WO2003055470A1 - Nouvelle microsphere et son procede de production - Google Patents
Nouvelle microsphere et son procede de production Download PDFInfo
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- WO2003055470A1 WO2003055470A1 PCT/JP2002/013476 JP0213476W WO03055470A1 WO 2003055470 A1 WO2003055470 A1 WO 2003055470A1 JP 0213476 W JP0213476 W JP 0213476W WO 03055470 A1 WO03055470 A1 WO 03055470A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
- A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
- B01J13/02—Making microcapsules or microballoons
- B01J13/06—Making microcapsules or microballoons by phase separation
- B01J13/12—Making microcapsules or microballoons by phase separation removing solvent from the wall-forming material solution
Definitions
- the present invention relates to a microsphere having improved dispersibility, a method for producing the microsphere, a sustained-release composition containing the microsphere, and the like.
- a method for producing sustained-release microspheres from a WZO-type emulsion using a biodegradable polymer is described in, for example, JP-A-57-118185, JP-A-57-150600. No. 9 and JP-A-6-145046.
- a biodegradable polymer having sustained release properties is useful, for example, as a base material for microspheres or the like for encapsulating a physiologically active substance.
- biodegradable polymers those containing polylactic acid, copolymers of lactic acid and glycolic acid (Japanese Patent Application Laid-Open No. 11-269904, etc.) are known to be useful. I have.
- biodegradable polymers were used as they were made by conventional synthetic methods.However, as-synthesized polymers had little usefulness as a sustained-release base material because the amount of terminal lipoxyl groups was small. I knew it. Therefore, it has been studied to use a biodegradable polymer having a high molecular weight as described above as a base material for a sustained-release preparation after hydrolyzing the polymer to make the weight average molecular weight appropriate. However, those obtained by hydrolysis treatment and washing with water, even though having an appropriate weight average molecular weight and terminal lipoxyl group content, are likely to cause initial burst and are not suitable as a sustained-release base material. It was something. Therefore, there is a demand for improvement.
- JP-A-7-977334 discloses a sustained-release preparation comprising a physiologically active peptide or a salt thereof and a biodegradable polymer having a free lipoxyl group at a terminal, and a method for producing the same. ing. However, these documents do not describe a method for improving the dispersibility of microspheres.
- An object of the present invention is to provide a microsphere having improved dispersibility, a method for producing the same, and the like. Disclosure of the invention
- the present inventors have conducted intensive studies in view of the above problems, and as a result, unexpectedly, the presence of an osmotic pressure regulator in the external aqueous phase in the microsphere production method by the underwater drying method Also found that the dispersibility of the produced microspheres was significantly improved.
- the present inventors have further studied based on these findings, and as a result, have completed the present invention.
- a method for producing microspheres with improved dispersibility characterized by adding an osmotic pressure regulator to the external aqueous phase during the production of microspheres by the underwater drying method;
- Improved dispersibility Is sufficient to disperse about 400 to about 700 mg of microspheres in 1.5 mL of a dispersing medium for injection in less than 2 minutes;
- osmotic pressure adjusting agent is an alcohol, a saccharide, an amino acid, a peptide, a protein, a salt of a water-soluble amino acid, or a derivative thereof, or a mixture thereof.
- Y is DLeu, DAI a, DTrp, DSer (tBu), shows the D2Nal or DHis (ImBzl), Z represents a NH- C 2 H 5 or Gly-NH 2.
- (22) a sustained-release composition
- a sustained-release composition comprising the microsphere according to (21);
- prostate cancer benign prostatic hyperplasia, endometriosis, uterine fibroids, uterine fibroma, precocious puberty, menstruation
- prostate cancer benign prostatic hyperplasia, endometriosis, uterine fibroids, uterine fibroma, precocious puberty, menstruation
- Prostate cancer Prostatic hyperplasia, endometriosis, uterine fibroids, uterine fibroids, comprising administering to a mammal an effective amount of the sustained-release composition according to (22).
- microsphere according to (30) wherein about 400 to about 700 mg of the sustained-release composition containing the microsphere according to (30) is dispersed in 1.5 mL of a dispersion medium in less than 2 minutes;
- microsphere according to (30) which can be produced by causing an osmotic pressure regulator to be present in an external aqueous phase during the production of microspheres by an in-water drying method;
- the sustained release composition according to the above (32), wherein the underwater drying method is a W / O / W type; (34) the sustained release composition according to the above (32), wherein the underwater drying method is an OZW type; (35) The sustained-release composition according to the above (32), wherein the drying in water is of the SZOZW type; (36) a solution containing a physiologically active substance or a salt thereof is used as an internal aqueous phase, and the weight average molecular weight is 50 A solution containing a lactic acid polymer or a salt thereof having a weight average molecular weight of 15,000 to 50,000 or a salt thereof having a polymer content of about 5% by weight or less, and an oil phase containing a WZO-type emulsion containing osmotic pressure regulator.
- the microsphere according to the above (30) which can be produced by being dispersed in a phase and subjected to a water drying method;
- Y is DLeu, DAI a, DTrp, DSer (tBu), shows the D2Nal or DHis (ImBzl), Z represents an N HC 2 H 5 or Gly- NH 2.
- the osmotic pressure regulator is an alcohol, a saccharide, an amino acid, a peptide, a protein, a salt of a water-soluble amino acid, a derivative thereof, or a mixture thereof.
- amino acids are glycine, alanine, valine, leucine, isoleucine, fenylalanine, tyrosine, tryptophan, serine, threonine, proline, hydroxyproline, cystine, methionine, aspartic acid, glutamic acid, lysine, arginine or histidine.
- the salt of a water-soluble amino acid is glycine, alanine, norin, leucine, isocyanate isocyanate, feniralanine, tyrosine, tributofan, serine, threonine, proline, hydroxyproline, cystine, methionine, aspartic acid, g
- drug-retaining substance is albumin, gelatin, salicylic acid, cunic acid, or sodium ethylenediaminetetraacetate.
- dispersion medium is a dispersant, a preservative, a tonicity agent or a vegetable oil;
- microspheres with improved dispersibility are characterized by the presence of an osmotic pressure regulator in the external aqueous phase during the production of microspheres by the underwater drying method. Manufacturing method;
- a method for producing microcapsules characterized in that an osmotic pressure regulator is present in the external aqueous phase during the production of microspheres
- a liquid containing a physiologically active substance or a salt thereof is used as an internal aqueous phase, and the content of a polymer having a weight average molecular weight of 5,000 or less is about 5% by weight or less.
- a lactic acid polymer having a weight average molecular weight of 15,000 to 50000 or a lactic acid polymer thereof A W / 0 emulsion containing a salt-containing solution as an oil phase is dispersed in an aqueous phase containing an osmotic pressure regulator and subjected to a water-in-water drying method.
- sustained release composition according to the above (69) or (70), which is for injection (72) the sustained release composition according to the above (69) to (71), further comprising mannitol;
- Prostate cancer prostatic hypertrophy, uterus characterized by administering to a mammal an effective amount of the microspheres described in (43) or a sustained-release composition comprising the same. How to prevent or treat endometriosis, uterine fibroids, uterine fibroids, precocious puberty, dysmenorrhea or breast cancer, or contraceptive methods;
- microcapsules produced by in-water drying for producing the microspheres having improved dispersibility in a composition for injection containing a microsphere containing a physiologically active substance or a salt thereof and a polymer.
- osmotic pressure regulator in the external water phase in
- FIG. 1 shows an electron micrograph of the microsphere of Comparative Example 1.
- FIG. 2 shows an electron micrograph of the microspheres of Example 1. BEST MODE FOR CARRYING OUT THE INVENTION
- a substance having strong hydrophilicity and a small oil-water partition ratio between water and n-octanol is used.
- a material having a small oil-water partition ratio for example, one having a water solubility ratio of n-butanol of 1 or less is preferable, and a ratio of 0.1 or less is more preferable.
- the measurement of the oil-water partition ratio may be performed in accordance with the method described in "Physical Chemistry Experimental Method", published by Shozaburo Samejima, Shokabo, 1961. First, add n-butanol and pH 5.5 buffer solution (one-to-one equivalent mixture) to a test tube.
- the buffer include Selsen (S ⁇
- physiologically active substance examples include, but are not limited to, a physiologically active substance, an antitumor agent, an antibacterial substance, antipyretic, analgesic, antiphlogistic, antitussive expectorant, sedative, muscle relaxant, antiepileptic agent, antiulcer agent, Antidepressants, antiallergic agents, cardiotonic agents, arrhythmia treatment agents, vasodilators, antihypertensive diuretics, diabetes treatment agents, anticoagulants, hemostatic agents, antituberculous agents, hormones, narcotics, bone resorption inhibitors And angiogenesis inhibitors.
