CN115518033A - 一种高稳定辅酶q10注射液 - Google Patents
一种高稳定辅酶q10注射液 Download PDFInfo
- Publication number
- CN115518033A CN115518033A CN202110705672.2A CN202110705672A CN115518033A CN 115518033 A CN115518033 A CN 115518033A CN 202110705672 A CN202110705672 A CN 202110705672A CN 115518033 A CN115518033 A CN 115518033A
- Authority
- CN
- China
- Prior art keywords
- injection
- coenzyme
- solution
- cyclodextrin
- hydroxypropyl
- 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.)
- Pending
Links
- ACTIUHUUMQJHFO-UHFFFAOYSA-N Coenzym Q10 Natural products COC1=C(OC)C(=O)C(CC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UHFFFAOYSA-N 0.000 title claims abstract description 51
- 235000017471 coenzyme Q10 Nutrition 0.000 title claims abstract description 51
- ACTIUHUUMQJHFO-UPTCCGCDSA-N coenzyme Q10 Chemical compound COC1=C(OC)C(=O)C(C\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UPTCCGCDSA-N 0.000 title claims abstract description 51
- 229940110767 coenzyme Q10 Drugs 0.000 title claims abstract description 50
- 238000002347 injection Methods 0.000 title claims abstract description 41
- 239000007924 injection Substances 0.000 title claims abstract description 41
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims abstract description 21
- 239000002202 Polyethylene glycol Substances 0.000 claims abstract description 15
- 229920001223 polyethylene glycol Polymers 0.000 claims abstract description 15
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 claims abstract description 15
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims abstract description 14
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims abstract description 13
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 claims abstract description 13
- 229930003427 Vitamin E Natural products 0.000 claims abstract description 7
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 claims abstract description 7
- 235000019165 vitamin E Nutrition 0.000 claims abstract description 7
- 229940046009 vitamin E Drugs 0.000 claims abstract description 7
- 239000011709 vitamin E Substances 0.000 claims abstract description 7
- 239000000243 solution Substances 0.000 claims description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 22
- 238000002156 mixing Methods 0.000 claims description 11
- 239000008215 water for injection Substances 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 8
- 239000005515 coenzyme Substances 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 7
- 229930003231 vitamin Natural products 0.000 claims description 7
