CN1649603A - 包含甲硝唑的含水组合物 - Google Patents
包含甲硝唑的含水组合物 Download PDFInfo
- Publication number
- CN1649603A CN1649603A CNA028283163A CN02828316A CN1649603A CN 1649603 A CN1649603 A CN 1649603A CN A028283163 A CNA028283163 A CN A028283163A CN 02828316 A CN02828316 A CN 02828316A CN 1649603 A CN1649603 A CN 1649603A
- Authority
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- China
- Prior art keywords
- aqueous solution
- solution
- concentration
- metronidazole
- bcd
- 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.)
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- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 title claims abstract description 146
- 229960000282 metronidazole Drugs 0.000 title claims abstract description 144
- 239000000203 mixture Substances 0.000 title description 9
- 239000000243 solution Substances 0.000 claims abstract description 104
- 239000007864 aqueous solution Substances 0.000 claims abstract description 78
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 61
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 claims abstract description 52
- 229920000858 Cyclodextrin Polymers 0.000 claims abstract description 46
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims abstract description 44
- 238000000034 method Methods 0.000 claims abstract description 26
- 150000001875 compounds Chemical class 0.000 claims abstract description 11
- PVNIIMVLHYAWGP-UHFFFAOYSA-N nicotinic acid Natural products OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims description 73
- 230000002708 enhancing effect Effects 0.000 claims description 67
- 235000001968 nicotinic acid Nutrition 0.000 claims description 38
- 229960003512 nicotinic acid Drugs 0.000 claims description 38
- 239000011664 nicotinic acid Substances 0.000 claims description 38
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 35
- 238000011282 treatment Methods 0.000 claims description 21
- 239000003814 drug Substances 0.000 claims description 19
- 201000010099 disease Diseases 0.000 claims description 18
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 18
- 238000002360 preparation method Methods 0.000 claims description 15
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 claims description 8