- a physiologically active substance examples include, but are not limited to, a physiologically active substance, an antitumor agent, an antibacterial substance, antipyretic, analgesic, antiphlogistic, antitussive expectorant, sedative, muscle relaxant, antiepileptic agent, antiulcer agent, Antidepressants, antiallergic agents, cardiotonic agents, arrhythmia treatment
- the physiologically active substance used in the present invention is not particularly limited as long as it is pharmacologically useful, and may be a non-peptide compound or a peptide compound.
- the non-peptidic compound include agonist, angonist, and a compound having an enzyme inhibitory action.
- the peptide compound for example, a bioactive peptide is preferable, and a bioactive peptide having a molecular weight of about 300 to about 40,000, preferably about 400 to about 30,000, more preferably about 500 to about 20,000, and the like. Is preferred
- physiologically active peptide examples include luteinizing hormone-releasing hormone (LH-RH), insulin, somatosustin, growth hormone, growth hormone-releasing hormone (GH-RH), prolactin, erythropoietin, adrenocortical hormone, Melanocyte stimulating hormone, thyroid hormone releasing hormone (TRH), thyroid stimulating hormone, luteinizing hormone, follicle stimulating hormone, vasopressin, oxytocin, calcitonin, gastrin, secretin, pancreozymine, cholecystokine Nin, angiotensin, human placental lactogen, human chorionic gonadotropin, enkephalin, endorphin, kiyoutorphin, tuftsin, thymopoietin, thymosin, thymothymulin, thymic humoral factor, blood thymic factor, tumor necrosis factor, colony-inducing factor, motilin ,
- LH-RH derivatives which are hormone-dependent diseases, especially sex hormone-dependent cancers (eg, prostate cancer, uterine cancer, breast cancer, pituitary tumor, etc.), prostatic hypertrophy, etc. Sex hormone-dependent diseases such as dysmenorrhea, endometriosis, uterine fibroids, precocious puberty, dysmenorrhea, amenorrhea, premenstrual syndrome, multilocular ovary syndrome, and contraception (or after withdrawal) When the rebound effect is used, an LH-RH derivative or a salt thereof that is effective for infertility) can be mentioned. Furthermore, LH-RH derivatives or salts thereof that are effective for benign or malignant tumors that are sex hormone-independent but LH-RH sensitive are also included.
- LH-RH derivatives or salts thereof that are effective for benign or malignant tumors that are sex hormone-independent but LH-RH sensitive are also included.
- LH-RH derivative or a salt thereof include, for example, treatment with GnRH analog: contraversis and perspectives (retroment with GnRH analogs: Controversies and perspectives) [The ⁇ Rhenrethenone Publishing Group Ltd. (The Parthenon Publishing Group Ltd.) .), Published in 1996], JP-A-3-503165, JP-A-3-101695, JP-A-7-97334, and JP-A-8-259460.
- LH-RH derivatives include LH-RH agonists and LH-RH antagonists
- LH-RH antagonists include those of the general formula [I] X-D2Na l-D4ClPhe-D3Pal-Ser-A- B- Leu- C- Pro-DA 1 aNH 2
- X is N (4H 2 - furoyl) a Gly or NAc
- A is NMeTyr, Tyr, Aph (Atz) , a residue selected from NMeAp h (Atz)
- B is DLys (Nic), DCit, DLys (AzaglyNic), DLys (Azag lyFur), DhArg (Et 2 ), DAph (Atz) and DhCi.
- the residue selected is C, Lys (Nisp), Arg or hArg (Et 2 ), respectively.
- the physiologically active peptide represented or a salt thereof is used.
- Y is DLeu, DAla, DTrp, DSer ( tBu), a D2Nal and DHis residues Ru is selected from (ImBzl), Z represents NH-C 2 H 5 or Gly- Saku 2 respectively] represented by Bioactive peptides or salts thereof are used.
- Z is NH- C 2 H 5 in Arupepu tides (i.e., 5- 0X0- Pro- His- Ti "p -Ser-Tyr- DLeu-Leu-Arg- Pro- NH- C peptide represented by 2 H 5 a; leuprorelin) or a salt thereof (e.g., acetate) is suitable.
- peptides having a physiological activity include LH-RH antagonists (U.S. Pat. Nos. 4,086,219, 4,124,577, 4,253,997, 4,317). 815).
- peptides having further physiological activity include, for example, insulin, somatosustin, and somatostatin derivatives (US Pat. Nos. 4,087,390, 4,093,574, 4,100,117). No. 4, 253, 998), growth hormone, prolactin, adrenocorticotropic hormone (ACTH), melanocyte stimulating hormone (MSH), thyroid hormone releasing hormone [(Pyr) Glu-His-ProNH2 structural formula And sometimes abbreviated as TRH in the following.] Salts and derivatives thereof (see Japanese Patent Application Laid-Open Nos.
- TSH thyroid stimulating hormone
- LH Luteinizing hormone
- FSH follicle stimulating hormone
- pasopressin vasopressin derivatives ⁇ see desmopressin [Journal of the Japanese Society of Endocrinology, Vol. 54, No. 5, pp. 676-691 (1978)] ⁇ , oxytocin, calcitonin, parathyroid hormone, glucagon, gastrin, secretin, noncreozymine.
- Cholecystokinin angiotensin, human placental lactogen, human chorionic gonadotropin (HCG), enkephalin, enkephalin derivative [see US Pat. No.
- Tumor necrosis factor TNF
- Colony-inducing factor CSF
- Motilin Dynorphin
- Bombesin Neurotensin, Cerulein, Bradykinin, Perokinase, Asparaginase, Kallikrein, Substances II, Nerve growth factor, Cell growth factor, Neurotrophic factor, Blood coagulation factor Factor VIII, Factor IX, lysozyme chloride, polymyxin II, colistin, dalamicin, bacitracin and erythropoietin (II), peptides having endothelin antagonistic activity (European Patent Publication Nos. 436189, 457195, 496452).
- Examples of the above antitumor agents include bleomycin, methotrexet, actinomycin D, mitomycin C, vinblastine sulfate, vincristine sulfate, daunorubicin, adriamycin, neocarzinostatin, cytosine arapinoside, fluorouracil, and tetrahydrofuryl 1.5-. Fluorouracil, krestin, picibanil, lentinan, levamisole, vesuvin, azimexone, glycyrrhizin, poly I: C, poly A: U, poly I CLC.
- the above antibiotics include, for example, gentamicin, dibekacin, cannedomica , Rividomycin, tobramycin, amikacin, fradiomycin, situmaisin, tetracycline hydrochloride, oxytetracycline hydrochloride, lolitetracycline, doxycycline hydrochloride, ampicillin, piperacillin, ticarcillin, cephalotin, cephaloridin, cefotiam, ceflosime, cefulozine, cefulosime, ceflosomme Cefazolin, cefotaxime, cefoperazone, ceftizoxime, moxalactam, chenamycin, sulfazecin, and azthreonam.
- antipyretic, analgesic, and anti-inflammatory agents examples include salicylic acid, sulpyrine, flufenamic acid, diclofenac, indomethacin, morphine, pethidine hydrochloride, levolphanol tartrate, and oxymorphone.
- Antitussive expectorants include ephedrine hydrochloride, methylephedrine hydrochloride, noseptin hydrochloride, codine phosphate, dihydrocodine phosphate, aloclamide hydrochloride, clofedanol hydrochloride, picoperi'damine hydrochloride, cloperastine, protochlorol hydrochloride, isoproterenol hydrochloride , Sulbuyl sulfate sulfate, terbutaline sulfate, and the like.
- sedatives examples include chlorpromazine, prochlorperazine, trifluoroperazine, atopine sulfate, methylscopolamine bromide and the like.
- muscle relaxant examples include pridinol methanesulfonate, Shidani Doppocurarine, and panclodium bromide.
- antiepileptic agents examples include phenytoin, ethosuximide, sodium azoramidona, chlordazepoxide and the like.
- anti-ulcer agents examples include metoclopromide and histidine hydrochloride.
- Antidepressants include imibramine, clomipramine, noxiptiline, phenelzine sulfate and the like.
- antiallergic agents examples include diphenhydramine hydrochloride, chlorpheniramine maleate, triberenamine hydrochloride, methdilazine hydrochloride, clemizole hydrochloride, diphenylviraline hydrochloride, and methoxyphenamine hydrochloride.
- Cardiotonic agents include transpioxocamphor, theophyllol, aminophylline, ethirefrine hydrochloride and the like.
- arrhythmic treatment agents include probranol, alprenolol, bufetrol, oxyprenolol and the like.
