CN1832726A - 包含羟甲唑啉和/或赛洛唑啉的水性药物溶液 - Google Patents
包含羟甲唑啉和/或赛洛唑啉的水性药物溶液 Download PDFInfo
- Publication number
- CN1832726A CN1832726A CNA2004800227931A CN200480022793A CN1832726A CN 1832726 A CN1832726 A CN 1832726A CN A2004800227931 A CNA2004800227931 A CN A2004800227931A CN 200480022793 A CN200480022793 A CN 200480022793A CN 1832726 A CN1832726 A CN 1832726A
- Authority
- CN
- China
- Prior art keywords
- zinc
- weight
- aqueous pharmaceutical
- pharmaceutical solution
- oxymetazoline
- 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
- WYWIFABBXFUGLM-UHFFFAOYSA-N oxymetazoline Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C)=C1CC1=NCCN1 WYWIFABBXFUGLM-UHFFFAOYSA-N 0.000 title claims abstract description 70
- HUCJFAOMUPXHDK-UHFFFAOYSA-N Xylometazoline Chemical compound CC1=CC(C(C)(C)C)=CC(C)=C1CC1=NCCN1 HUCJFAOMUPXHDK-UHFFFAOYSA-N 0.000 title claims abstract description 54
- 229960001528 oxymetazoline Drugs 0.000 title claims abstract description 35
- 229960000833 xylometazoline Drugs 0.000 title claims abstract description 27
- 239000003186 pharmaceutical solution Substances 0.000 title claims description 17
- 239000007864 aqueous solution Substances 0.000 claims abstract description 38
- 239000000337 buffer salt Substances 0.000 claims abstract description 27
- 150000003751 zinc Chemical class 0.000 claims abstract description 14
- 239000003513 alkali Substances 0.000 claims description 16
- WHMDKBIGKVEYHS-IYEMJOQQSA-L Zinc gluconate Chemical compound [Zn+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O WHMDKBIGKVEYHS-IYEMJOQQSA-L 0.000 claims description 13
- 239000002253 acid Substances 0.000 claims description 13
- 239000011670 zinc gluconate Substances 0.000 claims description 13
- 235000011478 zinc gluconate Nutrition 0.000 claims description 13
- 229960000306 zinc gluconate Drugs 0.000 claims description 13
- 239000000243 solution Substances 0.000 claims description 12
- 239000001509 sodium citrate Substances 0.000 claims description 11
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical group O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 7
- 150000001875 compounds Chemical class 0.000 claims description 7
- 229910052725 zinc Inorganic materials 0.000 claims description 7
- 239000011701 zinc Substances 0.000 claims description 7
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 6
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical group [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 4
- 206010020565 Hyperaemia Diseases 0.000 claims description 3
- 125000000129 anionic group Chemical group 0.000 claims description 3
- 125000002091 cationic group Chemical group 0.000 claims description 3
