CN1121691A - 稳定的注射剂及注射剂的稳定方法 - Google Patents
稳定的注射剂及注射剂的稳定方法 Download PDFInfo
- Publication number
- CN1121691A CN1121691A CN94191931A CN94191931A CN1121691A CN 1121691 A CN1121691 A CN 1121691A CN 94191931 A CN94191931 A CN 94191931A CN 94191931 A CN94191931 A CN 94191931A CN 1121691 A CN1121691 A CN 1121691A
- Authority
- CN
- China
- Prior art keywords
- injection
- acid
- light stability
- dihydro
- oxo
- 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
- 238000002347 injection Methods 0.000 title claims abstract description 51
- 239000007924 injection Substances 0.000 title claims abstract description 51
- 238000000034 method Methods 0.000 title abstract description 5
- 230000000087 stabilizing effect Effects 0.000 title 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 claims abstract description 10
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims abstract description 7
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 30
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical group [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 14
- 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 8
- 239000004615 ingredient Substances 0.000 claims description 8
- LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical compound [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 claims description 8
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 claims description 7
- 235000010262 sodium metabisulphite Nutrition 0.000 claims description 7
- 235000010265 sodium sulphite Nutrition 0.000 claims description 7
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000000463 material Substances 0.000 claims description 6
- 235000013878 L-cysteine Nutrition 0.000 claims description 4
- 239000004201 L-cysteine Substances 0.000 claims description 4
- 235000010323 ascorbic acid Nutrition 0.000 claims description 4
- 239000011668 ascorbic acid Substances 0.000 claims description 4
- 229940072107 ascorbate Drugs 0.000 claims description 3
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims description 3
- DJEHXEMURTVAOE-UHFFFAOYSA-M potassium bisulfite Chemical compound [K+].OS([O-])=O DJEHXEMURTVAOE-UHFFFAOYSA-M 0.000 claims description 3
- RWPGFSMJFRPDDP-UHFFFAOYSA-L potassium metabisulfite Chemical compound [K+].[K+].[O-]S(=O)S([O-])(=O)=O RWPGFSMJFRPDDP-UHFFFAOYSA-L 0.000 claims description 3
- 229940043349 potassium metabisulfite Drugs 0.000 claims description 3
- 235000010263 potassium metabisulphite Nutrition 0.000 claims description 3
- BHZRJJOHZFYXTO-UHFFFAOYSA-L potassium sulfite Chemical compound [K+].[K+].[O-]S([O-])=O BHZRJJOHZFYXTO-UHFFFAOYSA-L 0.000 claims description 3
- 235000019252 potassium sulphite Nutrition 0.000 claims description 3
- 229960004889 salicylic acid Drugs 0.000 claims description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 abstract description 9
- 239000004611 light stabiliser Substances 0.000 abstract description 3
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 abstract description 2
- CWERGRDVMFNCDR-UHFFFAOYSA-N thioglycolic acid Chemical compound OC(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-N 0.000 abstract 2
- WUKZPHOXUVCQOR-UHFFFAOYSA-N N-(1-azabicyclo[2.2.2]octan-3-yl)-6-chloro-4-methyl-3-oxo-1,4-benzoxazine-8-carboxamide Chemical compound C1N(CC2)CCC2C1NC(=O)C1=CC(Cl)=CC2=C1OCC(=O)N2C WUKZPHOXUVCQOR-UHFFFAOYSA-N 0.000 abstract 1
- 239000004480 active ingredient Substances 0.000 abstract 1
- 229940027987 antiseptic and disinfectant phenol and derivative Drugs 0.000 abstract 1
- 125000003289 ascorbyl group Chemical class [H]O[C@@]([H])(C([H])([H])O*)[C@@]1([H])OC(=O)C(O*)=C1O* 0.000 abstract 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 150000001875 compounds Chemical class 0.000 description 8
- 239000011780 sodium chloride Substances 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 239000012153 distilled water Substances 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 5
- 239000003708 ampul Substances 0.000 description 5
- 230000008485 antagonism Effects 0.000 description 4
- 201000009310 astigmatism Diseases 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000006303 photolysis reaction Methods 0.000 description 4
- 230000015843 photosynthesis, light reaction Effects 0.000 description 4
- 230000001954 sterilising effect Effects 0.000 description 4
- 238000004659 sterilization and disinfection Methods 0.000 description 4
- 102000035037 5-HT3 receptors Human genes 0.000 description 3
- 108091005477 5-HT3 receptors Proteins 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 206010047700 Vomiting Diseases 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 230000009876 antimalignant effect Effects 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 3
- 229960004316 cisplatin Drugs 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 206010061428 decreased appetite Diseases 0.000 description 3
- 206010025482 malaise Diseases 0.000 description 3
- 230000003204 osmotic effect Effects 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 238000007789 sealing Methods 0.000 description 3
- 230000008673 vomiting Effects 0.000 description 3
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 238000012856 packing Methods 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 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
- 208000007882 Gastritis Diseases 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- ABBQHOQBGMUPJH-UHFFFAOYSA-M Sodium salicylate Chemical compound [Na+].OC1=CC=CC=C1C([O-])=O ABBQHOQBGMUPJH-UHFFFAOYSA-M 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 208000023652 chronic gastritis Diseases 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Substances OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 150000002304 glucoses Chemical class 0.000 description 1
- 230000002949 hemolytic effect Effects 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 208000002551 irritable bowel syndrome Diseases 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- SBYHFKPVCBCYGV-UHFFFAOYSA-N quinuclidine Chemical compound C1CC2CCN1CC2 SBYHFKPVCBCYGV-UHFFFAOYSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 229960004025 sodium salicylate Drugs 0.000 description 1
- GNBVPFITFYNRCN-UHFFFAOYSA-M sodium thioglycolate Chemical compound [Na+].[O-]C(=O)CS GNBVPFITFYNRCN-UHFFFAOYSA-M 0.000 description 1
- 229940046307 sodium thioglycolate Drugs 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
-
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—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
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—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
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—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
- 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
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
-
- 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
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- General Chemical & Material Sciences (AREA)
- Dermatology (AREA)
- Inorganic Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Medicinal Preparation (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
以配合抗光剂为特征的，以(±)-6-氯-3，4-二氢-4-甲基-3-氧代-N-3-奎宁环基-2H-1，4-苯并噁嗪-8-甲酰胺-盐酸盐为有效成分的稳定注射剂及其稳定方法。通过配合选自亚硫酸、亚硫酸盐、抗坏血酸盐、L-半胱氨酸或其酸加成盐、巯基乙酸或其金属盐，1，2-乙二胺、水杨酸或其金属盐、或者苯酚或其衍生物的1种或2种以上抗光剂，可望防止着色。
Description
技术领域
本发明涉及具有强烈选择性血清素-3受体拮抗作用，可用作改善、治疗伴随顺氯氨铂等抗恶性肿瘤剂的给药的恶心、呕吐、食欲不振等的药剂的(±)-6-氯-3，4-二氢-4-甲基-3-氧代-N-3-奎宁环基-2 H-1，4-苯并噁嗪-8-甲酰胺一盐酸盐的稳定注射剂及含有该化合物的注射剂的稳定剂。
背景技术
特开平2-28182号公报公开了具有强烈选择性血清素-3受体拮抗作用，可用作改善、治疗伴随顺氯氨铂等抗恶性肿瘤剂的给药的恶心、呕吐、食欲不振等的药剂的(±)-6-氯-3，4-二氢-4-甲基-3-氧代-N-3-奎宁环基-2H-1，4-苯并噁嗪-8-甲酰胺一盐酸盐(以下称作本化合物)，还公开了采用锭剂等经口剂和注射剂等非经口剂的药剂形式。
但是已发现本化合物容易遇光分解，特别是在水溶液或悬浊液状态下稳定性差，发生显著着色变化，对于这些液体制剂，通常采用遮光容器盛放而避免光分解。采用该方法固然可以在药品的流通过程或保存中间抑制其光分解，但在临床使用时往往处于易曝光的状态，不难想象，随着场合的不同，很容易经常发生加速着色变化。
因此，本发明的目的是提供抑制光分解、特别是着色变化的稳定的含有(±)-6-氯-3，4-二氢-4-甲基-3-氧代-N-3-奎宁环基-2H-1，4-苯并噁嗪-8-甲酰胺一盐酸盐的注射剂及其稳定方法。
发明的公开
本发明者为解决上述课题进行了锐意研究，结果完成了本发明。也就是说，本发明涉及以配合抗光剂为特征的以(±)-6-氯-3，4-二氢-4-甲基-3-氧代-N-3-奎宁环基-2H-1，4-苯并噁嗪-8-甲酰胺一盐酸盐为有效成分的稳定注射剂，以及在以(±)-6-氯-3，4-二氢-4-甲基-3-氧代-N-3-奎宁环基-2H-1，4-苯并噁嗪-8-甲酰胺一盐酸盐为有效成分的注射剂中配入抗光剂为特征的注射剂稳定方法。
如上述特开平2-28182号公报所述，用于本发明的有效成分化合物(±)-6-氯-3，4-二氢-4-甲基-3-氧代-N-3-奎宁环基-2H-1，4-苯并噁嗪-8-甲酰胺一盐酸盐可按下列方法制得：优选在脱氧剂存在下，在对反应为惰性的溶剂中，使6-氯-3，4-二氢-4-甲基-3-氧代-2H-1，4-苯并噁嗪-8-甲酸的活性衍生物(酰氯等)与3-氢基奎宁环反应，然后用盐酸酸化。
另外，用于本发明的抗光剂为选自下列化合物的一种或两种以上物质：亚硫酸、亚硫酸盐、抗坏血酸盐、L-半胱氨酸或其酸加成盐、巯基乙酸或其金属盐、1，2-乙二胺、水杨酸或其金属盐、或者是苯酚或其衍生物。其中优选亚硫酸盐，例如包括焦亚硫酸盐、亚硫酸氢盐、例如亚硫酸钠、亚硫酸钾、亚硫酸氢钠、亚硫酸氢钾、焦亚硫酸钠、焦亚硫酸钾等、特别是焦亚硫酸钠(也可使用含此物的亚硫酸氢钠)在抑制着色变化方面效果优异。这些抗光剂的配合量可随抗光剂的种类变化而变，但对1重量份的本发明化合物有效成分约0.001～约5重量份，优选约0.01～约2重量份。
在本发明的稳定注射剂中也可再配合注射用添加剂，例如渗透压调节剂、pH调整剂、防腐剂、麻醉剂等均可作添加剂使用。其中渗透压调节剂可列举氯化钠等电解质、甘氨酸等氨基酸、葡萄糖等糖类和/或甘露糖醇等多元醇，其配比优选以等渗压浓度以下的浓度使用，对于注射剂的总量通常宜为5％重量/体积，用氯化钠时也可为约0.9％重量/体积。另外，pH调节剂优选将最终pH调至约3～约5的物质，可采用盐酸、柠檬酸、乙酸、乳酸等。必要时也可使用氢氧化钠等碱类。
本发明的注射制剂通过将本发明的化合物，抗光剂、渗透压调节剂和pH调节剂等上述添加剂溶于注射用蒸馏水中，过滤，填充到注射剂用容器中，熔封而制得。过滤可在氮气气氛中进行，另外还优选将填充用容器预先用氮气吹洗干净。再则，在将溶液填充到注射用容器中时，优选用氮气置换容器内空气。还有熔封以后，也可加热灭菌。这样得到的注射剂对曝光稳定，特别是表现出抑制着色变化的优异稳定效果。另外还无溶血性，并确认在血清中无结晶析出性，作为注射剂使用方面无问题。作为最终剂型装入例如遮光容器中时，则可望进一步提高稳定效果。
这样得到的本发明的稳定注射剂表现出优异的血清素-3受体拮抗作用，可用于改善、治疗将顺氯氨铂等抗恶性肿瘤剂投药给人类等伴随的恶心、呕吐、食欲不振，治疗慢性胃炎、过敏性肠疾病等消化器官疾病。
将本发明的稳定注射剂用于改善或治疗上述疾病时，可经静脉内给药，皮下给药，肌内给药等途径对患者安全给药。给药量一般为每个成年人每天约0.1～约50mg有效成分(游离碱)，优选约1～约30mg 。
实施发明的最佳方式
以下用实施例详细说明本发明，但无庸赘言，本发明不受这些实施例的限定。
实施例1
将(±)-6-氯-3，4-二氢-4-甲基-3-氧代-N-3-奎宁环基-2H-1，4-苯并噁嗪-8-甲酰胺一盐酸盐10g，焦亚硫酸钠0.5g以及预先在250℃加热灭菌30分钟以上的氯化钠18克溶于适量注射用蒸馏水中，调整为总量2000ml。所得溶液在氮气气氛下用膜滤器(孔径0.45μm)过滤，在2ml容积的安瓿瓶中填充2ml，用氮气置换除去空气，熔封后在115℃灭菌30分钟。
实施例2
将(±)-6-氯-3，4-二氢-4-甲基-3-氧代-N-3-奎宁环基-2 H-1，4-苯并噁嗪-8-甲酰胺一盐酸盐5g，L-半胱氨酸2g及氯化钠9g溶于适量注射用蒸馏水中，加入盐酸调至pH4，调节为总量1000ml的溶液。与上述实施例1一样，将该溶液封入安瓿瓶中，灭菌后得到2ml注射剂。
实施例3
用(±)-6-氯-3，4-二氢-4-甲基-3-氧代-N-3-奎宁环基-2H-1，4-苯并噁嗪-8-甲酰胺一盐酸盐5g、巯基乙酸钠3g、氯化钠9g以及适量的盐酸和注射用蒸馏水，与上述实施例1同样地配制总量为1000ml的注射剂。将该溶液与上述实施例1一样装入安瓿瓶中，灭菌后得到2ml注射剂。
实施例4
采用(±)-6-氯-3，4-二氢-4-甲基-3-氧代-N-3-奎宁环基-2H-1，4-苯并噁嗪-8-甲酰胺一盐酸盐5g、1，2-乙二胺5g、氯化钠9g以及适量盐酸和注射用蒸馏水，和上述实施例1一样，制得总量为1000ml的注射剂，然后得到2ml注射剂。
实施例5
和实施例1一样制得2ml注射剂，只是采用抗坏血酸、水杨酸钠和苯酚作为光稳定剂。
下面用实施例说明本发明注射剂的稳定效果。实验用的注射剂为上述实施例1～4的注射用安瓿瓶，比较用注射剂采用以下处方制剂。
比较用处方
采用(±)-6-氯-3，4-二氢-4-甲基-3-氧代-N-3-奎宁环基-2H-1，4-苯并噁嗪-8-甲酰胺一盐酸盐5g、氯化钠9g及适量注射用蒸馏水，与实施例1一样制得总量为1000ml的溶液，然后得到2ml注射剂。
实验例1
采用在上述实施例1～4以及比较用处方的白色安瓿瓶内注射剂，在室内散光(约700勒克司)下曝光1小时，然后用肉眼观察外观。结果示于表1中。同样在室内散光(约700勒克司)下曝光7小时后，用分光光度计在400nm和503nm下测定吸光度，结果示于表2。
表1样品名 室内散光下1小时后的外观实施例1得到的注射液 无色透明实施例2得到的注射液 无色透明实施例3得到的注射液 无色透明实施例4得到的注射液 极浅的黄色比较处方得到的注射液 淡橙黄色
表2样品名 室内散光下7小时后溶液的吸光度
400nm 503nm实施例1得到的注射液 0.00 0.00实施例2得到的注射液 0.07 0.01实施例3得到的注射液 0.04 0.00实施例4得到的注射液 0.23 0.04比较处方得到的注射液 0.49 1.30
产业实用性
从上述说明书，特别是实施例和实验例的描述可看出，根据本发明，可提供具有血清素-3拮抗作用，可作为药物的化合物的稳定注射剂以及注射剂的稳定方法。
Claims (10)
1.稳定注射剂，以(±)-6-氯-3，4-二氢-4-甲基-3-氧代-N-3-奎宁环基-2H-1，4-苯并噁嗪-8-甲酰胺一盐酸盐为有效成分，其特征在于配合了抗光剂。
2.按权利要求1的注射剂，其中抗光剂为选自亚硫酸、亚硫酸盐、抗坏血酸盐、L-半胱氨酸或其酸加成盐、巯基乙酸或其金属盐、1，2-乙二胺、水杨酸或其金属盐或者苯酚或其衍生物的1种或2种以上物质。
3.按权利要求1或2的注射剂，其中抗光剂为选自亚硫酸盐的1种或2种以上物质。
4.按权利要求1、2或3的注射剂，其中亚硫酸盐选自亚硫酸钠、亚硫酸钾、亚硫酸氢钠、亚硫酸氢钾、焦亚硫酸钠、焦亚硫酸钾。
5.稳定注射剂，其特征在于含有作为有效成分的(±)-6-氯-3，4-二氢-4-甲基-3-氧代-N-3-奎宁环基-2H-1，4-苯并噁嗪-8-甲酰胺一盐酸盐，作为抗光剂的焦亚硫酸钠。
6.注射剂的稳定方法，其特征在于在含有(±)-6-氯-3，4-二氢-4-甲基-3-氧代-N-3-奎宁环基-2H-1，4-苯并噁嗪-8-甲酰胺一盐酸盐作为有效成分的注射剂中配合抗光剂。
7.按权利要求6的稳定方法，其中抗光剂为选自亚硫酸、亚硫酸盐、抗坏血酸盐、L-半胱氨酸或其酸加成盐、巯基乙酸或其金属盐、1，2-乙二胺、水杨酸或其金属盐或者苯酚或其衍生物的1种或2种以上物质。
8.按权利要求7的稳定方法，其中抗光剂为选自亚硫酸盐的1种或2种以上物质。
9.按权利要求9、7或8的稳定方法，其中亚硫酸盐为选自亚硫酸钠、亚硫酸钾、亚硫酸氢钠、亚硫酸氢钾、焦亚硫酸钠、焦亚硫酸钾。
10.含有(±)-6-氯-3，4-二氢-4-甲基-3-氧代-N-3-奎宁环基-2H-1，4-苯并噁嗪-8-甲酰胺一盐酸盐的注射剂的稳定方法，其特征在于配合作为抗光剂的焦亚硫酸钠。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP124978/93 | 1993-04-28 | ||
| JP12497893 | 1993-04-28 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1121691A true CN1121691A (zh) | 1996-05-01 |
| CN1047076C CN1047076C (zh) | 1999-12-08 |
Family
ID=14898921
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN94191931A Expired - Fee Related CN1047076C (zh) | 1993-04-28 | 1994-04-25 | 稳定的注射剂及注射剂的稳定方法 |
Country Status (3)
| Country | Link |
|---|---|
| KR (1) | KR100188318B1 (zh) |
| CN (1) | CN1047076C (zh) |
| WO (1) | WO1994025032A1 (zh) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102164606A (zh) * | 2008-09-30 | 2011-08-24 | 电气化学工业株式会社 | 光稳定化药物组合物 |
| CN103432078A (zh) * | 2013-08-28 | 2013-12-11 | 芦红代 | 盐酸头孢甲肟的药物组合物 |
| CN106943310A (zh) * | 2017-01-25 | 2017-07-14 | 西安科艺诗生物技术有限公司 | 一种提高色素蛋白光稳定性的复合物及应用 |
| CN109562109A (zh) * | 2016-07-29 | 2019-04-02 | 东丽株式会社 | 光稳定性提高的固体制剂 |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5952387A (en) * | 1995-08-04 | 1999-09-14 | Hokuriku Seiyaku Co., Ltd. | Photostable aqueous solution containing benzyl alcohol derivatives |
| JP2008297277A (ja) * | 2007-06-01 | 2008-12-11 | Taiyo Yakuhin Kogyo Kk | 注射剤の安定化法 |
| CN116158429B (zh) * | 2021-11-25 | 2024-06-18 | 沈阳中化农药化工研发有限公司 | 一种含有联苯类化合物稳定的液体制剂 |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3597456A (en) * | 1969-05-20 | 1971-08-03 | Squibb & Sons Inc | Method for preparing sterile lecithin |
| JPS4819929B1 (zh) * | 1970-05-12 | 1973-06-18 | ||
| JPS51136818A (en) * | 1975-05-20 | 1976-11-26 | Yamanouchi Pharmaceut Co Ltd | Method for preparing stable prostaglandine pharma ceuticals |
| JPS5270014A (en) * | 1975-12-05 | 1977-06-10 | Senju Pharma Co | Stabilization of pyrido*3*22a*phenoxadine compounds |
| JPS58203910A (ja) * | 1982-05-20 | 1983-11-28 | Nikken Kagaku Kk | ドパミン含有点滴静注用剤 |
| JPS60169430A (ja) * | 1984-02-14 | 1985-09-02 | Teijin Ltd | プロスタグランジン類製剤用組成物 |
| JPH0778020B2 (ja) * | 1987-06-10 | 1995-08-23 | 日本化薬株式会社 | 安定な総合ビタミン凍結乾燥製剤 |
| CA1304082C (en) * | 1987-10-22 | 1992-06-23 | Tetsuya Tahara | Benzoxazine compounds and pharmaceutical use thereof |
| JP2761005B2 (ja) * | 1988-11-02 | 1998-06-04 | エーザイ株式会社 | セファロスポリン含有注射用組成物 |
| NL8901432A (nl) * | 1989-06-06 | 1991-01-02 | Pharmachemie Bv | Bij koelkasttemperatuur stabiele waterige folinaatoplossing, alsmede werkwijze ter bereiding daarvan. |
-
1994
- 1994-04-25 KR KR1019950704441A patent/KR100188318B1/ko not_active IP Right Cessation
- 1994-04-25 WO PCT/JP1994/000691 patent/WO1994025032A1/ja active Search and Examination
- 1994-04-25 CN CN94191931A patent/CN1047076C/zh not_active Expired - Fee Related
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102164606A (zh) * | 2008-09-30 | 2011-08-24 | 电气化学工业株式会社 | 光稳定化药物组合物 |
| CN102164606B (zh) * | 2008-09-30 | 2014-04-16 | 电气化学工业株式会社 | 光稳定化药物组合物 |
| CN103432078A (zh) * | 2013-08-28 | 2013-12-11 | 芦红代 | 盐酸头孢甲肟的药物组合物 |
| CN103432078B (zh) * | 2013-08-28 | 2015-06-17 | 芦红代 | 盐酸头孢甲肟的药物组合物 |
| CN109562109A (zh) * | 2016-07-29 | 2019-04-02 | 东丽株式会社 | 光稳定性提高的固体制剂 |
| CN106943310A (zh) * | 2017-01-25 | 2017-07-14 | 西安科艺诗生物技术有限公司 | 一种提高色素蛋白光稳定性的复合物及应用 |
Also Published As
| Publication number | Publication date |
|---|---|
| WO1994025032A1 (en) | 1994-11-10 |
| CN1047076C (zh) | 1999-12-08 |
| KR100188318B1 (ko) | 1999-06-01 |
| KR960701638A (ko) | 1996-03-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU695937B2 (en) | Intraocular irrigating solution containing agent for controlling IOP | |
| DK157168B (da) | Fremgangsmaade til fremstilling af farmaceutiske praeparater paa basis af cis-platin(ii)-diamindichlorid | |
| BG65304B1 (bg) | Воден състав, съдържащ моксифлоксацин и натриев хлорид | |
| Trissel et al. | Compatibility of parenteral nutrient solutions with selected drugs during simulated Y-site administration | |