- 239000012528 membrane Substances 0.000 claims description 8
- 230000003203 everyday effect Effects 0.000 claims description 6
- 208000002874 Acne Vulgaris Diseases 0.000 claims description 5
- 206010000496 acne Diseases 0.000 claims description 5
- 229960003966 nicotinamide Drugs 0.000 claims description 4
- 235000005152 nicotinamide Nutrition 0.000 claims description 4
- 239000011570 nicotinamide Substances 0.000 claims description 4
- 150000002634 lipophilic molecules Chemical class 0.000 claims description 3
- 125000000627 niacin group Chemical group 0.000 claims 3
- 230000001225 therapeutic effect Effects 0.000 abstract description 3
- 239000001116 FEMA 4028 Substances 0.000 abstract 1
- 235000011175 beta-cyclodextrine Nutrition 0.000 abstract 1
- 229960004853 betadex Drugs 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 abstract 1
- 239000000499 gel Substances 0.000 description 37
- 238000005352 clarification Methods 0.000 description 15
- 239000013078 crystal Substances 0.000 description 13
- 238000004090 dissolution Methods 0.000 description 8
- 238000002425 crystallisation Methods 0.000 description 7
- 230000008025 crystallization Effects 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 230000000699 topical effect Effects 0.000 description 7
- 210000004379 membrane Anatomy 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 4
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 208000017520 skin disease Diseases 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- 206010048768 Dermatosis Diseases 0.000 description 3
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 229940071826 hydroxyethyl cellulose Drugs 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000002674 ointment Substances 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 229940088594 vitamin Drugs 0.000 description 3
- 235000013343 vitamin Nutrition 0.000 description 3
- 239000011782 vitamin Substances 0.000 description 3
- 229930003231 vitamin Natural products 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- -1 BCD Chemical compound 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 241001597008 Nomeidae Species 0.000 description 2
- 229920002125 Sokalan® Polymers 0.000 description 2