- Vasodilators include oxifedrine hydrochloride, diltiazem, tolazoline hydrochloride, hexobendine, and bamethane sulfate.
- antihypertensive diuretics examples include hexamethonizumab amide, pentrinium, mecamylamine hydrochloride, ecarazine hydrochloride, and clonidine.
- Antidiabetic agents include glymidine sodium, glipizide, fenformin hydrochloride, pformin hydrochloride, metformin and the like.
- Anticoagulants include sodium heparin, sodium citrate and the like.
- hemostatic agents include thromboplastin, thrombin, menadione sodium bisulfite, acetomenaphthone, ⁇ -aminocaproic acid, tranexamic acid, sodium rubazochrome sulfonate, and adrenochrome monoaminoguanidine methanesulfonate. .
- antituberculous agents examples include isodiazide, etamptol, and paraanosalicylic acid.
- Hormonal agents include prednisolone, sodium prednisolone, dexamethasone sodium sulfate, betamethasone sodium phosphate, hexestrol phosphate, hexestrol acetate, methimazole and the like.
- Narcotic antagonists include levallorphan tartrate, nalorphin hydrochloride, naloxone hydrochloride and the like.
- bone resorption inhibitor examples include (sulfur-containing alkyl) aminomethylenebisphosphonic acid and the like.
- angiogenesis inhibitors examples include angiogenesis inhibitory steroids (see Science, Vol. 21, pp. 71, 19 (1989)), fumagillin (European Patent Publication No. 3,251, 199). Gazette), fumagillol derivative (European Patent Publication No. 3570) No. 61, No. 359036, No. 386667, and No. 415,294).
- the physiologically active substance used in the present invention may be itself or a pharmacologically acceptable salt.
- an inorganic acid also referred to as an inorganic free acid
- organic acids also referred to as organic free acids
- an inorganic base also referred to as an inorganic free base
- an organic base eg, an alkali metal such as sodium or potassium, an alkaline earth metal such as calcium or magnesium
- organic base Bases also referred to as organic free bases
- the physiologically active peptide may form a metal complex compound (eg, a copper complex, a zinc complex, etc.).
- the polymer used in the present invention is a polymer which is hardly soluble or insoluble in water and is biocompatible (biodegradable). Poorly soluble in water means that the polymer has a solubility in water of more than 0 and about 3% or less, more preferably in a water solubility of more than 0 and about 1% (W / W) or less. means.
- biodegradable polymers have a weight average molecular weight of about 10,000 to 5,000, preferably about 15,000 to 50,000, more preferably about 15,000 to 40,000, and particularly preferably about 17,000 to 26,000. Further, the dispersibility of the biodegradable polymer is preferably about 1.2 to 4.0, particularly preferably about 1.5 to 3.5.
- the weight average molecular weight and the dispersity used in this specification mean values measured by gel permeation chromatography (GPC).
- the amount of the polymer used depends on the strength of the pharmacological activity of the physiologically active substance or its salt and the rate and duration of release of the physiologically active substance or its salt.
- the polymer is prepared in an amount of about 0.5 to 100,000 times (weight ratio), but preferably about 1 to 100 times (weight ratio) of the polymer is used as a microsphere base. Is good.
- a biodegradable high molecular weight polymer for example, a biodegradable high molecular weight polymer is preferable.
- aliphatic polyesters eg, ⁇ -hydroxy acids (eg, glycolic acid, lactic acid, 2-hydroxybutyric acid, 2-hydroxy Valeric acid, 2-hydroxy-3-methylbutyric acid, 2-hydroxycaproic acid, 2-hydroxyisocabroic acid, 2-hydroxycaprylic acid, etc., cyclic dimers of ⁇ -hydroxy acid (eg, glycolide) , Lactide, etc.), homopolymers (eg, lactic acid polymer, etc.) such as hydroxydicarboxylic acids (eg, malic acid), hydroxytricaronic acid (eg, citric acid), or two or more copolymers (eg, , Lactic acid / glycolic acid copolymer, 2-hydroxybutyric acid / daricholic acid copolymer), or a mixture of these homopolymers and ⁇ or copolymers
- aliphatic polyesters poly-polyesters, etc. Preferred are cyanoacrylates, and more preferred are aliphatic polyesters Among the aliphatic polyesters, homopolymers or copolymers of ⁇ -hydroxy acids and cyclic dimers of ⁇ -hydroxy acids Or a mixture of these homopolymers and ⁇ or copolymers, and a homo- or copolymer of ⁇ -hydroxy acids. , Or mixtures of these homopolymers and or copolymers are preferred especially.
- ⁇ -hydroxy acids cyclic dimers of ⁇ -hydroxy acids, hydroxydicarboxylic acids, and hydroxytricarboxylic acids have an optically active center in the molecule.
- D-, L-, and DL-forms can be used.
- the aliphatic polyester can be produced by a known production method (for example, see JP-A-61-28521) without any problem. Further, the type of polymerization may be any of random, block, and graft.
- the weight average molecular weight of the aliphatic polyester is from about 10,000 to 50,000, preferably from about 15,000 to 50,000, more preferably from about 15,000 to 4000, particularly preferably from about 17,000 to 26,000.
- the dispersity of the aliphatic polyester is preferably about 1.2 to 4.0, particularly preferably about 1.5 to 3.5.
- the composition ratio is preferably about 100 to about 50/50 (weight ratio), and when the 2-hydroxybutyric acid / Z glycolic acid copolymer is used.
- the composition ratio is preferably about 100 to about 25/75 (weight ratio).
- the weight average molecular weight of the lactic acid polymer, lactic acid / daricholic acid copolymer, and 2-hydroxybutyric acid / glycolic acid copolymer is preferably about 15,000 to 50,000, more preferably about 15,000 to 40,000.
- the mixing ratio represented by (A) / (B) is about 10 to 90. Used in the range of about 90 to 10 (weight ratio). Preferably, it ranges from about 25Z75 to about 75-25 (weight ratio).
- the weight average molecular weight of the lactic acid polymer is preferably about 15,000 to 50,000, more preferably about 15,000 to 40,000.
- the dalicholic acid Z2-hydroxybutyric acid copolymer is composed of about 40 to 70 moles of dalicholic acid and the balance of 2-hydroxybutyric acid.
- the weight average molecular weight of the glycolic acid Z 2 -hydroxybutyric acid copolymer is preferably from about 15,000 to 50,000, more preferably from about 15,000 to 40,000.
- the high-molecular polymer used in the present invention is preferably a lactic acid polymer (hereinafter, sometimes abbreviated as the lactic acid polymer of the present invention).
- the content of the polymer having a weight average molecular weight of 5,000 or less is about 5% by weight or less, and the content of the polymer having a weight average molecular weight of 3,000 or less is about 1.5% by weight or less, and most preferably, the weight average molecular weight is 5,000 or less.
- the following polymer content is about 5% by weight or less, the weight average molecular weight of 3000 or less is about 1.5% by weight or less, and the weight average molecular weight of 1000 or less is about 0.1%. % By weight or less is used.
- the weight average molecular weight of the lactic acid polymer of the present invention is usually 15,000 to 50,000, preferably 15,000 to 40,000, more preferably 17,000 to 26,000, and particularly preferably 17,500 to 25,500.
- the high-molecular-weight lactic acid polymer used as a raw material of the lactic acid polymer of the present invention may be a commercially available product or a polymer produced by a known method, and its weight average molecular weight is usually 15,000 to 5,000, preferably 20,000 to 100,000. .
- Known polymerization methods include, for example, a method of condensation-polymerizing lactic acid and, if necessary, glycolic acid, for example, lactide and, if necessary, glycolide together with Lewis such as getyl zinc, triethyl aluminum, tin octylate, etc.
- a method of ring-opening polymerization using a catalyst such as an acid or a metal salt and a method of ring-opening polymerization of lactide in the presence of a hydroxycarboxylic acid derivative in which a carbonyl group is protected (for example, WO00 / 35990, etc.) and other methods of ring-opening polymerization by adding a catalyst to lactide under heating (eg, J. Med. Chem, 16, 897 (1973), etc.), eg, a method of copolymerizing lactide and glycolide And the like.
- polymerization form examples include bulk polymerization in which lactide or the like is melted and subjected to a polymerization reaction, and solution polymerization in which lactide or the like is dissolved in an appropriate solvent and subjected to a polymerization reaction.
- a polymer obtained by solution polymerization is particularly preferred.
- Use as a raw material of the lactic acid polymer of the present invention is preferable for industrial production.
- Solvents that dissolve lactide in solution polymerization include, for example, aromatic hydrocarbons such as benzene, toluene, and xylene, decalin, and dimethylformamide.
