CN112138165A - Valnemulin hydrochloride diluent and preparation method thereof - Google Patents
Valnemulin hydrochloride diluent and preparation method thereof Download PDFInfo
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- CN112138165A CN112138165A CN202011020529.1A CN202011020529A CN112138165A CN 112138165 A CN112138165 A CN 112138165A CN 202011020529 A CN202011020529 A CN 202011020529A CN 112138165 A CN112138165 A CN 112138165A
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- water
- diluent
- reaction kettle
- injection
- stirring
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- MFBPRQKHDIVLOJ-AFFLPQGKSA-N 133868-46-9 Chemical compound Cl.CC(C)[C@@H](N)C(=O)NCC(C)(C)SCC(=O)O[C@@H]1C[C@@](C)(C=C)[C@@H](O)[C@H](C)[C@@]23CC[C@@H](C)[C@]1(C)[C@@H]2C(=O)CC3 MFBPRQKHDIVLOJ-AFFLPQGKSA-N 0.000 title claims abstract description 42
- 239000003085 diluting agent Substances 0.000 title claims abstract description 39
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 42
- 238000003756 stirring Methods 0.000 claims abstract description 33
- 239000008215 water for injection Substances 0.000 claims abstract description 30
- 239000011259 mixed solution Substances 0.000 claims abstract description 26
- 239000003995 emulsifying agent Substances 0.000 claims abstract description 21
- 239000002738 chelating agent Substances 0.000 claims abstract description 19
- 239000003381 stabilizer Substances 0.000 claims abstract description 19
- 229920000858 Cyclodextrin Polymers 0.000 claims abstract description 14
- 239000001116 FEMA 4028 Substances 0.000 claims abstract description 14
- 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 claims abstract description 14
- 235000011175 beta-cyclodextrine Nutrition 0.000 claims abstract description 14
- 229960004853 betadex Drugs 0.000 claims abstract description 14
- 229920000642 polymer Polymers 0.000 claims abstract description 14
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims abstract description 14
- JVYDLYGCSIHCMR-UHFFFAOYSA-N 2,2-bis(hydroxymethyl)butanoic acid Chemical compound CCC(CO)(CO)C(O)=O JVYDLYGCSIHCMR-UHFFFAOYSA-N 0.000 claims abstract description 13
- 229920001531 copovidone Polymers 0.000 claims abstract description 11
- 238000007789 sealing Methods 0.000 claims abstract description 9
- 238000001914 filtration Methods 0.000 claims abstract description 8
- 230000001954 sterilising effect Effects 0.000 claims abstract description 8
- 238000010438 heat treatment Methods 0.000 claims abstract description 6
- 239000002994 raw material Substances 0.000 claims abstract description 5
- 238000000034 method Methods 0.000 claims abstract 5
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims description 10
- 239000007788 liquid Substances 0.000 claims description 8
- 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 description 6
- 239000002202 Polyethylene glycol Substances 0.000 claims description 6
- 229920001223 polyethylene glycol Polymers 0.000 claims description 6
- 239000001569 carbon dioxide Substances 0.000 claims description 5
- 229910002092 carbon dioxide Inorganic materials 0.000 claims description 5
- 239000008367 deionised water Substances 0.000 claims description 5
- 229910021641 deionized water Inorganic materials 0.000 claims description 5
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 claims description 4
- 229930024421 Adenine Natural products 0.000 claims description 4
- 229960000643 adenine Drugs 0.000 claims description 4
- 239000012153 distilled water Substances 0.000 claims description 4
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims description 3
- 229920002675 Polyoxyl Polymers 0.000 claims description 3
- 229930003427 Vitamin E Natural products 0.000 claims description 3
- 239000004359 castor oil Substances 0.000 claims description 3
- 235000019438 castor oil Nutrition 0.000 claims description 3
- 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 description 3
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 3
- 229920001451 polypropylene glycol Polymers 0.000 claims description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 3
- LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical compound [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 claims description 3
- 229940074439 potassium sodium tartrate Drugs 0.000 claims description 3
- 235000011006 sodium potassium tartrate Nutrition 0.000 claims description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 3
- YWYZEGXAUVWDED-UHFFFAOYSA-N triammonium citrate Chemical compound [NH4+].[NH4+].[NH4+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O YWYZEGXAUVWDED-UHFFFAOYSA-N 0.000 claims description 3
- 229940046009 vitamin E Drugs 0.000 claims description 3
