CN1140991A - 含微粉化奈必洛尔的组合物 - Google Patents
含微粉化奈必洛尔的组合物 Download PDFInfo
- Publication number
- CN1140991A CN1140991A CN95191662A CN95191662A CN1140991A CN 1140991 A CN1140991 A CN 1140991A CN 95191662 A CN95191662 A CN 95191662A CN 95191662 A CN95191662 A CN 95191662A CN 1140991 A CN1140991 A CN 1140991A
- Authority
- CN
- China
- Prior art keywords
- nebivolol
- pharmaceutical composition
- hydrochlorate
- tablet
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 229960000619 nebivolol Drugs 0.000 title claims abstract description 55
- KOHIRBRYDXPAMZ-YHBROIRLSA-N (S,R,R,R)-nebivolol Chemical compound C1CC2=CC(F)=CC=C2O[C@H]1[C@H](O)CNC[C@@H](O)[C@H]1OC2=CC=C(F)C=C2CC1 KOHIRBRYDXPAMZ-YHBROIRLSA-N 0.000 title claims abstract description 49
- 239000000203 mixture Substances 0.000 title claims abstract description 30
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 20
- 239000004480 active ingredient Substances 0.000 claims abstract description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 14
- 239000003814 drug Substances 0.000 claims description 13
- 239000007787 solid Substances 0.000 claims description 13
- 229920002261 Corn starch Polymers 0.000 claims description 11
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 11
- 239000008120 corn starch Substances 0.000 claims description 11
- 239000000080 wetting agent Substances 0.000 claims description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 10
- 238000004090 dissolution Methods 0.000 claims description 10
- 239000008101 lactose Substances 0.000 claims description 10
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 9
- 229920000053 polysorbate 80 Polymers 0.000 claims description 9
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 8
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 8
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 8
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 8
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 8
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- 238000004132 cross linking Methods 0.000 claims description 7
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- 238000002360 preparation method Methods 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
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- 238000000034 method Methods 0.000 description 9
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 8
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- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
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- 229920002642 Polysorbate 65 Polymers 0.000 description 2
- 229920002651 Polysorbate 85 Polymers 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
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- 239000013078 crystal Substances 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000002372 labelling Methods 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 2
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- 229940113171 polysorbate 85 Drugs 0.000 description 2
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 description 2
- 239000012744 reinforcing agent Substances 0.000 description 2
- 235000009566 rice Nutrition 0.000 description 2
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- GUBGYTABKSRVRQ-UHFFFAOYSA-N 2-(hydroxymethyl)-6-[4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxane-3,4,5-triol Chemical compound OCC1OC(OC2C(O)C(O)C(O)OC2CO)C(O)C(O)C1O GUBGYTABKSRVRQ-UHFFFAOYSA-N 0.000 description 1
- LODHFNUFVRVKTH-ZHACJKMWSA-N 2-hydroxy-n'-[(e)-3-phenylprop-2-enoyl]benzohydrazide Chemical compound OC1=CC=CC=C1C(=O)NNC(=O)\C=C\C1=CC=CC=C1 LODHFNUFVRVKTH-ZHACJKMWSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- WUBBRNOQWQTFEX-UHFFFAOYSA-N 4-aminosalicylic acid Chemical compound NC1=CC=C(C(O)=O)C(O)=C1 WUBBRNOQWQTFEX-UHFFFAOYSA-N 0.000 description 1
- KBIWNQVZKHSHTI-UHFFFAOYSA-N 4-n,4-n-dimethylbenzene-1,4-diamine;oxalic acid Chemical compound OC(=O)C(O)=O.CN(C)C1=CC=C(N)C=C1 KBIWNQVZKHSHTI-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 239000001836 Dioctyl sodium sulphosuccinate Substances 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Natural products OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-N Salicylic acid Natural products OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 238000010306 acid treatment Methods 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
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- 238000013019 agitation Methods 0.000 description 1
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- 150000001298 alcohols Chemical class 0.000 description 1
- 125000000266 alpha-aminoacyl group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
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- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
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- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
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- 210000004351 coronary vessel Anatomy 0.000 description 1
- HCAJEUSONLESMK-UHFFFAOYSA-N cyclohexylsulfamic acid Chemical compound OS(=O)(=O)NC1CCCCC1 HCAJEUSONLESMK-UHFFFAOYSA-N 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- VZMQWZVOXMCQKY-UHFFFAOYSA-L dimagnesium;octadecanoate Chemical compound [Mg+2].[Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O VZMQWZVOXMCQKY-UHFFFAOYSA-L 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- 235000019329 dioctyl sodium sulphosuccinate Nutrition 0.000 description 1
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
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- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical compound CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
- 125000000219 ethylidene group Chemical group [H]C(=[*])C([H])([H])[H] 0.000 description 1
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- 229910052736 halogen Inorganic materials 0.000 description 1
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- 229960002474 hydralazine Drugs 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 230000001631 hypertensive effect Effects 0.000 description 1
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- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
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- 235000014655 lactic acid Nutrition 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
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- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
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- IENZQIKPVFGBNW-UHFFFAOYSA-N prazosin Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1=CC=CO1 IENZQIKPVFGBNW-UHFFFAOYSA-N 0.000 description 1
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- 238000001953 recrystallisation Methods 0.000 description 1
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- 239000011780 sodium chloride Substances 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
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- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Substances CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- A61K9/2004—Excipients; Inactive ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
- A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
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Abstract
本发明涉及含有微粉化式(I)的奈必洛尔为活性成分的药物组合物及所述组合物的制备方法。
Description
本发明涉及含微粉化固体形式的奈必洛尔(nebivolol)或其可药用酸加成盐为活性成份的药物组合物及制备所述组合物的方法。
奈必洛尔是(±)-〔R*〔S*〔S*-(S*)〕〕〕-α,α ’-〔亚氨基二(亚甲基)]双-〔6-氟-3,4-二氢-2H-1-苯并吡喃-2-甲醇〕的通用名称。奈必洛尔的通式如式(I)所示。式(I)结构有四个立体源中心,每个都以星号表示。
奈必洛尔是两种对映体的等量混合物,这两种对映体分别具有SRRR-和RSSS-构型。SRRR-构型是指SR3-奈必洛尔(d-奈必洛尔),RSSS-构型是指RS3-奈必洛尔(1-奈必洛尔)。SR3-奈必洛尔在体外和体内都是有效的选择性β1-肾上腺素能拮抗剂。奈必洛尔不同于其它的β-肾上腺素能拮抗剂,因为它快速降低自发性高血压大鼠的血压,降低麻醉狗的总外围血管阻力并增加心搏动量。这些血液动力学作用主要可归因于RS3-奈必洛尔。还发现RS3-奈必洛尔是一系列抗高血压剂的增强剂,所述高血压剂例如氨酰心宁、心得安、哌唑嗪、肼苯哒嗪,并且令人感兴趣的是它还是其自身对映体,即SR3-奈必洛尔的增强剂。几项临床试验也表明了奈必洛尔作为β1-选择性β-阻断剂和抗高血压剂的可能性。
EP-0,145,067对用于治疗/或预防冠状动脉血管系统疾病的2,2’-亚氨基二乙醇衍生物进行了一般性描述。EP-0,334,429描述了包括奈必洛尔的〔亚氨基二亚甲基〕双〔3,4-二氢-2H-1-笨并吡喃-2-甲醇〕衍生物。
奈必洛尔可按照EP-0,145,067中所述方法和EP-0,334,429中更具体描述的方法进行制备。奈必洛尔具有碱性,可通过用适宜的酸处理转化成其可药用酸加成盐的形式。适宜的酸是例如无机酸,如氢卤酸(如盐酸、氢溴酸等)和硫酸、硝酸、磷酸;或者有机酸,例如乙酸、丙酸、羟基乙酸、2-羟基丙酸、2-氧代丙酸、乙二酸、丙二酸、丁二酸、(Z)-2-丁烯二酸、(E)-2-丁烯二酸、2-羟基丁二酸、2,3-二羟基丁二酸、2-羟基-1,2,3-丙三羧酸、甲磺酸、乙磺酸、苯磺酸、4-甲基苯磺酸、环己氨基磺酸、2-羟基苯甲酸、4-氨基-2-羟基苯甲酸等。本发明中优选的酸加成盐是盐酸加成盐。
本发明的药物组合物是固体或半固体药物组合物。有意义的固体药物组合物是,例如粉剂、丸剂、胶囊剂和片剂等。术语“半固体药物组合物”指主要由固体活性成份分散在(高)粘性配制剂中组成的药物组合物。有意义的半固体药物组合物是,例如栓剂、乳剂、胶凝剂和软膏剂等。
有意义的固体药物剂型是单一单位剂型,即非多颗粒剂型。
本发明范围内优选的固体剂型是片剂。本领域专业技术人员在研究组合物时须考虑片剂的特点。片剂的具体特点是形状、崩解时间,以及尤其是硬度。
口服是药物施用的一般优选途径,因为该途径特别方便并且易于为患者所接受。对于制备药物组合物领域的专业技术人员而言,要制备一种具有所有完美特性的固体口服剂型有时也构成一系列的挑战。为产生药效,药物须在服用后可接受的时间内在患者血液中达到适宜浓度。换言之,药物必须具有可接受的生物利用度。影响药物口服后的生物利用度的一个很重要的因素是溶解,即药物的溶解率,尤其是在胃液中的溶解率。据知,在37℃下,本发明固体药剂在0.1N HCl中45分钟内至少溶解75%。所述溶解是按照下文实施例5中描述的测试方法进行测定的。所述测试方法类似于药典中所述的方法,如美国药典XXII(U.S.Pharmacopoeia XXII)。
开发药物组合物领域的专业技术人员面临制备适于口服的固体剂型,以使式(I)化合物具有可接受溶解率的问题。并且,所述本领域专业人员受到其它限制性条件的束缚。由其开发的药物组合物将以工业规模进行制备并须符合内在和外在质量控制要求。
当奈必洛尔盐酸盐是普通结晶形式时,其口服由于极差的溶解性而受到阻碍。在提高奈必洛尔盐酸盐生物利用度的研究过程中,该产物是微粉化的。不幸的是,如在实施例3所见的一样,微粉化奈必洛尔盐酸盐的溶解甚至比其普通结晶形式更差。
然而,本发明者意外地发现当将微粉化的奈必洛尔盐酸盐配入如下文所述的、用本领域已知配制剂配制的组合物中时,它具有适宜的溶解性并达到内在和外在质量控制要求。
因此,本发明提供了一种特别有益的奈必洛尔盐酸盐配制方法。如此,本发明提供了一种具有适宜溶解性的药物组合物,更具体地说提供了一种包含微粉化奈必洛尔盐酸盐的固体药剂口服药物组合物。
微粉化的奈必洛尔盐酸盐可采用本领域已知的方法进行制备,例如,在适宜研磨机上进行研磨和通过适合筛子过筛。
所述微粉化物的比表面积至少应为约23×103cm2/g(2.3×103m2/kg),优选地该比表面积量应大于25×103cm2/g(2.5×103m2/kg),更优选大于28×103cm2/g(2.8×103m2/kg),最优选大于31×103cm2/g(3.1×103m2/kg)。
依据本发明,微粉化奈必洛尔盐酸盐的特性如下。至多有50%的颗粒直径大于10μm,即DL50的最大值为10μm。优选地,DL50值应小于8μm。至多有10%的颗粒直径大于20μm,即DL10的最大值为20μm。优选地,DL10值应小于18μm。
本发明的组合物优选含有可药用载体和赋形剂,例如填充剂,如乳糖、蔗糖、甘露醇、玉米淀粉、微晶纤维素或磷酸氢钙;润滑剂,如硬脂酸、聚乙二醇、硬脂酸镁、滑石粉或硅石;崩解剂,如大米、土豆或玉米淀粉,淀粉甘醇酸钠或交联羧甲基纤维素钠(即羧甲基纤维素钠);粘合剂,如预明胶化玉米淀粉、聚乙烯吡咯烷酮或羟丙甲基纤维素及润湿剂,如二辛基磺基琥珀酸钠和聚山梨醇酯(Polysorbates)。
有意义的填充剂是乳糖、蔗糖或微晶纤维素;优选乳糖和微晶纤维素。有意义的滑动剂是硬脂酸、聚乙二醇、氢化植物油、硬脂酰富马酸钠或硬脂酸镁,优选硬脂酸镁。有意义的润滑剂是大米、土豆和玉米淀粉,优选交联羧甲基纤维素钠。优选的粘合剂是羟丙甲基纤维素。
还发现可选择聚山梨醇酯为润湿剂。有意义的润湿剂是聚山梨醇酯20(吐温20)、聚山梨醇酯40(吐温40)、聚山梨醇酯60(吐温60)、聚山梨醇酯80(吐温80)、聚山梨醇酯65(吐温65)、聚山梨醇酯85(吐温85)。更富有意义的润湿剂是聚山梨醇酯20、聚山梨醇酯40、聚山梨醇酯60、聚山梨醇酯80。优选的润湿剂是聚山梨醇酯80。
有意义的组合物含有(以占组合物总重的重量计):
奈必洛尔盐酸盐: 1%-4%
填充剂 : 60%-90%
崩解剂 : 3%-1 0%
粘合剂 : 0.5%-5%
润湿剂 : 0.1%-1.0%
更有意义的组合物含有(以占组合物总重的重量计):
奈必洛尔盐酸盐: 1%-4%
填充剂 : 75%-85%
崩解剂 : 4%-8%
粘合剂 : 1%-3%
润滑剂 : 0.4%-0.9%
润湿剂 : 0.1%-0.8%
优选的组合物含有(以占组合物总重的重量计):
奈必洛尔盐酸盐 : 2%-3%
乳糖 : 55%-65%
玉米淀粉 : 15%-25%
交联羧甲基纤维素钠: 5%-7%
羟丙甲基纤维素 : 1%-3%
聚山梨醇酯 : 0.1%-0.5%
硬脂酸镁 : 0.4%-0.6%
为制备本发明的组合物,将微粉化奈必洛尔盐酸盐与适宜赋形剂混合并制粒。优选地将奈必洛尔盐酸盐在与其它赋形剂混合之前与一种或多种填充剂混合。更优选地使用乳糖和玉米淀粉为填充剂。
润湿剂/奈必洛尔盐酸盐的比率(w/w)是一个重要因素。为获得良好的溶解性,活性成份必须充分润湿。另一方面润湿剂在组合物中的含量太高时,所得片剂的硬度不适当,结果不适于工业生产。
润湿剂/奈必洛尔盐酸盐比率可在约0.025和0.5之间变动。所述比率优选范围是约0.025-约0.3。更优选是约0.04-约0.25。最优选是约0.06-约0.1。
本发明的片剂可以是正圆柱形或似棒状,其底表面可以是水平的或凸形的并且其边缘平整。所述片剂可以有划线或断开标记,也可以带有符号或其它标记。
本发明的另一方面是向患有与冠脉疾病或高血压有关病症的患者提供了一种治疗方法,它包括口服含微粉化奈必洛尔盐酸盐的固体剂型药物组合物
应该知道活性成份的准确治疗剂量取决于患者的年龄、状况和所治疗病症的性质,该量最终是由参与治疗医生决定。
但是,治疗与冠脉疾病或高血压有关病症的每单位药剂中活性成份的一般有效剂量范围处于约0.1-约50mg之间,最优选为约1-约10mg,例如5mg,所述药剂可以以单次或分次剂量施用,如每日1-4次。实验部分实施例1:奈必洛尔盐酸盐的制备
在乙醇(1000ml)中将(±)-〔2R*〔1S*,5S*(S*)〕〕+〔2R*〔1S*,5R*(R*)〕〕-α,α ’-〔亚氨基二(亚甲基)〕双〔6-氟-3,4-二氢-2H-1-苯并吡喃-2-甲醇〕(142g)转化成盐酸盐。滤出结晶并用乙醇进行结晶。结晶的第二馏份用乙醇进行重结晶,得到10.3g(6.6%)(±)-〔2R*〔1S*,5S*(S*)〕〕-α,α’-〔亚氨基二(亚乙基)〕双〔6-氟-3,4-二氢-2H-1-苯并吡喃-2-甲醇〕盐酸盐;mp.224.9℃,奈必洛尔盐酸盐(结晶化合物1)实施例2:奈必洛尔盐酸盐的微粉化
使用以石头安装的研磨盘的空气分粒研磨机(Air ClassifyingMill)将11kg量的奈必洛尔盐酸盐微粉化。最佳研磨速度为13,500转/分。当颗粒小到足以被空气流带走,形成风筛时,将它们收集得到微粉化的化合物I。实施例3,溶解试验
比面积(m2/kg) 60分钟后溶解率结晶化合物1 0.226×103 28.1%微粉化化合物1 3.012×103 17.4%实施例4含化合物1的片剂的制备
成品片剂组成:
奈必洛尔盐酸盐: 5.45mg 2.40%
乳糖: 141.75mg 61.6%
玉米淀粉: 46.00mg 20.0%
交联羧甲基纤维素钠:13.80mg 6.00%
胶态无水二氧化硅: 0.60mg 0.26%
硬脂酸镁: 1.15mg 0.50%
羟丙甲基纤维素
(Hypromellose)
2910 15cps(*): 4.60mg 2.00%
聚山梨醇酯80: 0.46mg 0.20%
微晶纤维素: 16.10mg 7.00%
(*)Hypromellose是英国批准的名称并且推荐为羟丙甲基纤维素的国际非标准名称。羟丙甲基纤维素的级类由四位数字代码区分,在此为2910。这前两位数字代表甲氧基的近似百分组成,第三和第四位数字则表示羟丙基的近似百分组成。示数“15cps”指于20℃测定的2%溶液的粘度为15厘泊(15mpa.s)。粘合剂溶液的制备
在90 ℃和磁力搅拌下,将92g羟丙甲基纤维素2910 15cps和9.2g聚山梨醇酯80溶于1,840g无盐水中。颗粒的制备
在5-6巴工作压力下,在流化床制粒机中混合109g奈必洛尔盐酸盐、138g交联羧甲基纤维素钠、2,835g乳糖和920g玉米淀粉。通入空气温度为60℃。该混合过程持续进行直至排出空气温度达到30 ℃。随后将粘合剂溶液喷雾于粉末混合物上。喷雾后通入温度为75 ℃的空气干燥颗粒。压缩混合物的制备
使干燥颗粒、322g微晶纤维素、138g交联羧甲基纤维素钠、13g胶态无水二氧化硅和硬脂酸镁通过不锈钢筛(目:0.95mm),并在行星式粉末混合机中进行混合直至获得均匀混合物。片剂的制备
使用旋转压片机由上述压缩混合物制备230mg的片剂。实施例5:溶解试验标准溶液的制备
在50ml容量瓶中精确称量约54.5mg的奈必洛尔盐酸盐。将上述量的奈必洛尔盐酸盐溶于甲醇并用甲醇稀释至刻度(50ml)。参照溶液的制备
将5ml量的标准溶液(见上)吸移到500ml容量瓶中。加入空白对照片及300ml 0.1N盐酸。将该溶液加热至37℃并机械振荡30分钟。用0.1N盐酸将该溶液再稀释到500ml。之后,使该溶液滤经15μm滤器。样品溶液的制备
将含微粉化奈必洛尔盐酸盐的片(如实施例4中所述制备)放入Paddle装置的溶解皿(如欧洲药典中所述)中,转速设置在50±2转/分,溶解介质为0.1N HCl并且温度固定于37℃±0.5℃。测量
搅拌45分钟后,从溶解器中取出6ml样品并使其滤经15μm试剂滤器。使用分光光度计测定样品(第2次滤经0.2μm滤器后)在近280nm的最大吸收值,测定在10mm池中对照0.1N盐酸组成的“空白溶液”进行。计算
其中,As=测定的参照溶液吸收度,
结果显示如实施例4中制备的片剂在45分钟后的溶解率为75%,即75%溶解。实施例6:含结晶与微粉化奈必洛尔的片剂溶解率的比较
片剂1 | 片剂2 | |
化合物1结晶 | 化合物1微粉 | 5.45mg |
聚山梨醇酯80 | 聚山梨醇酯80 | 2.30mg |
羟丙甲基纤维素2910 15cps | 羟丙甲基纤维素2910 15cps | 4.60mg |
乳糖 | 乳糖 | 139.91mg |
玉米淀粉 | 玉米淀粉 | 46.00mg |
acdisol | acdisol | 13.80mg |
微晶纤维素 | 微晶纤维素 | 16.10mg |
胶态无水二氧化硅 | 胶态无水二氧化硅 | 0.69mg |
硬脂酸镁 | 硬脂酸镁 | 1.15mg |
采用实施例5中所述的类似方法测定片剂的溶解率。将片剂放入Paddle装置的溶解皿,旋转速度设定于100转/分,溶解介质是人工胃液,温度固定在37℃。45分钟后,含结晶奈必洛尔的片剂(片剂1)的溶解率低于50%,但含微粉化的片剂(片剂2)的溶解率高于75%。
Claims (10)
1.一种包含可药用载体和奈必洛尔或其可药用盐为活性成份的药物组合物,其特征在于该活性成份是微粉化固体形式的。
2.如权利要求1的药物组合物,其中药物组合物是固体药物组合物。
3.如权利要求1或2的药物组合物,其中活性成份是微粉化形式的奈必洛尔盐酸盐。
4.如权利要求3的药物组合物,其中微粉化形式的奈必洛尔盐酸盐的比表面积至少为23×103cm2/g(2.3×103m2/kg)。
5.如权利要求3的药物组合物,其中所述药物组合物包含1-4%的微粉化奈必洛尔盐酸盐。
6.如权利要求3的药物组合物,其中所述药物组合物还包含聚山梨醇酯为润湿剂,其中聚山梨醇酯与奈必洛尔盐酸盐的比率范围为0.025-0.5。
7.如权利要求2的药物组合物,其中所述药物组合物是片剂。
8.如权利要求3的药物组合物,其中所述药物组合物是基本组成如下的片剂:
奈必洛尔盐酸盐: 2.40%
乳糖: 61.6%
玉米淀粉: 20.0%
交联羧甲基纤维素钠: 6.00%
胶态无水二氧化硅: 0.26%
硬脂酸镁: 0.50%
Hypromellose 2910 15cps: 2.00%
聚山梨醇酯80: 0.20%
微晶纤维素: 7.00%
9.如权利要求7的片剂,其特征在于45分钟后其溶解率为75%。
10.微粉化形式的奈必洛尔盐酸盐的比表面积至少为23×103cm2/g。
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US19798894A | 1994-02-17 | 1994-02-17 | |
US08/197,988 | 1994-02-17 |
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US (1) | US5759580A (zh) |
EP (1) | EP0744946B1 (zh) |
JP (1) | JP3810079B2 (zh) |
KR (1) | KR100361636B1 (zh) |
CN (1) | CN1112921C (zh) |
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SI (1) | SI0744946T1 (zh) |
SK (1) | SK283250B6 (zh) |
TW (1) | TW355683B (zh) |
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RU2378272C2 (ru) | 2004-07-30 | 2010-01-10 | Торрент Фармасьютикалз Лимитед | Небиволол и его фармацевтически приемлемые соли, способ их получения и фармацевтические композиции небиволола |
ES2341250T3 (es) * | 2004-08-11 | 2010-06-17 | Hetero Drugs Limited | Procedimiento novedoso de preparacion de intermediarios de nebivolol. |
US7344907B2 (en) * | 2004-11-19 | 2008-03-18 | International Business Machines Corporation | Apparatus and methods for encapsulating microelectromechanical (MEM) devices on a wafer scale |
EP1848424B1 (en) * | 2005-01-31 | 2017-04-05 | Mylan Laboratories, Inc | Pharmaceutical composition comprising hydroxylated nebivolol |
WO2006084684A1 (de) * | 2005-02-11 | 2006-08-17 | Stada Arzneimittel Ag | Pharmazeutische zusammensetzungen nebivolo und ein hydrophiles polymer |
EP1803716B1 (en) * | 2005-12-28 | 2012-07-25 | Acino Pharma AG | A process for preparation of racemic nebivolol |
US7560575B2 (en) * | 2005-12-28 | 2009-07-14 | Acino Pharma Ag | Process for preparation of racemic Nebivolol |
US7858812B2 (en) * | 2006-01-18 | 2010-12-28 | Hetero Drugs Limited | Process for isolation of desired isomers of nebivolol intermediates |
EP1839658A1 (en) * | 2006-03-30 | 2007-10-03 | Hexal A/S | Pharmaceutical composition comprising micronized nebivolol |
DE102006036579A1 (de) * | 2006-08-04 | 2008-02-07 | Alfred E. Tiefenbacher Gmbh & Co.Kg | Pharmazeutische Zusammensetzung |
EP1886674B1 (de) * | 2006-08-04 | 2010-03-31 | Alfred, E. Tiefenbacher Gmbh & Co. Kg | Pharmazeutische Zusammensetzung enthaltend Nebivolol |
UA97813C2 (uk) * | 2006-12-05 | 2012-03-26 | Янссен Фармацевтика Н.В. | Фумаратна сіль (альфа s, бета r)-6-бром-альфа-[2-(диметиламіно)етил]-2-метоксі-альфа-1-нафталеніл-бета-феніл-3-хінолінетанолу |
JP5448844B2 (ja) | 2007-01-22 | 2014-03-19 | ミラン ファーマシューティカルズ ユーエルシー | ネビボロールを含む固体の医薬組成物 |
US20100172972A1 (en) * | 2007-05-21 | 2010-07-08 | Sun Pharmaceutical Industries Limited | Enteric coated pharmaceutical compositions |
CA2637979A1 (en) * | 2007-07-26 | 2009-01-26 | Mylan Laboratories, Inc. | Treatment of cardiovascular disease in mexican americans using nebivolol |
CN101463024B (zh) | 2007-12-21 | 2011-06-08 | 上海现代制药股份有限公司 | 一种制备rrrs和sssr型的奈必洛尔中间体混合物的方法 |
WO2009091777A1 (en) * | 2008-01-15 | 2009-07-23 | Forest Laboratories Holdings Limited | Nebivolol in the treatment of sexual dysfunction |
EP2163551B1 (en) | 2008-09-08 | 2011-11-16 | Cadila Pharmaceuticals Ltd. | An improved process for the preparation of nebivolol hydrochloride |
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IT1397962B1 (it) | 2010-02-11 | 2013-02-04 | Menarini Int Operations Lu Sa | Processo per la preparazione del nebivololo. |
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CN102985077A (zh) * | 2010-07-02 | 2013-03-20 | Fmc有限公司 | 固体形式 |
CN105085499B (zh) * | 2015-08-07 | 2018-09-25 | 上海现代制药海门有限公司 | 盐酸奈必洛尔中间体混合物的结晶分离方法 |
CN117503775A (zh) * | 2017-04-28 | 2024-02-06 | 自由生物有限公司 | 治疗特应性皮炎以及提高活性药物成分稳定性的制剂、方法、试剂盒和剂型 |
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