CN113398068A - Injection and preparation method thereof - Google Patents
Injection and preparation method thereof Download PDFInfo
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- CN113398068A CN113398068A CN202110898776.XA CN202110898776A CN113398068A CN 113398068 A CN113398068 A CN 113398068A CN 202110898776 A CN202110898776 A CN 202110898776A CN 113398068 A CN113398068 A CN 113398068A
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- Prior art keywords
- injection
- peramivir
- sodium
- preparation
- acid
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- 238000002347 injection Methods 0.000 title claims abstract description 47
- 239000007924 injection Substances 0.000 title claims abstract description 47
- 238000002360 preparation method Methods 0.000 title claims description 22
- 229940090044 injection Drugs 0.000 claims abstract description 44
- XRQDFNLINLXZLB-CKIKVBCHSA-N peramivir Chemical compound CCC(CC)[C@H](NC(C)=O)[C@@H]1[C@H](O)[C@@H](C(O)=O)C[C@H]1NC(N)=N XRQDFNLINLXZLB-CKIKVBCHSA-N 0.000 claims abstract description 39
- 229960001084 peramivir Drugs 0.000 claims abstract description 38
- 229940011070 peramivir injection Drugs 0.000 claims abstract description 23
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 24
- 230000001954 sterilising effect Effects 0.000 claims description 24
- 238000004659 sterilization and disinfection Methods 0.000 claims description 16
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 12
- 239000011780 sodium chloride Substances 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 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
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- 239000000872 buffer Substances 0.000 claims description 7
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 5
- 239000007951 isotonicity adjuster Substances 0.000 claims description 5
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 4
- 239000006172 buffering agent 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
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 235000017550 sodium carbonate Nutrition 0.000 claims description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 3
- 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 3
- 235000011054 acetic acid Nutrition 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 3
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 3
- HELHAJAZNSDZJO-OLXYHTOASA-L sodium L-tartrate Chemical compound [Na+].[Na+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O HELHAJAZNSDZJO-OLXYHTOASA-L 0.000 claims description 3
- 239000001632 sodium acetate Substances 0.000 claims description 3
- 235000017281 sodium acetate Nutrition 0.000 claims description 3
- 239000001509 sodium citrate Substances 0.000 claims description 3
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 3
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 3
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 3
- 239000001433 sodium tartrate Substances 0.000 claims description 3
- 229960002167 sodium tartrate Drugs 0.000 claims description 3
- 235000011004 sodium tartrates Nutrition 0.000 claims description 3
- 239000011975 tartaric acid Substances 0.000 claims description 3
- 235000002906 tartaric acid Nutrition 0.000 claims description 3
- SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-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
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 229960002684 aminocaproic acid Drugs 0.000 claims description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 2
- 239000004327 boric acid Substances 0.000 claims description 2
- 235000015165 citric acid Nutrition 0.000 claims description 2
- 229910000397 disodium phosphate Inorganic materials 0.000 claims description 2
- 235000019800 disodium phosphate Nutrition 0.000 claims description 2
- 235000011167 hydrochloric acid Nutrition 0.000 claims description 2
- 239000004310 lactic acid Substances 0.000 claims description 2
- 235000014655 lactic acid Nutrition 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- 239000001103 potassium chloride Substances 0.000 claims description 2
- 235000011164 potassium chloride Nutrition 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 235000011083 sodium citrates Nutrition 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims 4
- 238000004519 manufacturing process Methods 0.000 abstract description 7
- 238000003860 storage Methods 0.000 abstract description 7
- 238000009509 drug development Methods 0.000 abstract description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- 238000000034 method Methods 0.000 description 12
- 239000003814 drug Substances 0.000 description 9
- 239000003125 aqueous solvent Substances 0.000 description 8
- 230000000052 comparative effect Effects 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000008215 water for injection Substances 0.000 description 6
- 239000006184 cosolvent Substances 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 241000712461 unidentified influenza virus Species 0.000 description 5
- 206010022000 influenza Diseases 0.000 description 4
- 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 3
- 229930195725 Mannitol Natural products 0.000 description 3
- 102000005348 Neuraminidase Human genes 0.000 description 3
- 108010006232 Neuraminidase Proteins 0.000 description 3
- 239000000594 mannitol Substances 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- GUJOJGAPFQRJSV-UHFFFAOYSA-N dialuminum;dioxosilane;oxygen(2-);hydrate Chemical compound O.[O-2].[O-2].[O-2].[Al+3].[Al+3].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O GUJOJGAPFQRJSV-UHFFFAOYSA-N 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 229910052901 montmorillonite Inorganic materials 0.000 description 2
- 239000003002 pH adjusting agent Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000002911 sialidase inhibitor Substances 0.000 description 2
- 239000008354 sodium chloride injection Substances 0.000 description 2
- 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
- SQUHHTBVTRBESD-UHFFFAOYSA-N Hexa-Ac-myo-Inositol Natural products CC(=O)OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O SQUHHTBVTRBESD-UHFFFAOYSA-N 0.000 description 1
- 102000012750 Membrane Glycoproteins Human genes 0.000 description 1
- 108010090054 Membrane Glycoproteins Proteins 0.000 description 1
- 229940123424 Neuraminidase inhibitor Drugs 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 229940124393 anti-influenza virus drug Drugs 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 229940042406 direct acting antivirals neuraminidase inhibitors Drugs 0.000 description 1
- 229940126534 drug product Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 description 1
- 229960000367 inositol Drugs 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 238000009533 lab test Methods 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229960003752 oseltamivir Drugs 0.000 description 1
- VSZGPKBBMSAYNT-RRFJBIMHSA-N oseltamivir Chemical compound CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@@H](N)C1 VSZGPKBBMSAYNT-RRFJBIMHSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 229960001028 zanamivir Drugs 0.000 description 1
- ARAIBEBZBOPLMB-UFGQHTETSA-N zanamivir Chemical compound CC(=O)N[C@@H]1[C@@H](N=C(N)N)C=C(C(O)=O)O[C@H]1[C@H](O)[C@H](O)CO ARAIBEBZBOPLMB-UFGQHTETSA-N 0.000 description 1
Classifications
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
-
- 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
- A61K47/12—Carboxylic acids; Salts or anhydrides 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
Abstract
The invention discloses an injection, which is one of aqueous injections containing peramivir or peramivir salt with the concentration of 0.1-100mg/ml, discovers potential safety hazards possibly existing in the existing peramivir injection, can obtain the peramivir injection with better stability and safety performance by further adjusting a prescription, and ensures the pH stability of a product during storage. The peramivir injection provided by the invention has better safety and stability, can ensure the pH stability of the product during storage, and meets the drug development and production concepts with higher requirements.
Description
Technical Field
The invention relates to the technical field of injection preparation, in particular to an injection and a preparation method thereof.
Background
Peramivir (Peramivir), developed by american biological crystal drug products gmbh, is another novel Neuraminidase (NA) inhibitor anti-influenza virus drug after the successful development of zanamivir and oseltamivir and the marketing in 1999, and is used for the treatment and prevention of influenza a and b in adults and children.
Peramivir has been developed to date as an antiviral drug and in particular for use in influenza therapy. As neuraminidase inhibitors, peramivir is effective in inhibiting replication of all types of influenza viruses. Peramivir can be used by injection and is known to be well tolerated and cause only minor side effects. The peramivir is an influenza neuraminidase inhibitor, can kill highly pathogenic H5N1 avian influenza virus, and can effectively resist the H5N1 avian influenza virus. Results of preclinical studies show that it can effectively act on a variety of influenza viruses (including the H5N1 virus). It is a novel cyclopentane anti-influenza drug taking influenza virus surface glycoprotein neuraminidase as an action target. Laboratory tests have shown that peramivir is effective against each of the known H5N1 viruses and is extremely virulent and resistant to the virus.
The peramivir has low oral availability, is mainly prepared into parenteral preparations such as injection and the like, for example, CN101314579A discloses an anhydrous peramivir crystal and a pharmaceutical composition thereof, and comprises an injection containing 200mg of the peramivir crystal: 200mg of anhydrous peramivir crystal, mannitol, a proper amount of hydrochloric acid and water for injection are added to 100 mL. And freeze-dried powder injection: 200mg of anhydrous peramivir crystal, mannitol, a proper amount of hydrochloric acid and water for injection are added to 20mL for freeze-drying. The problems in the invention are that 1) the concentration of peramivir in the injection is small, about 2 mg/ml; 2) the freeze-drying needle separation preparation process adopts filtration sterilization, needs an aseptic production process, and has a lower aseptic guarantee level than a terminal sterilization process.
CN102058522A discloses a peramivir injection and a preparation method thereof, which comprises peramivir, a non-aqueous solvent, a cosolvent and water for injection. The weight volume ratio (g/ml) of the peramivir to the non-aqueous solvent is 1: 10-100, the dosage ratio of the non-aqueous solvent in the formula is 20-60% (v/v), the dosage of the cosolvent is 1-20% (w/v), the non-aqueous solvent is one or a mixed solvent of ethanol, propylene glycol, glycerol and polyethylene glycol, and the cosolvent is one or more of glucose, sorbitol, mannitol and inositol. Provides a peramivir injection which can be diluted by water for injection, sodium chloride or glucose infusion in any proportion and can keep the clarity of the solution, and a preparation method thereof. The injection can improve the solubility of the peramivir, can meet the reasonable preparation formula and preparation method of injection medication requirements, increases the solubility of the peramivir and maintains the stability of the solution by using a proper amount of non-aqueous solvent and cosolvent, avoids the problems of turbid solution, incapability of administration and the like during clinical dilution use, reduces the using amount of the non-aqueous solvent as far as possible, and improves the concentration of original drugs. The invention has the problems that a non-aqueous solvent and a cosolvent are required to be used for increasing the solubility of the peramivir and maintaining the stability of the solution, but the non-aqueous solvent such as ethanol, propylene glycol, glycerol and polyethylene glycol has certain vascular irritation, and the clinical medication is influenced.
Patent CN107281096A discloses a water injection containing peramivir and a preparation method thereof, which is characterized in that the water injection consists of the peramivir, pharmaceutic adjuvant and water for injection, wherein the pharmaceutic adjuvant contains nano-scale montmorillonite, the average particle size is 12nm-15nm, the water for injection is boiled and then cooled to 45 ℃ for liquid preparation, and the sterilization process is sterilization at 121 ℃ for 10 min. The invention has the problems that 1) the safety of the medicine has certain challenge when the nano-scale montmorillonite which is an unusual auxiliary material is added into the injection; 2) the injection water needs to be boiled and then cooled to 45 ℃ for liquid preparation, and the boiling of the injection water in the production process needs special production equipment for treatment, so that the production process is complex and is not beneficial to commercial production; 3) the sterilization process is sterilization at 121 ℃ for 10min, a residual probability method is adopted, and the sterility assurance level is not high as the terminal sterilization process.
Patent CN 112245388A discloses a sodium chloride injection containing peramivir and a preparation method thereof, which is characterized in that each ml of the formula contains 10mg of peramivir and 9mg of sodium chloride, and the pH value of the solution is adjusted to 5.0-8.5 by using a pH regulator hydrochloric acid or sodium hydroxide. A terminal sterilization process, namely a sterilization process at 121 ℃ for 12min, is adopted in the process of preparing the peramivir sodium chloride injection. The invention has the problems that when the pH value of the injection is 5.0-8.5, the pH value of a product is unstable during storage, related substances are increased, the stability of the quality of a medicine is influenced, and potential safety hazards are brought to clinical application of the medicine. Therefore, the injection and the preparation method thereof are provided, so that the product has better stability, and the clinical medication safety is ensured.
Disclosure of Invention
In order to obtain the peramivir injection with better quality stability and safety and solve the problem of unstable pH of the product during storage, the inventor conducts a great deal of exploration and analysis, and the pH stability of the product during storage can be ensured by adding a buffering agent in a preparation formula, so that the product quality stability and the medication safety of the peramivir injection are improved.
The invention provides a peramivir injection, which comprises peramivir, a pharmaceutically-addable additive, a pH regulator and water, wherein the concentration of the peramivir is 0.1-100mg/ml, preferably 1-20mg/ml, and more preferably 1.5-10 mg/ml.
Preferably, the injection contains a buffering agent, an isotonic agent and a pH regulator.
Preferably, the buffer is selected from one or more of acetic acid, sodium acetate, citric acid, sodium citrate, lactic acid, tartaric acid, sodium tartrate, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium hydrogen phosphate, sodium carbonate and epsilon-aminocaproic acid.
Preferably, the isotonic agent is selected from one or more of sodium chloride, potassium chloride, boric acid and glycerol.
Preferably, the pH adjusting agent is selected from hydrochloric acid, sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium bicarbonate or potassium carbonate.
Preferably, the pH regulator keeps the pH of the peramivir injection at 4-9, preferably 5-8.5.
The raw materials and auxiliary materials involved in the invention can be non-hydrate or hydrate.
Compared with the prior art, the invention has the beneficial effects that:
the invention discovers potential safety hazards of the existing peramivir injection, and can further obtain the peramivir injection with better stability and safety performance by adjusting the prescription, thereby ensuring the pH stability of the product during storage. The peramivir injection provided by the invention has better safety and stability, can ensure the pH stability of the product during storage, and meets the drug development and production concepts with higher requirements.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The injection of the present invention can be prepared by a conventional method, and pharmaceutically acceptable additives can be added as needed by using a conventional technique: such as buffering agents, isotonic agents, pH adjusting agents and the like.
The pH of the injection of the present invention may be within a range acceptable for injection preparations, and is preferably 4 to 9, more preferably 5 to 8.5.
The temperature of the injection preparation of the present invention may be within the range allowed by the injection preparation, and is usually 20 to 80 ℃, preferably 25 to 65 ℃, more preferably 30 to 40 ℃.
The injection of the invention has no special requirements on the sequence, and the raw materials and the auxiliary materials can be fed separately or simultaneously.
The injection can adopt terminal sterilization, filtration sterilization and other modes.
When the terminal sterilization mode is adopted for the injection of the invention, the sterilization condition is usually 110-.
Example 1
peramivir injection at pH 5.0 containing buffer: dissolving peramivir 1.5g, acetic acid 0.33 g, sodium acetate 1.2 g and sodium chloride 1.35g in water at 30 ℃, adjusting the pH to 5.0 by using a pH regulator, fixing the volume to 150mL, subpackaging, and sterilizing at 121 ℃ for 15 minutes.
Comparative example 1 is a peramivir injection with pH 5.0: dissolving peramivir 1.5g and sodium chloride 1.35g in water at 30 ℃, adjusting the pH to 5.0 by using a pH regulator, fixing the volume to 150mL, subpackaging, and sterilizing at 121 ℃ for 15 minutes.
Example 2
peramivir injection with buffer at pH 6.0: dissolving peramivir 1.5g, citric acid 0.75 g, sodium citrate 0.6 g and sodium chloride 1.35g in water at 30 ℃, adjusting the pH to 6.0 by using a pH regulator, fixing the volume to 150mL, subpackaging, and sterilizing at 121 ℃ for 15 minutes.
Comparative example 2 is a peramivir injection with pH 6.0: dissolving peramivir 1.5g and sodium chloride 1.35g in water at 30 ℃, adjusting the pH to 6.0 by using a pH regulator, fixing the volume to 150mL, subpackaging, and sterilizing at 121 ℃ for 15 minutes.
Example 3
peramivir injection at pH 7.0 containing buffer: dissolving peramivir 1.5g, tartaric acid 0.975 g, sodium tartrate 0.18 g and sodium chloride 1.35g in water at 30 ℃, adjusting the pH to 7.0 by using a pH regulator, fixing the volume to 150mL, subpackaging, and sterilizing at 121 ℃ for 15 minutes.
Comparative example 3 is a peramivir injection with pH 7.0: dissolving peramivir 1.5g and sodium chloride 1.35g in water at 30 ℃, adjusting the pH to 7.0 by using a pH regulator, fixing the volume to 150mL, subpackaging, and sterilizing at 121 ℃ for 15 minutes.
Example 4
peramivir injection with buffer at pH 8.5: dissolving peramivir 1.5g, disodium hydrogen phosphate 0.255 g, sodium dihydrogen phosphate 1.06 g and sodium chloride 1.35g in water at 30 ℃, adjusting the pH to 8.5 by using a pH regulator, fixing the volume to 150mL, subpackaging, and sterilizing at 121 ℃ for 15 minutes.
Comparative example 4 is a peramivir injection with pH 8.5: dissolving peramivir 1.5g and sodium chloride 1.35g in water at 30 ℃, adjusting the pH to 8.5 by using a pH regulator, fixing the volume to 150mL, subpackaging, and sterilizing at 121 ℃ for 15 minutes.
The indexes of pH, related substances and the like of the peramivir injection in 0 month and 6 months are respectively examined under the accelerated stability condition specified by the current Chinese pharmacopoeia, and the results are shown in the table.
| pH | Total impurities (%) | pH | Total impurities (%) | |
| Comparative example 1 | 5.0 | 0.10 | 5.4 | 0.28 |
| Comparative example 2 | 6.0 | 0.12 | 6.3 | 0.30 |
| Comparative example 3 | 7.0 | 0.11 | 6.8 | 0.26 |
| Comparative example 4 | 8.5 | 0.13 | 8.0 | 0.32 |
| Example 1 | 5.0 | 0.11 | 5.1 | 0.15 |
| Example 2 | 6.0 | 0.09 | 6.0 | 0.14 |
| Example 3 | 7.0 | 0.10 | 7.0 | 0.15 |
| Example 4 | 8.5 | 0.12 | 8.4 | 0.16 |
As can be seen from the table, the addition of a certain concentration of buffer in the formula of the peramivir injection can keep the pH of the product stable and reduce the increase of related substances.
It is noted that, herein, relational terms such as first and second, and the like may be used solely to distinguish one entity or action from another entity or action without necessarily requiring or implying any actual such relationship or order between such entities or actions. Also, the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus.
Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (10)
1. An injection, characterized by: the injection is one of aqueous injections containing peramivir or a salt thereof with the concentration of 0.1-100 mg/ml.
2. An injection according to claim 1, wherein: the injection contains a buffering agent, an isotonic agent and a pH regulator.
3. An injection according to claim 2, wherein: the buffer is one or more selected from acetic acid, sodium acetate, citric acid, sodium citrate, lactic acid, tartaric acid, sodium tartrate, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium hydrogen phosphate, sodium carbonate and epsilon-aminocaproic acid.
4. An injection according to claim 2, wherein: the isotonic agent is selected from one or more of sodium chloride, potassium chloride, boric acid and glycerol.
5. An injection according to claim 2, wherein: the pH regulator is selected from one of hydrochloric acid, sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium bicarbonate or potassium carbonate.
6. An injection according to claim 1, wherein: the temperature of the pharmaceutical liquid is controlled within the range of 20-80 ℃ during the preparation of the injection.
7. An injection according to claim 1, wherein: the concentration of the peramivir or the salt thereof in the injection is 1-20 mg/ml.
8. An injection according to claim 1, wherein: the concentration of the peramivir or the salt thereof in the injection is 1.5-10 mg/ml.
9. An injection according to claim 1, wherein: the pH value of the peramivir injection is kept between 4 and 9.
10. A preparation method of an injection, which is a preparation method of an aqueous injection containing peramivir or a salt thereof with the concentration of 0.1-100mg/ml, is characterized in that: the injection can adopt one of terminal sterilization or filtration sterilization; the sterilization condition is 110-130 ℃ and 10-60 minutes.
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| CN102058522A (en) * | 2009-11-13 | 2011-05-18 | 天津金世制药有限公司 | Peramivir injection and preparation method thereof |
| CN107281096A (en) * | 2016-04-01 | 2017-10-24 | 天津市汉康医药生物技术有限公司 | A kind of liquid drugs injection containing Peramivir and preparation method thereof |
| CN109771398A (en) * | 2019-02-25 | 2019-05-21 | 广州南鑫药业有限公司 | A kind of Peramivir solution-type inhalant and preparation method thereof |
| CN112245388A (en) * | 2020-11-23 | 2021-01-22 | 苏州二叶制药有限公司 | Sodium chloride injection containing peramivir and preparation method thereof |
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- 2021-08-05 CN CN202110898776.XA patent/CN113398068A/en active Pending
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| CN102058522A (en) * | 2009-11-13 | 2011-05-18 | 天津金世制药有限公司 | Peramivir injection and preparation method thereof |
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