| CN1047076C (zh) | 稳定的注射剂及注射剂的稳定方法 | |
| EP1911447A1 (en) | Eye drop preparation comprising xanthan gum and terpenoid | |
| US6211169B1 (en) | Stable calcitriol solution for packaging into vials | |
| EP2055304A1 (en) | Stabilized pharmaceutical composition | |
| DE10303229A1 (de) | α-Liponsäure, Ambroxol und/oder Inhibitoren des Angiotensin Converting-Enzyms (ACE) umfassende Arzneimittel-Zubereitung und ihre Verwendung zur Behandlung von neurodegenerativen Erkrankungen | |
| DE4228552A1 (de) | Diphosphonsäuren und deren Salze enthaltende Arzneimittel | |
| RU2271800C2 (ru) | Новые препараты альфа-2,4-дисульфофенил-n-трет-бутилнитрона | |
| EP1073469B1 (de) | Stabile mitoxantron-lösungen | |
| KR20110022686A (ko) | 술폰아미드 화합물을 함유하는 안정적인 수용액 조성물 | |
| Grubstein et al. | Stabilization of epinephrine in a local anesthetic injectable solution using reduced levels of sodium metabisulfite and EDTA | |
| JP3949184B2 (ja) | 塩酸アンブロキソール水性液剤 | |
| JP2770571B2 (ja) | 安定化された注射剤および注射剤の安定化法 | |
| CN1334725A (zh) | 普鲁泊福(2,6－二异丙基苯酚)和2,5－二－氧－甲基－1,4;3,6－双脱水－d－葡萄糖醇作为溶剂的胃肠外的溶液 | |
| SK284711B6 (sk) | Farmaceutická kompozícia s protinádorovým účinkom na báze karboplatiny | |
| JPH0867638A (ja) | エリスリトール含有注射剤 | |
| RU1819613C (ru) | Способ получени антиглаукомного средства | |
| JPH05262644A (ja) | アミノ酸含有輸液の安定化方法 | |
| CN100335053C (zh) | 一种药物制剂及其制备方法 | |
| RU2613019C1 (ru) | Фармацевтическая композиция для парентерального введения 2-этил-6-метил-3-гидроксипиридина сукцината и способ получения этой композиции | |
| EP3932391A1 (en) | Method to prepare pharmaceutical compositions | |
| CN1198670A (zh) | 含光稳定的苄醇衍生物的水溶液 |
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 | ||
| C53 | Correction of patent of invention or patent application | ||
| COR | Change of bibliographic data |
Free format text: CORRECT: PATENTEE; FROM: YOSHITOMI PHARMACEUTICAL INDUSTRIES CO., LTD. TO: WEIFU CO., LTD. |
|
| CP01 | Change in the name or title of a patent holder |
Patentee after: WELFIDE Corp. Patentee before: Yoshitomi Pharmaceutical Industries, Ltd. |
|
| C56 | Change in the name or address of the patentee |
Owner name: MITSUBISHI PHARMACEUTICAL CORP. Free format text: FORMER NAME OR ADDRESS: WEIFU CO., LTD. |
|
| CP01 | Change in the name or title of a patent holder |
Patentee after: MITSUBISHI PHARMA Corp. Patentee before: WELFIDE Corp. |
|
| C19 | Lapse of patent right due to non-payment of the annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |