolic acid homopolymer isalso referred to as a glycolic acid polymer, polyglycolicacid, or polyglycolide], and poly(α-cyanoacrylic acidester). More preferred are lactic acid-glycolic acidpolymers, and even more preferred are lactic acid-glycolicacid polymers having free terminal carboxyl.
    [0059] The biodegradable polymer may be in the form of a salt.Examples of such a salt include salts with inorganic bases(e.g., alkali metals such as sodium and potassium, alkalineearth metals such as calcium and magnesium, etc.), saltswith organic bases (e.g., organic amines such as triethylamine, basic amino acids such as arginine, etc.),salts with transition metals (e.g., zinc, iron, copper,etc.) and complex salts.
    [0060] When a lactic acid-glycolic acid polymer is used asthe biodegradable polymer, the composition ratio (mol%) ispreferably in the range of 100/0 to about 40/60, morepreferably in the range of 100/0 to about 50/50. When thesustained-release composition of the present invention is along-term sustained-release microcapsule that releases aphysiologically active substance over 2 months or more, alactic acid polymer having a composition ratio of 100/0 isalso preferably used.
    [0061] The optical isomer ratio [D-form/L-form (mol/mol%)] oflactic acid, which is one of the minimum repeat units ofthe "lactic acid-glycolic acid polymer" is preferably inthe range of about 75/25 to about 25/75. In particular, alactic acid-glycolic acid polymer having a D-form/L-form(mol/mol%) ratio in the range of about 60/40 to about 30/70is generally used.
    [0062] The weight average molecular weight of the "lacticacid-glycolic acid polymer" is usually in the range ofabout 3,000 to about 100,000, preferably in the range ofabout 5,000 to about 50,000, more preferably in the rangeof about 8,000 to about 30,000, even more preferably in therange of about 17,000 to about 30,000.
    [0063] The degree of dispersion (weight average molecularweight/number average molecular weight) is usually in therange of about 1.1 to about 4.0, preferably in the range ofabout 1.2 to about 3.5. Herein, weight average molecularweights and degrees of dispersion are measured by gelpermeation chromatography (GPC). Specifically, the weightaverage molecular weight means a weight average molecularweight based on polystyrene determined by gel permeationchromatography (GPC) using monodisperse polystyrene as astandard, and the content of each polymer is calculatedusing the weight average molecular weight thus obtained.Measurements were carried out by using a high-performanceGPC apparatus (HLC-8120 GPC, manufactured by TosohCorporation) (column: Super H4000 x 2 and Super H2000(manufactured by Tosho Corportaion); mobile phase:tetrahydrofuran; flow rate: 0.6 mL/min). Detection iscarried out by differential refractometry.
    [0064] The amount of free terminal carboxyl contained in the"lactic acid-glycolic acid polymer" is preferably about 20to about 1,000 µmol, more preferably about 40 to about 300µmol per unit mass (gram) of the polymer.
    [0065] In the present invention, the molar amount of the freeterminal carboxyl of the biodegradable polymer ispreferably about 0.1 to about 5 times, more preferably about 0.2 to about 4 times, even more preferably about 0.3to about 3.5 times that of the "physiologically activesubstance".
    [0066] The amount of free terminal carboxyl described aboveis determined by a labeling method (hereinafter referred toas "the amount of carboxyl as determined by a labelingmethod"). Specifically, in the case of polylactic acid, Wmg of polylactic acid is dissolved in 2 mL of a 5 Nhydrochloric acid/acetonitrile (v/v=4/96) mixture, and 2 mLof a 0.01 M solution of o-nitrophenylhydrazinehydrochloride (ONPH) (5 N hydrochloricacid/acetonitrile/ethanol = 1.02/35/15) and 2 mL of a 0.15M solution of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimidehydrochloride (pyridine/ethanol = 4v/96v) areadded to react them at 40°C for 30 minutes. After thesolvent is removed, the residue is washed with water (x4)and then dissolved in 2 mL of acetonitrile, and 1 mL of a0.5 mol/L ethanolic solution of potassium hydroxide isadded to react them at 60°C for 30 minutes. The reactionmixture is diluted with a 1.5 N aqueous solution of sodiumhydroxide to Y mL. Absorbance A (/cm) at 544 nm ismeasured using a 1.5 N aqueous solution of sodium hydroxideas a control. The amount of free carboxyl (C mol/L)thereof is determined by alkali titration with an aqueoussolution of DL-lactic acid as a reference substance. When the absorbance at 544 nm of the DL-lactic hydrazideprepared by the ONPH labeling method is defined as B (/cm),the molar amount of free terminal carboxyl per unit mass(gram) of the polymer can be calculated by the followingformula:[COOH] (mol/g) = (AYC)/(WB).
    [0067] Although "the amount of carboxyl" can also bedetermined by dissolving the biodegradable polymer in atoluene-acetone-methanol mixed solvent and titrating thesolution for a carboxyl group with an alcoholic solution ofpotassium hydroxide using phenolphthalein as an indicator(hereinafter, a value determined by this method will bereferred to as "the amount of carboxyl as determined by analkali titration method"), it is preferably determined bythe labeling method described above because the end pointof the titration may be indefinite as a result ofcompetition with hydrolysis of the polyester main chainduring titration in the case of the alkali titration method.
    [0068] The "lactic acid-glycolic acid polymer" can beproduced by, for example, catalyst-free dehydrationpolycondensation from lactic acid and glycolic acid (JP-A61-28521) or ring-opening polymerization from cyclicdiester compounds such as lactide and glycolide by the useof a catalyst (Encyclopedic Handbook of Biomaterials andBioengineering Part A: Materials, Volume 2, Marcel Dekker, Inc. (1995)). Although a polymer obtained by the above-describedknown ring-opening polymerization method may nothave free terminal carboxyl, it can be modified so as tohave some carboxyl groups per unit mass by, for example,hydrolysis reaction described in EP-A-0839525 and then theresulting polymer can be used in the present invention.
    [0069] The above-described "lactic acid-glycolic acid polymerhaving free terminal carboxyl" can be produced by a knownmethod (e.g., catalyst-free dehydration polycondensationmethod; see JP-A 61-28521) or a method pursuant to it.
    [0070] A polymer used in the present invention is preferablya lactic acid polymer (hereinafter, also referred to as"the lactic acid polymer of the present invention") andexamples thereof include a lactic acid homopolymer andcopolymers of lactic acid and other monomers (e.g., acopolymer of lactic acid and glycolic acid). In the lacticacid polymer of the present invention, the content of apolymer having a weight average molecular weight of 5,000or less is usually about 10 wt% or less, preferably about 5wt% or less, but not limited to them.
    [0071] The weight average molecular weight of the lactic acidpolymer of the present invention is usually in the range of15,000 to 50,000, preferably in the range of 15,000 to40,000, more preferably in the range of 17,000 to 30,000.
    [0072] A high-molecular weight lactic acid polymer to be used as a raw material of the lactic acid polymer of the presentinvention may be commercially available or prepared by aknown polymerization method. The weight average molecularweight of the high-molecular weight lactic acid polymer isusually in the range of 15,000 to 500,000, preferably inthe range of 20,000 to 100,000. A known polymerizationmethod includes condensation polymerization of lactic acidtogether with, if necessary, glycolic acid; ring-openingpolymerization of lactide together with, if necessary,glycolide using a catalyst such as Lewis acid (e.g.,diethyl zinc, triethylaluminum, tin octylate, etc.) ormetal salts; the above described ring-openingpolymerization of lactide in the presence of ahydroxycarboxylic acid derivative in which the carboxylgroup is protected (e.g., WO 00/35990); ring-openingpolymerization of lactide using a catalyst under heating(e.g., J. Med. Chem, 16, 897 (1973)); and copolymerizationof lactide and glycolide.