- 235000019165 vitamin E Nutrition 0.000 claims description 3
- 239000011709 vitamin E Substances 0.000 claims description 3
- UBHWBODXJBSFLH-UHFFFAOYSA-N hexadecan-1-ol;octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO.CCCCCCCCCCCCCCCCCCO UBHWBODXJBSFLH-UHFFFAOYSA-N 0.000 claims description 2
- 238000004659 sterilization and disinfection Methods 0.000 claims description 2
- 238000002347 injection Methods 0.000 abstract description 7
- 239000007924 injection Substances 0.000 abstract description 7
- 230000007012 clinical effect Effects 0.000 abstract description 6
- 239000003814 drug Substances 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 3
- 230000035515 penetration Effects 0.000 abstract description 2
- 239000002131 composite material Substances 0.000 abstract 1
- 230000000052 comparative effect Effects 0.000 description 5
- LLYYNOVSVPBRGV-MVNKZKPCSA-N valnemulin Chemical compound CC(C)[C@@H](N)C(=O)NCC(C)(C)SCC(=O)O[C@@H]1C[C@@](C)(C=C)[C@@H](O)[C@H](C)[C@@]23CC[C@@H](C)[C@]1(C)[C@@H]2C(=O)CC3 LLYYNOVSVPBRGV-MVNKZKPCSA-N 0.000 description 4
- 241000282887 Suidae Species 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000002504 physiological saline solution Substances 0.000 description 3
- 229950008166 valnemulin Drugs 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- ZRZNJUXESFHSIO-UHFFFAOYSA-N Pleuromutilin Natural products CC1C(O)C(C)(C=C)CC(OC(=O)CO)C2(C)C(C)CCC31C2C(=O)CC3 ZRZNJUXESFHSIO-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 230000035699 permeability Effects 0.000 description 2
- ZRZNJUXESFHSIO-VYTKZBNOSA-N pleuromutilin Chemical compound C([C@H]([C@]1(C)[C@@H](C[C@@](C)(C=C)[C@@H](O)[C@@H]2C)OC(=O)CO)C)C[C@]32[C@H]1C(=O)CC3 ZRZNJUXESFHSIO-VYTKZBNOSA-N 0.000 description 2
- 206010059866 Drug resistance Diseases 0.000 description 1
- 241000204031 Mycoplasma Species 0.000 description 1
- 241000589970 Spirochaetales Species 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 229930004069 diterpene Natural products 0.000 description 1
- 150000004141 diterpene derivatives Chemical class 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 244000144977 poultry Species 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- UURAUHCOJAIIRQ-QGLSALSOSA-N tiamulin Chemical compound CCN(CC)CCSCC(=O)O[C@@H]1C[C@@](C)(C=C)[C@@H](O)[C@H](C)[C@@]23CC[C@@H](C)[C@]1(C)[C@@H]2C(=O)CC3 UURAUHCOJAIIRQ-QGLSALSOSA-N 0.000 description 1
- 229960004885 tiamulin Drugs 0.000 description 1
- 239000000273 veterinary drug Substances 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
- A61K47/08—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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
-
- 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
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- 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
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
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- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- 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
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- 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
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
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- 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
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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Abstract
The invention belongs to the technical field of veterinary medicines, and discloses a valnemulin hydrochloride diluent and a preparation method thereof. The composite material consists of the following raw materials in percentage by weight: 85-90% of water for injection, 1-3% of 2, 2-dimethylolbutyric acid, 1-3% of water-soluble beta cyclodextrin polymer, 1-2% of copovidone S6301, 1-2% of chelating agent, 1-3% of emulsifier and 2-3% of stabilizer. The method comprises the following steps: putting 2, 2-dimethylolbutyric acid, water-soluble beta cyclodextrin polymer, copovidone S630 and part of water for injection into a reaction kettle and sealing the reaction kettle; stirring the mixed solution, pressurizing and heating the reaction kettle to 50-70 ℃ and 2-6 MPa while stirring, and relieving pressure after keeping for 5-10 min; adding a chelating agent, an emulsifier and a stabilizer into the mixed solution, stirring, and adding the rest water for injection into the mixed solution while stirring; taking out the mixed solution, filtering and sterilizing to obtain the diluent. The valnemulin hydrochloride prepared by the diluent has good needle penetration, no bulge on the injection part, good stability and stable clinical effect.
Description
Technical Field
The invention belongs to the technical field of veterinary medicines, and particularly relates to a valnemulin hydrochloride diluent and a preparation method thereof.
Background
Valnemulin hydrochloride (Valnemulin) is a new generation of pleuromutilin semi-synthetic antibiotic, belongs to diterpene and is a similar drug of tiamulin. In 1984, Bemer et al, Sandoz, switzerland, by using pleuromutilin, succeeded first. In 1999, Norvatis corporation, Switzerland made it into premix, with the trade name Econor, which is now on the market in many countries, mainly used for preventing and treating mycoplasma and enteric spirochete infections in livestock and poultry. Valnemulin hydrochloride has the characteristics of safety, high efficiency, low toxicity, difficulty in generating drug resistance and the like, and is widely used in many countries at present. However, valnemulin has low solubility and relatively poor stability, and is inconvenient for veterinary clinical use, so that the clinical use of the valnemulin is limited.
At present, the clinical veterinarian finds that the valnemulin hydrochloride mixed feed has poor administration effect, and the clinical effect is excellent when the valnemulin hydrochloride mixed feed is orally administered or injected. Currently, veterinarians mainly use deionized water or normal saline as a diluent of valnemulin hydrochloride. However, the valnemulin hydrochloride has poor solubility and unstable aqueous solution, and when water or normal saline is used as a diluting carrier, the problems of difficult injection, easy swelling, compounding and layering with oil seedlings, unstable clinical effect and the like exist.
Disclosure of Invention
The invention aims to provide a valnemulin hydrochloride diluent and a preparation method thereof, solves the problems in the background art, and meets the actual use requirements.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
the valnemulin hydrochloride diluent consists of the following raw materials in percentage by weight: 85-90% of water for injection, 1-3% of 2, 2-dimethylolbutyric acid, 1-3% of water-soluble beta cyclodextrin polymer, 1-2% of copovidone S6301, 1-2% of chelating agent, 1-3% of emulsifier and 2-3% of stabilizer.
Preferably, the material comprises the following raw materials in percentage by weight: 88% of water for injection, 2% of 2, 2-dimethylolbutyric acid, 3% of water-soluble beta-cyclodextrin polymer, polyvidone S6301%, 2% of chelating agent, 2% of emulsifier and 2% of stabilizer.
Preferably, the water for injection is one or a combination of deionized water and distilled water.
Preferably, the emulsifier is one or more of polyethylene glycol hexadecanol octadecanol 20, vitamin E polyethylene glycol succinate, and castor oil polyoxyl 35.
Preferably, the chelating agent is one or more of potassium sodium tartrate, ammonium citrate and ethylenediamine tetraacetic acid.
Preferably, the stabilizer is one or a combination of two of adenine and polypropylene glycol.
A preparation method of the valnemulin hydrochloride diluent comprises the following steps:
(a) putting 2, 2-dimethylolbutyric acid, water-soluble beta cyclodextrin polymer, copovidone S630 and part of water for injection into a reaction kettle, and sealing the reaction kettle;
(b) stirring the mixed liquid in the step (a) by a stirring mechanism in the reaction kettle, pressurizing and heating the interior of the reaction kettle while stirring, raising the temperature in the reaction kettle to 50-70 ℃, charging carbon dioxide until the pressure in the reaction kettle reaches 2-6 MPa, keeping the temperature and the pressure for 5-10 min after the temperature and the pressure reach set values, and continuously releasing the pressure to normal pressure to obtain the mixed liquid;
(c) opening the reaction kettle, adding a chelating agent, an emulsifying agent and a stabilizing agent into the mixed solution obtained in the step (b), stirring, and continuously adding the rest water for injection into the mixed solution while stirring;
(d) and (c) taking out the mixed liquid obtained in the step (c), and filtering and sterilizing the mixed liquid to obtain the diluent.
Preferably, in the step (a), the amount of the part of the water for injection is 40 to 60 wt% of the total amount of the water for injection.
Preferably, in the step (b), the rotating speed of the stirring is 5000-8000 rpm, and the time is 10-15 min; in the step (c), the stirring speed is 3000-4000 rpm, and the time is 8-10 min.
Preferably, in the step (b), the temperature and the pressure in the reaction kettle are increased to set values within 8 min; in step (d), the filtration sterilization was performed using a 0.22 μm filter.
Compared with the prior art, the invention has the following beneficial effects:
the valnemulin hydrochloride diluent provided by the invention has good needle permeability and no bulge on the injection part, and is prepared by the aqueous diluent; the valnemulin hydrochloride prepared by the diluent has good stability and stable clinical effect; because the diluent contains the emulsifier, the emulsifier can be used together with the oil seedlings.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all 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.
Example 1
The valnemulin hydrochloride diluent comprises the following components in percentage by weight: 88% of water for injection, 2-dimethylolbutyric acid, 3% of water-soluble beta-cyclodextrin polymer, copovidone S6301%, 2% of chelating agent, 2% of emulsifier and 2% of stabilizer; wherein the water for injection is deionized water; the emulsifier is polyethylene glycol hexadecanol ether 20; the chelating agent is potassium sodium tartrate; the stabilizer is adenine.
The preparation method comprises the following steps:
(a) sequentially putting 2, 2-dimethylolbutyric acid, water-soluble beta-cyclodextrin polymer, copovidone S630 and injection water accounting for 40 wt% of the total amount of the injection water into a reaction kettle, closing a bin gate of the reaction kettle and sealing the reaction kettle;
(b) fully stirring the mixed solution obtained in the step (a) by a stirring mechanism in a reaction kettle, wherein the rotating speed is 5000 rpm, and the time is 15 min;
(c) pressurizing and heating the interior of the reaction kettle while stirring, raising the temperature in the reaction kettle to 70 ℃ within 8 min, charging carbon dioxide to 6 MPa, keeping the temperature and pressure for 5 min after the temperature and pressure reach a set value, and continuously releasing the pressure to normal pressure to obtain a mixed solution;
(d) opening the reaction kettle, adding a chelating agent, an emulsifier and a stabilizer into the mixed solution obtained in the step (c), fully stirring at the rotating speed of 3000 rpm for 10 min, and continuously adding the rest of the water for injection into the mixed solution while stirring;
(e) and (d) taking out the mixed solution obtained in the step (d), filtering and sterilizing the mixed solution by adopting a 0.22-micron filter to obtain the diluent, filling and sealing for storage.
Example 2
The valnemulin hydrochloride diluent comprises the following components in percentage by weight: 85% of water for injection, 3% of 2, 2-dimethylolbutyric acid, 3% of water-soluble beta cyclodextrin polymer, 2% of copovidone S6302%, 2% of chelating agent, 2% of emulsifier and 3% of stabilizer; wherein the water for injection is distilled water; the emulsifier is vitamin E polyethylene glycol succinate; the chelating agent is ammonium citrate; the stabilizer is polypropylene glycol.
The preparation method comprises the following steps:
(a) sequentially putting 2, 2-dimethylolbutyric acid, water-soluble beta-cyclodextrin polymer, copovidone S630 and 50 wt% of water for injection in the total amount of the water for injection into a reaction kettle, closing a bin gate of the reaction kettle and sealing the reaction kettle;
(b) fully stirring the mixed solution obtained in the step (a) by a stirring mechanism in the reaction kettle, wherein the rotating speed is 8000 rpm, and the time is 10 min;
(c) pressurizing and heating the interior of the reaction kettle while stirring, raising the temperature in the reaction kettle to 60 ℃ within 8 min, charging carbon dioxide to 4 MPa, keeping the temperature and pressure for 7 min after the temperature and pressure reach a set value, and continuously releasing the pressure to normal pressure to obtain a mixed solution;
(d) opening the reaction kettle, adding a chelating agent, an emulsifying agent and a stabilizing agent into the mixed solution obtained in the step (c), fully stirring at the rotation speed of 4000 rpm for 8 min, and continuously adding the rest of the water for injection into the mixed solution while stirring;
(e) and (d) taking out the mixed solution obtained in the step (d), filtering and sterilizing the mixed solution by adopting a 0.22-micron filter to obtain the diluent, filling and sealing for storage.
Example 3
The valnemulin hydrochloride diluent comprises the following components in percentage by weight: 90% of water for injection, 1% of 2, 2-dimethylolbutyric acid, 2% of water-soluble beta cyclodextrin polymer, polyvidone S6301%, 1% of chelating agent, 3% of emulsifier and 2% of stabilizer; wherein the water for injection is deionized water; the emulsifier is castor oil polyoxyl ester 35; the chelating agent is ethylenediamine tetraacetic acid; the stabilizer is adenine.
The preparation method comprises the following steps:
(a) sequentially putting 2, 2-dimethylolbutyric acid, water-soluble beta-cyclodextrin polymer, copovidone S630 and 60 wt% of water for injection in the total amount of the water for injection into a reaction kettle, closing a bin gate of the reaction kettle and sealing the reaction kettle;
(b) fully stirring the mixed solution obtained in the step (a) by a stirring mechanism in a reaction kettle, wherein the rotating speed is 6000 rpm, and the time is 12 min;
(c) pressurizing and heating the interior of the reaction kettle while stirring, raising the temperature in the reaction kettle to 50 ℃ within 8 min, charging carbon dioxide to 2 MPa, keeping the temperature and pressure for 10 min after the temperature and pressure reach a set value, and continuously releasing the pressure to normal pressure to obtain a mixed solution;
(d) opening the reaction kettle, adding the chelating agent, the emulsifier and the stabilizer into the mixed solution obtained in the step (c), fully stirring at 3500 rpm for 9 min, and continuously adding the rest of the water for injection into the mixed solution while stirring;
(e) and (d) taking out the mixed solution obtained in the step (d), filtering and sterilizing the mixed solution by adopting a 0.22-micron filter to obtain the diluent, filling and sealing for storage.
Clinical effects
An experiment was performed on 60 commercial pigs, the 60 commercial pigs were randomly divided into 4 groups, each group was 15, valnemulin hydrochloride was diluted with 3 diluents obtained in examples 1 to 3, respectively, and a physiological saline was used for the comparative example, the concentration of valnemulin hydrochloride in all samples after dilution was 5% (m/v, g/mL), and the commercial pigs were injected into each group, and the results were observed on the 15 th day of injection, respectively, and are shown in table 1.
As can be seen from Table 1: the clinical effect of the medicine prepared by the diluent of the invention after injection is better than that of the comparative example.
Needle penetration test
Valnemulin hydrochloride was diluted with the 3 diluents obtained in examples 1 to 3, and in a comparative example, valnemulin hydrochloride was diluted with physiological saline, and the concentration of valnemulin hydrochloride in all samples after dilution was 5% (m/v, g/mL). The time required to withdraw 5ml of the contents was calculated using a 7 gauge needle, 5ml syringe. The results are shown in Table 2.
As can be seen from Table 2: the needle permeability of the diluent diluted valnemulin hydrochloride obtained in the examples 1, 2 and 3 is far higher than that of the diluent diluted valnemulin hydrochloride obtained in the comparative example.
Stability test
Valnemulin hydrochloride was diluted with the diluent 1 obtained in example 1, and in comparative examples, valnemulin hydrochloride was diluted with physiological saline, and the concentration of valnemulin hydrochloride in all samples after dilution was 5% (m/v, g/mL). And (3) respectively placing each sample at 40 ℃ and RH 75% for 24 h, and monitoring the content of valnemulin hydrochloride (the content is not less than 90% and is qualified). Note: according to the quality standard compilation of veterinary drugs (2006-2011). The results are shown in Table 3.
As can be seen from Table 3: the stability of the diluent diluted valnemulin hydrochloride obtained in example 1 is obviously superior to that of the valnemulin hydrochloride diluted by distilled water.
Finally, it should be noted that: although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that changes may be made in the embodiments and/or equivalents thereof without departing from the spirit and scope of the invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. The valnemulin hydrochloride diluent is characterized by comprising the following raw materials in percentage by weight: 85-90% of water for injection, 1-3% of 2, 2-dimethylolbutyric acid, 1-3% of water-soluble beta cyclodextrin polymer, 1-2% of copovidone S6301, 1-2% of chelating agent, 1-3% of emulsifier and 2-3% of stabilizer.
2. The valnemulin hydrochloride diluent as in claim 1, which is prepared from the following raw materials in percentage by weight: 88% of water for injection, 2% of 2, 2-dimethylolbutyric acid, 3% of water-soluble beta-cyclodextrin polymer, polyvidone S6301%, 2% of chelating agent, 2% of emulsifier and 2% of stabilizer.
3. The valnemulin hydrochloride diluent of claim 1, wherein: the water for injection is one or the combination of two of deionized water and distilled water.
4. The valnemulin hydrochloride diluent of claim 1, wherein: the emulsifier is one or a combination of polyethylene glycol hexadecanol octadecanol 20, vitamin E polyethylene glycol succinate and castor oil polyoxyl 35.
5. The valnemulin hydrochloride diluent of claim 1, wherein: the chelating agent is one or more of potassium sodium tartrate, ammonium citrate and ethylenediamine tetraacetic acid.
6. The valnemulin hydrochloride diluent of claim 1, wherein: the stabilizer is one or the combination of two of adenine and polypropylene glycol.
7. A process for the preparation of a valnemulin hydrochloride diluent according to any one of claims 1 to 6, comprising the steps of:
(a) putting 2, 2-dimethylolbutyric acid, water-soluble beta cyclodextrin polymer, copovidone S630 and part of water for injection into a reaction kettle, and sealing the reaction kettle;
(b) stirring the mixed liquid in the step (a) by a stirring mechanism in the reaction kettle, pressurizing and heating the interior of the reaction kettle while stirring, raising the temperature in the reaction kettle to 50-70 ℃, charging carbon dioxide until the pressure in the reaction kettle reaches 2-6 MPa, keeping the temperature and the pressure for 5-10 min after the temperature and the pressure reach set values, and continuously releasing the pressure to normal pressure to obtain the mixed liquid;
(c) opening the reaction kettle, adding a chelating agent, an emulsifying agent and a stabilizing agent into the mixed solution obtained in the step (b), stirring, and continuously adding the rest water for injection into the mixed solution while stirring;
(d) and (c) taking out the mixed liquid obtained in the step (c), and filtering and sterilizing the mixed liquid to obtain the diluent.
8. A method of preparing a valnemulin hydrochloride diluent as in claim 7, wherein: in the step (a), the amount of the part of the water for injection is 40-60 wt% of the total amount of the water for injection.
9. A method of preparing a valnemulin hydrochloride diluent as in claim 7, wherein: in the step (b), the rotating speed of stirring is 5000-8000 rpm, and the time is 10-15 min; in the step (c), the stirring speed is 3000-4000 rpm, and the time is 8-10 min.
10. A method of preparing a valnemulin hydrochloride diluent as in claim 7, wherein: in the step (b), the temperature and the pressure in the reaction kettle are increased to set values within 8 min; in step (d), the filtration sterilization was performed using a 0.22 μm filter.
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| CN101912359A (en) * | 2010-06-02 | 2010-12-15 | 广州天王动物保健品有限公司 | Enrofloxacin injection |
| CN102415989A (en) * | 2011-09-30 | 2012-04-18 | 上海恒丰强动物药业有限公司 | Valnemulin hydrochloride solution and preparation method of same |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101912359A (en) * | 2010-06-02 | 2010-12-15 | 广州天王动物保健品有限公司 | Enrofloxacin injection |
| CN102415989A (en) * | 2011-09-30 | 2012-04-18 | 上海恒丰强动物药业有限公司 | Valnemulin hydrochloride solution and preparation method of same |
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Application publication date: 20201229 |