- aromatic hydrocarbons such as benzene, toluene, and xylene
- decalin decalin
- dimethylformamide dimethylformamide
- the solvent for dissolving the high-molecular-weight lactic acid polymer may be any solvent that can dissolve the lactic acid polymer in an amount not more than 10 times the weight of the lactic acid polymer.
- Halogenated hydrocarbons such as toluene, o-xylene, m-xylene, and p-xylene; cyclic ethers such as tetrahydrofuran; acetone; N, N-dimethylformamide;
- the amount of the solvent used for dissolving the high molecular weight lactic acid polymer is usually 0.1 to 100 times, preferably 1 to 10 times the amount of the solute lactic acid polymer.
- the amount of water to be added is usually 0.01 to 1 times, preferably 0.01 to 0.1 times the weight of the high molecular weight lactic acid polymer.
- Examples of the acid to be added as necessary include inorganic acids such as hydrochloric acid, sulfuric acid, and nitric acid, and organic acids such as lactic acid, acetic acid, and trifluoroacetic acid, and preferably lactic acid.
- inorganic acids such as hydrochloric acid, sulfuric acid, and nitric acid
- organic acids such as lactic acid, acetic acid, and trifluoroacetic acid, and preferably lactic acid.
- the amount of the acid to be added is usually 0 to 10 times the weight of the high molecular weight lactic acid polymer, preferably Or 0.1 to 1 times the weight
- the hydrolysis reaction temperature is generally 0 to 50 ° C, preferably 20 to 80.
- the hydrolysis reaction time varies depending on the weight average molecular weight of the high molecular weight lactic acid polymer and the reaction temperature, and is usually 10 minutes to 100 hours, preferably 1 to 20 hours.
- the end time of the hydrolysis treatment is determined based on the weight average molecular weight of the hydrolysis product.
- sampling is appropriately performed during the hydrolysis treatment, and the weight-average molecular weight of the hydrolysis product in the sample is measured by gel permeation chromatography (GPC), and the molecular weight is about 15,000 to 50000, preferably about 1500
- the hydrolysis treatment is stopped when it can be confirmed that the value is about 30,000, more preferably about 17,000 to 26,000, particularly preferably 17,500 to 25,500.
- GPC gel permeation chromatography
- a method for precipitating a target lactic acid polymer contained therein from a solution containing a hydrolysis product which is obtained by performing an operation of hydrolyzing a high molecular weight lactic acid polymer as described above, the following method is used.
- a method of contacting the hydrolysis product-containing solution with a solvent contained therein, which can precipitate a desired lactic acid polymer, may be mentioned.
- Preferred embodiments of the hydrolysis product-containing solution include, for example, halogenated hydrocarbons such as chloroform, dichloromethane and the like, aromatic hydrocarbons such as toluene, o-xylene, m-xylene and p-xylene, for example tetrahydrofuran
- halogenated hydrocarbons such as chloroform, dichloromethane and the like
- aromatic hydrocarbons such as toluene, o-xylene, m-xylene and p-xylene
- tetrahydrofuran In a solvent dissolving a high molecular weight lactic acid polymer such as a cyclic ether such as acetone, acetone, N, N-dimethylformamide or the like, and a dichloromethane-xylene, the weight average molecular weight is 15,000 to 5,000, preferably 15,000 to 30,000, more preferably 17,000. ⁇ 260 00, particularly preferably 17500 ⁇
- Solvents capable of precipitating the target lactic acid polymer contained in the hydrolysis product-containing solution include, for example, alcohols such as methanol and ethanol, chain ethers such as isopropyl ether, and aliphatic solvents such as hexane. Examples include hydrocarbons and water.
- the amount of the solvent capable of precipitating the desired lactic acid polymer is usually 0.1 to 100 times, preferably 1 to 10 times the weight of the solvent of the hydrolysis product-containing solution.
- Preferred specific examples of the combination of the type and amount of each solvent include, for example, a solvent that reduces the solubility in a solution containing a hydrolysis product in which dichloromethane is used in an amount of 1 to 5 times the weight of the solute as a solvent.
- isopropyl ether is used in an amount of 2 to 10 times the weight of the dichloromethane.
- the temperature of the solvent is usually ⁇ 20 to 60, preferably 0 to 40 ° C.
- the temperature of the decomposition product-containing solution is usually 0 to 40 ° C, preferably 10 to 30 ° C.
- the lactic acid polymer of the present invention obtained as described above is preferable as a substrate for a sustained-release preparation because the terminal lipoxyl group content is in a preferable range as a substrate for a sustained-release preparation.
- biocompatible high molecular weight polymers include, for example, polystyrene, polymer acrylic acid, a copolymer of acrylic acid and methacrylic acid, polyamino acid, dextranstearate, ethyl cellulose, acetyl cellulose, Nitrocellose, maleic anhydride copolymer, ethylene vinyl acetate copolymer, polyvinyl acetate, polyacrylamide and the like are used.
- These high molecular weight polymers may be one kind, two or more kinds of copolymers or a simple mixture, or a salt thereof.
- the concentration of the high molecular weight polymer in the oil phase is about 0.5 to about 90% (W / W), and more preferably about 2 to about 60% (WZW).
- the drug-retaining substance used in the present invention includes, for example, polyol compounds such as albumin, gelatin, cunic acid, salicylic acid, sodium ethylenediaminetetraacetate, dextrin, sodium bisulfite, polyethylene glycol, agar, alginic acid, polyvinyl alcohol, and base. Sex amino acids and the like are used.
- microspheres of the present invention can be produced using an underwater drying method, preferably a (WZ ⁇ ) ZW type underwater drying method, an OZW type underwater drying method, or a SZOZW type underwater drying method.
- an underwater drying method preferably a (WZ ⁇ ) ZW type underwater drying method, an OZW type underwater drying method, or a SZOZW type underwater drying method.
- a solution containing a physiologically active substance or a salt thereof is used as an internal aqueous phase, and a solution containing a polymer is used as an oil phase to form a WZO-type emulsion, and the emulsion is prepared. It is dispersed in an aqueous phase containing an osmotic pressure regulator (WZO) to form a W-type emulsion, which is subjected to a water drying method, and the solvent in the oil phase is removed to remove a physiologically active substance or its salts and polymers.
- WZO osmotic pressure regulator
- the oil phase consisting of a physiologically active substance or a salt thereof and a polymer is converted to an aqueous phase containing an osmotic pressure regulator
- the microspheres containing a physiologically active substance or a salt thereof and a high molecular weight polymer are produced by dispersing in an oil phase to form an OZW emulsion and subjecting it to a drying in water method to remove the solvent in the oil phase.
- a physiologically active substance or a salt thereof is dispersed in an oil phase, which is a solution containing a high molecular weight polymer, and this is dispersed in an aqueous phase containing an osmotic pressure regulator to form an SZOZW emulsion.
- a microsphere containing a physiologically active substance or a salt thereof and a high molecular weight polymer is produced by removing the solvent in the oil phase by subjecting it to a water-in-water drying method.
- the osmotic pressure adjusting agent used in the present invention may be any substance that exhibits an osmotic pressure when used as an aqueous solution.
- osmotic pressure regulator examples include alcohols such as polyhydric alcohols and monohydric alcohols; saccharides such as monosaccharides, disaccharides, and oligosaccharides; water-soluble amino acids, peptides, proteins, and water-soluble amino acids. Salt; or a derivative thereof is used.
- alcohols such as polyhydric alcohols and monohydric alcohols
- saccharides such as monosaccharides, disaccharides, and oligosaccharides
- water-soluble amino acids peptides, proteins, and water-soluble amino acids. Salt; or a derivative thereof is used.
- polyhydric alcohols examples include trihydric alcohols such as glycerin, pentahydric alcohols such as arabitol, xylitol, and aditol, mannitol, sorby] ⁇ 1, sulsi 1 ⁇ 1 And the like. Of these, hexahydric alcohols are preferred, and mannitol is particularly preferred.
- Examples of the above monohydric alcohols include methanol, ethanol, isopropyl alcohol and the like, and among them, ethanol is preferred.
- Examples of the above-mentioned monosaccharides include pentoses such as arabinose, xylose, reportose, and 2-deoxyribose, and hexoses such as glucose, fructose, galactose, mannose, sorbose, rhamnose, and fucose. Sugars are preferred.
- maltose, cellobiose, ⁇ , ⁇ -trehalose, lactose, sucrose and the like are used. Of these, lactose and sucrose are preferred.
- oligosaccharides for example, trisaccharides such as maltotriose and raffinose monosaccharide, tetrasaccharides such as stachyose and the like are used, among which trisaccharides are preferable.