    [0073] Polymerization is attained by bulk polymerizationcomprising melting lactide or the like and then subjectingit to polymerization reaction or solution polymerizationcomprising dissolving lactide or the like in a suitablesolvent and then subjecting it to polymerization reaction.It is preferable that a polymer obtained by solutionpolymerization be used as a raw material of the lactic acid polymer of the present invention from the viewpoint ofindustrial productivity.
    [0074] Examples of a solvent to be used for dissolvinglactide in solution polymerization include aromatichydrocarbons such as benzene, toluene and xylene, decalin,and dimethylformamide.
    [0075] Hydrolysis of the high-molecular weight lactic acidpolymer thus obtained is attained by a per se knownhydrolysis method. For example, the high-molecular weightlactic acid polymer may be dissolved in a suitable solventand then reacted in the presence of water and, if necessary,an acid.
    [0076] Examples of a solvent to be used for dissolving thehigh-molecular weight lactic acid polymer includehalogenated hydrocarbons such as chloroform anddichloromethane; aromatic hydrocarbons such as toluene, o-xylene,m-xylene and p-xylene; cyclic ethers such astetrahydrofuran; acetone; and N,N-dimethylformamide. Whenthe high-molecular weight lactic acid polymer is producedby polymerization using a solvent that can be also used forhydrolysis of the high-molecular weight lactic acid polymer,the polymerization and hydrolysis can be continuouslyperformed without isolating the high-molecular weightlactic acid polymer after the polymerization.
    [0077] The amount used of a solvent for dissolving the high-molecular weight lactic acid polymer is usually about 0.1to about 100 times, preferably about 1 to about 10 timesthe weight of the high-molecular weight lactic acid polymer,which is the solute.
    [0078] The amount of water to be added is usually about 0.001to about 1 time, preferably about 0.01 to about 0.1 timethe weight of the high-molecular weight lactic acid polymer.
    [0079] Examples of an acid to be added if necessary includeinorganic acids such as hydrochloric acid, sulfuric acidand nitric acid, and organic acids such as lactic acid,acetic acid and trifluoroacetic acid. Trifluoroacetic acidis preferably used.
    [0080] The amount of an acid to be added is usually about 0to about 10 times, preferably about 0.1 to about 1 time theweight of the high-molecular weight lactic acid polymer.
    [0081] The hydrolysis temperature is usually about 0 to about150°C, preferably about 20 to about 80°C.
    [0082] The hydrolysis time varies depending on the weightaverage molecular weight of the high-molecular weightlactic acid polymer to be used and the reaction temperature,but is usually about 10 minutes to about 100 hours,preferably about 1 to about 20 hours.
    [0083] Completion of hydrolysis is decided based on theweight average molecular weight of a hydrolysis product.Specifically, samples are appropriately collected during hydrolysis and the weight average molecular weight of ahydrolysis product in the samples is determined by gelpermeation chromatography (GPC). When the weight averagemolecular weight is in the range of about 15,000 to about50,000, preferably in the range of about 15,000 to about40,000, more preferably in the range of about 17,000 toabout 30,000, hydrolysis is allowed to be terminated.
    [0084] After the high-molecular weight lactic acid polymer ishydrolyzed as described above, a solution containing ahydrolysis product is obtained. For precipitation of thetargeted lactic acid polymer from the solution, a methodcomprising contacting the hydrolysis product-containingsolution with a solvent capable of precipitating thetargeted lactic acid polymer contained in the solution, orthe like is used.
    [0085] Preferred aspect of such hydrolysis product-containingsolution is, for example, an about 10 to about 50 wt%solution of a lactic acid polymer having a weight averagemolecular weight of 15,000 to 50,000, preferably 15,000 to40,000, more preferably 17,000 to 30,000 in a solventcapable of dissolving a high-molecular weight lactic acidpolymer, such as halogenated hydrocarbon (e.g., chloroform,dichloromethane, etc.), aromatic hydrocarbon (e.g., toluene,o-xylene, m-xylene, p-xylene, etc.), cyclic ether (e.g.,tetrahydrofuran, etc.), acetone, or N,N-dimethylformamide.
    [0086] Examples of a solvent used for precipitating thetargeted lactic acid polymer contained in the hydrolysisproduct-containing solution include alcohols such asmethanol and ethanol, linear ethers such as isopropyl ether,aliphatic hydrocarbons such as hexane, and water.
    [0087] The amount of a solvent to be used for precipitatingthe targeted lactic acid polymer is usually about 0.1 toabout 100 times, preferably about 1 to about 10 times theweight of the solvent of the hydrolysis product-containingsolution.
    [0088] In a preferred example of a combination of suchsolvents and their amounts to be used, the solvent of ahydrolysis product-containing solution is dichloromethanein an amount of about 1 to about 5 times the weight of thesolute and the solvent for decreasing the solubility of thesolute is isopropyl ether in an amount of about 2 to about10 times the weight of dichloromethane.
    [0089] When a solvent capable of precipitating the targetedlactic acid polymer solute is contacted with a hydrolysisproduct-containing solution, the temperature of the solventis usually about -20 to about 60°C, preferably about 0 toabout 40°C and the temperature of the hydrolysis product-containingsolution is usually about 0 to about 40°C,preferably about 10 to about 30°C.
    [0090] Contacting the solvent with a hydrolysis product-containing solution is attained by adding the hydrolysisproduct-containing solution into the solvent in one step,adding dropwise the hydrolysis product-containing solutioninto the solvent, adding the solvent into the hydrolysisproduct-containing solution in one step, adding dropwisethe solvent into the hydrolysis product-containing solution,or the like.
    [0091] The lactic acid polymer of the present invention thusobtained has terminal carboxyl in a preferred amount foruse as a base material for sustained-release preparations,and therefore it is preferably used as a base material forsustained-release preparations. Additional examples of thebiocompatible polymer include polystyrene, polymethacrylicacid, a copolymer of acrylic acid and methacrylic acid,polyamino acid, dextran stearate, ethyl cellulose, acetylcellulose, nitro cellulose, maleic anhydride-basedcopolymers, ethylenevinylacetate-based copolymers,polyvinyl acetate, and polyacrylamide.
    [0092] One of these polymers may be used alone, or two ormore of these may be used in the form of a copolymer or asimple mixture, or any salt thereof may be used.
    [0093] Hereinafter, a method of producing a sustained-releasecomposition (e.g., a microcapsule) containing aphysiologically active substance or a salt thereof and a lactic acid polymer or a salt thereof according to thepresent invention will be exemplified.
    [0094] In the process as described below, the followingingredients (1) to (4) may be added by a per se knownmethod if necessary: (1) Drug carrier: albumin, gelatin, citric acid,salicylic acid, sodium ethylenediaminetetraacetate, dextrin,sodium hydrogen sulfite, polyol compounds such aspolyethylene glycol, agar, alginic acid, polyvinyl alcohol,basic amino acid, or the like; (2) pH regulator for keeping the stability andsolubility of a physiologically active substance or a saltthereof: carbonic acid, acetic acid, oxalic acid, citricacid, phosphoric acid, hydrochloric acid, sodium hydroxide,arginine, lysine, a salt thereof, or the like; (3) Stabilizer for a physiologically active substanceor the salt thereof: albumin, gelatin, citric acid, sodiumethylenediaminetetraacetate, dextrin, sodium hydrogensulfite, polyol compounds such as polyethylene glycol, orthe like; (4) Preservative: para-hydroxybenzoate esters (e.g.,methyl paraben, propyl paraben, etc.), benzyl alcohol,chlorobutanol, thimerosal, or the like.
    [0095] In this method, first, a solution of a biodegradablepolymer in preferably an organic solvent, more preferably alow water-soluble organic solvent is prepared. Thesolution for use in producing the sustained-releasecomposition of the present invention (preferably in theform of a microparticle, more preferably in the form of amicrosphere or a microcapsule) is preferably a solution ina low water-soluble organic solvent having a boiling pointof about 120°C or less.
    [0096] Examples of such an organic solvent includehalogenated hydrocarbons (e.g., dichloromethane, chloroform,dichloroethane, trichloroethane, carbon tetrachloride,etc.), ethers (e.g., ethyl ether, isopropyl ether, etc.),fatty acid esters (e.g., ethyl acetate, butyl acetate,etc.), aromatic hydrocarbons (e.g., benzene, toluene,xylene, etc.), alcohols (e.g., ethanol, methanol, etc.),and acetonitrile. Among them, preferred are halogenatedhydrocarbons and particularly preferred is dichloromethane.These organic solvents may be used in combination at anappropriate ratio. In the case where a mixture of theorganic solvents is used, a mixture of halogenatedhydrocarbon and alcohol is preferably used, and a mixtureof dichloromethane and ethanol is particularly preferablyused.
    [0097] The concentration of the biodegradable polymer in the solution varies depending on the molecular weight of thebiodegradable polymer and the kind of the solvent. Forexample, when dichloromethane is as the solvent, theconcentration of the biodegradable polymer is usually about0.5 to about 70 wt%, preferably about 1 to about 60 wt%,more preferably about 2 to about 50 wt%.
    [0098] When a mixture of dichloromethane and ethanol is usedas the organic solvent, the volume ratio of dichloromethaneto ethanol is usually about 0.01 to about 50 %(v/v),preferably about 0.05 to about 40 %(v/v), more preferablyabout 0.1 to about 30 %(v/v).
    [0099] Next, as described above, a physiologically activesubstance is dissolved in an aqueous solution containing anacid or base in a molar amount of about 1.5 times or morethat of the physiologically active substance, or in anaqueous solution containing about 0.1 to about 20 wt% of anacid or base. The physiologically active substance may bealso dissolved in the form of a salt with a suitable acidor base. The solvent of the aqueous solution may be wateror a mixture of water and alcohol (e.g., methanol, ethanol,etc.)
    [0100] The physiologically active substance or a salt thereofis added so that its concentration in the solution liesusually in the range of about 0.001 mg/mL to about 10 g/mL,preferably about 0.1 mg/mL to about 5 g/mL, more preferably about 10 mg/mL to about 3 g/mL.
    [0101] Further, a well known solubilizer or stabilizer may beused. For dissolving or dispersing a physiologicallyactive substance and additives, heating, shaking, agitationor the like may be carried out to the extent that theactivities thereof are not impaired. The aqueous solutionthus obtained is referred to as the inner aqueous phase.
    [0102] The oil phase and inner aqueous phase thus obtainedare emulsified by a well known method such ashomogenization or sonication to form a W/O type emulsion.
    [0103] The biodegradable polymer and the physiologicallyactive substance are mixed so that the amount of theterminal carboxyl (mol) per unit mass (gram) of thebiodegradable polymer is usually about 0.01 to about 10times, preferably about 0.1 to about 5 times the molaramount of the physiologically active substance.
    [0104] The weight of the oil phase to be mixed is about 1 toabout 1,000 times, preferably about 2 to about 100 times,more preferably about 3 to about 30 times the weight of theinner aqueous phase.
    [0105] The viscosity of the W/O type emulsion thus obtainedis usually in the range of about 10 to about 10,000 cp,preferably in the range of about 100 to about 5,000 cp,more preferably in the range of about 200 to about 3,000 cp,even more preferably in the range of about 300 to about 2,000 cp, at about 12 to about 25°C.
    [0106] When the method of the present invention is employedin industrial production, the viscosity of the W/O typeemulsion is preferably in the range of about 3,000 cp orless, more preferably in the range of about 2,000 cp orless, even more preferably in the range of about 300 toabout 2,000 cp, at about 12 to about 25°C.
    [0107] Next, the W/O type emulsion thus obtained is added toan aqueous phase to form a W (inner aqueous phase)/O (oilphase)/W (outer aqueous phase) type emulsion. Thereafter,the solvent in the oil phase is volatilized or diffusedinto the outer aqueous phase to prepare microcapsules. Atthis time, the weight of the outer aqueous phase is usuallyabout 1 to about 10,000 times, preferably about 5 to about5,000 times, more preferably about 10 to about 2,000 times,particularly preferably about 20 to about 500 times theweight of the oil phase.
    [0108] An emulsifier may be added into the outer aqueousphase. The emulsifier may be usually any emulsifiercapable of forming a stable W/O/W type emulsion. Specificexamples of such an emulsifier include anionic surfactants(e.g., sodium oleate, sodium stearate, sodium laurylsulfate, etc.), nonionic surfactants [e.g., polyoxyethylenesorbitan fatty acid esters (e.g., Tween 80 and Tween 60manufactured by Atlas powder), polyoxyethylene castor oil derivatives (e.g., HCO-60 and HCO-50 manufactured by NikkoChemicals)], polyvinyl pyrrolidone, polyvinyl alcohol,carboxymethyl cellulose, lecithin, gelatin, and hyaluronicacid. These emulsifiers can be used singly or incombination of two or more of them. The emulsifier isadded so that its concentration in the outer aqueous phaselies preferably in the range of about 0.01 to about 10 wt%,more preferably in the range of about 0.05 to about 5 wt%.
    [0109] An osmotic pressure regulating agent may be added tothe outer aqueous phase. Any osmotic pressure regulatingagent may be used as long as it can produce an osmoticpressure in an aqueous solution.
    [0110] Examples of such an osmotic pressure regulating agentinclude polyhydric alcohols, monohydric alcohols,monosaccharides, disaccharides, oligosaccharides, aminoacids, and derivatives thereof.
    [0111] Examples of the polyhydric alcohol include trihydricalcohols such as glycerin, pentahydric alcohols such asarabitol, xylitol and adonitol, and hexahydric alcoholssuch as mannitol, sorbitol and dulcitol. Among them,hexahydric alcohol is preferred and mannitol isparticularly preferred.
    [0112] Examples of the monohydric alcohol include methanol,ethanol and isopropyl alcohol. Among them, ethanol ispreferred.
    [0113] Examples of the monosaccharide include pentoses suchas arabinose, xylose, ribose and 2-deoxyribose, and hexosessuch as glucose, fructose, galactose, mannose, sorbose,rhamnose and fucose. Among them, hexose is preferred.
    [0114] Examples of the oligosaccharide include trisaccharidessuch as maltotriose and raffinose, and tetrasaccharidessuch as stachyose. Among them, trisaccharide is preferred.
    [0115] Examples of the derivative of monosaccharide,disaccharide or oligosaccharide include glucosamine,galactosamine, glucuronic acid, and galacturonic acid.
    [0116] The amino acids may be any L-amino acid and examplesthereof include glycine, leucine and arginine. Among them,L-arginine is preferred.
    [0117] These osmotic pressure regulating agents can be usedsingly or in combination of two or more of them. Theosmotic pressure regulating agent is used at such aconcentration that the osmotic pressure of the outeraqueous phase is about 1/50 to about 5 times, preferablyabout 1/25 to about 3 times that of a physiological saline.When mannitol is used as the osmotic pressure regulatingagent, its concentration is preferably about 0.5 to about1.5 %.
    [0118] The organic solvent is removed by a per se knownmethod or a method pursuant to it. Examples of such amethod include a method comprising evaporating an organic solvent under normal atmospheric pressure or graduallyreduced pressure while stirring with a propeller stirrer, amagnetic stirrer or the like, and a method comprisingevaporating an organic solvent under a regulated vacuumwith a rotary evaporator or the like.
    [0119] The microcapsules thus obtained are collected bycentrifugation or filtration, washed with distilled waterseveral times to remove the free physiologically activesubstance, the emulsifier, the osmotic pressure regulatingagent and the like adhered to their surfaces, dispersed indistilled water or the like again, and then lyophilized.
    [0120] An antiflocculant may be added for preventingflocculation of the particles during the process ofproducing the microcapsules. Examples of such anantiflocculant include mannitol, lactose, glucose, water-solublepolysaccharide such as starch (such as cornstarch),amino acid such as glycine, and protein such as fibrin andcollagen. In particular, mannitol is preferred.
    [0121] The amount of the antiflocculant such as mannitol tobe added is usually about 0 to about 24 wt% of the totalweight amount of the microcapsules.
    [0122] After lyophilization, if desired, water and theorganic solvent may be removed from the microcapsules byheating under such a condition that the microcapsules arenot fused with each other. Preferably, the microcapsules are heated at around the intermediate glass transitiontemperature of the microcapsules, which is determined witha differential scanning calorimeter at a temperature risingrate of 10°C to 20°C per minute, or a slightly highertemperature than the intermediate glass transitiontemperature of the microcapsules. More preferably, themicrocapsules are heated at around their intermediate glasstransition temperature to about 30°C higher temperaturethan the intermediate glass transition temperature of themicrocapsules. Particularly when the biodegradable polymeris a lactic acid-glycolic acid polymer, the microcapsulesare preferably heated at around their intermediate glasstransition temperature to about 10°C higher temperaturethan the intermediate glass transition temperature of themicrocapsules, more preferably at around their intermediateglass transition temperature to about 5°C highertemperature than the intermediate glass transitiontemperature of the microcapsules.
    [0123] The heating time varies depending on the amount of themicrocapsules or the like. It is generally from about 12hours to about 168 hours, preferably from about 24 hours toabout 120 hours, particularly preferably from about 48hours to about 96 hours after the microcapsules reach thedesired temperature.
    [0124] A method for heating the microcapsules may be any method capable of heating a population of microcapsulesuniformly and is not particularly limited.
    [0125] Examples of the heat drying method include a method ofheat drying in a constant-temperature bath, a fluidized-bedbath, a mobile bath or a kiln and a method of heat dryingwith a microwave. Preferred is a method of heat drying ina constant-temperature bath. (II) Phase separation method
    [0126] When microcapsules are produced by this method, acoacervation agent is added slowly to the W/O type emulsioncontaining a composition composed of a physiologicallyactive substance and a biodegradable polymer as describedin the in-water drying method of the above (I) withstirring to precipitate microcapsules, which is thensolidified. The amount of the coacervation agent to beadded is about 0.01 to about 1,000 times, preferably about0.05 to about 500 times, particularly preferably about 0.1to about 200 times the volume of the oil phase.
    [0127] The coacervation agent includes polymer-based, mineraloil-based, or vegetable oil-based compounds which aremiscible with an organic solvent and do not dissolve thebiodegradable polymer of the present invention. Specificexamples of such a coacervation agent include silicone oil,sesame oil, soybean oil, corn oil, cottonseed oil, coconut oil, linseed oil, mineral oil, n-hexane and n-heptane.They may be used in combination of two or more of them.
    [0128] The microcapsules thus obtained are collected, washedrepeatedly with heptane or the like to remove thecoacervation agent and the like other than the compositioncomposed of a physiologically active substance and abiodegradable polymer, and then dried under reducedpressure. Alternatively, the microcapsules may be washedin the same manner as described in the in-water dryingmethod of the above (I), then lyophilized and further heat-dried. (III) Spray drying method
    [0129] When microcapsules are produced by this method, theW/O type emulsion containing a composition composed of aphysiologically active substance and a biodegradablepolymer as described in the in-water drying method of theabove (I) is sprayed using a nozzle into the drying chamberof a spray drier and the organic solvent contained in theatomized droplets are then volatilized in an extremelyshort period of time to obtain microcapsules. Examples ofsuch a nozzle include a two-fluid nozzle, a pressure nozzle,and a rotary disc nozzle. Thereafter, if necessary, themicrocapsules may be washed in the same manner as describedin the in-water drying method of the above (I), then lyophilized and further heat-dried.
    [0130] As a dosage form other than the above-describedmicrocapsule, a microparticle can be mentioned. Such amicroparticle may be prepared in such a manner as describedbelow. First, the organic solvent solution or dispersioncontaining a composition composed of a physiologicallyactive substance and a biodegradable polymer as describedin the in-water drying method of the above (I) is subjectedto vacuum drying using, for example, a rotary evaporator orthe like to evaporate the organic solvent and water. Next,the residue is ground with a jet mill or the like to obtainmicroparticles.
    [0131] In addition, the microparticles may be washed in thesame manner as described in the process for producingmicrocapsules of the above (I), then lyophilized andfurther heat-dried.
    [0132] In the present invention, it is preferable that anacid or base in a molar amount of about 1.5 to about 5times that of a physiologically active substance be used.
    [0133] When the physiologically active substance is acompound represented by the general formula:
    [0134] The biodegradable polymer is preferably a lactic acid-glycolicacid polymer. The composition ratio (molar ratio)of the lactic acid-glycolic acid polymer is preferably100:0 to about 50:50, more preferably 100:0. Thebiodegradable polymer is preferably a lactic acid polymerhaving a weight average molecular weight of 15,000 to50,000 wherein the content of a polymer having a weightaverage molecular weight of 5,000 or less is about 5 wt% orless.
    [0135] The solution of the biodegradable polymer ispreferably prepared using a low water-soluble organicsolvent, particularly preferably dichloromethane.
    [0136] In the present invention, it is preferable that 1) anaqueous solution containing a physiologically activesubstance and an acid or base and 2) a solution of abiodegradable polymer be mixed homogeneously. Morepreferably, the mixture thus obtained is an emulsion.
    [0137] Even more preferably, such an emulsion is a W/O typeemulsion wherein the particle size is very small.
    [0138] Drying of the mixture is preferably carried out by anin-water drying method. In particular, an osmotic pressure regulating agent is preferably added to an outer aqueousphase in the in-water drying method.
    [0139] The osmotic pressure regulating agent is preferablymannitol.
    [0140] The sustained-release composition of the presentinvention may be administered as it is, or as a rawmaterial may be formulated into various dosage forms suchas an injection or implant for administration into muscle,subcutis, organ or the like; a transmucosal agent foradministration into nasal cavity, rectum, uterus or thelike; or an oral agent (such as a capsule (such as a hardcapsule and a soft capsule), a solid preparation such as agranule and a powder, and a liquid preparation such as asyrup, an emulsion and a suspension).
    [0141] For example, the sustained-release composition of thepresent invention may be mixed with a dispersion mediumsuch as a dispersing agent (e.g., a surfactant such asTween 80 or HCO-60; polysaccharide such as sodiumhyaluronic acid, carboxymethylcellulose or sodium alginate,etc.), a preservative (e.g., methyl paraben, propyl paraben,etc.), and an isotonic agent (e.g., sodium chloride,mannitol, sorbitol, glucose, proline, etc.) to prepare anaqueous suspension, or mixed with a dispersion medium suchas a vegetable oil such as sesame oil or corn oil toprepare an oily suspension, so that a practical sustained-release injection can be prepared.
    [0142] The particle diameter of the sustained-releasecomposition of the present invention for use as asuspension injection should be in such a range that it hasa satisfactory dispersibility and a satisfactory ability topass through a needle. For example, the average particlediameter is in the range of about 0.1 to 300 µm, preferablyabout 0.5 to 150 µm, more preferably about 1 to 100 µm.
    [0143] The sustained-release composition of the presentinvention may be formulated into a sterile preparation byany method including, but not limited to, sterileconditions during all production steps, sterilization withgamma radiation and addition of an antiseptic.
    [0144] For the above-described sustained-release injection ofthe sustained-release composition, an excipient (e.g.,mannitol, sorbitol, lactose, glucose, etc.) may be added tothe components of the above-described suspension, and theresultant suspension may be re-dispersed and then freeze-driedor spray-dried to obtain a solid. At the time ofadministration, distilled water for injection or anyappropriate dispersion medium may be added to the solid toobtain a more stable sustained-release injection.