- LQZFQLVBZRVDLJ-DKWTVANSSA-N (2s)-2-aminobutanedioic acid;zinc Chemical compound [Zn].OC(=O)[C@@H](N)CC(O)=O LQZFQLVBZRVDLJ-DKWTVANSSA-N 0.000 claims description 2
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 claims description 2
- CANRESZKMUPMAE-UHFFFAOYSA-L Zinc lactate Chemical compound [Zn+2].CC(O)C([O-])=O.CC(O)C([O-])=O CANRESZKMUPMAE-UHFFFAOYSA-L 0.000 claims description 2
- ZOIORXHNWRGPMV-UHFFFAOYSA-N acetic acid;zinc Chemical compound [Zn].CC(O)=O.CC(O)=O ZOIORXHNWRGPMV-UHFFFAOYSA-N 0.000 claims description 2
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 claims description 2
- 229960002885 histidine Drugs 0.000 claims description 2
- WGIWBXUNRXCYRA-UHFFFAOYSA-H trizinc;2-hydroxypropane-1,2,3-tricarboxylate Chemical compound [Zn+2].[Zn+2].[Zn+2].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O WGIWBXUNRXCYRA-UHFFFAOYSA-H 0.000 claims description 2
- 239000004246 zinc acetate Substances 0.000 claims description 2
- 229960000314 zinc acetate Drugs 0.000 claims description 2
- 239000011592 zinc chloride Substances 0.000 claims description 2
- 235000005074 zinc chloride Nutrition 0.000 claims description 2
- 229960001939 zinc chloride Drugs 0.000 claims description 2
- 239000011746 zinc citrate Substances 0.000 claims description 2
- 235000006076 zinc citrate Nutrition 0.000 claims description 2
- 229940068475 zinc citrate Drugs 0.000 claims description 2
- 239000011576 zinc lactate Substances 0.000 claims description 2
- 235000000193 zinc lactate Nutrition 0.000 claims description 2
- 229940050168 zinc lactate Drugs 0.000 claims description 2
- 229940046253 zinc orotate Drugs 0.000 claims description 2
- NWONKYPBYAMBJT-UHFFFAOYSA-L zinc sulfate Chemical compound [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 claims description 2
- 229960001763 zinc sulfate Drugs 0.000 claims description 2
- 229910000368 zinc sulfate Inorganic materials 0.000 claims description 2
- YNMDOZLVAPMCBD-UHFFFAOYSA-L zinc;2,4-dioxo-1h-pyrimidine-6-carboxylate Chemical compound [Zn+2].[O-]C(=O)C1=CC(=O)NC(=O)N1.[O-]C(=O)C1=CC(=O)NC(=O)N1 YNMDOZLVAPMCBD-UHFFFAOYSA-L 0.000 claims description 2
- 239000007979 citrate buffer Substances 0.000 claims 1
- 210000004400 mucous membrane Anatomy 0.000 abstract 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 238000002360 preparation method Methods 0.000 description 9
- 239000008215 water for injection Substances 0.000 description 9
- BEEDODBODQVSIM-UHFFFAOYSA-N oxymetazoline hydrochloride Chemical compound Cl.CC1=CC(C(C)(C)C)=C(O)C(C)=C1CC1=NCCN1 BEEDODBODQVSIM-UHFFFAOYSA-N 0.000 description 8
- 229960005162 oxymetazoline hydrochloride Drugs 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 239000003814 drug Substances 0.000 description 5