- 230000003796 beauty Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 230000001965 increasing effect Effects 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 239000012744 reinforcing agent Substances 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 229920001450 Alpha-Cyclodextrin Polymers 0.000 description 1
- 208000004926 Bacterial Vaginosis Diseases 0.000 description 1
- NAIKCHJVANAEKA-UHFFFAOYSA-N C(C)ON1C(=NC=C1[N+](=O)[O-])C Chemical class C(C)ON1C(=NC=C1[N+](=O)[O-])C NAIKCHJVANAEKA-UHFFFAOYSA-N 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- 206010056340 Diabetic ulcer Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 241001026509 Kata Species 0.000 description 1
- 208000009675 Perioral Dermatitis Diseases 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 208000037009 Vaginitis bacterial Diseases 0.000 description 1
- HFHDHCJBZVLPGP-RWMJIURBSA-N alpha-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO HFHDHCJBZVLPGP-RWMJIURBSA-N 0.000 description 1
- 229940043377 alpha-cyclodextrin Drugs 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- LLEMOWNGBBNAJR-UHFFFAOYSA-N biphenyl-2-ol Chemical compound OC1=CC=CC=C1C1=CC=CC=C1 LLEMOWNGBBNAJR-UHFFFAOYSA-N 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- BEGBSFPALGFMJI-UHFFFAOYSA-N ethene;sodium Chemical group [Na].C=C BEGBSFPALGFMJI-UHFFFAOYSA-N 0.000 description 1
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 description 1
- 229940080345 gamma-cyclodextrin Drugs 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 229940063189 metrogel Drugs 0.000 description 1
- 210000002200 mouth mucosa Anatomy 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 229940099674 noritate Drugs 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 239000007971 pharmaceutical suspension Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- LXNHXLLTXMVWPM-UHFFFAOYSA-N pyridoxine Chemical compound CC1=NC=C(CO)C(CO)=C1O LXNHXLLTXMVWPM-UHFFFAOYSA-N 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 229960004418 trolamine Drugs 0.000 description 1
- 229940099259 vaseline Drugs 0.000 description 1
- 229940011671 vitamin b6 Drugs 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
Classifications
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
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- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/716—Glucans
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
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- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
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- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
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- C08J2305/16—Cyclodextrin; Derivatives thereof
Abstract
本发明涉及一种水溶液,其中甲硝唑的浓度高于0.75重量%。该水溶液包含作为第一溶解度增强剂的环糊精如β-CD以及除环糊精以外的第二溶解度增强剂。本发明还涉及该溶液的制备方法以及治疗用途。
Description
技术领域
本发明涉及用于治疗皮肤和粘膜疾病的局部给药药物领域。具体而言,本发明涉及包含甲硝唑作为活性成分的含水组合物。
背景技术
甲硝唑,1-(2-羟乙基)-2-甲基-5-硝基咪唑,已知是一种治疗各种疾病的有效药物,而且特别是已知用于治疗各种原虫疾病。作为局部疗法,还证实甲硝唑可用于治疗各种皮肤疾病,包括红斑痤疮、细菌性溃疡、以及口周皮炎,参见:Borgman的美国专利4,837,378。在局部使用以治疗皮肤疾病时,已经发现甲硝唑具有抗炎活性,参见Czemielewski等人的美国专利5,849,776。甲硝唑也可用作阴道治疗剂,用于治疗细菌性阴道病,参见Borgman的美国专利5,536,743。
用于治疗皮肤疾病的甲硝唑组合物可以乳膏、洗液和凝胶形式得到。一种市售的甲硝唑乳膏产品,NORITATETM(Dermik Laboratories,Inc.,Collegeville,PA 19426 USA),包含1%甲硝唑,其中不溶的药物悬浮在不透明的乳膏中。一种市售的甲硝唑凝胶产品,METROGEL(GaldermaLaboratories,Inc.Fort Worth,Texas,76133 USA),包含0.75%的溶解甲硝唑,以制备澄清凝胶。
为治疗许多皮肤和粘膜疾病,经常优选使用增溶的水基制剂,如凝胶,而不是使用乳膏、洗液或软膏。乳膏、洗液(通常为水包油型乳液)和软膏(通常为矿脂基组合物)经常是产生粉刺的、致痤疮性的,或者对于患者不具有美容上的吸引性。增溶的局部用产品通常要比含有不溶性活性成分的产品更易得到。
油基乳膏和软膏甲硝唑制剂与目前可以得到的凝胶基制剂相比具有以下优势:油基制剂可包含1%浓度的甲硝唑。水基凝胶组合物受限于仅0.75%浓度的甲硝唑,这是因为甲硝唑在水中的溶解度差。
已知环糊精可增强各种药物在水溶液中的溶解度。两亲性或亲脂性药物如甲硝唑被部分或者完全包封在该笼形结构中,由此增加药物在含水介质中的溶解度。但是,环糊精也具有某些缺陷,包括花费、环糊精溶解度的限制、在某些载体中的不相容性、以及潜在的局部和全身毒性。
多位作者已描述了β-环糊精(BCD)与甲硝唑的联合使用。Kata和Antal,Acta Pharmaceutica Hungarica,54:116-122(1984)公开了当在37℃下溶解于包含BCD的溶液中时,甲硝唑的溶解速率显著增加。没有注意BCD/甲硝唑溶液的稳定性。在使用BCD来增溶药物如甲硝唑时的主要问题是BCD在水中具有相对较低的溶解度,而且是相对不太有效的增溶剂,特别是对于亲脂性或者两亲性药物如甲硝唑。另外,环糊精如BCD及其衍生物是很昂贵的,而且包含BCD作为增溶剂的药物制剂同样也是昂贵的。仍然需要在降低BCD浓度的同时增加药物的溶解度的方法。
已有人描述了除环糊精以外的溶解度增强剂。Yie W.Chien,Journalof Parenteral Science and Technology,38(1):32-36(1984年1月)披露了烟酰胺是溶解度增强剂,可增加MTZ的水溶解度。Chien进一步披露了水溶性维生素抗坏血酸、以及吡哆素是用于水溶液的溶解度增强剂。Chien公开了甲硝唑在水中的溶解度相对于这些水溶性维生素在溶液中的浓度线性增加。Chien的文章在此并入作为参考。该现有技术没有致力于环糊精如BCD与其他溶解度增强剂如烟酰胺或者其他水溶性维生素的组合。
发明内容
现已令人惊奇地发现,环糊精与第二溶解度增强剂如烟酰胺或烟酸的组合对于两亲性或亲脂性化合物如甲硝唑的水溶解度具有协同作用。第二溶解度增强剂也可以不是烟酰胺或烟酸。由环糊精与第二溶解度增强剂的组合提供的协同作用允许使用更低浓度的环糊精,低于在没有第二溶解度增强剂存在时达到所希望的化合物溶解度水平所需要的浓度。因为环糊精是昂贵的,具有有限的水溶解度,而且不是完全没有毒性的,所以本发明对于大大降低药物制剂配制和制备中的成本、增加环糊精如BCD的增溶能力、以及得到所希望浓度的药理活性化合物并同时使环糊精的用量最小化提供了一个重要的方法。
在此所用术语“溶解度增强剂”是指当存在于溶剂的溶液中时能够增加第二化合物如活性成分在所述溶剂中的溶解度的化合物,但该化合物本身不是所述第二化合物的溶剂。
本说明书中所用的所有浓度都是重量%,除非另有说明。
以下参考具体的环糊精——BCD和具体的化合物——甲硝唑描述本发明。但是,本发明也适用于其他的环糊精,微晶和非微晶的,包括α和γ环糊精及其微晶和非微晶衍生物,以及除甲硝唑以为的其他两亲性和亲脂性化合物。
在溶液中组合第一溶解度增强剂和第二溶解度增强剂,由此可以得到包含0.75%以上甲硝唑(MTZ)的物理稳定的水溶液,其中所述第一溶解度增强剂是环糊精如β-环糊精(BCD),而所述第二溶解度增强剂例如是烟酰胺或烟酸。环糊精与第二溶解度增强剂的组合对于增强MTZ在水中的溶解度提供了协同作用。这些发现允许制备MTZ水溶液,其包括凝胶状的包含1%或更高MTZ的溶液。在此等水平下,MTZ可以被有效地用作局部药物。
在一个实施方案中,本发明是一种水溶液,其中MTZ的浓度高于0.75重量%,优选为约1%或更高。该水溶液包含作为第一溶解度增强剂的环糊精如BCD以及第二溶解度增强剂如烟酸或烟酰胺。优选地,环糊精和第二溶解度增强剂的各自浓度低于在没有其他溶解度增强剂存在时使MTZ的溶解浓度达到本发明水溶液中的浓度时所需要的浓度。但是如果需要的话,该溶液可包含过量的第二溶解度增强剂。最优选的是,MTZ在该组合溶液中的增强溶解度高于MTZ在两种分别包含单个溶解度增强剂的溶液中的增强溶解度之和,在所述两种溶液中所述单个溶解度增强剂的浓度与组合溶液中的相同。优选地,该溶液基本上不包含除环糊精和第二溶解度增强剂以外的水溶解度增强剂。优选地,该溶液是含水凝胶。
在另一个实施方案中,本发明是一种用于制造MTZ浓度高于0.75%、优选约为1.0%或更高的水溶液的方法。该方法包括在水基溶液中组合使用MTZ以及两种溶解度增强剂,其中一种是环糊精如BCD,MTZ最终水溶液的浓度高于0.75%。优选地,环糊精和第二溶解度增强剂的各自浓度低于在没有其他溶解度增强剂存在时使MTZ的溶解浓度达到本发明水溶液中的浓度时所需要的浓度。但是如果需要的话,可使用过量的第二溶解度增强剂。最优选的是,MTZ在该组合溶液中的增强溶解度高于MTZ在两种分别包含单个溶解度增强剂的溶液中的增强溶解度之和,在所述两种溶液中所述单个溶解度增强剂的浓度与组合溶液中的相同。优选地,在溶液中进一步组合使用凝胶剂,并优选在添加MTZ和溶解度增强剂之后。
在另一个实施方案中,本发明涉及用于治疗皮肤或粘膜疾病的方法。该方法包括向受影响区域局部施用包含MTZ和环糊精如BCD以及第二溶解度增强剂如烟酸或烟酰胺的水溶液,该溶液中MTZ的浓度高于0.75%,优选为约1.0%或更高。优选地,环糊精和第二溶解度增强剂的各自浓度低于在没有其他溶解度增强剂存在时使MTZ的溶解浓度达到本发明水溶液中的浓度时所需要的浓度。但是如果需要的话,该溶液可包含过量的第二溶解度增强剂。最优选的是,MTZ在该组合溶液中的增强溶解度高于MTZ在两种分别包含单个溶解度增强剂的溶液中的增强溶解度之和,在所述两种溶液中所述单个溶解度增强剂的浓度与组合溶液中的相同。优选地,该水溶液是凝胶。
在另一个实施方案中,本发明涉及用于治疗皮肤或粘膜疾病的药盒。
本发明的药盒包括一包含MTZ水溶液的容器,而该水溶液包含为环糊精如BCD的第一溶解度增强剂以及第二溶解度增强剂如烟酸或烟酰胺。优选地,环糊精和第二溶解度增强剂的各自浓度低于在没有其他溶解度增强剂存在时使MTZ的溶解浓度达到本发明水溶液中的浓度时所需要的浓度。但是如果需要的话,该溶液可包含过量的第二溶解度增强剂。最优选的是,MTZ在该组合溶液中的增强溶解度高于MTZ在两种分别包含单个溶解度增强剂的溶液中的增强溶解度之和,在所述两种溶液中所述单个溶解度增强剂的浓度与组合溶液中的相同。优选地,该水溶液是凝胶。
附图说明
图1显示了本发明药盒的优选实施方案的示意图。
具体实施方式
出乎意料地发现,通过使用组合溶解度增强剂,其中一种溶解度增强剂是环糊精如BCD,以及第二溶解度增强剂不是环糊精,能够得到稳定的甲硝唑(MTZ)水溶液,该水溶液中的甲硝唑(MTZ)含量大于0.75重量%,并甚至为1.0%或更高。合适的第二增强剂的例子包括烟酸和烟酰胺。
在本发明之说明书中使用的术语“稳定的”是指物理上的稳定性,而不是化学上的稳定性。根据本发明,在5℃的冷藏温度下储存至少7天时,本发明的甲硝唑溶液是物理稳定的,基本上没有晶体或沉淀物从溶液中析出。
在基本上不存在对完整或者受损皮肤或粘膜表面具有刺激性的水混溶有机溶剂如乙醇或丙二醇时,可得到浓度大于0.75%的甲硝唑物理稳定水溶液。这些有机溶液的消除使治疗溶液具有更低的刺激作用,而且使该溶液特别适用于局部治疗皮肤病症如红斑痤疮,而治疗制剂中如果存在刺激性化学品将会加重该病症。但是,如果需要,溶液中也可包含此等有机溶剂,浓度最高为约10%。在优选实施方案中,本发明的水溶液基本上不包含用于MTZ的有机溶剂。
在本发明的稳定MTZ水溶液中,MTZ的浓度大于0.75重量%。优选地,MTZ在本发明溶液中的浓度为约1.0%。根据本发明,MTZ在水溶液中的浓度甚至可以更高,例如为1.25%、1.5%、2.0%或2.5%或更高。MTZ的浓度为1%或更高时,本发明的水溶液可有效地用作局部治疗制剂。
本发明的溶液优选为凝胶形式的。因此,MTZ水溶液优选包含凝胶剂。任何可在水中分散并形成基本上均匀的含水凝胶的凝胶剂都适合用于本发明的溶液中,只要该凝胶剂不实质性地影响MTZ的水溶解度或者溶液的治疗效力。“实质性地影响”是指所包含的凝胶剂降低MTZ在水溶液中的溶解度至0.75重量%或更低。优选的凝胶剂是羟乙基纤维素(NATROSOLTM,Hercules Inc.,Wilmington,DE,USA)。其他合适凝胶剂的例子包括羧乙烯基聚合物如CARBOPOL934、940和941(Noveon,Inc.,Akron,Ohio,USA)。
环糊精在溶液中的浓度可根据所希望的MTZ溶解浓度而变化。通常优选使用在得到所希望的MTZ浓度的情况下尽可能低的环糊精浓度,这是因为环糊精较贵,具有有限的水溶解度,并非完全无毒性的,而且环糊精的存在对于某些完整的以及患病的皮肤和粘膜表面具有刺激作用。根据本发明,水溶液中的环糊精浓度可在0.1%-20%之间,或者更高。优选地,该溶液中的环糊精浓度不超过约5重量%。如果是β-环糊精,其在水溶液中的浓度受限于其在水中的溶解度。β-环糊精的水溶液如凝胶,在5℃(冰箱温度)时约0.5%的浓度即达到饱和。
水溶液、特别是凝胶剂型的水溶液是不粘的、快速干燥的、以及美容高雅的。该溶液、包括凝胶制剂在5℃(冰箱温度)或者室温下在至少7天中都是物理稳定的。在5℃下1周后没有观察到形成晶体或沉淀。
优选的是,本发明的水溶液基本上不包含除MTZ以外的、水溶解度可被环糊精增强的其他药物活性化合物。这些其他化合物对于粘合剂笼形结构中的螯合位可起到竞争剂的作用,而且降低环糊精对MTZ溶解度的增强作用。在溶液中可使用用环糊精增强溶解度的多种溶质,只要溶液中的环糊精和第二溶解度增强剂的浓度足够高,以在即使有竞争溶质存在时仍形成所希望的MTZ溶解浓度。
在本发明的优选实施方案中,环糊精在溶液中的浓度低于将MTZ的溶解度增强至所希望的程度时的浓度,而第二溶解度增强剂如烟酰胺或烟酸在溶液中的浓度应能够得到MTZ在水溶液中的希望浓度。例如,如果希望稳定的1%MTZ水溶液,可使用0.1%-1.0%的BCD,而且烟酰胺或烟酸在溶液中的混合量应使MTZ的溶解度达到1%。待混合在溶液中的烟酰胺的量低于当溶液中不存在BCD时增强MTZ的溶解度以得到1%MTZ溶液或者任何所希望的MTZ浓度时的量。根据本发明的该实施方案,对于1%的MTZ水溶液,BCD在该溶液中的浓度优选为1.0重量%或更低,而烟酰胺或烟酸的浓度等于或者高于BCD的浓度。
本发明包括含水凝胶的水溶液可以按照产生大于0.75%、优选1.0%或更高的稳定MTZ浓度的方式来制备。优选地,在添加凝胶剂之前,或者至少在发生溶液凝胶化之前,使溶解度增强剂和MTZ在水或水基溶液中进行混合。优选地,在添加MTZ之前,将溶解度增强剂溶解在水中。
在制备本发明水溶液的优选方法中,制备BCD和烟酰胺或烟酸的水溶液,其中BCD和烟酰胺或烟酸的量如上所述。然后在溶液中添加甲硝唑。在溶液中添加的甲硝唑的量可以进行计算,以使MTZ达到所希望的浓度,或者是过量的MTZ。溶液优选在升高的温度下进行搅拌,然后冷却至室温或者冰箱温度。如果需要,优选在添加MTZ之后的任意时间处向溶液中添加凝胶剂。最优选的是在搅拌溶液后、在冷却溶液期间、或者在冷却溶液后向溶液中添加凝胶剂。
本发明的溶液、包括凝胶,可用于局部治疗对甲硝唑疗法有反应的皮肤或粘膜疾病。根据本发明的治疗方法,向需要此等治疗的皮肤或粘膜表面局部地施用包含浓度高于0.75重量%、优选为约1%或更高的甲硝唑的稳定水溶液。所施用的溶液优选包含如上所述的环糊精如BCD以及如上所述的烟酸或烟酰胺。
本发明的治疗方法可用于治疗对甲硝唑疗法有反应或者强烈反应的任意疾病。适合用本发明的方法治疗的疾病的例子包括皮肤、口腔粘膜或者阴道粘膜上的炎症损伤、糖尿病性足溃疡、以及可局部进行治疗的某些感染性疾病。在优选的实施方案中,本发明的方法是用于治疗红斑痤疮。
在约1%或更高的浓度时,优选每日仅施用一次甲硝唑溶液。该溶液以每日基础施用,每日1或多次,施用时间应足以对所述疾病产生缓解或者治愈作用。对于某些慢性疾病,本发明的溶液可每日1或多次长时间地施用,以防止所述疾病的恶化。
在本发明的另一个实施方案中,药盒(图1)是用于局部治疗皮肤或粘膜疾病。该药盒包含罐101或者适合容纳本发明的甲硝唑水溶液的其他容器,以及向皮肤或粘膜表面的受损区域局部地施用该溶液的说明(未示出)。优选地,甲硝唑溶液中的甲硝唑浓度为约1%或更高,而且所述说明要求向受损区域每日施用甲硝唑溶液1次。罐101优选包装在盒102中,在该盒上可写上额外的信息如使用指南。
以下非限制性的实施例用于进一步描述本发明。
实施例1
在以下实施例中的所有溶液都包含如通式所列的成分或者如表1中所示的凝胶载体。
表1
组分 | 重量% |
对羟基苯甲酸甲酯 | 0.15 |
对羟基苯甲酸丙酯 | 0.05 |
苯氧基乙醇 | 0.7 |
乙二胺四乙酸钠 | 0.05 |
羟乙基纤维素(HEC) | 1.25 |
β-环糊精(BCD) | 如表2-6中所示 |
烟酰胺或烟酸 | 如表2-6中所示 |
纯水 | 至100.00 |
改变β-环糊精(BCD)的浓度,制备根据表1的不同溶液。BCD的溶液保存在5℃下,每周观察形成结晶或沉淀物的迹象,共进行2周。所得结果如表2所示。数据表明在5℃下水溶液中饱和的BCD溶解度为约0.5%。
表2
BCD重量% | 在5℃下储存后的结果 |
0.5 | 2周后澄清 |
0.6 | 2周后形成晶体 |
0.7 | 1周时形成晶体 |
0.9 | 1周时形成晶体 |
1.0 | 1周时形成晶体 |
1.2 | 1周时形成晶体 |
1.4 | 1周时形成晶体 |
1.5 | 1周时形成晶体 |
实施例2
用实施例1中包含0.5%BCD的凝胶载体制备不同浓度的甲硝唑。甲硝唑(MTZ)/BCD溶液在5℃下保存1周。结果示于表3中。
表3
BCD重量% | MTZ重量% | 5℃下1周的结果 |
0.5 | 0.9 | 形成晶体 |
0.5 | 0.8 | 澄清 |
0.5 | 0.7 | 澄清 |
从该研究可以看出,甲硝唑在包含0.5%BCD的凝胶载体中的稳定溶解度在5℃下测定为约0.8重量%。
实施例3
使用各种浓度的烟酰胺进行类似的研究,结果表明为得到1.0%甲硝唑的稳定水凝胶溶液所需要的烟酰胺为约3%。制备表1中的各种凝胶溶液,其中甲硝唑的浓度为1.0%,包含0.5%或1.0%的BCD以及不同浓度的烟酰胺。这些凝胶保存在5℃下1周,以观察沉淀和晶体的形成。结果如表4所示。
表4
BCD,重量% | 烟酰胺,重量% | 甲硝唑,重量% | 5℃下1周的结果 |
0.5 | 0.5 | 1.0 | 形成晶体 |
0.5 | 1.0 | 1.0 | 澄清 |
0.5 | 2.0 | 1.0 | 澄清 |
1.0 | 0.5 | 1.0 | 形成沉淀物 |
1.0 | 1.0 | 1.0 | 澄清 |
1.0 | 2.0 | 1.0 | 澄清 |
表4中的结果表明,分别低至0.5%和1.0%的BCD和烟酰胺浓度可一起使用以得到1.0%的物理稳定的甲硝唑水凝胶溶液。
实施例4
制备表1中的各种凝胶溶液,其中甲硝唑的浓度为1.0%,并包含各种浓度的烟酸。用trolamine将pH调节为5.0+/-0.15。该溶液在5℃下保存1周,以观察形成沉淀物或晶体的证据。结果示于表5中。
表5
烟酸,重量% | MTZ,重量% | 5℃下1周的结果 |
2.0 | 1.0 | 澄清 |
1.8 | 1.0 | 澄清 |
1.5 | 1.0 | 澄清 |
1.2 | 1.0 | 澄清 |
1.0 | 1.0 | 澄清 |
0.75 | 1.0 | 澄清 |
0.5 | 1.0 | 澄清/形成结晶* |
0.25 | 1.0 | 形成结晶 |
0.25 | 1.0 | 形成结晶 |
0.15 | 1.0 | 形成结晶 |
0.10 | 1.0 | 形成结晶 |
*8个样品中有7个显示形成结晶
表5中的结果表明,为得到1.0%甲硝唑的稳定凝胶溶液所需要的最小烟酸浓度高于0.5%,并优选为约0.75%。
实施例5
制备根据表1的各种溶液,其包含1%的甲硝唑、0.5%的烟酸以及各种浓度的BCD,而且pH调节至5.0+/-0.15。该溶液在5℃下保存1周,以观察沉淀物或晶体的形成。结果示于表6中。
表6
BCD,重量% | 烟酸,重量% | MTZ,重量% | 5℃下1周后的结果 |
0.2 | 0.5 | 1.0 | 形成晶体 |
0.3 | 0.5 | 1.0 | 形成晶体 |
0.5 | 0.5 | 1.0 | 澄清 |
如表6中所示,通过使用0.5%烟酸与0.5%BCD的组合,可制得稳定的1.0%甲硝唑含水凝胶溶液。
在上述实施例1-5中的数据表明,在最大水可溶性浓度下的BCD于5℃将MTZ在水溶液如凝胶中的稳定溶解度提高1%,即、从7%到8%。为将MTZ的水溶解度提高0.3%-1%,则需要3%浓度的烟酰胺。因此,约3%浓度的烟酰胺将MTZ在含水凝胶中的物理稳定的溶解度提高约为最大可溶性浓度的BCD所提供的溶解度增加量的3倍。
当在溶液中联合使用BCD和烟酰胺时,这两个化合物起到协同作用,增加MTZ在水中的溶解度。实施例1-5中的数据表明,当BCD在水溶液中的添加量预期可产生0.1%的溶解度增加,而烟酰胺的添加量为能够使MTZ的溶解度增加0.3%的烟酰胺量的三分之一,它们的组合可使MTZ的溶解度比单独使用时的溶解度高0.3%。
用0.5%浓度的烟酸可得到类似的结果,该浓度低于产生1%甲硝唑稳定水溶液时所需要的浓度。当该浓度的烟酸与0.5%的BCD(该浓度仅可使MTZ的水溶解度增加0.1%,达到0.8%)组合使用时,在pH为约5时将MTZ的溶解度协同地增加至1%。
上述发明的各种改进对于本领域技术人员是显而易见的。例如,可以使用1种以上的环糊精,如β-环糊精和羟丙基β-环糊精。类似地,第二溶解度增强剂可以是多种溶解度增强剂,如烟酸和烟酰胺。此等改进都应包括在以下权利要求书所限定的范围内。
Claims (44)
1、在5℃下物理稳定至少1周的水溶液,其包含两亲性或亲脂性化合物、为环糊精的第一溶解度增强剂和第二溶解度增强剂。
2、如权利要求1所述的水溶液,其中所述化合物是甲硝唑。
3、如权利要求2所述的水溶液,其中溶液中的甲硝唑浓度高于0.75%。
4、如权利要求3所述的水溶液,其中溶液中的甲硝唑浓度为约1.0%或更高。
5、如权利要求1所述的水溶液,其中所述环糊精是β-环糊精(BCD)。
6、如权利要求5所述的水溶液,其中所述BCD是微晶BCD。
7、如权利要求2所述的水溶液,其中所述环糊精是β-环糊精(BCD)。
8、如权利要求7所述的水溶液,其中所述BCD是微晶BCD。
9、如权利要求1所述的水溶液,其中所述第二溶解度增强剂是烟酰胺。
10、如权利要求2所述的水溶液,其中所述第二溶解度增强剂是烟酰胺。
11、如权利要求5所述的水溶液,其中所述第二溶解度增强剂是烟酰胺。
12、如权利要求1所述的水溶液,其中所述第二溶解度增强剂是烟酸。
13、如权利要求2所述的水溶液,其中所述第二溶解度增强剂是烟酸。
14、如权利要求5所述的水溶液,其中所述第二溶解度增强剂是烟酸。
15、如权利要求1所述的水溶液,其是凝胶。
16、如权利要求2所述的水溶液,其是凝胶。
17、如权利要求11所述的水溶液,其中溶液中的BCD浓度为1.0%或更低,而烟酰胺浓度为约1.0%或更高。
18、如权利要求17所述的水溶液,其是凝胶。
19、如权利要求14所述的水溶液,其中溶液中的BCD浓度为1.0%或更低,而烟酰胺浓度为约0.5%或更高。
20、如权利要求11所述的水溶液,其中溶液中的烟酰胺浓度低于不存在BCD时将甲硝唑的水溶解度增加至所述溶液中的甲硝唑浓度所需要的浓度。
21、如权利要求11所述的水溶液,其中溶液中的BCD浓度低于不存在烟酰胺时将甲硝唑的水溶解度增加至所述溶液中的甲硝唑浓度所需要的浓度。
22、如权利要求15所述的水溶液,其中溶液中的烟酸度低于不存在BCD时将甲硝唑的水溶解度增加至所述溶液中的甲硝唑浓度所需要的浓度。
23、如权利要求11所述的水溶液,其中溶液中的BCD浓度低于不存在烟酰胺时将甲硝唑的水溶解度增加至所述溶液中的甲硝唑浓度所需要的浓度。
24、制备甲硝唑的浓度大于0.75%的水溶液的方法,其包括在水中混合甲硝唑、β-环糊精(BCD)、以及烟酸或烟酰胺。
25、如权利要求24所述的方法,其中在将BCD和烟酸或烟酰胺溶解在水中之后,向水中添加甲硝唑。
26、如权利要求24所述的方法,其进一步包括在混合甲硝唑、BCD、和烟酸或烟酰胺之后,添加凝胶剂。
27、如权利要求24所述的方法,其中混合烟酰胺而不是烟酸。
28、如权利要求24所述的方法,其中混合烟酸而不是烟酰胺。
29、根据如权利要求24所述的方法制备的水溶液。
30、根据如权利要求26所述的方法制备的水溶液。
31、根据如权利要求27所述的方法制备的水溶液。
32、根据如权利要求28所述的方法制备的水溶液。
33、用于治疗皮肤或粘膜疾病的方法,其包括向患病部位局部地使用有效量的甲硝唑水溶液,该水溶液中甲硝唑的浓度高于0.75重量%,并使甲硝唑治疗所述疾病,其中所述溶液包括β-环糊精(BCD)和烟酸或烟酰胺。
34、如权利要求33所述的方法,其中甲硝唑的浓度为约1%或更高。
35、如权利要求34所述的方法,其中每日施用1次。
36、如权利要求33所述的方法,其中所述疾病是红斑痤疮。
37、如权利要求33所述的方法,其中所述溶液包括烟酸而且基本上不含烟酰胺。
38、如权利要求33所述的方法,其中所述溶液包含烟酰胺而且基本上不含烟酸。
39、如权利要求33所述的方法,其中所述水溶液是凝胶。
40、用于治疗皮肤或粘膜疾病的药盒,其包括容器以及在所述容器中的甲硝唑、β-环糊精、和烟酸或烟酰胺水溶液,其中在所述溶液中甲硝唑的浓度高于0.75%。
41、如权利要求40所述的药盒,其中甲硝唑的浓度为约1%或更高。
42、如权利要求40所述的药盒,其中所述水溶液是凝胶。
43、如权利要求40所述的药盒,其中所述溶液包含烟酰胺而且基本上不含烟酸。
44、如权利要求40所述的药盒,其中所述溶液包含烟酸并且基本上不含烟酰胺。
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2001
- 2001-12-24 US US10/033,835 patent/US6881726B2/en not_active Expired - Lifetime
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2002
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105903028A (zh) * | 2010-12-31 | 2016-08-31 | 东塘实验室有限公司 | 含有环糊精的细胞水合组合物 |
CN105903028B (zh) * | 2010-12-31 | 2020-10-16 | 东塘实验室有限公司 | 含有环糊精的细胞水合组合物 |
CN111840632A (zh) * | 2019-04-25 | 2020-10-30 | 广东泰宝医疗科技股份有限公司 | 一种含止血微囊的液体敷料及其制备方法 |
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