CN103417552A - Veterinary aditoprim (ADP)-sulfamethoxazole (SMZ) compound injection and preparation method thereof - Google Patents
Veterinary aditoprim (ADP)-sulfamethoxazole (SMZ) compound injection and preparation method thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of preparation of veterinary drugs and particularly relates to a veterinary aditoprim (ADP)-sulfamethoxazole (SMZ) compound injection and a preparation method thereof. The injection comprises effective ingredients of ADP and SMZ of which the concentrations by weight/volume percent are respectively 2% and 10%. Propylene glycol serves as a cosolvent of which the concentration by weight/volume percent is 50% in the injection always; water for injection serves as a solvent; anhydrous sodium thiosulfate serves as an anti-oxidant of which the concentration by weight/volume percent is 0.15% always. ADP and SMZ are salified with an additive at first, then various auxiliary materials and the inject solvent are added, the mixture is continually stirred to be uniformly mixed and then subjected to rough filtration and fine filtration, after that, filling and sealing are performed quickly, sterilization under hot press is carried out for 20 min, and finally, leak detection, light inspection and the like are performed to obtain the veterinary ADP-SMZ compound injection. The injection has a simple preparation process, the quality meets the requirements specified in pharmacopeia, a long-acting slow release effect can be taken, and the injection is suitable for treating digestive and respiratory tract infection of livestock, caused by sensitive bacteria.
Description
Technical field
The invention belongs to the veterinary drug preparing technical field, being specifically related to is a kind of Chinese mugwort for animals ground general quinoline-sulfamethoxazole compound injection and preparation method thereof and application.
Background technology
The disease of respiratory system, urinary system and the intestinal caused by escherichia coli, streptococcus pneumoniae, hemophilus influenza, staphylococcus aureus etc., perplexing for a long time the livestock breeding industry of China always, become a large obstacle of aquaculture development, brought huge economic loss to the aquaculture of China, in order to control this type of disease, country has dropped into a large amount of material resources and financial resources.Sulfa drugs can suppress most of gram positive bacterias and negative bacterium, brought into play huge effect in controlling bacterial infection disease, to non-product enzyme staphylococcus aureus, micrococcus scarlatinae, streptococcus pneumoniae, escherichia coli, Klebsiella, Salmonella, Proteus, Morganella, the enterobacteriaceae lactobacteriaceaes such as Shigella, gonococcus, Neisseria meningitidis, hemophilus influenza all has good antibacterial action, especially escherichia coli, streptococcus pneumoniae, hemophilus influenza, staphylococcus aureus, can effectively control and suppress above bacterial respiratory system, the disease of urinary system etc.
At present in sulfa drugs antibiotic the most by force and also commonly used be sulfamethoxazole (SMZ) and trimethoprim (Trimethoprim, TMP) compound preparation of making, but there are some problems in this compound preparation: biological half-life in animal body is relatively short, does not reach long-term antibiotic effect; Apparent volume of distribution is little, is not suitable for the treatment of systemic infection.Chinese mugwort ground general quinoline (ADP) is that at first the Roche company by Switzerland researches and develops a kind of novel animal specific Trimethoprim (Antibacterial Synerists) be synthesized, for dihydrofolate reductase (dihydrofolatere-ductase, DHFR) inhibitor class Trimethoprim, structure is similar to TMP, and gram positive bacteria and gram negative bacteria are had to fungistatic effect.With TMP, compare, ADP organize penetration and affinity stronger, after administration, intramuscular drug level is higher than in blood; With fibrous tissue, very strong binding ability is arranged, the elimination half-life is shorter, biological half-life is long, bioavailability is high, apparent volume of distribution is large, body is interior widely distributed, has more wide application prospect.
Sulfa drugs and DHFR inhibitor class Trimethoprim are synergism clinically usually, infer ADP and SMZ are made to compound preparation, as proper as compatibility, can improve the cost of the antibacterial activity of medicine, the antimicrobial spectrum that enlarges medicine, the toxicity that reduces medicine, the consumption that reduces medicine, reduction medicine etc.; The half-life of energy prolong drug, reach long-term antibiotic effect; The apparent volume of distribution that can increase medicine is little, is applicable to the treatment of systemic infection, is an effective method of the new veterinary drug of development both at home and abroad at present, can be for rationally using antibiotics, strengthen antibiotic curative effect, the generation that reduces fastbacteria provides powerful mean.
Summary of the invention
The object of the invention is to overcome the prior art defect, a kind of Chinese mugwort for animals ground general quinoline-sulfamethoxazole compound injection and preparation method thereof and application are provided.It is crude drug that Chinese mugwort ground general quinoline (ADP) and sulfamethoxazole (SMZ) are take in the present invention, water for injection is solvent, add the adjuvants such as cosolvent propylene glycol, triethanolamine, antioxidant Sodium Thio Sulphate(Anhydrous) and lactic acid, successfully develop that a kind of technique is simple, the Chinese mugwort of stability and high efficiency ground general quinoline-sulfamethoxazole compound injection.It is short that preparation of the present invention has peak time, absorbs soon, and apparent volume of distribution is large, is applicable to the characteristics of systemic infection treatment.
The present invention is achieved through the following technical solutions:
The preparation method of a kind of Chinese mugwort for animals ground general quinoline-sulfamethoxazole compound injection, the effective ingredient of this injection is the Chinese mugwort general quinoline in ground and sulfamethoxazole, the dicyandiamide solution of medicine is mainly water for injection, make into salt system with additives, the Chinese mugwort general quinoline in ground and sulfamethoxazole can effectively be dissolved.Various adjuvants and injection solvent thereof are added wherein, lasting stirring obtains Chinese mugwort ground general quinoline-sulfamethoxazole compound injection again, and its step comprises:
(1) add a small amount of water for injection in the general quinoline in Chinese mugwort ground, then add the lactic acid salify, obtain into salt system 1;
(2) sulfamethoxazole is used to the triethanolamine salify, obtained into salt system 2;
(3) add cosolvent in the one-tenth salt system 2 of step (2), and stir, make it abundant dissolving, put under room temperature standby;
(4) the one-tenth salt system 1 of blend step (1) and step (3) become salt system 2, and stir, make it abundant dissolving, obtain mixed system;
(5) add antioxidant in the mixed system of step (4), and stir, make it abundant dissolving;
(6) use the water for injection standardize solution;
(7) carry out coarse filtration, fine straining with the microporous filter membrane of common filter paper and 0.22 μ m, rapidly filling and sealing;
(8) in 100 ℃ of pressure sterilizing 20min, leak detection, lamp inspection, packing gets product;
Wherein, the formula of described Chinese mugwort ground general quinoline-sulfamethoxazole compound injection comprises: the Chinese mugwort general quinoline in ground and sulfamethoxazole crude drug, and its weight/volume percent concentration in preparation is respectively 2% and 10%; Described cosolvent is propylene glycol, and its weight/volume percent concentration in preparation is 50%; Described solvent is water for injection; Described antioxidant is Sodium Thio Sulphate(Anhydrous), and its weight/volume percent concentration in preparation is 0.15%.
The applicant provides a kind of Chinese mugwort for animals ground general quinoline-sulfamethoxazole compound injection, and component and the proportioning of pressing formula ratio are as follows:
(1) the general quinoline crude drug in Chinese mugwort ground, account for weight/volume percent concentration 2% in preparation;
(2) sulfamethoxazole crude drug, account for weight/volume percent concentration 10% in preparation;
(3) water for injection
(4) cosolvent is propylene glycol, and by weight/concentration of volume percent is 50%
(5) antioxidant is Sodium Thio Sulphate(Anhydrous), and by weight/concentration of volume percent is 0.15%;
It prepares according to following step:
(1) add a small amount of water for injection in the general quinoline in Chinese mugwort ground, then add the lactic acid salify, obtain into salt system 1;
(2) sulfamethoxazole is used to the triethanolamine salify, obtained into salt system 2;
(3) add cosolvent in the one-tenth salt system 2 of step (2), and stir, make it abundant dissolving, put under room temperature standby;
(4) what blend step (1) became salt system 1 and step (3) becomes salt system 2, and stirs, and makes it abundant dissolving, obtains mixed system;
(5) add antioxidant in the mixed system of step (4), and stir, make it abundant dissolving;
(6) use the water for injection standardize solution;
(7) carry out coarse filtration, fine straining with the microporous filter membrane of common filter paper and 0.22 μ m, rapidly filling and sealing;
(8) in 100 ℃ of pressure sterilizing 20min, leak detection, lamp inspection, packing gets product.
Chinese mugwort of the present invention ground general quinoline-sulfamethoxazole compound injection active constituent content is 96%～101%, and total impurities is no more than 1.5%.
Chinese mugwort for animals of the present invention ground general quinoline-sulfamethoxazole compound injection can be applicable to the treatment in livestock and birds respiratory disease infects.
The concrete application process of Chinese mugwort for animals of the present invention ground general quinoline-sulfamethoxazole compound injection is: intramuscular injection, once measure the per kilogram of body weight Chinese mugwort general quinoline 5mg in ground, sulfamethoxazole 25mg.
The Chinese mugwort ground general quinoline-off-drug period of sulfamethoxazole compound injection in the pig body for animals of the present invention is 24d.
The present invention compared with prior art has the following advantages:
(1) Chinese mugwort for animals ground general quinoline-sulfamethoxazole compound injection that the present invention makes has larger distribution volume in the pig body, and the longer elimination half-life, relative bioavailability is high.Single administration (intramuscular injection) 1mL/10kg (containing the general quinoline 2mg in Chinese mugwort ground, sulfamethoxazole 10mg) dosage can maintain effective blood drug concentration 1 day, and quantity is generally the 1mL/10kg body weight, and serious case can be injected once after 1 day again.
Chinese mugwort for animals ground general quinoline-sulfamethoxazole compound injection technique that the present invention obtains is simple, have good stability, reliable in quality, can improve the cost of the antibacterial activity of medicine, the antimicrobial spectrum that enlarges medicine, the toxicity that reduces medicine, the consumption that reduces medicine, reduction medicine etc.; After intramuscular injection, can maintain the valid density of long period in the pig body, reach long-term antibiotic effect; The apparent volume of distribution that can increase medicine is little, is applicable to the treatment of systemic infection.
The accompanying drawing explanation
Fig. 1: the ultraviolet absorpting spectrum that is effective ingredient sulfamethoxazole of the present invention.
Fig. 2: the ultraviolet absorpting spectrum that is the general woods in effective ingredient Chinese mugwort ground of the present invention.
Fig. 3: be pig blank plasma chromatogram.
Fig. 4: be the sample chromatogram figure that the pig blank plasma adds the general quinoline in Chinese mugwort ground.
Fig. 5: be the sample chromatogram figure that the pig blank plasma adds sulfamethoxazole.
Fig. 6: be the chromatogram of the general quinoline in Chinese mugwort ground in porcine blood plasma after pig muscle injection gained preparation of the present invention.
Fig. 7: be the chromatogram of sulfamethoxazole in porcine blood plasma after pig muscle injection gained preparation of the present invention.
The specific embodiment
Below in conjunction with specific embodiment, further set forth the present invention.These embodiment only do not limit the scope of protection of present invention in any form for the present invention is described.Described percent concentration is mass/volume (W/V) percent concentration or volume/volume (V/V) percent concentration if no special instructions.Optical microscope commonly used is used in the morphologic observation of test Chinese medicine particle diameter, and particle size determination is used microscope micrometer commonly used, and the medicament contg of compound injection adopts high performance liquid chromatography-uv detection method commonly used.
Pu Lin-sulfamethoxazole process for preparation of injection-1, embodiment 1 Chinese mugwort for animals ground
The concrete technology step is as follows:
(1) add a small amount of water for injection (1mL) in the Chinese mugwort general quinoline crude drug in ground (0.2g), then add lactic acid (295 μ l) salify, be into salt system 1;
(2) by triethanolamine for sulfamethoxazole (1g) (1340 μ l) city salt, be into salt system 2;
(3) add propylene glycol (4.5mL) in the one-tenth salt system 2 of step (2), and stir, make it abundant dissolving, put under room temperature standby;
(4) two kinds of blend step (1) and step (3) become salt system, and stir, and make it abundant dissolving, are mixed system;
(5) add antioxidant Sodium Thio Sulphate(Anhydrous) (0.005g) in the mixed system of step (4), and stir, make it abundant dissolving;
(6) use the water for injection standardize solution;
(7) carry out coarse filtration, fine straining with the microporous filter membrane of common filter paper and 0.22 μ m, rapidly filling and sealing;
(8) in 100 ℃ of pressure sterilizing 20min, leak detection, lamp inspection, packaging into products.
With reference to " People's Republic of China's veterinary drug allusion quotation " 2005 editions, the projects such as the appearance character of Chinese mugwort ground for animals of the present invention general quinoline-sulfamethoxazole compound injection, insoluble granule, pH value, visible foreign matters, heat source check are detected, the indices such as appearance character, insoluble granule, pH value, visible foreign matters, heat source check all meet the requirements, and the Chinese mugwort general quinoline in ground for animals of the present invention and sulfamethoxazole medicament contg are respectively 99.9% and 99.7% of dosage.
Pu Lin-sulfamethoxazole process for preparation of injection-2, embodiment 2 Chinese mugwort for animals ground
The concrete technology step is as follows:
(1) add a small amount of water for injection 1mL in the Chinese mugwort general quinoline in ground (0.2g), then add lactic acid (300 μ l) salify, be into salt system 1;
(2) by triethanolamine for sulfamethoxazole (1g) (1340 μ l) salify, be into salt system 2;
(3) add propylene glycol (5mL) in the one-tenth salt system of step (2), and stir, make it abundant dissolving, put under room temperature standby;
(4) two kinds of blend step (1) and step (3) become salt system, and stir, and make it abundant dissolving, are mixed system;
(5) add antioxidant Sodium Thio Sulphate(Anhydrous) (0.0075g) in the mixed system of step (4), and stir, make it abundant dissolving;
(6) use the water for injection standardize solution;
(7) carry out coarse filtration, fine straining with the microporous filter membrane of common filter paper and 0.22 μ m, rapidly filling and sealing;
(8) in 100 ℃ of pressure sterilizing 20min, leak detection, lamp inspection, packaging into products.
With reference to " People's Republic of China's veterinary drug allusion quotation " 2005 editions, the projects such as the appearance character of Chinese mugwort ground for animals of the present invention general quinoline-sulfamethoxazole compound injection, insoluble granule, pH value, visible foreign matters, heat source check are detected, the indices such as appearance character, insoluble granule, pH value, visible foreign matters, heat source check all meet the requirements, and the Chinese mugwort general quinoline in ground for animals of the present invention and sulfamethoxazole medicament contg are respectively 100% and 99.9% of dosage.
Pu Lin-sulfamethoxazole process for preparation of injection-3, embodiment 3 Chinese mugwort for animals ground
The concrete technology step is as follows:
(1) add a small amount of water for injection 1mL in the Chinese mugwort general quinoline in ground (0.2g), then add lactic acid (305 μ l) salify, be into salt system 1;
(2) by triethanolamine for sulfamethoxazole (1g) (1340 μ l) salify, be into salt system 2;
(3) add propylene glycol (5.5mL) in the one-tenth salt system 2 of step (2), and stir, make it abundant dissolving, put under room temperature standby;
(4) two kinds of blend step (1) and step (3) become salt system, and stir, and make it abundant dissolving, are mixed system;
(5) add antioxidant Sodium Thio Sulphate(Anhydrous) (0.01g) in the mixed system of step (4), and stir, make it abundant dissolving;
(6) use the water for injection standardize solution;
(7) carry out coarse filtration, fine straining with the microporous filter membrane of common filter paper and 0.22 μ m, rapidly filling and sealing;
(8) in 100 ℃ of pressure sterilizing 20min, leak detection, lamp inspection, packaging into products.
With reference to " People's Republic of China's veterinary drug allusion quotation " 2005 editions, the projects such as the appearance character of Chinese mugwort ground for animals of the present invention general quinoline-sulfamethoxazole compound injection, insoluble granule, pH value, visible foreign matters, heat source check are detected, the indices such as appearance character, insoluble granule, pH value, visible foreign matters, heat source check all meet the requirements, and the Chinese mugwort general quinoline in ground for animals of the present invention and sulfamethoxazole medicament contg are respectively 99.7% and 99.9% of dosage.
Pu Lin-sulfamethoxazole process for preparation of injection-4, embodiment 4 Chinese mugwort for animals ground
The concrete technology step is as follows:
(1) add a small amount of water for injection 1mL in the Chinese mugwort general quinoline in ground (0.2g), then add lactic acid (295 μ l) salify, be into salt system 1;
(2) by triethanolamine for sulfamethoxazole (1g) (1360 μ l) salify, be into salt system 2;
(3) add propylene glycol (5mL) in the one-tenth salt system 2 of step (2), and stir, make it abundant dissolving, put under room temperature standby;
(4) two kinds of blend step (1) and step (3) become salt system, and stir, and make it abundant dissolving, are mixed system;
(5) add antioxidant Sodium Thio Sulphate(Anhydrous) (0.01g) in the mixed system of step (4), and stir, make it abundant dissolving;
(6) use the water for injection standardize solution;
(7) carry out coarse filtration, fine straining with the microporous filter membrane of common filter paper and 0.22 μ m, rapidly filling and sealing;
(8) in 100 ℃ of pressure sterilizing 20min, leak detection, lamp inspection, packaging into products.
With reference to " People's Republic of China's veterinary drug allusion quotation " 2005 editions, the projects such as the appearance character of Chinese mugwort ground for animals of the present invention general quinoline-sulfamethoxazole compound injection, insoluble granule, pH value, visible foreign matters, heat source check are detected, the indices such as appearance character, insoluble granule, pH value, visible foreign matters, heat source check all meet the requirements, and the Chinese mugwort general quinoline in ground for animals of the present invention and sulfamethoxazole medicament contg are respectively 100.1% and 100.3% of dosage.
Pu Lin-sulfamethoxazole process for preparation of injection-5, embodiment 5 Chinese mugwort for animals ground
The concrete technology step is as follows:
(1) add a small amount of water for injection 1mL in the Chinese mugwort general quinoline in ground (0.2g), then add lactic acid (300 μ l) salify, be into salt system 1;
(2) by triethanolamine for sulfamethoxazole (1g) (1360 μ l) salify, be into salt system 2;
(3) add propylene glycol (5.5mL) in the one-tenth salt system 2 of step (2), and stir, make it abundant dissolving, put under room temperature standby;
(4) two kinds of blend step (1) and step (3) become salt system, and stir, and make it abundant dissolving, are mixed system;
(5) to step 4) mixed system in add antioxidant Sodium Thio Sulphate(Anhydrous) (0.005g), and stir, make it abundant dissolving;
(6) use the water for injection standardize solution;
(7) carry out coarse filtration, fine straining with the microporous filter membrane of common filter paper and 0.22 μ m, rapidly filling and sealing;
(8) in 100 ℃ of pressure sterilizing 20min, leak detection, lamp inspection, packaging into products.
With reference to " People's Republic of China's veterinary drug allusion quotation " 2005 editions, the projects such as the appearance character of Chinese mugwort ground for animals of the present invention general quinoline-sulfamethoxazole compound injection, insoluble granule, pH value, visible foreign matters, heat source check are detected, the indices such as appearance character, insoluble granule, pH value, visible foreign matters, heat source check all meet the requirements, and the Chinese mugwort general quinoline in ground for animals of the present invention and sulfamethoxazole medicament contg are respectively 99.8% and 99.7% of dosage.
Pu Lin-sulfamethoxazole process for preparation of injection-6, embodiment 6 Chinese mugwort for animals ground
The concrete technology step is as follows:
(1) add a small amount of water for injection 1mL in the Chinese mugwort general quinoline in ground (0.2g), then add lactic acid (305 μ l) salify, be into salt system 1;
(2) by triethanolamine for sulfamethoxazole (1g) (1360 μ l) salify, be into salt system 2;
(3) to step 2) one-tenth salt system 2 in add propylene glycol (4.5mL), and stir, make it abundant dissolving, put under room temperature standby;
(4) two kinds of blend step (1) and step (3) become salt system, and stir, and make it abundant dissolving, are mixed system;
(5) add antioxidant Sodium Thio Sulphate(Anhydrous) (0.0075g) in the mixed system of step (4), and stir, make it abundant dissolving;
(6) use the water for injection standardize solution;
(7) carry out coarse filtration, fine straining with the microporous filter membrane of common filter paper and 0.22 μ m, rapidly filling and sealing;
(8) in 100 ℃ of pressure sterilizing 20min, leak detection, lamp inspection, packaging into products.
With reference to " People's Republic of China's veterinary drug allusion quotation " 2005 editions, the projects such as the appearance character of Chinese mugwort ground for animals of the present invention general quinoline-sulfamethoxazole compound injection, insoluble granule, pH value, visible foreign matters, heat source check are detected, the indices such as appearance character, insoluble granule, pH value, visible foreign matters, heat source check all meet the requirements, and the Chinese mugwort general quinoline in ground for animals of the present invention and sulfamethoxazole medicament contg are respectively 99.6% and 100% of dosage.
Pu Lin-sulfamethoxazole process for preparation of injection-7, embodiment 7 Chinese mugwort for animals ground
The concrete technology step is as follows:
(1) add a small amount of water for injection 1mL in the Chinese mugwort general quinoline in ground (0.2g), then add lactic acid (295 μ l) salify, be into salt system 1;
(2) by triethanolamine for sulfamethoxazole (1g) (1380 μ l) salify, be into salt system 2;
(3) add propylene glycol (4.5mL) in the one-tenth salt system 1 of step (2), and stir, make it abundant dissolving, put under room temperature standby;
(4) two kinds of blend step (1) and step (3) become salt system, and stir, and make it abundant dissolving, are mixed system;
(5) to step 4) mixed system in add the anhydrous thin sodium thiosulfate of antioxidant (0.0075g), and stir, make it abundant dissolving;
(6) use the water for injection standardize solution;
(7) carry out coarse filtration, fine straining with the microporous filter membrane of common filter paper and 0.22 μ m, rapidly filling and sealing;
(8) in 100 ℃ of pressure sterilizing 20min, leak detection, lamp inspection, packaging into products.
With reference to " People's Republic of China's veterinary drug allusion quotation " 2005 editions, the projects such as the appearance character of Chinese mugwort ground for animals of the present invention general quinoline-sulfamethoxazole compound injection, insoluble granule, pH value, visible foreign matters, heat source check are detected, the indices such as appearance character, insoluble granule, pH value, visible foreign matters, heat source check all meet the requirements, and the Chinese mugwort general quinoline in ground for animals of the present invention and sulfamethoxazole medicament contg are respectively 99.8% and 99.7% of dosage.
Pu Lin-sulfamethoxazole process for preparation of injection-8, embodiment 8 Chinese mugwort for animals ground
The concrete technology step is as follows:
(1) add a small amount of water for injection 1mL in the Chinese mugwort general quinoline in ground (0.2g), then add lactic acid (300 μ l) salify, be into salt system 1;
(2) by triethanolamine for sulfamethoxazole (1g) (1380 μ l) salify, be into salt system 2;
(3) add propylene glycol (4.5mL) in the one-tenth salt system 2 of step (2), and stir, make it abundant dissolving, put under room temperature standby;
(4) two kinds of blend step (1) and step (3) become salt system, and stir, and make it abundant dissolving, are mixed system;
(5) add antioxidant Sodium Thio Sulphate(Anhydrous) (0.01g) in the mixed system with step (4), and stir, make it abundant dissolving;
(6) use the water for injection standardize solution;
(7) carry out coarse filtration, fine straining with the microporous filter membrane of common filter paper and 0.22 μ m, rapidly filling and sealing;
(8) in 100 ℃ of pressure sterilizing 20min, leak detection, lamp inspection, packaging into products.
With reference to " People's Republic of China's veterinary drug allusion quotation " 2005 editions, the projects such as the appearance character of Chinese mugwort ground for animals of the present invention general quinoline-sulfamethoxazole compound injection, insoluble granule, pH value, visible foreign matters, heat source check are detected, the indices such as appearance character, insoluble granule, pH value, visible foreign matters, heat source check all meet the requirements, and the Chinese mugwort general quinoline in ground for animals of the present invention and sulfamethoxazole medicament contg are respectively 99.9% and 100.1% of dosage.
Pu Lin-sulfamethoxazole process for preparation of injection-9, embodiment 9 Chinese mugwort for animals ground
The concrete technology step is as follows:
(1) add a small amount of water for injection 1mL to (0.2g) in the general quinoline in Chinese mugwort ground, then add lactic acid (305 μ l) salify, be into salt system 1;
(2) by triethanolamine for sulfamethoxazole (1g) (1380 μ l) salify, be into salt system 2;
(3) add propylene glycol (5mL) in the one-tenth salt system 2 of step (2), and stir, make it abundant dissolving, put under room temperature standby;
(4) two kinds of blend step (1) and step (3) become salt system, and stir, and make it abundant dissolving, are mixed system; (5) add antioxidant Sodium Thio Sulphate(Anhydrous) (0.005g) in the mixed system of step (4), and stir, make it abundant dissolving;
(6) use the water for injection standardize solution;
(7) carry out coarse filtration, fine straining with the microporous filter membrane of common filter paper and 0.22 μ m, rapidly filling and sealing;
(8) in 100 ℃ of pressure sterilizing 20min, leak detection, lamp inspection, packaging into products.
With reference to " People's Republic of China's veterinary drug allusion quotation " 2005 editions, the projects such as the appearance character of Chinese mugwort ground for animals of the present invention general quinoline-sulfamethoxazole compound injection, insoluble granule, pH value, visible foreign matters, heat source check are detected, the indices such as appearance character, insoluble granule, pH value, visible foreign matters, heat source check all meet the requirements, and the Chinese mugwort general quinoline in ground for animals of the present invention and sulfamethoxazole medicament contg are respectively 99.8% and 99.9% of dosage.
Appearance character: observe the outward appearance of compound injection, color and luster, show that this product is colourless or faint yellow clear liquid, and pH value is 7.6 left and right.
Identify:
(1) chemical method.Sulfamethoxazole: get the about 0.1g of this product, add water and each 3mL of 0.4% sodium hydroxide solution, jolting makes to dissolve, and filters, and gets filtrate, adds 1 of copper sulfate test solution, generates the grass green precipitation.The general woods in Chinese mugwort ground: get the about 20mg of this product, after adding dilute sulfuric acid 2mL dissolving, add 2 of iodine test solutions, generate brown precipitation.
(2) UV detects.Sulfamethoxazole: sample dissolution, in methanol, is usingd to methanol as reference solution, measure on the Agilent8453 ultraviolet spectrophotometer, absorption maximum (seeing Fig. 1) is arranged at the 270nm place.The general woods in Chinese mugwort ground: sample dissolution, in methanol, is usingd to methanol as reference solution, measure on the Agilent8453 ultraviolet spectrophotometer, absorption maximum (seeing Fig. 2) is arranged at the 284nm place.
(3) chromatography.Sulfamethoxazole: according to detection method of content, carry out the HPLC detection, prepare the reference substance solution of same concentrations simultaneously and carry out the HPLC detection, record both chromatograms, find that in animal compound injection of the present invention, SMZ is consistent with the retention time of reference substance solution.The general woods in Chinese mugwort ground: carry out the HPLC detection according to detection method of content, prepare the reference substance solution of same concentrations simultaneously and carry out the HPLC detection, record both chromatograms, in animal compound injection of the present invention, SMZ is consistent with the retention time of reference substance solution.
Visible foreign matters: get 20 of test samples, clean container outer wall, rotation and inverting container suspend the visible foreign matters existed in medicinal liquid gently, put test sample in dark slide edge, in the distance of distinct vision, respectively under black and half color background, look with visual inspection, all be no less than for 5 seconds, do not find visible foreign matters.
Particulate matter: get test sample, water is cleaned container outer wall, on laminar flow station, careful upset is 20 times, make mix homogeneously, careful openable container immediately, directly extract the complete soln in each container by suitable method, slowly inject pretreated filter (filter membrane diameter 13mm) along the filter inwall, standing 1 minute, slowly sucking filtration is closely dry to filter membrane, use again the microparticles water appropriate, along the filter inwall, slowly inject, washing sucking filtration are closely dry to filter membrane, then with blunt-ended forceps by filter membrane dislocation plate (in case of necessity, the glycerol that can smear thin layer makes the filter membrane smooth), after micro-opening makes the suitable drying of filter membrane, by the plate closure, put on microscope carrier.Mix up incident illumination, amplify 100 times and carry out micrometering, regulate microscope clear to the filter membrane grid, the moving coordinate axle, measure respectively and effectively filter the particle number that the longest particle diameter on area is greater than 10 μ m and 25 μ m.Examine under a microscope, preparation meets the requirement that particulate matter checks, in each test sample container, containing 10 μ m, above microgranule is no more than 3000, and the microgranule above containing 25 μ m is no more than 300.
Sterility Test: animal compound injection of the present invention is carried out to sterility test by " Pharmacopoeia of People's Republic of China was second one in 2005 " appendix XI H.Sterility test should or carry out in shielding system in the way flow air section of 100 grades of 10000 grades of environment cleanliness and local cleanliness factors, and its overall process must strictly observe sterile working, prevents microbial contamination.Adopt direct inoculation, get THIOGLYCOLLIC ACID salt fluid culture medium 8 pipes of suitable loading amount, add respectively each two pipe of bacterium liquid of staphylococcus aureus, bacillus subtilis, Pseudomonas aeruginosa, clostridium sporogenes; Get improvement Martin culture medium 4 pipes of suitable loading amount, add respectively Candida albicans, each two pipe of Aspergillus niger bacterium liquid.Every pipe adds the bacterium amount and is less than 100cfu.Wherein 1 pipe accesses the test sample of ormal weight, and another 1 pipe is as positive control, and each developmental tube, by the temperature of respective specified, is cultivated 3～5 days.
Pyrogen test: animal compound injection of the present invention is carried out to pyrogen test by " Pharmacopoeia of People's Republic of China was second one in 2005 " appendix XIIIA.Each test sample is used 3 of rabbit, administration in 15 minutes after measuring normal body temperature, slowly inject prescribed dose and be warmed to the approximately need testing solution of 38 ℃ from ear vein, then measured its body temperature 1 time every 30 minutes by front method, survey altogether 6 times, with the highest normal body temperature that once deducts in 6 body temperature, be this rabbit body temperature the rising temperature (℃).As 1 fervescence arranged more than 0.6 ℃ or 0.6 ℃ in 3 rabbit, or 3 rabbit body temperatures raise all lower than 0.6 ℃, but the summation of fervescence reaches more than 1.4 ℃ or 1.4 ℃, should separately get 5 rabbit retrials, and inspection method is the same.The results are shown in Table 1 in 3 rabbit of preliminary examination, fervescence is all lower than 0.6 ℃, and 3 rabbit body temperature rising summations are 0.81 ℃, lower than 1.4 ℃; In 5 rabbit of retrial, fervescence, all lower than 0.6 ℃, calculates by pharmacopeia, and the intensification summation of 8 animal subjects is 1.28 ℃, and lower than 3.5 ℃, the pyrogen test that is judged to test sample is up to specification.
Table 1 thermal source experimental result
Content uniformity: get 5 of test samples, note avoiding loss during unlatching, content is taken out to the greatest extent with the dry injection device of respective volume and injection needle respectively, then inject in the measurer of markization (size of measurer should make volume to be measured at least account for its nominal volume 40%), at room temperature inspect.Accurately read the loading amount of content in each graduated cylinder, and average, average loading amount must not be less than 95% of sign loading amount, and each graduated cylinder loading amount must not be less than 93% of sign loading amount.The loading amount of three batches of injection is (as table 2) between 96.4%～98.0%, and average is between 96.7%～97.3%, all higher than the minimum fill 93% of injection defined.
Related substance: the accurate Chinese mugwort ground general quinoline-sulfamethoxazole compound injection for animals of the present invention (approximately being equivalent to SMZ50mg) of drawing is placed in the 100mL volumetric flask, add methanol appropriate, sonic oscillation 5min, after making fully to dissolve, add methanol to scale, shake up, filter, the accurate 5mL that draws, be placed in the 50mL volumetric flask, add mobile phase and be diluted to scale, shake up, as need testing solution; With 100 times of mobile phase dilution need testing solutions, with solution in contrast, HPLC detects.Measure respectively need testing solution and contrast solution, record to the main constituent retention time 5 times of chromatogram, each impurity peak area summation in the need testing solution chromatogram and contrast solution main peak area are compared.
The minimum fill of table 2 injection
In the three batches of injection, the related substance of ADP is respectively 1.41%, 1.39% and 1.43%, and total impurities is no more than 1.5%.In the three batches of injection, the related substance of SMZ is respectively 1.21%, 1.38% and 1.27%, and total impurities is no more than 1.5%, the results are shown in Table 3 and 4.
The related substance inspection of the general quinoline in Chinese mugwort ground in table 3 Chinese mugwort for animals of the present invention ground general quinoline-sulfamethoxazole compound preparation
Assay: the accurate Chinese mugwort ground general quinoline-sulfamethoxazole compound injection for animals of the present invention (approximately being equivalent to SMZ50mg) of drawing is placed in the 100mL volumetric flask, add methanol appropriate, sonic oscillation 5min, after making fully to dissolve, add methanol to scale, shake up, filter, the accurate 5mL that draws, be placed in the 50mL volumetric flask, add mobile phase and be diluted to scale, shake up, as need testing solution.Two kinds of medicines all calculate content by following formula:
C
Mixed=C
RightA
Sample/ A
Right
C
Mixed: the content of compound preparation Chinese medicine; C
Right: the content of reference substance; A
Sample: the sample peak area; A
Right: the reference substance peak area.
In table 4 Chinese mugwort for animals of the present invention ground general quinoline-sulfamethoxazole compound injection, the related substance of sulfamethoxazole detects
In the three batches of compound recipe injections, the relative amount of ADP is respectively 96.8%, 97.3% and 98.4%, between 90～110%; The relative amount of SMZ is respectively 98.5%, 99.3% and 101.4%, between 90～110% (tables 5).
The assay of table 5 Chinese mugwort for animals of the present invention ground general quinoline-sulfamethoxazole compound injection
Embodiment 11 Application Examples (stability study of Chinese mugwort ground general quinoline-sulfamethoxazole compound injection)
Influence factor's test: (1) hot test: get with batch compound recipe ADP-SMZ injection, put in the sealing clean container, place 10 days under 60 ℃ of conditions, in the 5th day and sampling in the 10th day, detect related index.As test sample generation significant change (as formulation content descends 5%), under 40 ℃, with method, tested.Without significant change, needn't carry out 40 ℃ of tests as 60 ℃.(2) strong illumination test: get with batch compound recipe ADP-SMZ injection, put in the sealing clean container, under the condition of illumination (4500 ± 500lx), place 10d.Respectively at 0,5, the 10d sampling, by stability high spot reviews project, the projects such as compound recipe ADP-SMZ injection content, character, pH value are detected and record.Result shows, the variation (in Table 6) of the emphasis test items such as the color of preparation, character, pH value, content, find out that thus the general quinoline sulfamethoxazole compound injection in Chinese mugwort for animals ground of the present invention is unstable under high temperature and high light condition, be not suitable for preserving under high temperature and high light condition.
Table 6ADP-SMZ compound preparation influence factor experiment
* related substance calculates by area normalization method
Accelerate experiment: get compound recipe ADP-SMZ injection prepared by 3 crowdes of the present invention appropriate, simulation listing packing is placed 6 months under the condition of 30 ℃ ± 2 ℃ of temperature, relative humidity 60% ± 5%.Respectively at sampling at 0,1,2,3,6 the end of month, by stability high spot reviews project, the projects such as compound recipe ADP-SMZ injection content, character, pH value are detected and record.The indices such as injection liquid samples color, character, pH value, content have no significant change, and show that this preparation is to temperature, moisture stable (in Table 7).
Table 7 Chinese mugwort for animals of the present invention ground general quinoline-sulfamethoxazole injection accelerated test result
The explanation of table 7: the * related substance calculates by area normalization method.
Long-term stable experiment: get compound recipe ADP-SMZ injection prepared by 3 crowdes of the present invention appropriate, simulation listing packing is placed 12 months under the condition of 25 ± 2 ℃ of temperature, relative humidity 60 ± 5%.Respectively at sampling at 0,3,6,9,12 the end of month, by stability high spot reviews project, the projects such as compound recipe ADP-SMZ injection content, character, pH value are detected and record.After 12 months, still need to continue to investigate, detected with sampling at 18,24,36 the end of month respectively, the effect duration (in Table 8) to determine medicine by result and comparison in 0 month.
Table 8 Chinese mugwort for animals of the present invention ground general quinoline-sulfamethoxazole compound injection long-term test results
* related substance calculates by area normalization method.
The calculating of effect duration: the numerical value of measuring by long term test, with labelled amount %, the time is done to rectilinear regression, obtain regression equation.Obtain the value of calculation of each time point labelled amount, calculate the confidence interval of labelled amount 95% one-sided fiducial limit, obtain respectively the value of calculation (y ') of each time point labelled amount by regression equation, then the confidence interval of calculating labelled amount (y ') 95% one-sided fiducial limit, y ' ± z
In formula, tn-2 is that probability is 0.05, and the one-sided Distribution Value of the t that degree of freedom is n-2 can be found from statistics, and n is the group number.X
0For given independent variable,
Meansigma methods for independent variable X.
Q=Lyy-bLxy; B is straight slope; The sum of deviation square that Lyy is y; The deviation sum of products that Lxy is xy.
Lyy＝∑y
2-(∑y)
2/N，Lxy＝∑xy-∑x∑y/N
Calculate y '-z value, y '-z value is carried out to rectilinear regression with the time, obtain lower limit of confidence interval value regression equation, get y '-z=90 (being the qualified minimum requirements of general content), calculate the effect duration of medicine.This long-term stable experiment has only detected 9 months, and the regulation according to the Ministry of Agriculture of middle colored people's republic to the preparation stability test requirements document, show that the regression equation of ADP and SMZ in three batch samples is in Table 9 as calculated at the effect duration of calculating the ADP-SMZ compound injection.
The lower limit regression equation of the Chinese mugwort general quinoline in ground and sulfamethoxazole in preparation prepared by three crowdes of the present invention of table 9
Embodiment 12 Application Examples (the bioavailability test of Chinese mugwort ground general quinoline-sulfamethoxazole compound injection in the pig body)
Select 18 healthy DLY three way crosses (Du Luoke * length is white * Yorkshire, be the commercial breed that promote in the whole nation) market pig (20 ± 5kg), before administration, 1d weighs.18 pigs are divided into to A, B, C3 group at random, 6 every group, by 3 intersection 3 cycle designs, are tested (in Table 10).
Trial design in the experiment of table 10 bioavailability
Administered intramuscular.Gather vena cava anterior blood 3～5mL after administration, after extraction and cleaning, the content of the Chinese mugwort general quinoline in ground and sulfamethoxazole in Plasma By Hplc.The detection method of ADP and SMZ has been set up in this test.Endogenous material in blood plasma is all noiseless to ADP and SMZ, and impurity separates well with the medicine peak, and chromatogram is shown in Fig. 3,4,5,6,7.
After administration, the average blood drug level of each sampled point Chinese mugwort general quinoline in ground and sulfamethoxazole is in Table 11; With the non-compartment model of pharmacokinetics software Winnorlin, data are carried out to matching, pharmacokinetic parameters is in Table 12; In the general quinoline aqueous solution in Chinese mugwort ground, sulfamethoxazole aqueous solution and compound preparation, the Chinese mugwort general quinoline in ground and the average time front of blood concentration of sulfamethoxazole in 18 pigs are shown in Fig. 7.
The average blood drug level (Mean ± S.D., μ g/mL) of each sampled point after table 1118 a pig intramuscular injection Chinese mugwort general quinoline in ground and sulfamethoxazole aqueous solution and Chinese mugwort ground general quinoline-sulfamethoxazole compound injection
Table 11 explanation: ND: lower than quantitative limit or do not detect
-: undetermined or not sampling
The non-compartment model matching of table 12Winnorlin pharmacokinetic parameters
Annotate: λ z in table: end elimination rate constant; T
1/2 λ z: eliminate the half-life; T
max: the time that reaches peak concentration; C
max: peak concentration; AUC
all: area under the drug-time curve; Vz: apparent volume of distribution; CLz: elimination rate constant; MRT: mean residence time.
After compound preparation prepared by 18 pig muscle injection the present invention, the Tmax of ADP and T
1/2 λBe respectively 1.06 ± 0.16h, 12.96 ± 1.10h, shorter than aqueous solution; Cmax is 1.79 ± 0.10 μ g/mL, lower than aqueous solution.The Tmax of SMZ is 1.94 ± 0.17h, shorter than aqueous solution; T
1/2 λBe 4.84 ± 0.93h, than the length of aqueous solution, Cmax is 15.47 ± 0.81 μ g/mL, lower than aqueous solution.With aqueous solution, compare, the medicine peak time of compound preparation is short, absorbs faster; Apparent volume of distribution increases, and peak concentration reduces, and eliminates speed and accelerates, but all not obvious, this shows, after ADP and SMZ share, the absorption and distribution of ADP and SMZ is not had to too much influence.
Embodiment 13 Application Examples (the elimination regularity experiment of Chinese mugwort ground general quinoline-sulfamethoxazole compound injection in the pig body)
After 20 the conventional raising of health pig 7d, Chinese mugwort ground general quinoline-sulfamethoxazole compound injection prepared by intramuscular injection the present invention (the general quinoline 5mg/kg in Chinese mugwort ground, sulfamethoxazole 25mg/kg), inject 1 time, and the labelling injection site.After administration 1,3,6,15,30d butchers respectively, butchers at random 4 at every turn, separates longissimus dorsi muscle, liver, kidney, injection site muscle and stomach fat.Sample after extraction and cleaning, the content of the general quinoline in Chinese mugwort ground and sulfamethoxazole in each tissue of high effective liquid chromatography for measuring.The Chinese mugwort general quinoline in ground of formulating according to European drug administration (EMEA) and the sulfamethoxazole MRL (MRL) in each tissue of pig, the method that adopts EMEA to recommend, used WT1.4 software to calculate this two kinds of medicine off-drug periods in each tissue with bilateral 95% confidence limit.
After 20 pig single intramuscular injection compound preparations, ADP and the SMZ mean concentration in each sampling time point and various tissue is in Table 13.After drug withdrawal in various tissues elimination equation, half-life and the off-drug period of total residual in Table 14.
Compound preparation prepared by the table 13 the present invention residual quantity in the pig edible tissue
ND: do not detect.
ADP is residual mainly to be concentrated in liver and kidney, and in four kinds of edible tissues, liver Chinese medicine concentration is higher than concentration in its hetero-organization, after administration 30 days, in five kinds of tissues, all can't detect.Suppose that ADP is respectively 50 μ g/kg at the MRL of pig liver, kidney, muscle, sebum, calculates the t of ADP in muscle, liver, kidney, fat and injection site by the WDT formula
1/2Be respectively 83.5,86.6,81.5,84.5 and 67.3h, ADP eliminates the slowest in liver, in kidney, eliminates the fastest; Be respectively 21,24,24,18 and 23d in the off-drug period of muscle, liver, kidney, fat and injection site.
Compound preparation prepared by table 14 the present invention is residual eliminating equation, half-life and off-drug period in each tissue of pig
SMZ is residual mainly to be concentrated in liver and kidney, and in four kinds of edible tissues, liver Chinese medicine concentration is higher than concentration in its hetero-organization, is secondly kidney, after administration 30 days, only in injection site, drug level detected.SMZ is respectively 100 μ g/kg at the MRL of pig liver, kidney, muscle, sebum, by the WDT formula, calculates the t of SMZ in muscle, liver, kidney, fat and injection site
1/2Be respectively 48.1,47.5,60.5,73.7 and 75.3h, except injection site, SMZ eliminates the slowest in fat, in muscle, eliminates the fastest; Be respectively 16,15,18,20 and 31d in the off-drug period of muscle, liver, kidney, fat and injection site.
Claims (6)
1. the preparation method of Chinese mugwort ground for animals general quinoline-sulfamethoxazole compound injection, it is characterized in that, the general quinoline in ground that first will end is made into respectively salt system with sulfamethoxazole, again adjuvant and injection solvent are added wherein, lasting stirring obtains Chinese mugwort for animals ground general quinoline-sulfamethoxazole compound injection, and its preparation process comprises:
(1) add a small amount of water for injection in the general quinoline in Chinese mugwort ground, then add the lactic acid salify, obtain into salt system 1;
(2) sulfamethoxazole is used to the triethanolamine salify, obtained into salt system 2;
(3) add cosolvent in the one-tenth salt system 2 of step (2), and stir, make it abundant dissolving, put under room temperature standby;
(4) salt system that becomes of blend step (1) and step (3), and stir, make it abundant dissolving, obtain mixed system;
(5) add antioxidant in the mixed system of step (4), and stir, make it abundant dissolving;
(6) use the water for injection standardize solution;
(7) carry out coarse filtration, fine straining with the microporous filter membrane of common filter paper and 0.22 μ m, rapidly filling and sealing;
(8) in 100 ℃ of pressure sterilizing 20min, leak detection, lamp inspection, packing gets product;
Wherein, the formula of described Chinese mugwort for animals ground general quinoline-sulfamethoxazole compound injection comprises: the Chinese mugwort general quinoline in ground and sulfamethoxazole crude drug, and its weight/volume percent concentration in preparation is respectively 2% and 10%; Described cosolvent is propylene glycol, and its weight/volume percent concentration in preparation is 50%; Described solvent is water for injection; Described antioxidant is Sodium Thio Sulphate(Anhydrous), and its weight/volume percent concentration in preparation is 0.15%.
2. Chinese mugwort for animals ground general quinoline-sulfamethoxazole compound injection, is characterized in that, the component of pressing formula ratio is as follows:
(1) the general quinoline crude drug in Chinese mugwort ground, account for weight/volume percent concentration 2% in preparation;
(2) sulfamethoxazole crude drug, account for weight/volume percent concentration 10% in preparation;
(3) water for injection
(4) cosolvent is propylene glycol, and by weight/concentration of volume percent is 50%
(5) antioxidant is anhydrous thin sodium thiosulfate, and by weight/concentration of volume percent is 0.15%;
It prepares according to following step:
(1) add a small amount of water for injection in the general quinoline in Chinese mugwort ground, then add the lactic acid salify, obtain into salt system 1;
(2) sulfamethoxazole is used to the triethanolamine salify, obtained into salt system 2;
(3) add cosolvent in the one-tenth salt system 2 of step (2), and stir, make it abundant dissolving, put under room temperature standby;
(4) salt system that becomes of blend step (1) and step (3), and stir, make it abundant dissolving, obtain mixed system;
(5) add antioxidant in the mixed system of step (4), and stir, make it abundant dissolving;
(6) use the water for injection standardize solution;
(7) carry out coarse filtration, fine straining with the microporous filter membrane of common filter paper and 0.22 μ m, rapidly filling and sealing;
(8) in 100 ℃ of pressure sterilizing 20min, leak detection, lamp inspection, packing gets product.
3. Chinese mugwort for animals claimed in claim 2 ground general quinoline-sulfamethoxazole compound injection, is characterized in that, its active constituent content is 96%～101%, and total impurities is no more than 1.5%.
4. the application of Chinese mugwort for animals ground general quinoline-sulfamethoxazole compound injection claimed in claim 2 in livestock and birds respiratory disease infects.
5. by the described application of claim 4, it is characterized in that, described application process is: intramuscular injection, once measure the per kilogram of body weight Chinese mugwort general quinoline 5mg in ground, sulfamethoxazole 25mg.
6. by application claimed in claim 4, it is characterized in that, the Chinese mugwort ground general quinoline-off-drug period of sulfamethoxazole compound injection in the pig body for animals is 24d.
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| CN111189938A (en) * | 2020-01-10 | 2020-05-22 | 华中农业大学 | Quantitative detection method for adefovir dipivoxil and sulfamethoxazole in pig plasma and alveolar fluid |
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| CN1879633A (en) * | 2006-05-18 | 2006-12-20 | 天津生机集团有限公司 | Compound sulfamethoxazole injection for animal, its preparation method and use |
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| CN1879633A (en) * | 2006-05-18 | 2006-12-20 | 天津生机集团有限公司 | Compound sulfamethoxazole injection for animal, its preparation method and use |
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| J.-L.RIOND, ET AL.: "THE INFLUENCE OF AGE ON THE PHARMACOKINETICS OF ADITOPRIM IN PIGS AFTER INTRAVENOUS AND ORAL ADMINISTRATION", 《VETERINARY RESEARCH COMMUNICATIONS》 * |
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| CN107468645A (en) * | 2017-07-18 | 2017-12-15 | 华中农业大学 | The general woods parenteral solution and preparation method thereof for animals that ends |
| CN111189938A (en) * | 2020-01-10 | 2020-05-22 | 华中农业大学 | Quantitative detection method for adefovir dipivoxil and sulfamethoxazole in pig plasma and alveolar fluid |
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