    [0145] In the case where an excipient such as mannitol isadded to the sustained-release injection of the sustained-releasecomposition, the content of the excipient is from about 0 to 50% by weight, preferably from about 1 to 20% byweight of the whole injection.
    [0146] In the case where the sustained-release injection ofthe sustained-release composition is dispersed in distilledwater for injection or any appropriate dispersion medium atthe time of administration, the content of the sustained-releasecomposition is from about 1 to 80% by weight,preferably from about 10 to 60% by weight of the totalamount of the dispersion medium and the sustained-releasecomposition.
    [0147] The sustained-release composition of the presentinvention may be formulated into an oral preparationaccording to a per se known method. For example, thesustained-release composition of the present invention maybe mixed with an excipient (e.g., lactose, white sugar,starch, etc.), a disintegrant (e.g., starch, calciumcarbonate, etc.), a binder (e.g., starch, gum arabic,carboxymethyl cellulose, polyvinylpyrrolidone,hydroxypropyl cellulose, etc.), a lubricant (e.g., talc,magnesium stearate, polyethylene glycol 6000, etc.)or thelike, compression-molded, and then, if necessary, coated bya per se known method for the purpose of masking the tasteor giving enteric or sustained-release property to obtain aoral preparation. Examples of such a coating agent includehydroxypropylmethyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose,polyoxyethylene glycol, Tween 80, Pluronic F68, celluloseacetate phthalate, hydroxypropylmethyl cellulose phthalate,hydroxymethyl cellulose acetate succinate, Eudragit(manufactured by Rohm Company, Germany, methacrylic acid-acrylicacid copolymer), and a pigment such as titaniumdioxide or colcothar.
    [0148] The sustained-release composition produced accordingto the method of the present invention may be formulatedinto a nasal preparation in the form of a solid, semi-solidor liquid by a per se known method. For example, the solidnasal preparation may be a powdered composition made of thesustained-release composition by itself, or a powderedcomposition produced by mixing the sustained-releasecomposition with an excipient (e.g., glucose, mannitol,starch, microcrystalline cellulose, etc.), a thickener(e.g., natural gum, a cellulose derivative, an acrylic acidpolymer, etc.) or the like, followed by pulverization. Theliquid nasal preparation may be produced as an oily oraqueous suspension in a similar manner to the aboveinjection. The semi-solid preparation is preferablyproduced as an aqueous or oily gel or an ointment. Thesenasal preparations may contain a pH regulator (e.g.,carbonic acid, phosphoric acid, citric acid, hydrochloricacid, sodium hydroxide, etc.), an antiseptic (e.g., para-hydroxybenzoate esters, chlorobutanol, benzalkoniumchloride, etc.) or the like.
    [0149] The sustained-release composition of the presentinvention may be formulated into a suppository in the formof an oily or aqueous solid or semi-solid or a liquidaccording to a per se known method. An oily base used forthe above suppository may be any oily base that does notdissolve a microcapsule. Examples of such an oily baseinclude glyceride of higher fatty acid [e.g., cacao butter,Witepsol-series products (Dynamite Nobel), etc.], mediumfatty acid [e.g., Miglyol-series products (Dynamite Nobel),etc.] and vegetable oil (e.g., sesame oil, soybean oil,cottonseed oil, etc.). Examples of an aqueous base includepolyethylene glycol and propylene glycol. Examples ofaqueous gel base include natural gums, cellulosederivatives, vinyl polymers and acrylic acid polymers.
    [0150] The sustained-release composition of the presentinvention is preferably used as an injection.
    [0151] The sustained-release composition of the presentinvention is less toxic and thus can be used as a safepharmaceutical or the like for a mammal (e.g., human,bovine, swine, dog, cat, mouse, rat, rabbit, etc.).
    [0152] The dosage of the sustained-release composition of thepresent invention varies depending on the type and content of a physiologically active substance or a salt thereof asthe main drug, the dosage form, the duration of release ofa physiologically active substance or a salt thereof, thetargeted disease, the targeted animal, or the like, but maybe an effective amount of the physiologically activesubstance or a salt thereof. When the sustained-releasecomposition is a six month preparation, for example, a doseof the physiologically active substance or a salt thereofas the main drug may be selected from the range of about0.01 mg to about 10 mg/kg, more preferably about 0.05 mg toabout 5 mg/kg of body weight for an adult.
    [0153] A dose of the sustained-release composition may beselected preferably from the range of about 0.05 mg toabout 50 mg/kg, more preferably from about 0.1 mg to about30 mg/kg of body weight for an adult.
    [0154] The administration frequency may be once every severalweeks, once a month, once every several months (e.g., three,four or six months) or the like and appropriately selecteddepending on the type and content of a physiologicallyactive substance or a salt thereof as the main drug, thedosage form, the duration of release of a physiologicallyactive substance or a salt thereof, the targeted disease,the targeted animal, or the like.
    [0155] The sustained-release composition of the presentinvention can be used as an agent for preventing or treating various diseases depending on the type of aphysiologically active substance or a salt thereofcontained therein. In the case where the physiologicallyactive substance or a salt thereof is an LH-RH derivative,for example, the sustained-release composition of thepresent invention can be used as an agent for preventing ortreating hormone-dependent disease, especially hormone-dependentcancer (e.g., prostatic cancer, uterus cancer,breast cancer, pituitary tumor, etc.) or sex hormone-dependentdisease such as prostatic hypertrophy,endometriosis, hysteromyoma, precocious puberty,dysmenorrheal, amenorrhea, premenstrual syndrome, ormultilocular ovarian syndrome; an agent for contraception(or for preventing or treating infertility, if a reboundeffect is used after the drug holiday); or an agent forpreventing or treating disease such as Alzheimer's diseaseor immunodeficiency. The sustained-release composition ofthe present invention can also be used as an agent forpreventing or treating benign or malignant tumor that isindependent of sex hormone but sensitive to LH-RH.
    [0156] It has been believed that it is difficult toadminister a hormone therapy agent including leuprorelinacetate as an agent for preventing postoperative recurrenceof breast cancer to a premenopausal patient because some breast cancer cells are sensitive to hormone and are grownby estrogen. However, an agent containing an LH-RH agonistor antagonist (preferably leuprorelin or a salt thereof,more preferably leuprorelin acetate), preferably an agentcontaining sustained-release microcapsules containingleuprorelin or a salt thereof (preferably leuprorelinacetate), prepared according to the above-described methodor a method pursuant to it can be unexpectedly used as anagent for preventing or suppressing postoperativerecurrence of premenopausal breast cancer.
    [0157] An sustained-release composition comprising the above-describedagent containing an LH-RH agonist or antagonist(preferably leuprorelin or a salt thereof, more preferablyleuprorelin acetate) [referably the agent containingsustained-release microcapsules containing leuprorelin or asalt thereof (preferably leuprorelin acetate)] can beeasily administered as it is in the form of an injection oran implant (preferably an injection) subcutaneously,intramuscularly or intravascualrly (preferablysubcutaneously). Such a sustained-release composition canbe also formulated into the above-described various dosageforms or may be also used as a raw material in producingsuch dosage forms.
    [0158] The dosage of the sustained-release compositioncontaining an LH-RH agonist or antagonist varies depending on targeted disease, the content of the LH-RH agonist orantagonist (preferably leuprorelin or a salt thereof, morepreferably leuprorelin acetate), the dosage form, theduration of release of the LH-RH agonist or antagonist(preferably leuprorelin or a salt thereof, more preferablyleuprorelin acetate), the targeted animal [e.g., a warm-bloodedmammal (e.g., human, mouse, rat, rabbit, sheep,swine, bovine, horse, etc.)] and the like, but may be aneffective amount of the LH-RH agonist or antagonist(preferably leuprorelin or a salt thereof, more preferablyleuprorelin acetate). For example, a dose of the LH-RHagonist or antagonist (preferably leuprorelin or a saltthereof, more preferably leuprorelin acetate) may beselected from the range of about 0.01 mg to about 100 mg/kg,preferably about 0.02 mg to about 50 mg/kg, more preferablyabout 0.05 mg to about 20 mg/kg of body weight for a warm-bloodedmammal.
    [0159] In the case where the sustained-release compositioncontaining the LH-RH agonist or antagonist is administeredin the form of an injection, usually about 0.01 to about 50mg, preferably about 0.1 to about 20 mg, more preferablyabout 0.1 to about 15 mg per month of the LH-RH agonist orantagonist (preferably leuprorelin or a salt thereof, morepreferably leuprorelin acetate) may be administeredsubctaneously or intramuscularly to an adult (60 kg body weight).
    [0160] The dosing period of the agent containing an LH-RHagonist or antagonist (preferably leuprorelin or a saltthereof, more preferably leuprorelin acetate) [referablythe agent containing sustained-release microcapsulescontaining leuprorelin or a salt thereof (preferablyleuprorelin acetate)] is not particularly limited, but isusually about 1 to 5 years, preferably about 2 years.
    [0161] For administration to other animals, the above-describeddosage per 60 kg body weight may be converted toa dosage per their body weights.
    [0162] The LH-RH agonist or antagonist [referably a peptiderepresented by the formula: 5-oxo-Pro-His-Trp-Ser-Tyr-DLeu-Leu-Arg-Pro-NH-C2H5or a salt thereof (hereinafter, alsosimply referred to as "leuprorelin or a salt thereof")],more preferably leuprorelin acetate can be administeredorally in the form of a tablet optionally coated with sugar,a capsule, elixir or a sustained-release preparation, orparenterally in the form of an injection such as an asepticsolution or suspension in water or a pharmaceuticallyacceptable liquid other than water, or a sustained-releasepreparation (particularly, a sustained-releasemicrocapsule), an implant (e.g., an implant shaped using abiodegradable polymer as a base material, or an implantprepared by filling an active ingredient into a tube made of a biocompatible metal such as titanium so as to releasethe active ingredient at a constant rate), an injectionprepared by dissolving or dispersing a biodegradablepolymer and a drug in an organic solvent acceptable to aliving body, or a nasal preparation such as a solution orsuspension. It is preferably administered in the form of asustained-release preparation, particularly preferably inthe form of a sustained-release injection. Further, in thecase where the sustained-release preparation is asustained-release microcapsule, the sustained-releasemicrocapsule is preferably a long-term sustained-releasemicrocapsule capable of releasing the LH-RH agonist orantagonist over about 2 months or more.
    [0163] The above-mentioned preparation can be produced bymixing leuprorelin or a salt thereof, preferablyleuprorelin acetate with a known physiologically acceptablecarrier, a flavoring agent, an excipient, a vehicle, apreservative, a stabilizer, a binder, and the like in anunit dosage form required for generally acceptedpharmaceutical practice.
    [0164] Additives that may be incorporated into a tablet, acapsule or the like include a binder such as gelatin, cornstarch, tragacanth or gum arabic, an excipient such ascrystalline cellulose, a swelling agent such as corn starch,gelatin or alginic acid, a lubricant such as magnesium stearate, a sweetening agent such as sucrose, lactose orsaccharin, and a flavoring agent such as peppermint,akamono oil or cherry. In the case where the unit dosageform is a capsule, a liquid carrier such as oil and fat maybe further incorporated together with the ingredientsdescribed above. An aseptic composition for injection maybe formulated according to conventional pharmaceuticalpractice, for example, by dissolving or suspending anactive ingredient in a vehicle such as water for injectionin naturally occurring vegetable oil such as sesame oil orcoconut oil.
    [0165] An aqueous liquid for injection includes aphysiological saline and an isotonic solution containingglucose or other auxiliary agents (e.g., D-sorbitol, D-mannitol,sodium chloride, etc.) and may be used incombination with a suitable solubilizing agent such asalcohol (e.g., ethanol), polyalcohol (e.g., propyleneglycol, polyethylene glycol), a nonionic surfactant (e.g.,polysorbate 80(TM), HCO-50) or the like. An oily liquidfor injection includes sesame oil and soybean oil and maybe used in combination with a solubilizing agent such asbenzyl benzoate or benzyl alcohol.
    [0166] The above-described preparation may further contain abuffer (e.g., phosphate buffer, sodium acetate buffer,etc.), a soothing agent (e.g., benzalkonium chloride, procaine hydrochloride, etc.), a stabilizer (e.g., humanserum albumin, polyethylene glycol, etc.), a preservative(e.g., benzyl alcohol, phenol, etc.), an antioxidant, orthe like. The injection thus prepared is usually filled ina suitable sealed container such as an ampule or vial. Examples
    [0167] Hereinafter, the present invention will be describedin more detail with reference to Examples. Example 1
    [0168] A solution of a DL-lactic acid polymer (weight averagemolecular weight: 21,900) (206.6 g) in dichloromethane(354.8 g) was adjusted to about 30°C. The solution (381.5g) was mixed with an aqueous solution of leuprorelinacetate (15.8 g) in aqueous acetic acid (prepared bydissolving 0.6 g of glacial acetic acid in 31.75 g ofdistilled water) (16.6 g) which had been previously warmedto about 55°C. The mixture thus obtained was emulsified at10,000 rpm with a minimixer (manufactured by Tokushu KikaKogyo Co., Ltd.) to obtain a W/O type emulsion. Next, theW/O type emulsion was cooled to about 18°C and then pouredinto an aqueous solution (25 L) containing 0.1%(w/w)polyvinyl alcohol (EG-40, manufactured by The NipponSynthetic Chemical Industry Co., Ltd.) and 1% mannitol which had been adjusted to about 18°C in advance, which wassubjected to secondary emulsification with HOMOMIC LINEFLOW (manufactured by Tokushu Kika Kogyo Co., Ltd.) toobtain a W/O/W type emulsion (turbine rotation rate; about7,000 rpm, circulating pump rotation rate; about 2,000 rpm).The W/O/W type emulsion was dried in water for about 3hours, sieved through a standard sieve with 75 µm pore size,and then centrifuged (H-600S, manufactured by KokusanEnshinki K.K.) (rotation rate; about 2,000 rpm, flow rate;about 600 mL/min) to allow microspheres to settlecontinuously, which were collected. The collectedmicrospheres were again dispersed in a small amount ofdistilled water and then sieved through a standard sievewith 90 µm pore size. To the dispersion was added mannitol(18.9 g) and the mixture was freeze-dried with a freezedryer (TRIOMASTER, manufactured by Kyowa Shinku K.K.) toobtain powder (microsphere powder). The content ofleuprorelin acetate in the microsphere thus obtained was8.2% and the yield was about 75%.
    [0169] Addition of acetic acid makes it possible to obtain aW/O type emulsion satisfactorily and addition of mannitolinto an outer aqueous phase makes it possible to improvethe dispersibility of the obtained microspheres. Experimental Example 1
    [0170] A solution of a DL-lactic acid polymer (weight averagemolecular weight: 21,900) (151.3 g) in dichloromethane(259.9 g) was adjusted to about 30°C. The solution (373.7g) was mixed with an aqueous solution of leuprorelinacetate (15.5 g) in aqueous acetic acid (prepared bydissolving 0.6 g of glacial acetic acid in 31.75 g ofdistilled water) (16.2 g) which had been previously warmedto about 55°C. The mixture thus obtained was emulsified at10,000 rpm with a minimixer (manufactured by Tokushu KikaKogyo Co., Ltd.) to obtain a W/O type emulsion. After 2, 5,and 8 minutes from the beginning of emulsification, a partof the W/O type emulsion was taken and then subjected toviscosity measurement (with a vibration viscometer). Theresults are shown in Table 1. Emulsification Time Viscosity Measurement Temperature 2 minutes 798 cp 19.7°C 5 minutes 1440 cp 19.7°C 8 minutes 2290 cp 18.9°C
    [0171] As seen in the Table 1, a stable W/O type emulsion wasobtained. The W/O type emulsion had a slightly highviscosity after emulsification for 8 minutes. Although theviscosity of the W/O type emulsion after emulsification for5 minutes was also increased, it was not such a level as tocause a problem in production. Comparative Example 1
    [0172] A solution of a DL-lactic acid polymer (weight averagemolecular weight: 21,900) (151.1 g) in dichloromethane(259.8 g) was adjusted to about 30°C. The solution (374.6g) was mixed with an aqueous solution of leuprorelinacetate (15.5 g) in distilled water (15.9 g) which had beenpreviously warmed to about 55°C. The mixture thus obtainedwas emulsified at 10,000 rpm with a minimixer (manufacturedby Tokushu Kika Kogyo Co., Ltd.) to obtain a W/O typeemulsion. After 2 and 4 minutes from the beginning ofemulsification, a part of the W/O type emulsion was takenand then subjected to viscosity measurement (with avibration viscometer). The results are shown in Table 2. Emulsification Time Viscosity Measurement Temperature 2 minutes 1870 cp 22.1°C 4 minutes 4750 cp 19.9°C
    [0173] The viscosity of the W/O type emulsion was increasedafter emulsification for 4 minutes. As compared withExperimental Example 1 in which acetic acid was added, theviscosity of the W/O type emulsion was remarkably increased. Experimental Example 2
    [0174] Leuprorelin acetate (drug content: 97.4 %, acetic acidcontent: 6.0 %) (each 0.2061 g) was dissolved in aqueous acetic acid solutions having various concentrations (each0.2116 g), and thereto was added a solution of a DL-lacticacid polymer (weight average molecular weight: 21,900)(1.82 g) in dichloromethane (3.15 g). The resultingmixtures were stirred with a vortex mixer for about 30seconds to obtain W/O type emulsions. The appearances ofthe W/O type emulsions thus obtained were compared. Theresults are shown in Fig. 1. In the W/O type emulsionprepared using acetic acid in a molar amount of about 1.8times that of the drug, it seemed that small emulsionparticles were formed. In the W/O type emulsion preparedusing acetic acid in a molar amount of about 1.4 times thatof the drug, the drug was gelatinized. In the W/O typeemulsion prepared using acetic acid in a molar amount ofabout 1.6 times that of the drug, the drug was slightlygelatinized. Using acetic acid in a molar amount of about1.8, 2.3 or 2.8 times that of the drug, a homogeneousemulsion was obtained. The W/O type emulsion preparedusing acetic acid in a molar amount of about 1.8 times thatof the drug had a bluish transparent color. On the otherhand, the W/O type emulsion prepared using acetic acid in amolar amount of about 2.3 times or more that of the drughad a whitish emulsion color. The W/O type emulsionprepared using acetic acid in a molar amount of about 1.7times that of the drug had also a bluish transparent color. From these results, it was found that the smallest emulsionparticles were formed in the bluish transparent W/O typeemulsion prepared using acetic acid in a molar amount of1.7 to 1.8 times that of the drug. Experimental Example 3
    [0175] Leuprorelin acetate (drug content: 97.4 %, acetic acidcontent: 6.0 %) (each 0.2 g) was dissolved in aqueousacetic acid solutions having various concentrations (each0.2116 g), and thereto was added a solution of a lacticacid-glycolic acid copolymer (weight average molecularweight: 10,500) (1.82 g) in dichloromethane (3.15 g). Theresulting mixtures were stirred with a vortex mixer forabout 30 seconds to obtain W/O type emulsions. Theappearances of the W/O type emulsions thus obtained werecompared. As a result, in the W/O type emulsion preparedusing acetic acid in a molar amount of about 1.8 times thatof the drug, it seemed that homogeneous emulsion particleswere formed. In the W/O type emulsions prepared usingacetic acid in a molar amount of about 1.3 and 1.4 timesthat of the drug, the oil phase and the inner aqueous phasewere separated. Experimental Example 4
    [0176] Leuprorelin acetate (drug content: 97.4 %, acetic acid content: 6.0 %) (each 0.2 g) was dissolved in aqueousacetic acid solutions having various concentrations (each0.2116 g), and thereto was added a solution of a DL-lacticacid polymer (weight average molecular weight: 14,500)(1.82 g) in dichloromethane (3.15 g). The resultingmixtures were stirred with a vortex mixer for about 30seconds to obtain W/O type emulsions. The appearances ofthe W/O type emulsions thus obtained were compared. As aresult, in the W/O type emulsion prepared using acetic acidin a molar amount of about 1.8 times that of the drug, itseemed that homogeneous emulsion particles were formed. Inthe W/O type emulsions prepared using acetic acid in amolar amount of about 1.3 and 1.4 times that of the drug,the oil phase and the inner aqueous phase were separated. Experimental Example 5
    [0177] The microspheres (110 mg) obtained in Example 1 weredispersed in a dispersion medium (0.3 mL) (prepared bydissolving 0.15 mg of carboxymethyl cellulose, 0.3 mg ofpolysorbate 80 and 15 mg of mannitol in distilled water)and then administered subcutaneously to the backs of 7-weekold male SD rats using 22G injection needles. Afterpredetermined times from administration, the rats wereslaughtered. Microspheres remaining at the administrationsite were excised. The content of Peptide A in the microspheres was quantified and the quantitative value wasdivided by the initial content to determine the remainingrate. The results are shown in Table 3. Remaining rate: Peptide A Remaining rate: Peptide A 1 day 96.6% 16 weeks 44.3% 2 weeks 89.8% 20 weeks 18.9% 4 weeks 84.1% 26 weeks 3.7% 8 weeks 73.6% 28 weeks 2.8% 12 weeks 56.4%
    [0178] As seen in Table 3, the microspheres of Example 1produced by formulating only Peptide A could contain thephysiologically active substance at a high trapping rate,and had excellent dispersibility. Further, themicrospheres of Example 1 suppressed initial excessiverelease of the physiologically active substance andreleased the physiologically active substance at a constantrate over a very long period of time. Experimental Example 6
    [0179] An acetic acid salt of Peptide A (0.6 g) was dissolvedin a 2 wt% aqueous acetic acid solution (0.65 g) (1.5 timesor more the molar amount of Peptide A). To this solution,a solution of polylactic acid (weight average molecularweight; 21,000) (5.4 g) in dichloromethane (9.45 g) wasadded. The resulting mixture was lightly dispersed byshaking it with a hand and then emulsified with Polytron(manufactured by Kinematica) for a predetermined time to obtain a W/O type emulsion. In the same manner except thatthe emulsification time was changed to various times,various emulsions were formed. The viscosities of the W/Oemulsions thus obtained was measured. The results areshown in Fig. 2.
    [0180] In the same manner as described above, Peptide A (0.6g) was dissolved in a 2 wt% aqueous acetic acid solution(0.635 g) (less than 1.5 times the molar amount of PeptideA). To this solution, a solution of polylactic acid(weight average molecular weight; 21,000) (5.4 g) indichloromethane (9.45 g) was added. The resulting mixturewas lightly dispersed by shaking it with a hand and thenemulsified with Polytron (manufactured by Kinematica) for apredetermined time to obtain a W/O type emulsion.
    [0181] The W/O type emulsion prepared using acetic acid in amolar amount less than 1.5 times that of Peptide A had anincreased viscosity when the emulsification time wasrelatively short. On the other hand, the W/O type emulsionprepared using acetic acid in a molar amount of 1.5 timesor more that of Peptide A was stable and did not have anincreased viscosity even if the emulsification time wasshort as shown in Fig 2, so that the W/O type emulsioncould be prepared easily.
    [0182] From these experimental results, it was found that the use of acetic acid in a molar amount of about 1.5 times ormore that of a drug made it possible to obtain a stable W/Otype emulsion and the use of acetic acid in a molar amountof about 1.65 times or more that of a drug made it possibleto obtain an emulsion with relatively smaller particle size.Furthermore, it was confirmed that a lactic acid polymer ora lactic acid-glycolic acid polymer could be used as apolymer for an oil phase, which improved the productivityof final pharmaceuticals. Industrial Applicability
    [0183] According to the method for producing a sustained-releasecomposition of the present invention, it ispossible to form a W/O type emulsion stably and suppressthe leakage of a drug during production, and thus increaseproductivity of the sustained-release composition. It isalso possible to obtain the sustained-release compositionwherein a large amount of a drug is incorporated and whichis capable of releasing the drug at a constant rate.Furthermore, the sustained-release composition obtained bythe method of the present invention is useful as apharmaceutical because it has a high content of a drug andstable drug-releasing property.
    [0184] According to the method of the present invention, itis possible to stabilize a mixture of an aqueous solution containing a physiologically active substance and asolution of a biodegradable polymer and obtain such amixture with a viscosity of 3,000 cp or less under normalconditions.
    [0185] The present invention is based on the Japanese PatentApplication No. 2002-185352 which is herein incorporated byreference as though fully set forth.
    权利要求:
    Claims (37)
    [1] A method for producing a sustained-release composition,which comprises mixing an aqueous solution containing aphysiologically active substance and an acid or base in amolar amount of about 1.5 or more times that of thephysiologically active substance with a solution of abiodegradable polymer, and then drying the mixture.
    [2] The method according to claim 1, wherein the aqueoussolution is obtained using a salt of the physiologicallyactive substance with the acid or base.
    [3] The method according to claim 1, wherein theproportion of the physiologically active substance in thesustained-release composition is about 0.001 to about 50%by weight.
    [4] A method for stabilizing a mixture of an aqueoussolution containing a physiologically active substance anda solution of a biodegradable polymer, which comprisesadding an acid or base in a molar amount of about 1.5 molor more times that of the physiologically active substance.
    [5] A method for allowing a mixture of an aqueous solutioncontaining a physiologically active substance and asolution of a biodegradable polymer to have a viscosity ofabout 3,000 cp or less, which comprises adding an acid orbase in a molar amount of about 1.5 mol or more times that of the physiologically active substance.
    [6] The method according to any one of claims 1, 4 and 5,wherein the physiologically active substance is aphysiologically active peptide.
    [7] The method according to claim 6, wherein thephysiologically active peptide is an LH-RH derivative.
    [8] The method according to claim 7, wherein the LH-RHderivative is a compound represented by the generalformula:
    [9] The method according to any one of claims 1, 4 and 5,wherein the acid or base in a molar amount of about 1.5 toabout 5 times that of the physiologically active substanceis used.
    [10] The method according to any one of claims 1, 4 and 5,wherein the acid or base in a molar amount of about 1.65 toabout 3 times that of the physiologically active substanceis used.
    [11] The method according to any one of claims 1, 4 and 5,wherein the acid is an organic acid.
    [12] The method according to claim 11, wherein the organicacid is a fatty acid.
    [13] The method according to claim 12, wherein the fatty acid is acetic acid.
    [14] The method according to any one of claims 1, 4 and 5,wherein the biodegradable polymer is an α-hydroxycarboxylicacid polymer.
    [15] The method according to claim 14, wherein the α-hydroxycarboxylicacid polymer is a lactic acid-glycolicacid polymer.
    [16] The method according to claim 15, wherein the molarratio of lactic acid to glycolic acid in the lactic acid-glycolicacid polymer is 100:0 to 50:50.
    [17] The method according to claim 16, wherein the molarratio of lactic acid to glycolic acid in the lactic acid-glycolicacid polymer is 100:0.
    [18] The method according to claim 15, wherein the weightaverage molecular weight of the lactic acid-glycolic acidpolymer is 5,000 to 50,000.
    [19] The method according to claim 15, wherein the weightaverage molecular weight of the lactic acid-glycolic acidpolymer is 17,000 to 30,000.
    [20] The method according to claim 1, wherein thebiodegradable polymer is a lactic acid polymer having aweight average molecular weight of 15,000 to 50,000 and thecontent of a polymer having a weight average molecularweight of 5,000 or less in said lactic acid polymer is 5%by weight or less.
    [21] The method according to claim 1, wherein thebiodegradable polymer is a lactic acid-glycolic acidpolymer having about 20 to about 1,000 µmol of terminalcarboxyl per unit mass (gram) of the polymer.
    [22] The method according to claim 1, wherein the molaramount of the terminal carboxyl of the biodegradablepolymer is about 0.1 to about 5 times that of thephysiologically active substance.
    [23] The method according to any one of claims 1, 4 and 5,wherein the solution of a biodegradable polymer is preparedusing a low water-soluble organic solvent.
    [24] The method according to claim 23, wherein the lowwater-soluble organic solvent is dichloromethane.
    [25] The method according to any one of claims 1, 4 and 5,wherein the mixture is a homogeneous mixture.
    [26] The method according to claim 25, wherein thehomogenous mixture is an emulsion.
    [27] The method according to claim 26, wherein the emulsionis a W/O type emulsion.
    [28] The method according to claim 27, wherein the particlesize of the W/O type emulsion is very small.
    [29] The method according to claim 1, wherein the drying ofthe mixture is in-water drying.
    [30] The method according to claim 29, wherein an aqueoussolution of an osmotic pressure regulating agent is used as an outer aqueous phase on the in-water drying.
    [31] The method according to claim 30, wherein the osmoticpressure regulating agent is mannitol.
    [32] The method according to claim 1, wherein thesustained-release composition is in the form of amicroparticle.
    [33] The method according to claim 32, wherein themicroparticle is a microsphere or a microcapsule.
    [34] A method for producing a sustained-release composition,which comprises mixing an aqueous solution containing 1) aphysiologically active substance and 2) an acid or base inan amount of about 0.1 to about 20% by weight of saidaqueous solution with a solution of a biodegradable polymer,and then drying the mixture.
    [35] The method according to claim 34, wherein the aqueoussolution is obtained using a salt of the physiologicallyactive substance with the acid or base.
    [36] A sustained-release composition produced by the methodaccording to claim 1.
    [37] A use of an aqueous solution containing aphysiologically active substance and an acid or base in amolar amount of about 1.5 or more times that of thephysiologically active substance, for producing asustained-release preparation containing thephysiologically active substance.
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    JP2003252751A|2003-09-10|New microsphere and method for producing the same
    JP2001081043A|2001-03-27|Sustained release composition, its production and use
    同族专利:
    公开号 | 公开日
    EP1532985B1|2016-10-12|
    KR20110050744A|2011-05-16|
    WO2004000363A1|2003-12-31|
    EP1532985A4|2008-04-16|
    US20050214330A1|2005-09-29|
    CA2490351A1|2003-12-31|
    CN1662260A|2005-08-31|
    AU2003244157A1|2004-01-06|
    KR101139112B1|2012-04-30|
    KR20050023334A|2005-03-09|
    DK1532985T3|2016-12-05|
    CA2490351C|2011-11-01|
    CN1662260B|2010-04-28|
    ES2605402T3|2017-03-14|
    US8088726B2|2012-01-03|
    PT1532985T|2017-01-20|
    KR101041767B1|2011-06-17|
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    PCT/JP2003/007950|WO2004000363A1|2002-06-25|2003-06-24|Process for producing sustained-release composition|
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