- disaccharides and oligosaccharides for example, dalcosamine, galactosamine, glucuronic acid, galacturonic acid and the like are used.
- any of the above amino acids may be used as long as it is in the L-form.
- glycine, leucine, arginine and the like are preferably used, and L-arginine is particularly preferred.
- salts of these water-soluble amino acids for example, salts of acids (eg, hydrochloric acid, sulfuric acid, phosphoric acid, etc.) or alkalis (eg, alkali metals such as sodium, potassium, etc.) of water-soluble amino acids may be used.
- acids eg, hydrochloric acid, sulfuric acid, phosphoric acid, etc.
- alkalis eg, alkali metals such as sodium, potassium, etc.
- water-soluble peptides, proteins or derivatives thereof include, for example, Casein, globulin, prolamin, albumin, gelatin, etc. are used. These osmotic pressure regulators may be used alone or as a mixture.
- the amount of the physiologically active substance or its salt varies depending on the type of drug, desired pharmacological effect and duration of effect, but the concentration in the internal aqueous phase is about 0.001% to about 90% (W / W), more preferably from about 0.01% to about 80% (W / W).
- it is about 0.01% to about 70% (W / W).
- Osmotic pressure regulators have an osmotic pressure in the external aqueous phase that is about 1/50 to about 5 times the osmotic pressure of physiological saline.
- it is used at a concentration of about 1 '25 to about 3 times, more preferably about 112 to about 2 times.
- the concentration of the osmotic agent in the outer aqueous phase is about 0.01% to about 60% (W / W), preferably about 0% when the osmotic agent is a nonionic substance. 01 to about 40% (W / W), more preferably about 0.05 to about 30% (W / W), and particularly preferably about 0.5 to about 1.5% (W / W).
- the osmotic pressure adjusting agent is an ionic substance
- a concentration obtained by dividing the above concentration by the total ionic value is used.
- the concentration of the osmotic pressure adjusting agent need not be lower than the solubility, and may be partially dispersed.
- the dispersibility of the produced microspheres can be improved by adding an osmotic pressure regulator to the external aqueous phase, and the degree thereof is not particularly limited.
- the microspheres can be dispersed in 1.5 mL of the dispersing medium for injection in less than 2 minutes.
- a method for producing microspheres by the (WZO) / W type in-water drying method of the present invention will be described.
- Polyol compounds such as albumin, gelatin, cunic acid, salicylic acid, sodium ethylenediaminetetraacetate, dextrin, sodium bisulfite, polyethylene glycol, agar, alginic acid, polyvinyl alcohol, and basic amino acids.
- pH regulator for maintaining the stability and solubility of the physiologically active substance or its salt Carbonic acid, acetic acid, oxalic acid, citric acid, phosphoric acid, hydrochloric acid, sodium hydroxide, arginine, lysine and salts thereof Such.
- Polyol compounds such as albumin, gelatin, cunic acid, sodium ethylenediaminetetraacetate, dextrin, sodium bisulfite, and polyethylene glycol.
- Paraoxybenzoic acid esters methyl paraben, propyl paraben, etc.
- benzyl alcohol chlorobutanol, thimerosal, etc.
- an organic solvent solution of a polymer is prepared.
- the organic solvent used for producing the microsphere of the present invention preferably has a boiling point of 12 Ot: or less.
- organic solvent examples include halogenated hydrocarbons (eg, dichloromethane, chloroform, dichloroethane, trichloroethane, carbon tetrachloride, etc.), ethers (eg, ethyl ether, isopropyl ether, etc.), fatty acid esters (eg, acetic acid) Examples include ethyl, butyl acetate, etc., aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.), alcohols (eg, ethanol, methanol, etc.), and acetonitrile. Of these, halogenated hydrocarbons are preferred, and dichloromethane is particularly preferred. These may be used in a mixture at an appropriate ratio. In that case, a mixture of a halogenated hydrocarbon and an alcohol is preferred, and a mixture of dichloromethane and ethanol is particularly preferred.
- halogenated hydrocarbons eg, dichloromethan
- the concentration of the polymer in the organic solvent solution varies depending on the molecular weight of the polymer and the type of the organic solvent.
- dichloromethane used as the organic solvent
- the concentration is generally about 0.5 to about 7 0% by weight, more preferably from about 1 to about 60% by weight, particularly preferably from about 2 to about 50% by weight.
- ethanol used as a mixed organic solvent with dichloromethane
- the ratio of the two is generally about 0.01 to about 50% (v / v), more preferably about 0.05 to about 50% (v / v).
- 40% (v / v) particularly preferably from about 0.1 to about 30% (v / v).
- a physiologically active substance or a salt thereof is added to an organic solvent solution of the polymer thus obtained and dissolved or dispersed.
- the amount of the physiologically active substance or its salt added is such that the upper limit of the weight ratio of the physiologically active substance or its salt: high molecular weight polymer is about 1: 1, preferably about 1: 2.
- an organic solvent solution containing the obtained composition comprising a physiologically active substance or a salt thereof and a polymer is added to an aqueous phase to form a ⁇ (oil phase) / W (aqueous phase) emulsion. Evaporate the solvent in the oil phase to prepare microspheres.
- the volume of the aqueous phase at this time is generally about 1 to about 100,000 times the oil phase volume, more preferably about 5 to about 500,000 times, and particularly preferably about 1 to 100,000 times. It is selected from 0x to about 2000x.
- An emulsifier may be added to the outer aqueous phase in addition to the osmotic pressure regulator.
- any emulsifier can be used as long as it can form a stable OZW emulsion.
- anionic surfactants sodium oleate, sodium stearate, sodium lauryl sulfate, etc.
- non-ionic surfactants polyoxyethylene sorbitan fatty acid ester [Tween 80, Tween (Tween 60, Atlas Powder), polyoxyethylene castor oil derivatives [HC0-60, HC0-50, Nikko Chemicals, etc.
- polyvinylpyrrolidone polyvinyl alcohol, carboxymethylcellulose, lecithin, gelatin, hyaluronic acid, etc.
- the concentration at the time of use is preferably in the range of about 0.01 to 10% by weight, and more preferably about 0 to 10% by weight. 0.5 to about 5% by weight.
- a method for removing the organic solvent a method known per se or a method analogous thereto is used. For example, a method in which an organic solvent is evaporated at normal pressure or gradually reduced pressure while stirring with a propeller type stirrer or a magnetic stirrer, There is a method of evaporating the organic solvent while adjusting the degree of vacuum using Lie-Vaporre Yuichi.
- microspheres obtained in this way are separated by centrifugation or filtration, and then the free bioactive substances and emulsifiers adhering to the surface of the microspheres are washed several times with distilled water and distilled again. Disperse in water and freeze-dry.
- an anti-agglomeration agent may be added to prevent aggregation of the particles.
- the aggregation inhibitor include water-soluble polysaccharides such as mannitol, lactose, glucose, starches (eg, corn starch), amino acids such as glycine, and proteins such as fibrin and collagen. Above all, Manni! One is preferred.
- the addition amount of an anti-agglomeration agent such as mannitol is usually 0 to about 24% by weight based on the whole microsphere.
- the water and the organic solvent in the microspheres may be removed by heating under reduced pressure so that the microspheres do not fuse with each other.
- the polymer is heated at a temperature close to or slightly higher than the midpoint glass transition temperature of the polymer obtained by a differential scanning calorimeter under a condition of a heating rate of 10 to 20 per minute. More preferably, the polymer is heated in the vicinity of the midpoint glass transition temperature of the high molecular weight polymer or in a temperature range higher by about 30%.
- the temperature range is preferably around the midpoint glass transition temperature or 10 ° C higher than that, more preferably, the midpoint glass transition temperature. Heat at or near the temperature 5 degrees higher.
- the heating time varies depending on the amount of microspheres and the like, but generally, about 12 hours to about 168 hours, preferably about 24 hours to after the microsphere itself reaches a predetermined temperature.
- the heating method for about 120 hours, particularly preferably about 48 hours to about 96 hours, is not particularly limited as long as the method is capable of uniformly heating the microspheres.
- the heating and drying method for example, a method of heating and drying in a constant temperature bath, a fluidized bath, a moving tank or a kiln, a method of heating and drying with a microwave, and the like are used. Of these, a method of heating and drying in a thermostat is preferred. (II) OZW method
- an organic solvent solution of the polymer is prepared.