- 239000011782 vitamin Substances 0.000 claims description 7
- 229940088594 vitamin Drugs 0.000 claims description 7
- 235000013343 vitamin Nutrition 0.000 claims description 7
- 150000003722 vitamin derivatives Chemical class 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- 238000002844 melting Methods 0.000 claims description 6
- 230000008018 melting Effects 0.000 claims description 6
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 6
- 238000004806 packaging method and process Methods 0.000 claims description 6
- 238000007789 sealing Methods 0.000 claims description 6
- 230000001954 sterilising effect Effects 0.000 claims description 6
- 230000001502 supplementing effect Effects 0.000 claims description 6
- 238000005303 weighing Methods 0.000 claims description 6
- 235000013772 propylene glycol Nutrition 0.000 claims description 3
- 239000003963 antioxidant agent Substances 0.000 claims 1
- 230000003078 antioxidant effect Effects 0.000 claims 1
- 235000006708 antioxidants Nutrition 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000003755 preservative agent Substances 0.000 claims 1
- 230000002335 preservative effect Effects 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 22
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 abstract description 19
- 229920000053 polysorbate 80 Polymers 0.000 abstract description 19
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 abstract description 9
- 229940068968 polysorbate 80 Drugs 0.000 abstract description 9
- 230000036541 health Effects 0.000 abstract description 2
- 239000000463 material Substances 0.000 abstract description 2
- 229920000136 polysorbate Polymers 0.000 abstract description 2
- 239000006184 cosolvent Substances 0.000 abstract 1
- 229940001607 sodium bisulfite Drugs 0.000 abstract 1
- 239000003814 drug Substances 0.000 description 11
- 238000000034 method Methods 0.000 description 11
- 229940079593 drug Drugs 0.000 description 7
- 239000002245 particle Substances 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- -1 polyoxyethylene Polymers 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 229920000858 Cyclodextrin Polymers 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 230000007547 defect Effects 0.000 description 3
- 238000011835 investigation Methods 0.000 description 3
- 239000000693 micelle Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 206010002198 Anaphylactic reaction Diseases 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 239000001116 FEMA 4028 Substances 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- 208000003455 anaphylaxis Diseases 0.000 description 2
- 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 description 2
- 235000011175 beta-cyclodextrine Nutrition 0.000 description 2
- 229960004853 betadex Drugs 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 238000005286 illumination Methods 0.000 description 2
- 238000010255 intramuscular injection Methods 0.000 description 2
- 239000007927 intramuscular injection Substances 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 230000003381 solubilizing effect Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 208000028185 Angioedema Diseases 0.000 description 1
- 208000032467 Aplastic anaemia Diseases 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 208000000059 Dyspnea Diseases 0.000 description 1
- 206010013975 Dyspnoeas Diseases 0.000 description 1
- 206010014561 Emphysema Diseases 0.000 description 1
- 206010019799 Hepatitis viral Diseases 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010047623 Vitamin C deficiency Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 238000009098 adjuvant therapy Methods 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000019522 cellular metabolic process Effects 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000000718 duodenal ulcer Diseases 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 230000002949 hemolytic effect Effects 0.000 description 1
- 206010019692 hepatic necrosis Diseases 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000036543 hypotension Effects 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000004151 quinonyl group Chemical group 0.000 description 1
- NPCOQXAVBJJZBQ-UHFFFAOYSA-N reduced coenzyme Q9 Natural products COC1=C(O)C(C)=C(CC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C)C(O)=C1OC NPCOQXAVBJJZBQ-UHFFFAOYSA-N 0.000 description 1
- 201000005404 rubella Diseases 0.000 description 1
- 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 description 1
- 208000010233 scurvy Diseases 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940035936 ubiquinone Drugs 0.000 description 1
- 201000001862 viral hepatitis Diseases 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
- A61K31/12—Ketones
- A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
-
- 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
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- 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
- 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
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- 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
- A61K47/30—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
- A61K47/40—Cyclodextrins; Derivatives thereof
-
- 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
-
- 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
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/06—Free radical scavengers or antioxidants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Immunology (AREA)
- Inorganic Chemistry (AREA)
- Biochemistry (AREA)
- Pulmonology (AREA)
- Dermatology (AREA)
- Heart & Thoracic Surgery (AREA)
- Gastroenterology & Hepatology (AREA)
- Cardiology (AREA)
- Toxicology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Molecular Biology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Abstract
本发明提供了一种高稳定性辅酶Q10注射液及其制备方法，该辅酶Q10注射液处方由辅酶Q10、聚乙二醇十二羟基硬脂酸酯、丙二醇、羟丙基‑β‑环糊精、亚硫酸氢钠、维生素E组成，该注射液制备方法通过聚乙二醇十二羟基硬脂酸酯、羟丙基‑β‑环糊精作为助溶剂，从而避免使用聚山梨酯80（吐温80）。吐温80是一种有潜在不安全性的辅料，使用不当会对人的健康造成很大影响，从而增加制剂的安全性隐患。
Description
技术领域
本发明涉及生化药物领域，特别是一种高稳定辅酶Q10注射液及其制备方法。
背景技术
辅酶Q10，又名“泛醌”，是一种普遍存在于多种生物体内的脂溶性天然维生素类物质，是线粒体氧化磷酸化的辅酶。辅酶Q10是一种多功能生化药品，具有天然抗氧化和细胞代谢激活的作用，能显著提高人体免疫力，该药品临 床主要用于心血管疾病、坏血病、再生障碍性贫血、十二指肠溃疡、急慢性 病毒性肝炎、亚急性肝坏死、充血性心脏病、肺气肿等病的治疗以及癌症患 者的辅助治疗，具有广泛的临床应用前景。
辅酶Q10极易溶于氯仿、苯，易溶于丙酮，难溶于乙醇，不溶于水和甲醇，另外由于辅酶Q10的分子结构中含有醌基，导致辅酶Q10见光和遇氧极易分解，将其用于静脉给药的注射剂难度很大。现已上市的辅酶Q10产品多为片剂、胶囊剂、软胶囊剂等剂型，这些剂型普遍存在的不足就是口服后生物利用度低。近年来也有不少有关辅酶Q10注射液的研究报道，通过将辅酶 Q10制成注射液直接静脉给药，以提高辅酶Q10的生物利用度。
中国专利申请号200410022007. X公开的“辅酶Q10注射液及其制备方法”，其提供了一种将辅酶Q10制成注射液的方法，该方法主要是通过添加高浓度的表面活性剂聚山梨酯80 （吐温80）对辅酶Q10进行增溶，从而成功将其制成注射液。
中国专利申请号200610086747. 9公开的“辅酶Q10注射液注射液”，其提供了另一种将辅酶Q10制成注射液的方法，该方法的关键是采用了一种复合增溶剂，该复合增溶剂是由聚山梨酯80（吐温80）和聚氧乙烯脂肪酸酯（聚氧乙烯脂肪酸40酯）按照一定比例配比后组成。
中国专利申请号200810120564. X公开的“一种辅酶Q10注射液及其制备方法”，其提供了一种将辅酶Q10制成注射液的方法，该方法主要是通过加入0.01%-0.5%注射用活性炭，不符合注射剂制剂要求，虽然能使澄明度合格，但由于活性炭吸附药液中主药辅酶Q10所得得到的制剂含量很难符合《中药药典》要求。
中国专利申请号CN 104771357 A公开的“一种辅酶Q10肌肉注射剂及其制备方法”，其提供了另外一种将辅酶Q10肌肉注射剂及其制备方法，该方法使用聚乙二醇十二羟基硬脂酸酯作为增溶剂，所得制剂配液时不溶性微粒多，药液浑浊乳化，经过滤虽然能除掉不溶性微粒，但所得制剂有效成分含量达不到《中药药典》要求。
通过上述辅酶Q10注射液剂及冻干粉针剂的公开内容可以发现，均采用了大比例的表面活性剂聚山梨酯80 （吐温80）对辅酶进行增溶处理。由于聚山梨酯80（吐温80）在临床应用中特别是静脉给药制剂中存在很大的安全性问题，医学界证实，聚山梨酯80 （吐温80）用于注射剂，会引起过敏反应，包括休克，呼吸困难，低血压，血管性水肿，风疹等过敏样反应症状。这些不良反 应在人的临床实验可以十分严重，有死亡报道。因此，使用聚山梨酯80（吐温80）是有严格限制条件的，它是一种有潜在不安全性的辅料，使用不当会对人的健康造成很大影响。
发明内容
本发明所要解决的技术问题是克服上述现有技术存在的缺陷，提供一种用药安全的辅酶Q10注射液。
为此，本发明采用以下的技术方案：辅酶Q10注射液，每 100ml注射液含有下列组分：
辅酶Q10 0.1g〜0.35g
聚乙二醇十二羟基硬脂酸酯 1.0g〜5.0g
丙二醇 10g〜30g
羟丙基-β-环糊精 0.1g〜5.0g
维生素E 0.1g〜5.0g
亚硫酸氢钠 0.01g〜0.1g
注射用水 定容至100ml。
该注射液采用了一种聚乙二醇十二羟基硬脂酸酯和羟丙基-β-环糊精作为增溶剂，成功将辅酶Q10制成质量符合要求的注射液。本发明避开使用存在安全性隐患的表面活性剂聚山梨酯80（吐温80）,从而使辅酶Q10注射液在临床应用安全性方面得到有效控制。
聚乙二醇十二羟基硬脂酸酯是一种可供注射用的新型非离子表面活性剂，由于其分子结构为一种既含有亲水性基团又含有亲脂性基团的两亲性高分子，当其溶解在水中后由于分子的定向排列即亲水性基团朝外而亲脂性基团朝内而形成胶束粒子，这种胶束粒子内部由亲脂性基团聚集而呈脂相，当先将脂溶性辅酶Q10与聚乙二醇十二羟基硬脂酸酯混合熔融再加入水后可将辅酶Q10溶解于胶束粒子的内脂相中形成稳定的溶液从而达到增溶辅酶Q10的目的
而羟丙基-β-环糊精，由于羟丙基的引入打破了β-环糊精的分子内环状氢键，在保持环糊精空腔的同时克服了β-环糊精水溶性差的主要缺点。该产品在水中的溶解度很好，相对表面活性和溶血活性比较低且对肌肉没有刺激性，是一种理想的注射剂增溶剂。可以提高难溶性药物的水溶性，增加药物稳定性、提高药物生物利用度，使药剂的疗效增加或服用量减少。
上述辅酶Q10注射液的制备方法，其步骤如下：
（1）按配方称取各组分，将辅酶Q10与聚乙二醇十二羟基硬脂酸酯于50℃-65℃水浴锅中混合熔融，接着加入10%-20%的注射用水、羟丙基-β-环糊精震荡混匀至溶液澄明，然后依次加入处方量的丙二醇、亚硫酸氢钠、维生素E，补液至全量。
（2）在步骤1得到的用10%稀盐酸溶液调pH值至4.3-4.8，后经过0.45µm及两级0.22µm精密过滤器然后再精滤至溶液澄明度合格；
（3）灌装、封口、灭菌、质量检测、包装。
具体实施方式
下面实施例只为进一步说明本发明，不以任何形式限制本发明范围
实施例1：
制剂处方：
辅酶Q10 0.25g
聚乙二醇十二羟基硬脂酸酯 2.5g
丙二醇 10g〜30g
羟丙基-β-环糊精 0.1g〜5.0g
维生素E 0.1g〜5.0g
亚硫酸氢钠 0.01g〜0.1g
注射用水 定容至100ml
制剂工艺：
工艺步骤：
（1）按配方称取各组分，将辅酶Q10与聚乙二醇十二羟基硬脂酸酯于50℃-65℃水浴锅中混合熔融，接着加入10%-20%的注射用水、羟丙基-β-环糊精震荡混匀至溶液澄明，然后依次加入处方量的丙二醇、亚硫酸氢钠、维生素E，补液至全量。
（2）在步骤1得到的用10%稀盐酸溶液调pH值至4.3-4.8，后经过0.45µm及两级0.22µm精密过滤器然后再精滤至溶液澄明度合格；
（3）灌装、封口、灭菌、质量检测、包装。
实施例2：
制剂处方：
辅酶Q10 0.25g
聚乙二醇十二羟基硬脂酸酯 1.0g〜5.0g
羟丙基-β-环糊精 0.1g〜5.0g
维生素E 0.1g〜5.0g
亚硫酸氢钠 0.01g〜0.1g
注射用水 定容至100ml
制剂工艺：
工艺步骤：
（1）按配方称取各组分，将辅酶Q10与聚乙二醇十二羟基硬脂酸酯于50℃-65℃水浴锅中混合熔融，接着加入10%-20%的注射用水、羟丙基-β-环糊精震荡混匀至溶液澄明，然后依次加入处方量的亚硫酸氢钠、维生素E，补液至全量。
（2）在步骤1得到的用10%稀盐酸溶液调pH值至4.3-4.8，后经过0.45µm及两级0.22µm精密过滤器然后再精滤至溶液澄明度合格；
（3）灌装、封口、灭菌、质量检测、包装。
对比例1：
制剂处方：
辅酶Q10 0.1g〜0.35g
聚乙二醇十二羟基硬脂酸酯 1.0g〜5.0g
维生素E 0.1g〜5.0g
亚硫酸氢钠 0.01g〜0.1g
注射用水 定容至100ml
制剂工艺：
工艺步骤：
（1）按配方称取各组分，将辅酶Q10与聚乙二醇十二羟基硬脂酸酯于50℃-65℃水浴锅中混合熔融，然后依次加入处方量的亚硫酸氢钠、维生素E，补液至全量。
（2）在步骤1得到的用10%稀盐酸溶液调pH值至4.3-4.8，后经过0.45µm及两级0.22µm精密过滤器然后再精滤至溶液澄明度合格；
（3）灌装、封口、灭菌、质量检测、包装。
对比例2：
制剂处方：
辅酶Q10 0.1g〜0.35g
吐温80 1.0g〜5.0g
羟丙基-β-环糊精 0.1g〜5.0g
维生素E 0.1g〜5.0g
亚硫酸氢钠 0.01g〜0.1g
注射用水 定容至100ml
制剂工艺：
工艺步骤：
（1）按配方称取各组分，将辅酶Q10与吐温80于50℃-65℃水浴锅中混合熔融，接着加入10%-20%的注射用水、羟丙基-β-环糊精震荡混匀至溶液澄明，然后依次加入处方量的亚硫酸氢钠、维生素E，补液至全量。
（2）在步骤1得到的用10%稀盐酸溶液调pH值至4.3-4.8，后经过0.45µm及两级0.22µm精密过滤器然后再精滤至溶液澄明度合格；
（3）灌装、封口、灭菌、质量检测、包装。
下面通过实验说明本发明所提供的技术方案的有益效果。对实施例1，2和对比例1，2 所制备的辅酶Q10注射液进行质量检测。同时进行于高温40°C、相对湿度75%±5%条件下试验,温度25°C、相对湿度60%±10%条件和温度25°C，光照强度为45001X±5001x下放样考察，于5天，10天，30天检测澄明度、PH值、含量还是有关物质各项质量指标的变化，所得数据如表1-4所示:
表1 0天质量检测结果
表2 髙温40°C，相对湿度75%±5%条件下实验
表3 稳定25°C，相对湿度60%±10%条件下实验
表4 温度25°C，光照强度为45001X ±5001x条件下实验
由以上数据结果可以看出,对比例1,2样品有效含量不合格，经过影响因素考察，经考察后，各项考察指标变化都很大，说明样品稳定性差；实施例1,2制得的辅酶Q10注射液除光照条件下均符合质量标准，说明了本发明制备的样品质量稳定性好。
Claims (6)
1.一种高稳定辅酶Q10注射液，其特征在于每100ml注射液含有下列组分:
辅酶Q10 0.1g〜0.35g
聚乙二醇十二羟基硬脂酸酯 1.0g〜5.0g
丙二醇 10g〜30g
羟丙基-β-环糊精 0.1g〜5.0g
维生素E 0.1g〜5.0g
亚硫酸氢钠 0.01g〜0.1g
注射用溶剂 定容至100ml。
2.根据权利要求1所述的辅酶Q10注射液，其特征在于所述的注射用溶剂为注射用水。
3.根据权利要求1所述的辅酶Q10注射液，其特征在于所述的增溶剂为聚乙二醇十二羟基硬脂酸酯和羟丙基-β-环糊精。
4.根据权利要求1所述的辅酶Q10注射液，其特征在于，所述抗氧化剂和防腐剂用量在01%-0.5%。
5.根据权利要求1-4任一项所述的辅酶Q10注射液的制备方法，其特征在于包括下述步骤：
（1）按配方称取各组分，将辅酶Q10与聚乙二醇十二羟基硬脂酸酯混合熔融，接着加入10%-20%的注射用水、羟丙基-β-环糊精震荡混匀至溶液澄明，然后依次加入处方量的丙二醇、亚硫酸氢钠、维生素E，补液至全量；
（2）在步骤1得到的用10%稀盐酸溶液调pH值至4.3-4.8，后经过0.45µm及两级0.22µm精密过滤器然后再精滤至溶液澄明度合格；
（3）灌装、封口、灭菌、质量检测、包装。
6.根据权利要求1-5任一项所述的辅酶Q10注射液，其特征在于，该注射液使用0.45µm、0.22µm两级精密过滤器。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110705672.2A CN115518033A (zh) | 2021-06-24 | 2021-06-24 | 一种高稳定辅酶q10注射液 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110705672.2A CN115518033A (zh) | 2021-06-24 | 2021-06-24 | 一种高稳定辅酶q10注射液 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN115518033A true CN115518033A (zh) | 2022-12-27 |
Family
ID=84694278
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110705672.2A Pending CN115518033A (zh) | 2021-06-24 | 2021-06-24 | 一种高稳定辅酶q10注射液 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115518033A (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115969782A (zh) * | 2023-02-16 | 2023-04-18 | 南京康川济医药科技有限公司 | 一种辅酶q10注射液及其制备方法 |
-
2021
- 2021-06-24 CN CN202110705672.2A patent/CN115518033A/zh active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115969782A (zh) * | 2023-02-16 | 2023-04-18 | 南京康川济医药科技有限公司 | 一种辅酶q10注射液及其制备方法 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101439031B (zh) | 一种含18种氨基酸的药物组合物 | |
| HU217839B (hu) | Eljárások taxánszármazékokat tartalmazó új stabil gyógyszerkészítmények előállítására | |
| US8426385B2 (en) | Pharmaceutical composition comprising cyclodextrin paclitaxel inclusion and preparation method thereof | |
| WO2008031285A1 (en) | Pharmaceutical composition containing docetaxel-cyclodextrin inclusion complex and its preparing process | |
| WO2015192720A1 (zh) | 大剂量甘油在可耐受冻融脂肪乳剂中的应用 | |
| CN103830204A (zh) | 一种含水飞蓟提取物的软胶囊及其制备方法 | |
| CN107412152B (zh) | 一种盐酸右美托咪定注射液组合物 | |
| CN113975234A (zh) | 一种羟基-α-山椒素纳米脂质体及其制备方法 | |
| CN101612121A (zh) | 紫杉醇微乳的制备方法 | |
| CN115518033A (zh) | 一种高稳定辅酶q10注射液 | |
| CN1723887A (zh) | 一种紫杉醇注射剂及其制备方法 | |
| CN107029248A (zh) | 白藜芦醇固体分散体及增加白藜芦醇在红酒中的溶解度的方法 | |
| CN101480375A (zh) | 一种辅酶q10静脉输液及其制备方法 | |
| CN110876719B (zh) | 一种维生素k1注射剂及其制备方法 | |
| WO2020062928A1 (zh) | 一种高纯度的聚山梨酯80的制备方法 | |
| CN104415041B (zh) | 一种13种复合维生素注射液药物组合物及其制备方法 | |
| CN101417105A (zh) | 一种莪术油葡萄糖注射液及其制备方法 | |
| CN115990262A (zh) | 不含乙醇和磷脂的湿热灭菌的尼莫地平组合物及其制备方法 | |
| CN111265474B (zh) | 一种帕立骨化醇注射液及其制备方法 | |
| CN115518037A (zh) | 一种安全质量稳定的左西孟旦注射剂组合物及其制备方法 | |
| CN114886848A (zh) | 一种纳米胶束组合物制备方法及制备的纳米胶束组合物 | |
| CN109820820B (zh) | 一种前列地尔注射液及其制备方法 | |
| CN108670950B (zh) | 一种不含有机溶剂的虎杖苷药物组合物及其制备方法 | |
| CN109828046B (zh) | 一种前列地尔注射液的检测方法 | |
| CN110721155B (zh) | 一种长效载药脂肪乳制剂及其制备方法 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination |