CN101808621A - 去氨加压素的经口药物组合物 - Google Patents
去氨加压素的经口药物组合物 Download PDFInfo
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- CN101808621A CN101808621A CN200880105631A CN200880105631A CN101808621A CN 101808621 A CN101808621 A CN 101808621A CN 200880105631 A CN200880105631 A CN 200880105631A CN 200880105631 A CN200880105631 A CN 200880105631A CN 101808621 A CN101808621 A CN 101808621A
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- Prior art keywords
- acid
- pharmaceutical composition
- desmopressin
- effective dose
- compositions
- Prior art date
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- Pending
Links
- 108010000437 Deamino Arginine Vasopressin Proteins 0.000 title claims abstract description 54
- 229960004281 desmopressin Drugs 0.000 title claims abstract description 54
- NFLWUMRGJYTJIN-NXBWRCJVSA-N desmopressin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSCCC(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(N)=O)=O)CCC(=O)N)C1=CC=CC=C1 NFLWUMRGJYTJIN-NXBWRCJVSA-N 0.000 title claims abstract description 54
- 239000000203 mixture Substances 0.000 title claims description 56
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 29
- 239000007788 liquid Substances 0.000 claims abstract description 11
- 208000032843 Hemorrhage Diseases 0.000 claims abstract description 10
- 201000010064 diabetes insipidus Diseases 0.000 claims abstract description 6
- 208000008967 Enuresis Diseases 0.000 claims abstract description 5
- 201000003542 Factor VIII deficiency Diseases 0.000 claims abstract description 5
- 208000003450 Neurogenic Diabetes Insipidus Diseases 0.000 claims abstract description 5
- 206010051077 Post procedural haemorrhage Diseases 0.000 claims abstract description 5
- 208000028235 central diabetes insipidus Diseases 0.000 claims abstract description 5
- 201000005119 neurohypophyseal diabetes insipidus Diseases 0.000 claims abstract description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 27
- 239000003814 drug Substances 0.000 claims description 19
- 230000002421 anti-septic effect Effects 0.000 claims description 17
- 239000003795 chemical substances by application Substances 0.000 claims description 13
- 210000004400 mucous membrane Anatomy 0.000 claims description 10
- 235000011054 acetic acid Nutrition 0.000 claims description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 9
- 238000010521 absorption reaction Methods 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- 239000006188 syrup Substances 0.000 claims description 8
- 235000020357 syrup Nutrition 0.000 claims description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 6
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 claims description 6
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 claims description 6
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 claims description 6
- 229960002216 methylparaben Drugs 0.000 claims description 6
- 230000000149 penetrating effect Effects 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- 239000003242 anti bacterial agent Substances 0.000 claims description 5
- 230000000843 anti-fungal effect Effects 0.000 claims description 5
- 229940121375 antifungal agent Drugs 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- ALRHLSYJTWAHJZ-UHFFFAOYSA-N 3-hydroxypropionic acid Chemical compound OCCC(O)=O ALRHLSYJTWAHJZ-UHFFFAOYSA-N 0.000 claims description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 4
- 102100026735 Coagulation factor VIII Human genes 0.000 claims description 4
- 208000009292 Hemophilia A Diseases 0.000 claims description 4
- 101000911390 Homo sapiens Coagulation factor VIII Proteins 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- 208000037486 Postoperative Hemorrhage Diseases 0.000 claims description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 4
- 239000003623 enhancer Substances 0.000 claims description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 claims description 4
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 claims description 4
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- 108010047303 von Willebrand Factor Proteins 0.000 claims description 4
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 3
- 150000005168 4-hydroxybenzoic acids Chemical class 0.000 claims description 3
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 3
- 235000015165 citric acid Nutrition 0.000 claims description 3
- 230000002496 gastric effect Effects 0.000 claims description 3
- 235000011167 hydrochloric acid Nutrition 0.000 claims description 3
- 239000001630 malic acid Substances 0.000 claims description 3
- 235000011090 malic acid Nutrition 0.000 claims description 3
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 claims description 2
- 239000005711 Benzoic acid Substances 0.000 claims description 2
- MOZDKDIOPSPTBH-UHFFFAOYSA-N Benzyl parahydroxybenzoate Chemical compound C1=CC(O)=CC=C1C(=O)OCC1=CC=CC=C1 MOZDKDIOPSPTBH-UHFFFAOYSA-N 0.000 claims description 2
- QFOHBWFCKVYLES-UHFFFAOYSA-N Butylparaben Chemical compound CCCCOC(=O)C1=CC=C(O)C=C1 QFOHBWFCKVYLES-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims description 2
- XPJVKCRENWUEJH-UHFFFAOYSA-N Isobutylparaben Chemical compound CC(C)COC(=O)C1=CC=C(O)C=C1 XPJVKCRENWUEJH-UHFFFAOYSA-N 0.000 claims description 2
- CMHMMKSPYOOVGI-UHFFFAOYSA-N Isopropylparaben Chemical compound CC(C)OC(=O)C1=CC=C(O)C=C1 CMHMMKSPYOOVGI-UHFFFAOYSA-N 0.000 claims description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- YVPYQUNUQOZFHG-UHFFFAOYSA-N amidotrizoic acid Chemical compound CC(=O)NC1=C(I)C(NC(C)=O)=C(I)C(C(O)=O)=C1I YVPYQUNUQOZFHG-UHFFFAOYSA-N 0.000 claims description 2
- 235000001014 amino acid Nutrition 0.000 claims description 2
- 150000001413 amino acids Chemical class 0.000 claims description 2
- 235000010323 ascorbic acid Nutrition 0.000 claims description 2
- 239000011668 ascorbic acid Substances 0.000 claims description 2
- 229960005070 ascorbic acid Drugs 0.000 claims description 2
- 235000003704 aspartic acid Nutrition 0.000 claims description 2
- 239000012752 auxiliary agent Substances 0.000 claims description 2
- 235000010233 benzoic acid Nutrition 0.000 claims description 2
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 claims description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 2
- 229960001617 ethyl hydroxybenzoate Drugs 0.000 claims description 2
- 239000004403 ethyl p-hydroxybenzoate Substances 0.000 claims description 2
- 235000010228 ethyl p-hydroxybenzoate Nutrition 0.000 claims description 2
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 claims description 2
- 239000004220 glutamic acid Substances 0.000 claims description 2
- 235000013922 glutamic acid Nutrition 0.000 claims description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 2
- 239000004310 lactic acid Substances 0.000 claims description 2
- 235000014655 lactic acid Nutrition 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- 239000011976 maleic acid Substances 0.000 claims description 2
- 229960002510 mandelic acid Drugs 0.000 claims description 2
- 239000011707 mineral Substances 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- 235000006408 oxalic acid Nutrition 0.000 claims description 2
- 235000011007 phosphoric acid Nutrition 0.000 claims description 2
- 239000001117 sulphuric acid Substances 0.000 claims description 2
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- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 2
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- PESXGULMKCKJCC-UHFFFAOYSA-M sodium;4-methoxycarbonylphenolate Chemical compound [Na+].COC(=O)C1=CC=C([O-])C=C1 PESXGULMKCKJCC-UHFFFAOYSA-M 0.000 description 3
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
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- BBBFJLBPOGFECG-VJVYQDLKSA-N calcitonin Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(N)=O)C(C)C)C(=O)[C@@H]1CSSC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 BBBFJLBPOGFECG-VJVYQDLKSA-N 0.000 description 2
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- YEKWZZLERWGFDG-UHFFFAOYSA-N benzyl 4-hydroxybenzoate;sodium Chemical compound [Na].C1=CC(O)=CC=C1C(=O)OCC1=CC=CC=C1 YEKWZZLERWGFDG-UHFFFAOYSA-N 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
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- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
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- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0065—Forms with gastric retention, e.g. floating on gastric juice, adhering to gastric mucosa, expanding to prevent passage through the pylorus
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- A—HUMAN NECESSITIES
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- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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Abstract
本发明涉及包含去氨加压素的经口给药用液体药物组合物，及其用于治疗中枢性尿崩症、原发性夜间遗尿症、甲型血友病患者的出血、血管性血友病患者的出血和术后出血的应用。
Description
技术领域
本发明总地涉及生物医学领域，特别涉及去氨加压素的新型的、剂量灵活的、液体经口药物组合物及其用于治疗中枢性尿崩症、原发性夜间遗尿症、甲型血友病患者的出血、血管性血友病患者的出血，和术后出血的应用。
背景技术
一段时间以来已知1-去氨基-8-D-精氨酸-加压素，一般被称为去氨加压素，具有有用的用于治疗尿崩症的生物学效果，提供了抗利尿活性并使延长的出血时间缩短和正常化。
去氨加压素作为药物通过不同的途径、以不同的表现方式并与不同的赋形剂相组合被给予。例如，已经描述了去氨加压素的经鼻、经口、经阴道、经直肠、皮下、静脉内和肌肉内途径的给药。采用去氨加压素的胃肠吸收的经口给药途径的问题是生物利用度明显低于通过其它给药途径获得的生物利用度，因为去氨加压素被胃和肠的酶所降解并在肝内被代谢。乙酸盐形式的去氨加压素的最常用的可供选择的给药途径是经鼻或口腔粘膜途径，这是出于与其它的非肠道给药路径相比，通过这些途径给药的便利性的考虑。
现有技术中已知其中活性物质通过粘膜被吸收的滴剂或喷雾剂形式的乙酸去氨加压素的经鼻药物组合物。例如，文件EP 0710122A1描述了借助于喷雾用于经鼻给药、在室温下是稳定的去氨加压素的水性组合物，该组合物含有缓冲剂、渗透压力控制剂和作为防腐剂的季胺类，特别是苯扎氯铵。还在实施例中描述了包含浓度为1mg/ml的对羟基苯甲酸酯类代替季铵类作为防腐剂的水性组合物。
文件WO 2004/014411A1涉及滴剂或喷雾剂形式的经鼻给药用水性组合物，该组合物包含去氨加压素和作为稳定剂和吸附剂的三(羟甲基)氨基甲烷。特别地，该组合物可包含助剂诸如对羟基苯甲酸甲酯和/或对羟基苯甲酸丙酯。
同样地，文件WO 03/97080A1描述了在室温下稳定并且在可接受的载体中的去氨加压素的水性经鼻组合物，所述可接受的载体另外包含pH缓冲剂、作为防腐剂的对羟基苯甲酸酯类和改善对羟基苯甲酸酯类的防腐性的助溶剂。
另外，文件WO 94/03157A1涉及脂质体分散体或微乳剂形式的经鼻或经阴道给药用组合物，其包含鲑鱼降钙素(尽管也提到了去氨加压素)以及热固性聚合物。该组合物还包含作为防腐剂的对羟基苯甲酸甲酯。
文件WO 01/60394A1和WO 2004/019910A2描述了借助于喷雾经口或经鼻给药并通过粘膜吸收的去氨加压素的药物组合物。特别地，文件WO 01/60394A1描述了去氨加压素与作为pH4-6的缓冲剂并同时作为防腐剂的苹果酸的经口、经鼻或舌下组合物，其可另外包含其它的防腐剂，诸如对羟基苯甲酸酯类。该组合物还必须包含渗透剂并且根据实施例借助于经鼻或舌下喷雾剂或糖浆剂被给予。另外，文件WO2004/019910A2描述了用于通过口腔粘膜给予活性物质的颊喷雾剂，其中去氨加压素作为可能的抗利尿活性物质之一被提及。
文件EP 0381345A1描述了包含去氨加压素和羧甲基纤维素的水性溶液形式的药物组合物，并且其以滴剂形式或使用喷雾器进行鼻内给药或借助于肌肉内、静脉内或皮下注射被给予。
同样地，文件WO 2005/115339A2描述了具有增加药物经过口粘膜、鼻粘膜、胃肠道粘膜或阴道粘膜的吸收的组分的液体、半固体或固体药物组合物。特别地，描述了包含去氨加压素作为药物和对羟基苯甲酸甲酯作为防腐剂并通过鼻粘膜给药或通过胃肠道、经口、经眼或阴道路径给药的液体组合物。
在本领域中还已知去氨加压素的固体剂量形式的其它的经口药物组合物。文件EP 0163723A1、EP 0689452A1、EP 752877A1、EP 1473029A1、EP 1500390A1、EP 1501534A1、EP 0517211A1、WO 2005/089724A1和WO 2005/046707A1描述了包含去氨加压素的片剂、胶囊或粉末形式的不同的经口组合物，并且该组合物通过口腔粘膜和/或通过胃肠道被吸收。然而，所有这些固体制剂具有有限的剂量变化性并且对于吞咽困难的人群的给药是复杂的。
最后，另外已知含有去氨加压素的颊贴剂。文件US 5298256A描述了粘附于口腔粘膜的颊贴剂形式并包含去氨加压素的药物组合物。
上面所引用的文件描述了借助于贴剂、胶囊、片剂或糖浆剂通过口或舌下粘膜给药或借助于滴剂或喷雾剂通过鼻粘膜给药的去氨加压素的组合物。然而，经鼻给药途径由于组合物的渗透剂和/或用于增加吸收的试剂而存在刺激性问题，以及在鼻腔内吸收可用的小区域的问题。相比之下，目前已知的经口给药形式具有非个体化的缺陷，也就是说，它们缺乏或没有允许以个体化方式治疗每个患者的灵活的剂量，如在去氨加压素的情况下，如果药物的药理学活性高，则这一问题会加剧。另外，目前用于去氨加压素经口给药的固体剂型对于特殊人群诸如吞咽困难的老年人以及不想吞咽的儿童而言，其给药是复杂的。
因此，仍然需要发现一种表现形式，其共同地解决了由经鼻途径所带来的刺激性和吸收区域容量问题，并且另外解决了目前经口给药形式所存在的缺乏灵活的剂量和特殊人群给药困难的问题。本发明的目的是用于经口给药的稳定的、剂量灵活的、液体药物组合物，其既不含渗透剂又不含吸收增强剂并包含治疗有效量的去氨加压素。
具有肽的药物，特别是具有硫桥的那些药物诸如去氨加压素，其问题是它们的水性溶液容易降解，因此在这些溶液中必需存在防腐剂。在目前已知的用于缩宫素肽家族的水性组合物的防腐剂中，是对羟基苯甲酸类或对羟基苯甲酸酯类。
除了上面所提及的描述含有对羟基苯甲酸酯类的组合物的文件之外，文件US 2004/0235956A1描述了溶液、糖浆剂、悬浮液或酏剂形式的用于对粘膜给药的卡贝缩官素的液体组合物。在具体实施方案中，卡贝缩官素的液体溶液包含对羟基苯甲酸酯类作为防腐剂。
发明描述
本发明提供了包含去氨加压素的经口给药用液体药物组合物，其可用于治疗中枢性尿崩症、原发性夜间遗尿症、甲型血友病患者的出血、血管性血友病患者的出血和术后出血。
因此，本发明的第一个方面涉及包含治疗有效量的去氨加压素并且既不包含渗透剂又不包含吸收增强剂的稳定的、剂量灵活的、液体药物组合物。
同样地，本发明的药物组合物不包含任何pH缓冲剂。
在本发明中，“稳定的”是指组合物的pH在25℃下被保持在3.5-5.0之间历时至少12个月。
在具体实施方案中，治疗有效量的去氨加压素以一种或多种其药学可接受的盐的形式，优选为乙酸去氨加压素的形式被给予。
本发明组合物中的去氨加压素的治疗有效量为0.001mg/ml到5mg/ml；优选0.01mg/ml到2mg/ml，更优选0.1mg/ml到1mg/ml。
在具体实施方案中，本发明的药物组合物另外包含一种或多种药学可接受的助剂，其选自防腐剂、抗细菌剂和抗真菌剂、和用于调节组合物pH的酸。
本发明的药物组合物中的防腐剂、抗细菌剂和抗真菌剂包括选自以下的那些：对羟基苯甲酸类或对羟基苯甲酸酯类，非限制性地为诸如对羟基苯甲酸甲酯，对羟基苯甲酸乙酯，对羟基苯甲酸丙酯，对羟基苯甲酸丁酯，对羟基苯甲酸异丁酯，对羟基苯甲酸异丙酯，对羟基苯甲酸苄酯等或其盐或这些化合物的混合物。在优选的实施方案中，在本发明组合物中使用的防腐剂是对羟基苯甲酸甲酯和对羟基苯甲酸丙酯的混合物。本发明组合物中对羟基苯甲酸酯类的总量是0.1mg/ml到4mg/ml；优选1mg/ml到3mg/ml，更优选1.5mg/ml到2.5mg/ml。
尽管本发明的组合物不含pH缓冲剂，但是有必要在最初调节组合物的pH为3.5-5.0以便组合物是稳定的。用于调节溶液pH为3.5-5.0的化合物是无机酸，有机酸和/或氨基酸，非限制性地为诸如盐酸，硝酸，磷酸，硫酸，乙酸，苯甲酸，柠檬酸，抗坏血酸，天冬氨酸，泛影酸，酒石酸，乳酸，羟基丙酸，谷氨酸，马来酸，琥珀酸，草酸，苹果酸，丙二酸，扁桃酸，丙酮酸，或其混合物。
本发明组合物的必须给药剂量根据包括以下的若干因素的不同而异：患者的年龄、状况，病变、病变的严重程度、剂量形式和给药频率。在任何情况下，滴剂和糖浆剂形式的液体剂量二者优于目前已知的去氨加压素经口组合物的优点是具有更大的灵活性，这使得根据患者的需要来更精确地调整去氨加压素的剂量。
本发明的组合物可通过本领域已知的任何方法制备。特别地，本发明的组合物通过在防腐剂的水性溶液中混合治疗有效量的去氨加压素并调节pH到3.5-5.0的值来制备。
在具体实施方案中，稳定的、剂量灵活的、液体药物组合物以被吸收经过口粘膜和/或舌下粘膜的经口给药用滴剂的形式存在于多剂量容器中。
在具体实施方案中，稳定的、剂量灵活的、液体药物组合物以经口胃肠道给药用糖浆剂或被吸收经过口粘膜和/或舌下粘膜的经口给药用糖浆剂的形式存在于多剂量容器中。
在另一个方面，本发明涉及本发明的组合物在制备用于治疗中枢性尿崩症、原发性夜间遗尿症、甲型血友病患者的出血、血管性血友病患者的出血和术后出血的药物中的应用。
发明详述
本发明人令人惊讶地发现了包含治疗有效量的去氨加压素并且既不包含渗透剂又不包含吸收增强剂的稳定的、剂量灵活的、液体药物组合物。
具体实施方式
本发明的实施例意欲说明而非限制本发明。
实施例1
去氨加压素的药物组合物(表1)。
表1
| 成分 | 量(mg)(mg/ml) |
| 乙酸去氨加压素 | 6(0.4) |
| 对羟基苯甲酸甲酯钠 | 31.5(2.1) |
| 对羟基苯甲酸丙酯钠 | 3.3(0.22) |
| 0.1N盐酸 | 适量，达pH 3.5-5.0 |
| 注射用水 | 适量，达15ml |
实施例2
去氨加压素的药物组合物(表2)。
表2
| 成分 | 量(mg)(mg/ml) |
| 乙酸去氨加压素 | 6(0.4) |
| 对羟基苯甲酸甲酯钠 | 22.5(1.5) |
| 对羟基苯甲酸丁酯钠 | 1.5(0.1) |
| 乙酸 | 适量，达pH 3.5-5.0 |
| 注射用水 | 适量，达15ml |
实施例3
去氨加压素的药物组合物(表3)。
表3
| 成分 | 量(mg)(mg/ml) |
| 乙酸去氨加压素 | 6(0.4) |
| 对羟基苯甲酸甲酯钠 | 27(1.8) |
| 对羟基苯甲酸苄酯钠 | 1.5(0.1) |
| 柠檬酸 | 适量，达pH 3.5-5.0 |
| 注射用水 | 适量，达15ml |
实施例4
上面实施例的药物组合物在25℃的稳定性。
实施例1的组合物的稳定性
| 试验 | 最初 | 15天 | 2个月 | 3个月 | 6个月 | 12个月 | 18个月 |
| pH | 4.40 | 4.41 | 4.44 | 4.52 | 4.56 | 4.51 | 4.56 |
| 去氨加压素滴定 | 99.4％ | 100.6％ | 100.6％ | 99.8％ | 100.0％ | 98.6％ | 98.7％ |
实施例2的组合物的稳定性
| 试验 | 最初 | 15天 | 2个月 | 3个月 | 6个月 | 12个月 | 18个月 |
| pH | 4.80 | 4.82 | 4.83 | 4.88 | 4.90 | 4.91 | 4.93 |
| 去氨加压素滴定 | 99.7％ | 99.6％ | 99.6％ | 99.7％ | 99.4％ | 98.9％ | 98.6％ |
实施例3的组合物的稳定性
| 试验 | 最初 | 15天 | 2个月 | 3个月 | 6个月 | 12个月 | 18个月 |
| pH | 3.60 | 3.62 | 3.65 | 3.66 | 3.68 | 3.71 | 3.77 |
| 试验 | 最初 | 15天 | 2个月 | 3个月 | 6个月 | 12个月 | 18个月 |
| 去氨加压素滴定 | 99.8％ | 100.2％ | 100.0％ | 99.8％ | 99.7％ | 99.3％ | 98.9％ |
Claims (15)
1.包含治疗有效量的去氨加压素并且既不包含渗透剂又不包含吸收增强剂的稳定的、剂量灵活的、经口给药用液体药物组合物。
2.权利要求1的药物组合物，其中治疗有效量的去氨加压素以一种或多种其药学可接受的盐的形式被给予。
3.权利要求1-2中任一项的药物组合物，其中治疗有效量的去氨加压素以乙酸去氨加压素的形式被给予。
4.权利要求1-3中任一项的药物组合物，其中治疗有效量的去氨加压素为0.001mg/ml到5mg/ml。
5.权利要求4的药物组合物，其中治疗有效量的去氨加压素为0.01mg/ml到2mg/ml。
6.权利要求5的药物组合物，其中治疗有效量的去氨加压素为0.1mg/ml到1mg/ml。
7.权利要求1-6中任一项的药物组合物，其包含一种或多种药学可接受的助剂，所述助剂选自防腐剂、抗细菌剂和抗真菌剂、和用于调节组合物pH的酸。
8.权利要求7的药物组合物，其中防腐剂、抗细菌剂和抗真菌剂选自对羟基苯甲酸类，其盐或混合物。
9.权利要求8的药物组合物，其中防腐剂、抗细菌剂和抗真菌剂选自对羟基苯甲酸甲酯，对羟基苯甲酸乙酯，对羟基苯甲酸丙酯，对羟基苯甲酸丁酯，对羟基苯甲酸异丁酯，对羟基苯甲酸异丙酯，对羟基苯甲酸苄酯，其盐或混合物。
10.权利要求7的药物组合物，其中组合物的pH被调节到3.5-5.0。
11.权利要求7的药物组合物，其中用于调节组合物的pH的酸选自无机酸，有机酸和/或氨基酸。
12.权利要求11的药物组合物，其中用于调节组合物的pH的酸选自盐酸，硝酸，磷酸，硫酸，乙酸，苯甲酸，柠檬酸，抗坏血酸，天冬氨酸，泛影酸，酒石酸，乳酸，羟基丙酸，谷氨酸，马来酸，琥珀酸，草酸，苹果酸，丙二酸，扁桃酸，丙酮酸，或其混合物。
13.前述权利要求中任一项的药物组合物，其中表现形式是被吸收经过口粘膜和/或舌下粘膜的经口给药用滴剂。
14.前述权利要求中任一项的药物组合物，其中表现形式是经口胃肠道给药用糖浆剂或被吸收经过口粘膜和/或舌下粘膜的经口给药用糖浆剂。
15.前述权利要求中任一项的药物组合物在制备用于治疗中枢性尿崩症、原发性夜间遗尿症、甲型血友病患者的出血、血管性血友病患者的出血和术后出血的药物中的应用。
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| CN201610700664.8A CN106265494A (zh) | 2007-08-06 | 2008-08-01 | 去氨加压素的经口药物组合物 |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ES200702215A ES2319054B1 (es) | 2007-08-06 | 2007-08-06 | Composicion farmaceutica oral de desmopresina. |
| ESP200702215 | 2007-08-06 | ||
| PCT/ES2008/000539 WO2009027561A2 (es) | 2007-08-06 | 2008-08-01 | Composición farmacéutica oral de desmopresina |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610700664.8A Division CN106265494A (zh) | 2007-08-06 | 2008-08-01 | 去氨加压素的经口药物组合物 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101808621A true CN101808621A (zh) | 2010-08-18 |
Family
ID=40032884
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
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| CN200880105631A Pending CN101808621A (zh) | 2007-08-06 | 2008-08-01 | 去氨加压素的经口药物组合物 |
| CN201610700664.8A Pending CN106265494A (zh) | 2007-08-06 | 2008-08-01 | 去氨加压素的经口药物组合物 |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610700664.8A Pending CN106265494A (zh) | 2007-08-06 | 2008-08-01 | 去氨加压素的经口药物组合物 |
Country Status (18)
| Country | Link |
|---|---|
| US (1) | US8993521B2 (zh) |
| EP (1) | EP2174652B1 (zh) |
| JP (1) | JP5626682B2 (zh) |
| CN (2) | CN101808621A (zh) |
| AR (1) | AR068337A1 (zh) |
| BR (1) | BRPI0814835B8 (zh) |
| CY (1) | CY1118459T1 (zh) |
| DK (1) | DK2174652T3 (zh) |
| ES (2) | ES2319054B1 (zh) |
| HR (1) | HRP20161676T1 (zh) |
| HU (1) | HUE032667T2 (zh) |
| LT (1) | LT2174652T (zh) |
| MX (1) | MX2010001456A (zh) |
| PL (1) | PL2174652T3 (zh) |
| PT (1) | PT2174652T (zh) |
| RU (1) | RU2474414C2 (zh) |
| SI (1) | SI2174652T1 (zh) |
| WO (1) | WO2009027561A2 (zh) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JO3400B1 (ar) * | 2010-09-30 | 2019-10-20 | Ferring Bv | مركب صيدلاني من كاربيتوسين |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1126440A (zh) * | 1993-06-29 | 1996-07-10 | 凡林有限公司 | 稳定的药用肽组合物 |
| US20030119728A1 (en) * | 2000-02-16 | 2003-06-26 | Helmut Scheidl | Stable, nasally, orally or sublingually applicable pharmaceutical preparation |
| US20030216302A1 (en) * | 2002-05-15 | 2003-11-20 | Sun Pharmaceutical Industries Limited | Stable aqueous composition of a peptide |
Family Cites Families (21)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE8306367L (sv) | 1983-11-18 | 1985-05-19 | Ferring Ab | Antidiuretiskt verkande farmaceutiskt preparat |
| DE69010518T2 (de) | 1989-01-30 | 1994-11-03 | Corint Ltd | Wässerige Desmopressin-CMC enthaltende Arzneizubereitung. |
| JP2653255B2 (ja) * | 1990-02-13 | 1997-09-17 | 武田薬品工業株式会社 | 長期徐放型マイクロカプセル |
| AU653026B2 (en) | 1991-06-07 | 1994-09-15 | Teikoku Seiyaku Kabushiki Kaisha | Physiologically active polypeptide-containing pharmaceutical composition |
| US5298256A (en) | 1992-04-28 | 1994-03-29 | Corint, Ltd. | Desmopressin buccal patch composition |
| IT1255460B (it) | 1992-07-28 | 1995-11-02 | Poli Ind Chimica Spa | Composizioni farmaceutiche in forma di microemulsioni o di dispersioni liposomiali bioadesive per la somministrazione transmucosale di sostanze peptidiche e di proteine farmacologicamente attive |
| SE9300937L (sv) | 1993-03-19 | 1994-09-20 | Anne Fjellestad Paulsen | Komposition för oral administrering av peptider |
| SE9400918L (sv) | 1994-03-18 | 1995-09-19 | Anne Fjellstad Paulsen | Stabiliserad komposition för oral administrering av peptider |
| US5763398A (en) * | 1996-06-20 | 1998-06-09 | Ferring B.V. | Nasal administration of desmopressin |
| US20030095926A1 (en) | 1997-10-01 | 2003-05-22 | Dugger Harry A. | Buccal, polar and non-polar spray or capsule containing drugs for treating disorders of the gastrointestinal tract or urinary tract |
| PT1135188E (pt) * | 1998-11-02 | 2008-03-19 | Alza Corp | Dispositivo de electrotransporte incluíndo um agente antimicrobiano compatível |
| US6894026B1 (en) | 2000-01-11 | 2005-05-17 | Atossa Healthcare, Inc. | Long-acting oxytocin analogues for the treatment and prevention of breast cancer and psychiatric disorders |
| EP1121935B1 (en) * | 2000-02-04 | 2008-08-13 | Patents Exploitation Company B.V. | Pharmaceutical composition containing a small or medium size peptide |
| GB0210397D0 (en) | 2002-05-07 | 2002-06-12 | Ferring Bv | Pharmaceutical formulations |
| ITMI20021684A1 (it) | 2002-07-29 | 2004-01-29 | Therapicon Srl | Composizione farmaceutica di peptide nasale |
| SI1617823T1 (sl) * | 2003-01-24 | 2019-07-31 | Nicachet Ab | Vrečka, ki obsega nikotinski sestavek za transmukozno dajanje |
| SI1473029T1 (en) | 2003-04-30 | 2005-10-31 | Ferring B.V. | Solid dosage form comprising desmopressin |
| ATE301990T1 (de) | 2003-07-25 | 2005-09-15 | Ferring Bv | Pharmazeutische desmopressin-zubereitung als feste darreichungsform und methode zu ihrer herstellung |
| EP2322197A2 (en) | 2003-11-10 | 2011-05-18 | Reprise Biopharmaceutics, LLC | Pharmaceutical compositions including low dosages of desmopressin |
| GB0406048D0 (en) | 2004-03-18 | 2004-04-21 | Ardana Bioscience Ltd | Drug formulations |
| US20050244502A1 (en) | 2004-04-28 | 2005-11-03 | Mathias Neil R | Composition for enhancing absorption of a drug and method |
-
2007
- 2007-08-06 ES ES200702215A patent/ES2319054B1/es active Active
-
2008
- 2008-08-01 ES ES08805367.3T patent/ES2608816T3/es active Active
- 2008-08-01 CN CN200880105631A patent/CN101808621A/zh active Pending
- 2008-08-01 WO PCT/ES2008/000539 patent/WO2009027561A2/es active Application Filing
- 2008-08-01 CN CN201610700664.8A patent/CN106265494A/zh active Pending
- 2008-08-01 BR BRPI0814835A patent/BRPI0814835B8/pt not_active IP Right Cessation
- 2008-08-01 LT LTEP08805367.3T patent/LT2174652T/lt unknown
- 2008-08-01 US US12/672,255 patent/US8993521B2/en active Active
- 2008-08-01 EP EP08805367.3A patent/EP2174652B1/en active Active
- 2008-08-01 PT PT88053673T patent/PT2174652T/pt unknown
- 2008-08-01 PL PL08805367T patent/PL2174652T3/pl unknown
- 2008-08-01 MX MX2010001456A patent/MX2010001456A/es active IP Right Grant
- 2008-08-01 DK DK08805367.3T patent/DK2174652T3/en active
- 2008-08-01 HU HUE08805367A patent/HUE032667T2/en unknown
- 2008-08-01 RU RU2010105031/15A patent/RU2474414C2/ru active
- 2008-08-01 JP JP2010519481A patent/JP5626682B2/ja not_active Expired - Fee Related
- 2008-08-01 SI SI200831737A patent/SI2174652T1/sl unknown
- 2008-08-06 AR ARP080103430A patent/AR068337A1/es not_active Application Discontinuation
-
2016
- 2016-12-08 HR HRP20161676TT patent/HRP20161676T1/hr unknown
-
2017
- 2017-01-03 CY CY20171100005T patent/CY1118459T1/el unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1126440A (zh) * | 1993-06-29 | 1996-07-10 | 凡林有限公司 | 稳定的药用肽组合物 |
| US20030119728A1 (en) * | 2000-02-16 | 2003-06-26 | Helmut Scheidl | Stable, nasally, orally or sublingually applicable pharmaceutical preparation |
| US20030216302A1 (en) * | 2002-05-15 | 2003-11-20 | Sun Pharmaceutical Industries Limited | Stable aqueous composition of a peptide |
Also Published As
| Publication number | Publication date |
|---|---|
| MX2010001456A (es) | 2010-06-02 |
| SI2174652T1 (sl) | 2017-04-26 |
| HUE032667T2 (en) | 2017-10-30 |
| DK2174652T3 (en) | 2017-01-23 |
| BRPI0814835B8 (pt) | 2021-05-25 |
| CY1118459T1 (el) | 2017-07-12 |
| RU2474414C2 (ru) | 2013-02-10 |
| BRPI0814835A2 (pt) | 2015-03-31 |
| AR068337A1 (es) | 2009-11-11 |
| US20110251123A1 (en) | 2011-10-13 |
| PL2174652T3 (pl) | 2017-06-30 |
| JP5626682B2 (ja) | 2014-11-19 |
| HRP20161676T1 (hr) | 2017-02-24 |
| ES2319054B1 (es) | 2010-02-12 |
| CN106265494A (zh) | 2017-01-04 |
| JP2010535745A (ja) | 2010-11-25 |
| RU2010105031A (ru) | 2011-09-20 |
| EP2174652B1 (en) | 2016-10-05 |
| PT2174652T (pt) | 2016-12-23 |
| EP2174652A2 (en) | 2010-04-14 |
| BRPI0814835B1 (pt) | 2020-10-27 |
| ES2608816T3 (es) | 2017-04-17 |
| LT2174652T (lt) | 2017-02-27 |
| US8993521B2 (en) | 2015-03-31 |
| ES2319054A1 (es) | 2009-05-01 |
| WO2009027561A3 (es) | 2009-07-16 |
| WO2009027561A2 (es) | 2009-03-05 |
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