- organic solvent examples include halogenated hydrocarbons (eg, dichloromethane, chloroform, dichloroethane, trichloroethane, carbon tetrachloride, etc.), ethers (eg, ethyl ether, isopropyl ether, etc.), fatty acid esters (eg, acetic acid) Examples include ethyl, butyl acetate, etc., aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.), alcohols (eg, ethanol, methanol, etc.), and acetonitrile. Of these, halogenated hydrocarbons are preferred, and dichloromethane is particularly preferred. These may be mixed and used at an appropriate ratio. In that case, a mixture of a halogenated hydrocarbon and an alcohol is preferred, and a mixture of dichloromethane and ethanol is particularly preferred.
- halogenated hydrocarbons eg, dichloromethane,
- the concentration of the polymer in the organic solvent solution varies depending on the molecular weight and the type of the organic solvent.
- the concentration is generally about 0.5 to about 70% by weight, It is preferably selected from about 1 to about 60% by weight, particularly preferably about 2 to about 50% by weight.
- a solution of a physiologically active substance or a salt thereof or a salt thereof in an organic solvent solution (oil phase) of a high-molecular polymer for example, water, a mixture of water and alcohols (eg, methanol, ethanol, etc.)
- a high-molecular polymer for example, water, a mixture of water and alcohols (eg, methanol, ethanol, etc.)
- This mixture is emulsified by a known method such as a homogenizer or an ultrasonic wave to form a WZO emulsion.
- the obtained WZ emulsion composed of a physiologically active substance or a salt thereof and a polymer is added to the aqueous phase, and the W (inner aqueous phase) / ⁇ (oil phase) / W (outer aqueous phase) emulsion is added.
- the solvent in the oil phase is evaporated to prepare microspheres.
- the volume of the external water phase is generally about 1 to about 100,000 times the oil phase volume, more preferably about 5 to about 50,000 times, and particularly preferably about 1 to 100,000 times. 0x to about 2, 0 0 0 3] Choose from double.
- the emulsifiers and osmotic pressure regulators that may be added to the external aqueous phase and the subsequent preparation method are the same as those described in the above section (I).
- An emulsifier may be added to the above external water phase.
- any emulsifier can be used as long as it can form a stable OZW emulsion.
- anionic surfactants sodium oleate, sodium stearate, sodium lauryl sulfate, etc.
- nonionic surfactants polyoxyethylene sorbitan fatty acid ester [Tween 80, Tween (Tween) 60, Atlas Powder Co., Ltd.), polyoxyethylene castor oil derivatives [HCO-60, HCO-50, Nikko Chemicals], etc., polyvinylpyrrolidone, polyvinyl alcohol, carboxymethylcellulose, lecithin, gelatin, hyaluronic acid
- concentration at the time of use is preferably in the range of about 0.01 to 10% by weight, more preferably in the range of about 0.05 to about 5% by weight.
- a method for removing the organic solvent a method known per se or a method analogous thereto is used. For example, a method of evaporating the organic solvent at normal pressure or gradually reducing the pressure while stirring with a propeller type stirrer or a magnetic stirrer or an ultrasonic generator, or adjusting the degree of vacuum using a rotary evaporator or the like. Examples include a method of evaporating the organic solvent and a method of gradually removing the organic solvent using a dialysis membrane.
- microspheres obtained in this way are separated by centrifugation or filtration, and then free bioactive substances or their salts or their salts, drug-retaining substances, emulsifiers, etc. attached to the surface of the microspheres Is repeatedly washed several times with distilled water, dispersed in distilled water and freeze-dried.
- an anti-agglomeration agent may be added to prevent aggregation of the particles.
- the aggregation inhibitor include water-soluble polysaccharides such as mannitol, lactose, glucose, starches (eg, corn starch), amino acids such as glycine, and proteins such as fibrin and collagen. Above all, mannitol It is suitable.
- the addition amount of an anti-agglomeration agent such as mannitol is usually 0 to about 24% by weight based on the whole microsphere.
- the microspheres may be heated under reduced pressure so that the microspheres do not fuse with each other to remove water and organic solvents from the microspheres.
- the polymer is heated at a temperature slightly higher than the midpoint glass transition temperature of the high-molecular polymer determined by a differential scanning calorimeter under the condition of a heating rate of 10 to 2 (TC).
- TC heating rate of 10 to 2
- the polymer is heated within a temperature range of about 30 ° C. higher than the midpoint glass transition temperature of the high molecular weight polymer, especially when the lactic acid-glycolic acid polymer is used as the lactic acid polymer. Heating is carried out in a temperature range higher than the transition temperature and higher than the midpoint glass transition temperature by 10 and more preferably in a temperature range higher than the midpoint glass transition temperature and higher by 5 than the midpoint glass transition temperature.
- the heating time varies depending on the amount of microspheres and the like, but is generally about 12 hours to about 168 hours after the microspheres themselves reach a predetermined temperature, preferably about 24 hours.
- the heating time is from about 120 hours to about 120 hours, particularly preferably from about 48 hours to about 96 hours.
- the heating method is not particularly limited as long as the assembly of microspheres can be uniformly heated.
- the heating and drying method for example, a method of heating and drying in a constant temperature bath, a fluidized bath, a moving tank or a kiln, a method of heating and drying with a microwave, and the like are used. Of these, the method of heating and drying in a thermostat is preferred.
- the microsphere of the present invention obtained by the production method of the present invention refers to injectable spherical microparticles that can be dispersed in a solution. The confirmation of the form can be performed, for example, by observation with a scanning electron microscope. As microspheres, microcapsules and microvesicles are used, but microcapsules are preferred.
- the weight ratio of the physiologically active substance or its salt in the microsphere of the present invention is although it depends on the type of the physiologically active substance or its salt, the desired pharmacological effect and the duration of the effect, about 0.001 to about 5 for the bioactive peptide or its salt relative to the entire microsphere.
- 0% by weight preferably from about 0.02 to about 40% by weight, more preferably from about 0.1 to about 30% by weight, even more preferably from about 0.1 to about 24% by weight, most preferably About 3 to about 24% by weight, and about 0.01 to about 80% by weight, preferably about 0.1 to about 50% by weight in the case of a non-peptide bioactive substance or a salt thereof. It is.
- the weight ratio of the high molecular weight polymer in the microspheres of the present invention is about 50 to about 100% by weight, preferably about 70 to about 100% by weight, more preferably about 50 to about 100% by weight, based on the whole microspheres. 85 to about 95% by weight.
- the weight ratio of the drug holding substance in the microspheres of the present invention is about 0.01 to about 50% by weight, preferably about 0.1 to about 30% by weight, more preferably about 0.1 to about 30% by weight, based on the whole microsphere. 5 to about 15% by weight.
- microspheres of the present invention have few pores on the surface and have excellent dispersibility in suspensions for injections and the like.
- microspheres of the present invention are excellent in dispersibility, a large amount of microspheres can be suspended in a suspension for injection or the like. Therefore, even if the microspheres do not contain a drug-retaining substance such as hydroxynaphthoic acid, a large amount of a physiologically active substance or a salt thereof can be contained in the suspension for injection as a result. it can.
- a drug-retaining substance such as hydroxynaphthoic acid
- microspheres of the present invention can be formulated into various dosage forms as they are or as raw materials, and can be injected or implanted into intramuscular, subcutaneous, organs, etc., transmucosal agent to nasal cavity, rectum, uterus, etc., It can be administered as oral preparations (eg, capsules (eg, hard capsules, soft capsules, etc.), solid preparations such as granules and powders, syrups, emulsions, solutions such as suspensions, etc.) .
- oral preparations eg, capsules (eg, hard capsules, soft capsules, etc.), solid preparations such as granules and powders, syrups, emulsions, solutions such as suspensions, etc.
- microspheres of the present invention are used as dispersants (eg, surfactants such as Tween 80, HC0-60, sodium hyaluronate,
- a dispersing medium such as polysaccharides such as lipoxymethylcellulose and sodium alginate, preservatives (eg, methylparaben, propylparaben, etc.), tonicity agents (eg, sodium chloride, mannitol, sorbitol, glucose, proline, etc.)
- aqueous suspension or a sustained-release injection that can be actually used as an oil suspension by dispersing with a dispersion medium such as a vegetable oil such as sesame oil and corn oil can be obtained.
- the particle size may be within a range that satisfies the degree of dispersion and needle penetration.
- the average particle size is about 0.1 to 30. 0 m, preferably in the range of about 0.5 to: 150 im, more preferably in the range of about 1 to 100 im.
- microspheres of the present invention can be made into a sterile preparation by, for example, a method of sterilizing the whole production process, a method of sterilizing with gamma rays, and a method of adding a preservative, but are not particularly limited.
- sustained-release injection of microspheres was redispersed as a suspension by adding excipients (eg, mannitol, sorbitol, lactose, budose sugar, etc.) in addition to the above composition. Thereafter, freeze-drying or spray-drying to solidify and adding distilled water for injection or an appropriate dispersion medium at the time of use provides a more stable sustained-release injection.