- 230000003301 hydrolyzing effect Effects 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 210000002850 nasal mucosa Anatomy 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 229910002651 NO3 Inorganic materials 0.000 description 3
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- 230000000875 corresponding effect Effects 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- 230000035479 physiological effects, processes and functions Effects 0.000 description 3
- YGWFCQYETHJKNX-UHFFFAOYSA-N 2-[(4-tert-butyl-2,6-dimethylphenyl)methyl]-4,5-dihydro-1h-imidazol-3-ium;chloride Chemical compound [Cl-].CC1=CC(C(C)(C)C)=CC(C)=C1CC1=NCC[NH2+]1 YGWFCQYETHJKNX-UHFFFAOYSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- -1 alkali metal salt Chemical class 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 210000001331 nose Anatomy 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000004033 plastic Substances 0.000 description 2
- 229920003023 plastic Polymers 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 150000005846 sugar alcohols Polymers 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 229960001095 xylometazoline hydrochloride Drugs 0.000 description 2
- PCNMALATRPXTKX-UHFFFAOYSA-N 1,4-dimethylcyclohexa-2,4-dien-1-ol Chemical compound CC1=CCC(C)(O)C=C1 PCNMALATRPXTKX-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 201000010927 Mucositis Diseases 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 description 1
- 239000000150 Sympathomimetic Substances 0.000 description 1
- 206010047139 Vasoconstriction Diseases 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 230000005660 hydrophilic surface Effects 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 229940097496 nasal spray Drugs 0.000 description 1
- 239000005022 packaging material Substances 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000009662 stress testing Methods 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 230000025033 vasoconstriction Effects 0.000 description 1
Classifications
-
- 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
- A61K31/395—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
- A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
-
- 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
- A61K31/395—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
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0043—Nose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/02—Nasal agents, e.g. decongestants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/14—Decongestants or antiallergics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/16—Otologicals
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Otolaryngology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Ophthalmology & Optometry (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
本发明涉及包含羟甲唑啉和/或赛洛唑啉、锌盐和缓冲盐的稳定水性溶液。该水性溶液特别适用于鼻内局部用药以解除粘膜充血。
Description
本发明涉及包含羟甲唑啉和/或赛洛唑啉、锌盐和缓冲盐的稳定水性溶液。该水性溶液特别适用于鼻内局部用药以解除粘膜充血。
羟甲唑啉[6-叔丁基-3-(4，5-二氢-1-H-咪唑-2-基甲基)-2，4-二甲基苯酚]和赛洛唑啉[2-(4-叔丁基-2，6-二甲基苯基)-4，5-二氢-1-H-咪唑]是具有血管收缩作用的咪唑类α-拟交感神经药，优选局部使用以解除鼻粘膜充血。具体而言，本文所用的是水性溶液。
羟甲唑啉和赛洛唑啉在水性溶液中不稳定。虽然羟甲唑啉和赛洛唑啉为它们的盐酸盐形式时在水性溶液中更稳定，但不希望的活性化合物的水解降解(特别是由咪唑环的水解裂解引起)也确实在其存贮中发生，特别是在高温情况下如此。不希望的降解产物形成，并且活性化合物的含量下降，其中降解产物当使用水性溶液作为药物时与有害副作用的风险相关。总的来说，该水性溶液的保存期限被缩短。
作为咪唑环水解裂解的结果，在水性溶液中的羟甲唑啉和赛洛唑啉分别具体形成N-(2-氨基乙基)-2-[4-(1，1-二甲基乙基)-3-羟基-2，6-二甲基苯基]-乙酰胺和N-(2-氨基乙基)-2-[4-(1，1-二甲基乙基)-2，6-二甲基苯基]乙酰胺。在2003版欧洲药典中涉及这些活性化合物的专论中，这些降解产物也被列为杂质。
如果使用非水溶剂如油类或有机溶剂来代替水性溶剂，则可以避免羟甲唑啉和赛洛唑啉的水解降解。然而，油类具有较高的粘性和较差的润湿亲水性表面的能力，这阻碍了鼻部用药时活性化合物在鼻粘膜上的良好分布。有机溶剂通常是毒理学不可接受的和/或导致鼻粘膜发炎。非水制剂还表现出不太适用于活性化合物溶液的开发，这归因于它们的粘性或可能与包装材料和给药系统(特别是用塑料制成的那些)之间相互作用。这特别适用于广泛用于鼻用药物的塑料制喷雾瓶。
本发明的目的是提供具有更高稳定性的羟甲唑啉和/或赛洛唑啉的水性溶液。具体而言，目的是减少咪唑啉环裂解导致的水解降解。
令人吃惊的是，已经发现：如果后者除羟甲唑啉和/或赛洛唑啉之外还含有锌盐和缓冲盐，则可以获得包含羟甲唑啉和/或赛洛唑啉的稳定水性溶液。因此，本发明涉及至少包含羟甲唑啉和/或赛洛唑啉、锌盐和缓冲盐的水性溶液。
对于本发明的目的，如果至少部分溶剂由水组成，则得到水性溶液。其它可出现的溶剂成分均为适用于鼻部给药的溶剂，特别是醇类，例如乙醇、丙醇、丙二醇或甘油。这种水性溶液优选包含水或乙醇/水混合物作为溶剂，溶剂特别优选由水组成。
在本发明的水性溶液中，羟甲唑啉和/或赛洛唑啉优选以其可药用盐之一的形式存在，例如盐酸盐或硝酸盐。羟甲唑啉和/或赛洛唑啉特别优选各自以盐酸盐形式存在。在本专利申请中的任何羟甲唑啉或赛洛唑啉的用量数据各自涉及其相应的盐酸盐。羟甲唑啉硝酸盐或赛洛唑啉硝酸盐的其它盐形式以对应于各自盐酸盐的等摩尔的量采用。
作为锌盐，可以依据本发明使用所有可药用的锌盐。优选是氯化锌、乳酸锌、硫酸锌、柠檬酸锌、醋酸锌、组胺酸锌、乳清酸锌、天冬氨酸锌和/或葡萄糖酸锌。所存在的锌盐特别优选是葡萄糖酸锌。
对于本发明的目的，缓冲盐是弱酸强碱盐或弱碱强酸盐，其在水性溶液中完全解离，并在各自的成盐酸或碱的存在下形成缓冲系统。根据本发明可以使用的缓冲盐是例如可药用有机或无机弱酸(例如乙酸或柠檬酸，或者硼酸)的碱金属盐，特别是钠盐和/或钾盐。所存在的缓冲盐特别优选是柠檬酸钠。
根据本发明有利的实施方案，该水性溶液还可包含可药用酸或碱。所存在的酸或碱可以是任何不会导致与本发明的水性溶液的其它成分不相容的可药用酸或碱。所存在的酸优选是形成缓冲盐的各自的酸，即缓冲盐中存在的阴离子的酸形式，或者所存在的碱优选是形成缓冲盐的碱，即缓冲盐中存在的阳离子的碱形式。例如，本发明的水性溶液除了缓冲盐柠檬酸钠外还可以包含柠檬酸，即缓冲盐中作为阴离子存在的柠檬酸根离子的酸形式，或者还可以包含NaOH，即缓冲盐中作为阳离子存在的钠离子的碱形式。
本发明的水性溶液就鼻部给药而言可以通过所有适于鼻部给药的药物形式(例如滴鼻剂或鼻喷剂)使用适于此目的的给药装置(例如带滴液装置或鼻喷雾泵的瓶子)来应用。
根据本发明有利的实施方案，该水性溶液的pH值为pH4至pH7.5，优选pH值为pH5.0至pH7.2，特别优选pH值为约pH6.0。pH可以通过加入与缓冲盐相应的酸或碱和/或通过加入另一生理可耐受的酸或碱来准确设定。例如，含有柠檬酸钠的溶液的预期pH可以通过加入缓冲盐中存在的阴离子的酸形式、即通过加入柠檬酸来设定，或者通过加入缓冲盐中存在的阳离子的碱形式、即通过加入NaOH来设定，和/或通过加入另一酸或碱、特别是通过加入盐酸或氢氧化钠溶液来进行设定。
为了提高该水性溶液在鼻粘膜给药时被耐受的能力，将其配制成等渗溶液是有利的。在同渗质量摩尔浓度为约280mOsm时为等渗。同渗质量摩尔浓度可以通过改变除了羟甲唑啉和/或赛洛唑啉之外的溶于水性溶液中的物质、即锌盐、缓冲盐和任何其它物质的量来进行设定，和/或通过加入等渗试剂、优选生理可耐受的盐(如氯化钠或氯化钾)或生理可耐受的多元醇(如糖醇，特别是山梨醇或甘油)来设定，浓度为等渗所需的浓度。优选选择在水性溶液中以任何方式存在的溶解物质的量来设定同渗质量摩尔浓度，因此不必要加入等渗试剂。
本发明的水性溶液包含浓度为0.005％重量至1.0％重量的羟甲唑啉和/或赛洛唑啉。羟甲唑啉和/或赛洛唑啉的浓度优选为0.01％重量至0.5％重量，特别优选为0.05％重量至0.1％重量。
本发明的水性溶液含有0.1％至10％重量比例的锌盐。锌盐优选以1.8-6.0％重量比例存在。缓冲盐以0.01％至3.0％重量比例存在。缓冲盐优选以0.2-1.5％重量比例存在。
根据有利的实施方案，本发明的水性溶液包含0.005％重量至0.1％重量的羟甲唑啉盐酸盐或赛洛唑啉盐酸盐、1％重量至10％重量的葡萄糖酸锌和0.5％重量至5％重量的柠檬酸盐，且pH为约6。
根据本发明有利的实施方案，该水性溶液仅包含活性化合物盐酸盐形式的羟甲唑啉和赛洛唑啉中的一种。
这些实施例解释本发明，但并不局限于此。
实施例1
盐酸羟甲唑啉 2.625g
葡萄糖酸锌 300.00g
NaOH，1mol/L 51.20ml
柠檬酸钠 41.440g
注射用水 4604.735g
pH 5.99
同渗质量摩尔浓度 280mOsm/l
制备方法
首先加入注射用水。称好的物质分批加入并搅拌溶解。将配好的溶液经0.2μm无菌滤器过滤，然后转入为此目的所提供的容器内。
实施例2：
盐酸羟甲唑啉 2.625g
葡萄糖酸锌 200g
NaOH，1mol/L 32ml
柠檬酸钠 65.94g
注射用水 4699.435g
pH 6.00
同渗质量摩尔浓度 280mOsm/l
该水性溶液的制备类似于实施例1。
实施例3
盐酸羟甲唑啉 2.625g
葡萄糖酸锌 90.0g
柠檬酸 2.140g
柠檬酸钠 105.84g
注射用水 4799.395g
pH 6.00
同渗质量摩尔浓度 280mOsm/l
该水性溶液的制备类似于实施例1。
实施例4(不含锌盐的比较实施例)
盐酸羟甲唑啉 2.625g
柠檬酸 8.480g
柠檬酸钠 144.100g
注射用水 4844.795g
pH 5.99
同渗质量摩尔浓度 291mOsm/l
该水性溶液的制备类似于实施例1。
实施例5
盐酸赛洛唑啉 1.000g
葡萄糖酸锌 60.00g
NaOH，1mol/L 10.24ml
柠檬酸钠 8.288g
注射用水 954.0g
pH 6.0
同渗质量摩尔浓度 290mOsm/l
该水性溶液的制备类似于实施例1。
实施例6
盐酸羟甲唑啉 0.500g
葡萄糖酸锌 60.00g
NaOH，1mol/L 22.0ml
柠檬酸钠 8.288g
注射用水 942.1g
pH 7.0
同渗质量摩尔浓度 302mOsm/l
该水性溶液的制备类似于实施例1。
实施例7
盐酸羟甲唑啉 0.500g
葡萄糖酸锌 60.00g
柠檬酸 1.441g
柠檬酸钠 8.288g
注射用水 963.7g
pH 5.0g
同渗质量摩尔浓度 302mOsm/l
该水性溶液的制备类似于实施例1。
实施例8
盐酸羟甲唑啉 0.525g
葡萄糖酸锌 60.00g
醋酸钠 9.935g
注射用水 959.5g
pH 6.0
同渗质量摩尔浓度 285mOsm/l
该水性溶液的制备类似于实施例1。
本发明的制剂的稳定性在应激实验中进行了检验。为此目的，将含有实施例1的溶液的容器和用于对比的含有实施例4的溶液的容器在30℃和65％相对空气湿度(RH)下贮存。在贮存前和贮存时间为52周或26周时，取出两个容器以测定羟甲唑啉含量并测定其分解产物，采用高压液相色谱法(HPLC)进行研究。
进行HPLC色谱研究，用缓冲液pH2.5/乙腈828/172(v/v)作为洗脱液。柱子：LiChrospher100CN，检测波长215nm。
稳定性检查结果列于表1。
表1羟甲唑啉和锌的稳定性数据
| 0.05％的羟甲唑啉不含锌(实施例4) | 0.05％的羟甲唑啉含1.8％锌(实施例3) | 0.05％的羟甲唑啉含6.0％锌(实施例1) | |||||
| 贮存[周] | 贮存条件 | 羟甲唑啉[％] | 水解产物[％] | 羟甲唑啉[％] | 水解产物[％] | 羟甲唑啉[％] | 水解产物[％] |
| 0 | 101.7 | ＜0.05 | 100.6 | ＜0.05 | 102.5 | ＜0.05 | |
| 26 | 30℃/65％RH | 103.4 | 0.33 | 101.9 | 0.27 | 104.0 | 0.27 |
| 26 | 40℃/75％RH | 100.2 | 1.50 | 99.6 | 1.17 | 98.3 | 0.98 |
| 52 | 30℃/65％RH | 101.5 | 0.68 | 101.1 | 0.58 | 102.5 | 0.59 |
结果清楚显示，本发明的制剂与不含锌的比较溶液相比稳定性显著升高。
Claims (17)
1.水性药物溶液，至少包含羟甲唑啉和/或赛洛唑啉、锌盐和缓冲盐。
2.根据权利要求1的水性药物溶液，其特征在于所存在的活性化合物是盐酸盐形式的羟甲唑啉和/或赛洛唑啉。
3.根据权利要求1或2的水性药物溶液，其特征在于所存在的锌盐是氯化锌、乳酸锌、硫酸锌、柠檬酸锌、醋酸锌、组胺酸锌、乳清酸锌、天冬氨酸锌和/或葡萄糖酸锌。
4.根据权利要求3的水性药物溶液，其特征在于所存在的锌盐为葡萄糖酸锌。
5.根据权利要求1至4中一项或多项的水性药物溶液，其特征在于所存在的缓冲盐为柠檬酸钠。
6.根据权利要求1至5中一项或多项的水性溶液，其特征在于还存在一种或多种酸或者一种或多种碱。
7.根据权利要求6的水性溶液，其特征在于所存在的酸是形成缓冲盐的各自的酸，即缓冲盐中存在的阴离子的酸形式，或者所存在的碱是形成缓冲盐的碱，即缓冲盐中存在的阳离子的碱形式。
8.根据权利要求1至7中一项或多项的水性药物溶液，其特征在于该溶液的pH为pH4至pH7.5。
9.根据权利要求8的水性药物溶液，其特征在于该溶液的pH为pH5.0至pH7.2，特别是pH约为pH6.0。
10.根据权利要求1至9中一项或多项的水性药物溶液，其特征在于该溶液具有约280mOsm的同渗质量摩尔浓度。
11.根据权利要求1至10中一项或多项的水性药物溶液，其特征在于羟甲唑啉和/或赛洛唑啉存在的浓度为0.005％重量至1.0％重量。
12.根据权利要求11的水性药物溶液，其特征在于羟甲唑啉和/或赛洛唑啉存在的浓度为0.01％重量至0.5％重量，特别是浓度为0.05％重量至0.1％重量。
13.根据权利要求1至12中一项或多项的水性药物溶液，其特征在于所存在的锌盐的浓度为0.1％重量至10％重量。
14.根据权利要求1至13中一项或多项的水性药物溶液，其特征在于所存在的缓冲盐的浓度为0.01％重量至3％重量。
15.根据权利要求1至14中一项或多项的水性药物溶液，其特征在于它包含约0.005％重量至0.1％重量的羟甲唑啉和/或赛洛唑啉、1％重量至10％重量的葡萄糖酸锌和pH约6.0的柠檬酸盐缓冲液。
16.根据权利要求1至15中一项或多项的水性药物溶液，其特征在于仅存在活性化合物羟甲唑啉和赛洛唑啉中的一种，为盐酸盐的形式。
17.根据权利要求1至16中一项或多项的水性药物溶液用于局部解除鼻内粘膜充血的用途。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10337186A DE10337186A1 (de) | 2003-08-13 | 2003-08-13 | Wässrige Wirkstoff-Lösung |
| DE10337186.9 | 2003-08-13 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1832726A true CN1832726A (zh) | 2006-09-13 |
| CN100531733C CN100531733C (zh) | 2009-08-26 |
Family
ID=34201503
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2004800227931A Expired - Fee Related CN100531733C (zh) | 2003-08-13 | 2004-07-14 | 包含羟甲唑啉和/或赛洛唑啉的水性药物溶液 |
Country Status (19)
| Country | Link |
|---|---|
| US (1) | US20060222718A1 (zh) |
| EP (1) | EP1663141B1 (zh) |
| JP (1) | JP4750703B2 (zh) |
| KR (1) | KR20060065677A (zh) |
| CN (1) | CN100531733C (zh) |
| AT (1) | ATE357212T1 (zh) |
| AU (1) | AU2004266443A1 (zh) |
| BR (1) | BRPI0413478A (zh) |
| CA (1) | CA2535533C (zh) |
| CY (1) | CY1107633T1 (zh) |
| DE (2) | DE10337186A1 (zh) |
| DK (1) | DK1663141T3 (zh) |
| ES (1) | ES2282871T3 (zh) |
| MX (1) | MXPA06001596A (zh) |
| PL (1) | PL1663141T3 (zh) |
| PT (1) | PT1663141E (zh) |
| RU (1) | RU2343918C2 (zh) |
| WO (1) | WO2005018601A1 (zh) |
| ZA (1) | ZA200602071B (zh) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101576539B (zh) * | 2009-06-19 | 2012-05-23 | 广东省药品检验所 | 一种盐酸赛洛唑啉中杂质a的测定方法 |
| CN107362141A (zh) * | 2017-08-16 | 2017-11-21 | 深圳大佛药业股份有限公司 | 一种盐酸羟甲唑啉鼻喷雾剂及其制备方法 |
| CN111888326A (zh) * | 2019-05-06 | 2020-11-06 | Rvl制药公司 | 羟甲唑啉组合物和用于治疗眼障碍的方法 |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2005075735A (ja) * | 2003-08-28 | 2005-03-24 | Rohto Pharmaceut Co Ltd | オキシメタゾリン含有組成物 |
| DE102007052380A1 (de) † | 2007-10-31 | 2009-05-07 | Bitop Ag | Osmolythaltige Zubereitungen zur Anwendung bei trockenen Schleimhäuten |
| DE102012005452A1 (de) * | 2011-12-30 | 2013-07-04 | Maria Clementine Martin Klosterfrau Vertriebsgesellschaft Mbh | Zusammensetzung für die nasale Applikation mit verbesserter Stabilität |
| US10598672B2 (en) | 2014-02-18 | 2020-03-24 | Cyrano Therapeutics, Inc. | Methods and compositions for diagnosing and treating loss and/or distortion of taste or smell |
| EP3236933B1 (en) | 2014-12-24 | 2018-11-14 | JADRAN - GALENSKI LABORATORIJ d.d. | A nasal composition containing sea water as stability-improving excipient |
| MX2018013475A (es) * | 2016-05-17 | 2019-08-12 | Proponent Biotech Gmbh | Acido carboxilico para tratar/prevenir congestion nasal. |
| DE102017117987A1 (de) | 2017-07-31 | 2019-01-31 | Maria Clementine Martin Klosterfrau Vertriebsgesellschaft Mbh | Neue Zusammensetzung für die nasale Applikation |
| WO2020009812A1 (en) * | 2018-07-02 | 2020-01-09 | Bayer Healthcare Llc | Stable pharmaceutical formulations of oxymetazoline |
| WO2023046590A1 (en) | 2021-09-22 | 2023-03-30 | Jadran - Galenski Laboratorij D.D. | An improved pharmaceutical composition for nasal use, preparation, and use thereof |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5478565A (en) * | 1990-03-27 | 1995-12-26 | Warner-Lambert Company | Treatment of sinus headache |
| DE19549421C2 (de) * | 1995-11-10 | 1999-11-18 | Klosterfrau Mcm Vetrieb Gmbh | Pharmazeutische Zubereitung zur Behandlung akuter Rhinitiden |
| AU741364B2 (en) * | 1998-01-30 | 2001-11-29 | Novartis Consumer Health S.A. | Nasal solutions |
| JPH11302184A (ja) * | 1998-04-21 | 1999-11-02 | Taisho Pharmaceut Co Ltd | 点鼻用組成物 |
| CA2376121C (en) * | 1999-06-22 | 2008-06-10 | Boehringer Ingelheim International Gmbh | Stable xylometazoline and oxymetazoline solution |
| EP1328214A4 (en) * | 2000-09-20 | 2009-07-29 | Shahinian Lee Jr | NASAL, INHALABLE AND LOCAL OPHTHALMIC PREPARATIONS AND MEDICATIONS WITH SPONTANEOUS CONSERVATION |
-
2003
- 2003-08-13 DE DE10337186A patent/DE10337186A1/de not_active Withdrawn
-
2004
- 2004-07-14 DE DE502004003305T patent/DE502004003305D1/de active Active
- 2004-07-14 MX MXPA06001596A patent/MXPA06001596A/es active IP Right Grant
- 2004-07-14 JP JP2006522915A patent/JP4750703B2/ja not_active Expired - Fee Related
- 2004-07-14 EP EP04740995A patent/EP1663141B1/de active Active
- 2004-07-14 BR BRPI0413478-8A patent/BRPI0413478A/pt not_active IP Right Cessation
- 2004-07-14 CN CNB2004800227931A patent/CN100531733C/zh not_active Expired - Fee Related
- 2004-07-14 ES ES04740995T patent/ES2282871T3/es active Active
- 2004-07-14 RU RU2006107446/15A patent/RU2343918C2/ru not_active IP Right Cessation
- 2004-07-14 AU AU2004266443A patent/AU2004266443A1/en not_active Abandoned
- 2004-07-14 US US10/567,845 patent/US20060222718A1/en not_active Abandoned
- 2004-07-14 WO PCT/EP2004/007780 patent/WO2005018601A1/de active IP Right Grant
- 2004-07-14 PT PT04740995T patent/PT1663141E/pt unknown
- 2004-07-14 AT AT04740995T patent/ATE357212T1/de active
- 2004-07-14 PL PL04740995T patent/PL1663141T3/pl unknown
- 2004-07-14 KR KR1020067002872A patent/KR20060065677A/ko not_active Application Discontinuation
- 2004-07-14 DK DK04740995T patent/DK1663141T3/da active
- 2004-07-14 CA CA2535533A patent/CA2535533C/en not_active Expired - Fee Related
-
2006
- 2006-03-10 ZA ZA200602071A patent/ZA200602071B/en unknown
-
2007
- 2007-05-21 CY CY20071100685T patent/CY1107633T1/el unknown
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101576539B (zh) * | 2009-06-19 | 2012-05-23 | 广东省药品检验所 | 一种盐酸赛洛唑啉中杂质a的测定方法 |
| CN107362141A (zh) * | 2017-08-16 | 2017-11-21 | 深圳大佛药业股份有限公司 | 一种盐酸羟甲唑啉鼻喷雾剂及其制备方法 |
| CN107362141B (zh) * | 2017-08-16 | 2018-06-05 | 深圳大佛药业股份有限公司 | 一种盐酸羟甲唑啉鼻喷雾剂及其制备方法 |
| CN111888326A (zh) * | 2019-05-06 | 2020-11-06 | Rvl制药公司 | 羟甲唑啉组合物和用于治疗眼障碍的方法 |
| CN111888326B (zh) * | 2019-05-06 | 2023-07-21 | Rvl制药公司 | 羟甲唑啉组合物和用于治疗眼障碍的方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| ES2282871T3 (es) | 2007-10-16 |
| CN100531733C (zh) | 2009-08-26 |
| CA2535533C (en) | 2011-10-18 |
| JP4750703B2 (ja) | 2011-08-17 |
| CA2535533A1 (en) | 2005-03-03 |
| MXPA06001596A (es) | 2006-05-19 |
| RU2343918C2 (ru) | 2009-01-20 |
| EP1663141B1 (de) | 2007-03-21 |
| ATE357212T1 (de) | 2007-04-15 |
| AU2004266443A1 (en) | 2005-03-03 |
| DE10337186A1 (de) | 2005-03-17 |
| EP1663141A1 (de) | 2006-06-07 |
| BRPI0413478A (pt) | 2006-10-17 |
| DE502004003305D1 (de) | 2007-05-03 |
| PT1663141E (pt) | 2007-06-27 |
| CY1107633T1 (el) | 2013-03-13 |
| US20060222718A1 (en) | 2006-10-05 |
| WO2005018601A1 (de) | 2005-03-03 |
| JP2007501817A (ja) | 2007-02-01 |
| RU2006107446A (ru) | 2007-09-20 |
| KR20060065677A (ko) | 2006-06-14 |
| ZA200602071B (en) | 2007-05-30 |
| PL1663141T3 (pl) | 2007-07-31 |
| DK1663141T3 (da) | 2007-07-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1832726A (zh) | 包含羟甲唑啉和/或赛洛唑啉的水性药物溶液 | |
| CN1145486C (zh) | 含eletriptan半硫酸盐和咖啡因的药用组合物 | |
| CN1236774C (zh) | 高浓缩稳定的美洛昔康溶液 | |
| CN1148226C (zh) | 瑞斯哌东水性制剂 | |
| CN1191060C (zh) | 输送前列腺素e1的表皮给药组合物 | |
| CN1929847A (zh) | 含有法舒地尔的制剂及改善其稳定性的方法 | |
| CN1531430A (zh) | 含有抗真菌剂的局部用组合物 | |
| CN1723012A (zh) | 包括芬太尼的鼻内递送用药物组合物 | |
| CN1278165A (zh) | 持续释放制剂 | |
| CN1684688A (zh) | 以拉坦前列素为有效成分的稳定的滴眼液 | |
| CN1638749A (zh) | 用于治疗口腔及咽腔疼痛症状的氨溴索 | |
| CN1438886A (zh) | 滴眼液 | |
| CN1152686C (zh) | 稳定化药用组合物 | |
| CN1164271C (zh) | 稳定的丁苄唑啉和氧甲唑啉溶液 | |
| CN1210028C (zh) | 水性液体制剂 | |
| CN1853628A (zh) | 含有苯并咪唑衍生物的注射剂的制备方法 | |
| CN1850046A (zh) | 一种含β－内酰胺酶抑制剂的缓释制剂及其应用 | |
| CN1473038A (zh) | 包含提欧川平盐溶液的可吸入制剂 | |
| CN1290578C (zh) | 聚乙二醇－干扰素水溶液 | |
| CN1105859A (zh) | 内用复合维生素的稳定液体制剂 | |
| CN1502335A (zh) | 硫酸奈替米星在制备滴眼液制剂中的应用 | |
| CN1579394A (zh) | 用于缓解癌症患者化疗导致的恶心和呕吐的组合物 | |
| CN1049358C (zh) | 含羧酸乙烯聚合物的滴眼剂及其制造方法 | |
| CN1498614A (zh) | 樟脑喷雾剂及其制备方法和制品 | |
| CN1596897A (zh) | 一种伊曲康唑注射剂及其制备方法 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| ASS | Succession or assignment of patent right |
Owner name: MARIA CLEMENTINE MARTIN NUN SALES COMPANY Free format text: FORMER OWNER: MERCK PATENT GESELLSCHAFT MIT BESCHRANKTER HAFTUNG (DE) POSTFACH 4119, 6100 DARM Effective date: 20110308 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| COR | Change of bibliographic data |
Free format text: CORRECT: ADDRESS; FROM: DARMSTADT, GERMANY TO: KOLN, GERMANY |
|
| TR01 | Transfer of patent right |
Effective date of registration: 20110308 Address after: Cologne, Germany Patentee after: Sister Maria Clementi Martin sales Address before: Darmstadt Patentee before: Merck Patent GmbH |
|
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20090826 Termination date: 20140714 |
|
| EXPY | Termination of patent right or utility model |