- excipients eg, mannitol, sorbitol, lactose, budose sugar, etc.
- the content of the excipient is about 0 to 50% by weight, preferably about 1 to 20% by weight, based on the whole injection. %.
- the content of microspheres is about 1 to 80% by weight based on the total amount of the dispersion medium and microspheres. %, Preferably about 10 to 60% by weight.
- the microsquare of the present invention can be prepared by, for example, excipients (eg, lactose, sucrose, starch, etc.), disintegrants (eg, starch, calcium carbonate) in accordance with a method known per se.
- binders eg, starch, arabia gum, carboxymethylcellulose, polyvinylpyrrolidone, hydroxyp Oral pill cellulose, etc.
- lubricants eg, talc, magnesium stearate, polyethylene glycol 600, etc.
- compression molding and then, if necessary, taste masking, enteric or persistent
- the coating agent include hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene glycol, tween 80, bullmouth nick F68, cellulose acetate tophthalate, and hydroxypropylmethylcellulose.
- the microsphere of the present invention into a preparation for nasal administration
- the microsphere produced by the method of the present invention can be made into a solid, semi-solid or liquid nasal preparation according to a method known per se.
- the microspheres can be used as they are or as excipients (eg, glucose, mannitol, starch, microcrystalline cellulose, etc.), thickeners (eg, natural gums, cellulose derivatives, a (Crylic acid polymer etc.) is added and mixed to form a powdery composition.
- the liquid form is almost the same as the injection form, and is an oily or aqueous suspension. In the case of semi-solid, an aqueous or oily gel or ointment is preferred.
- the microspheres of the present invention may be converted into oily or aqueous solid, semi-solid, or liquid suppositories according to a method known per se. it can.
- the oily base used in the above composition may be any one that does not dissolve the microspheres.
- dariseride a higher fatty acid, may be used.
- aqueous base examples include polyethylene glycols and propylene glycol
- examples of the aqueous gel base include natural gums, cellulose derivatives, vinyl polymers, and acrylic acid polymers.
- the microsphere of the present invention is preferably used as an injection.
- the content of the microsphere of the present invention in the sustained release composition of the present invention is not particularly limited, but is preferably about 70% by weight or more of the sustained release composition. Since the microspheres of the present invention have low toxicity, they can be used as a drug safe for mammals (eg, humans, cows, pigs, dogs, cats, mice, rats, and egrets).
- the dosage of the microspheres or the sustained-release composition of the present invention depends on the type and content of the physiologically active substance or its salt as the main drug, dosage form, duration of release of the physiologically active substance or its salt, target disease, and target Although it varies depending on the animal or the like, any effective amount of a physiologically active substance or a salt thereof may be used.
- the dose of the physiologically active substance or its salt as the main drug per dose is preferably about 0.01 mg / Omg / Omg / It can be appropriately selected from the range of kg body weight, more preferably from the range of about 0.05 mg to 5 mg kg body weight.
- the dose of microspheres per dose can be suitably selected from the range of preferably about 0.05 mg to 5 OmgZkg body weight, more preferably the range of about 0.1 mg to 30 mgZkg body weight per adult person.
- the frequency of administration should be once every few weeks, once a month, or once every few months (eg, 3 months, 4 months, 6 months, etc.). It can be appropriately selected depending on the type and content of the salt, the dosage form, the duration of release of the physiologically active substance or its salt, the target disease, the target animal, and the like.
- the microspheres or the sustained-release composition of the present invention can be used as prophylactic / therapeutic agents for various diseases, depending on the type of the contained physiologically active substance or a salt thereof.
- hormone-dependent diseases especially sex hormone-dependent cancers (eg, prostate cancer, uterine cancer, breast cancer, pituitary tumor, etc.), benign prostatic hyperplasia, endometriosis, Prevention of sex hormone-dependent diseases such as uterine fibroids, precocious puberty, dysmenorrhea, amenorrhea, premenstrual syndrome, and multilocular ovary syndrome.
- sex hormone-dependent cancers eg, prostate cancer, uterine cancer, breast cancer, pituitary tumor, etc.
- benign prostatic hyperplasia e.g., endometriosis
- Prevention of sex hormone-dependent diseases such as uterine fibroids, precocious puberty, dysmenorrhea, amenorrhea, premenstrual syndrome, and multilocular ovary syndrome.
- Therapeutic agents prevention of diseases such as Alzheimer's disease and immunodeficiency. It can be used as a therapeutic agent, and a contraceptive
- the osmotic pressure is adjusted in the external aqueous phase.
- Agents can be used.
- the weight-average molecular weights and the polymer contents were determined by gel permeation chromatography (GPC) using monodisperse polystyrene as a reference substance, and the weight-average molecular weights calculated in terms of polystyrene.
- the polymer content All measurements were performed with a high-speed GPC device (Tohoku Soichi Co., Ltd .; HLC-8 120GPC). The columns used were SuperH4000X2 and SuperH2000 (both from Tohso Soichi Co., Ltd.), and the mobile phase was Tetrahydrofuran was used at a flow rate of 0.6 mL / min. The detection method is based on the differential refractive index.
- GPC gel permeation chromatography
- the polymer obtained in Reference Example 1 was dissolved in 60 mL of dichloromethane, washed with water until the solution became neutral, 70 g of a 90% aqueous lactic acid solution was added, and the mixture was reacted with 40.
- the weight-average molecular weight of the polymer dissolved in the reaction solution reached about 20,000
- the solution was cooled to room temperature, 60 OmL of dichloromethane was injected to stop the reaction, and the reaction solution was neutralized. Washed with water until it was. After washing with water, the reaction solution was concentrated and dried to obtain a lactic acid polymer.
- the terminal carboxyl group of the obtained lactic acid polymer was about 80; umol / g of the polymer, and the content of the polymer having a weight average molecular weight of 5,000 or less was 7.29% by weight.
- the polymer obtained in Reference Example 1 was dissolved in 60 mL of dichloromethane, washed with water until the solution became neutral, 70 g of a 90% aqueous lactic acid solution was added, and the mixture was reacted with 40.
- the weight-average molecular weight of the polymer dissolved in the reaction solution reached about 20,000
- the solution was cooled to room temperature, 60 OmL of dichloromethane was injected to stop the reaction, and the reaction solution was neutralized. After washing with water until complete, the reaction solution was dropped into 280 OmL of isopropyl ether to precipitate the desired lactic acid polymer.
- the precipitate obtained by decantation was dissolved in 60 mL of dichloromethane, and the solution was concentrated and dried to obtain 160 g of a lactic acid polymer.
- the amount of terminal carboxyl groups of the obtained lactic acid polymer was about 70 ⁇ mol / g of polymer.
- Table 1 shows the weight average molecular weight of the high molecular weight lactic acid polymer used, the weight average molecular weight of the lactic acid polymer after hydrolysis treatment, the obtained weight average molecular weight of the target lactic acid polymer, and its molecular weight fraction.
- the lactic acid polymer of the present invention obtained by the method of the present invention has a weight average molecular weight of 5,000 or less, a polymer content of about 5% by weight or less, and a weight average molecular weight of 3,000 or less. It can be seen that the content of the polymer having a weight-average molecular weight of 1000 or less is about 0.1% by weight or less.
- Reference Example 3 205.5 g of DL-lactic acid polymer obtained by the same method as (1) (weight-average molecular weight: 21,400, lipoxyl group content by labeling assay: 76.1 mol Zg) The solution dissolved in 354.3 g of dichloromethane was subjected to pressure filtration through a 0.2 // m filter (EMFLOW, DFA4201 FRP), and adjusted to 28.8.
- Reference Example 3 DL-lactic acid polymer obtained by the same method as in (1) (weight average molecular weight 21,400, lipoxyl group content by labeling determination method 76.1 fio 1 / g) 2 05. 4 g was dissolved in 354.4 g of dichloromethane, and the temperature was adjusted to about 30. Weigh out 380.5 g of this solution, dissolve 16.1 leuprorelin acetate in 16.2 g of distilled water, mix with an aqueous solution heated to about 55, and use a mini-mixer (specialized machine) The mixture was emulsified with the aid of to form a WZO emulsion (rotational speed: about 10,000 rpm).
- the W / OZW emulsion was dried in water for about 3 hours, sieved using a standard 75-m sieve, and then continuously subjected to microspheres using a centrifuge (H-600S, manufactured by Domestic Centrifuge). The sediment was settled and collected (rotation speed: about 2,000 rpm, flow rate: about 600 ml Zmin). The collected microspheres were re-dispersed in a small amount of distilled water, sieved using a standard 90-zm sieve, and then added with 18.9 g of mannitol, followed by freeze-drying (TRIO MASTER, manufactured by Kyowa Vacuum) Lyophilized to obtain a powder (microsphere powder).
- Fig. 2 shows an electron micrograph of the obtained microspheres.
- microspheres of the present invention are excellent in dispersibility, they can be dispersed at a high concentration in a dispersing medium such as distilled water for injection.
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Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
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CA2471521A CA2471521C (en) | 2001-12-26 | 2002-12-25 | Novel microsphere and method for production thereof |
KR1020047009999A KR100994658B1 (ko) | 2001-12-26 | 2002-12-25 | 신규 마이크로스피어 및 이들의 제조 방법 |
AU2002367105A AU2002367105A1 (en) | 2001-12-26 | 2002-12-25 | Novel microsphere and method for production thereof |
US10/498,215 US20050064039A1 (en) | 2001-12-26 | 2002-12-25 | Novel microsphere and method for production thereof |
EP02790851.6A EP1466596B8 (en) | 2001-12-26 | 2002-12-25 | Microsphere and method for production thereof |
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JP2001394663 | 2001-12-26 | ||
JP2001-394663 | 2001-12-26 |
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WO2003055470A1 true WO2003055470A1 (fr) | 2003-07-10 |
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PCT/JP2002/013476 WO2003055470A1 (fr) | 2001-12-26 | 2002-12-25 | Nouvelle microsphere et son procede de production |
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US (1) | US20050064039A1 (ja) |
EP (1) | EP1466596B8 (ja) |
KR (1) | KR100994658B1 (ja) |
CN (2) | CN1620285A (ja) |
AU (1) | AU2002367105A1 (ja) |
CA (1) | CA2471521C (ja) |
WO (1) | WO2003055470A1 (ja) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN104226191A (zh) * | 2014-09-01 | 2014-12-24 | 南京理工大学 | 乙基纤维素多孔颗粒的常温制备方法 |
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TW200529890A (en) | 2004-02-10 | 2005-09-16 | Takeda Pharmaceutical | Sustained-release preparations |
TW200613012A (en) * | 2004-07-02 | 2006-05-01 | Takeda Pharmaceuticals Co | Sustained-release composition, process for producing the same and use of the same |
EP1679065A1 (en) * | 2005-01-07 | 2006-07-12 | OctoPlus Sciences B.V. | Controlled release compositions for interferon based on PEGT/PBT block copolymers |
CN100551376C (zh) * | 2006-05-22 | 2009-10-21 | 济南康泉医药科技有限公司 | 一种局部应用的抗生素的缓释制剂 |
CN101563068B (zh) | 2006-12-18 | 2013-03-20 | 武田药品工业株式会社 | 缓释组合物和其制备方法 |
KR100845009B1 (ko) * | 2007-08-07 | 2008-07-08 | 한국생명공학연구원 | 전하를 띠는 물질이 고착된 다공성 고분자 입자 및 그제조방법 |
WO2009060609A1 (ja) * | 2007-11-07 | 2009-05-14 | Kaneka Corporation | 固体脂を使ったマイクロカプセルの製造方法 |
KR101113044B1 (ko) * | 2008-08-29 | 2012-02-27 | 동국제약 주식회사 | 용매교류증발법에 의한 서방출성 미립구의 제조방법 |
JP2016527308A (ja) | 2013-08-06 | 2016-09-08 | ドン クック ファーマシューティカル カンパニー リミテッド | エンテカビル微小球及びこれを含む非経口投与用医薬組成物 |
US9956164B2 (en) | 2014-04-16 | 2018-05-01 | Veyx-Pharma Gmbh | Veterinary pharmaceutical composition and use thereof |
KR101686986B1 (ko) * | 2014-07-28 | 2016-12-16 | 에스케이케미칼주식회사 | 류프로라이드를 포함하는 속효성과 지속성을 동시에 갖는 약제학적 조성물 |
CN105963258B (zh) * | 2016-04-26 | 2021-01-22 | 广州帝奇医药技术有限公司 | 一种缓释微粒的制备方法 |
CN105963257B (zh) * | 2016-04-26 | 2021-01-22 | 广州帝奇医药技术有限公司 | 一种缓释微粒的制备方法 |
KR102212717B1 (ko) * | 2019-11-08 | 2021-02-08 | 환인제약 주식회사 | 지속 방출을 위한 마이크로스피어 및 이의 제조 방법 |
CN110882222B (zh) * | 2019-12-05 | 2021-12-03 | 北京博恩特药业有限公司 | 颗粒组合物及制备方法和应用 |
JP2024513509A (ja) * | 2021-04-08 | 2024-03-25 | ティオンラボ・セラピューティクス | 徐放性脂質前駆製剤 |
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EP0481732A1 (en) * | 1990-10-16 | 1992-04-22 | Takeda Chemical Industries, Ltd. | Prolonged release preparation and polymers thereof |
JPH10203962A (ja) * | 1997-01-27 | 1998-08-04 | Miyazaki Pref Gov | 薬物徐放性乳化製剤及びその製造方法 |
JP2002020269A (ja) * | 2000-06-28 | 2002-01-23 | Dong Kook Pharmaceut Co | 多重エマルジョン法による徐放出性微粒球の製造方法 |
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CA2040141C (en) * | 1990-04-13 | 2002-05-14 | Minoru Yamada | Biodegradable high-molecular polymers, production and use therof |
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CA2192782C (en) * | 1995-12-15 | 2008-10-14 | Nobuyuki Takechi | Production of microspheres |
WO1997035563A2 (en) * | 1996-03-28 | 1997-10-02 | Takeda Chemical Industries, Ltd. | Sustained-release preparation and its production |
AU5678398A (en) * | 1997-01-29 | 1998-08-18 | Takeda Chemical Industries Ltd. | Sustained-release microspheres, their production and use |
EP1048301A4 (en) * | 1998-01-16 | 2005-03-09 | Takeda Chemical Industries Ltd | COMPOSITIONS WITH DELAYED ACTIVE INGREDIENTS, PROCESS FOR THEIR PREPARATION AND THEIR USE |
PL352499A1 (en) * | 1999-07-15 | 2003-08-25 | Takeda Chemical Industries Ltd | Compositions of prolonged active substance release, method of obtaining them and their applications |
CN1662260B (zh) * | 2002-06-25 | 2010-04-28 | 武田药品工业株式会社 | 缓释组合物的制备方法 |
-
2002
- 2002-12-25 KR KR1020047009999A patent/KR100994658B1/ko active IP Right Grant
- 2002-12-25 CN CNA028283198A patent/CN1620285A/zh active Pending
- 2002-12-25 AU AU2002367105A patent/AU2002367105A1/en not_active Abandoned
- 2002-12-25 EP EP02790851.6A patent/EP1466596B8/en not_active Expired - Lifetime
- 2002-12-25 CN CN2008101818318A patent/CN101444476B/zh not_active Expired - Lifetime
- 2002-12-25 US US10/498,215 patent/US20050064039A1/en not_active Abandoned
- 2002-12-25 CA CA2471521A patent/CA2471521C/en not_active Expired - Fee Related
- 2002-12-25 WO PCT/JP2002/013476 patent/WO2003055470A1/ja active Application Filing
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
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EP0481732A1 (en) * | 1990-10-16 | 1992-04-22 | Takeda Chemical Industries, Ltd. | Prolonged release preparation and polymers thereof |
JPH10203962A (ja) * | 1997-01-27 | 1998-08-04 | Miyazaki Pref Gov | 薬物徐放性乳化製剤及びその製造方法 |
JP2002020269A (ja) * | 2000-06-28 | 2002-01-23 | Dong Kook Pharmaceut Co | 多重エマルジョン法による徐放出性微粒球の製造方法 |
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CN104226191A (zh) * | 2014-09-01 | 2014-12-24 | 南京理工大学 | 乙基纤维素多孔颗粒的常温制备方法 |
Also Published As
Publication number | Publication date |
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US20050064039A1 (en) | 2005-03-24 |
CN101444476B (zh) | 2011-11-30 |
CA2471521C (en) | 2010-11-02 |
KR100994658B1 (ko) | 2010-11-16 |
EP1466596B1 (en) | 2016-08-31 |
CN101444476A (zh) | 2009-06-03 |
EP1466596A1 (en) | 2004-10-13 |
CN1620285A (zh) | 2005-05-25 |
EP1466596B8 (en) | 2017-01-11 |
AU2002367105A1 (en) | 2003-07-15 |
EP1466596A4 (en) | 2009-12-02 |
KR20040066191A (ko) | 2004-07-23 |
CA2471521A1 (en) | 2003-07-10 |
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