CN104800229A - Compound sulfadiazine suspension and preparation method thereof - Google Patents
Compound sulfadiazine suspension and preparation method thereof Download PDFInfo
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- SEEPANYCNGTZFQ-UHFFFAOYSA-N sulfadiazine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)NC1=NC=CC=N1 SEEPANYCNGTZFQ-UHFFFAOYSA-N 0.000 title claims abstract description 71
- 229960004306 sulfadiazine Drugs 0.000 title claims abstract description 71
- 150000001875 compounds Chemical class 0.000 title claims abstract description 49
- 239000000725 suspension Substances 0.000 title claims abstract description 48
- 238000002360 preparation method Methods 0.000 title abstract description 20
- 239000000243 solution Substances 0.000 claims abstract description 64
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 57
- IEDVJHCEMCRBQM-UHFFFAOYSA-N trimethoprim Chemical compound COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 IEDVJHCEMCRBQM-UHFFFAOYSA-N 0.000 claims abstract description 26
- 229960001082 trimethoprim Drugs 0.000 claims abstract description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 23
- 239000004094 surface-active agent Substances 0.000 claims abstract description 21
- 239000008215 water for injection Substances 0.000 claims abstract description 18
- 229940006997 sulfadiazine and trimethoprim Drugs 0.000 claims abstract description 9
- 239000000706 filtrate Substances 0.000 claims abstract description 6
- 239000000203 mixture Substances 0.000 claims abstract description 6
- 239000000375 suspending agent Substances 0.000 claims description 80
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 57
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 48
- 238000003756 stirring Methods 0.000 claims description 40
- 238000010438 heat treatment Methods 0.000 claims description 25
- 239000011780 sodium chloride Substances 0.000 claims description 24
- 239000000230 xanthan gum Substances 0.000 claims description 24
- 235000010493 xanthan gum Nutrition 0.000 claims description 24
- 229920001285 xanthan gum Polymers 0.000 claims description 24
- 229940082509 xanthan gum Drugs 0.000 claims description 24
- 239000003963 antioxidant agent Substances 0.000 claims description 23
- 230000003078 antioxidant effect Effects 0.000 claims description 23
- 235000006708 antioxidants Nutrition 0.000 claims description 23
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 20
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 20
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 20
- 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 claims description 17
- 239000000600 sorbitol Substances 0.000 claims description 17
- 239000000126 substance Substances 0.000 claims description 17
- 102000019197 Superoxide Dismutase Human genes 0.000 claims description 14
- 108010012715 Superoxide dismutase Proteins 0.000 claims description 14
- 125000000467 secondary amino group Chemical class [H]N([*:1])[*:2] 0.000 claims description 14
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- 239000002245 particle Substances 0.000 claims description 10
- 230000001954 sterilising effect Effects 0.000 claims description 10
- 239000002994 raw material Substances 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 8
- 238000002156 mixing Methods 0.000 claims description 8
- 229920000136 polysorbate Polymers 0.000 claims description 8
- 239000007864 aqueous solution Substances 0.000 claims description 5
- 229960005070 ascorbic acid Drugs 0.000 claims description 5
- 235000010323 ascorbic acid Nutrition 0.000 claims description 5
- 239000011668 ascorbic acid Substances 0.000 claims description 5
- 239000000084 colloidal system Substances 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- 238000000227 grinding Methods 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 238000010008 shearing Methods 0.000 claims description 5
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 4
- 229920000053 polysorbate 80 Polymers 0.000 claims description 4
- NSENZNPLAVRFMJ-UHFFFAOYSA-N 2,3-dibutylphenol Chemical compound CCCCC1=CC=CC(O)=C1CCCC NSENZNPLAVRFMJ-UHFFFAOYSA-N 0.000 claims description 3
- AMOLXWJBJVZBAY-AXGXYNJNSA-N CC1C2CC([C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@]2(CCC1)C)C)[C@H](C)CCCC(C)C)O Chemical compound CC1C2CC([C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@]2(CCC1)C)C)[C@H](C)CCCC(C)C)O AMOLXWJBJVZBAY-AXGXYNJNSA-N 0.000 claims description 3
- 229920001213 Polysorbate 20 Polymers 0.000 claims description 3
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 claims description 3
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims 2
- IMOYOUMVYICGCA-UHFFFAOYSA-N 2-tert-butyl-4-hydroxyanisole Chemical compound COC1=CC=C(O)C=C1C(C)(C)C IMOYOUMVYICGCA-UHFFFAOYSA-N 0.000 claims 1
- 230000021736 acetylation Effects 0.000 abstract description 2
- 238000006640 acetylation reaction Methods 0.000 abstract description 2
- 230000003247 decreasing effect Effects 0.000 abstract description 2
- 210000002700 urine Anatomy 0.000 abstract description 2
- 239000013078 crystal Substances 0.000 abstract 1
- 229940083608 sodium hydroxide Drugs 0.000 abstract 1
- 239000003814 drug Substances 0.000 description 33
- 229940079593 drug Drugs 0.000 description 24
- 244000144972 livestock Species 0.000 description 17
- 238000004062 sedimentation Methods 0.000 description 10
- 241000588650 Neisseria meningitidis Species 0.000 description 8
- 241001138501 Salmonella enterica Species 0.000 description 7
- 238000010521 absorption reaction Methods 0.000 description 7
- 230000000844 anti-bacterial effect Effects 0.000 description 7
- 230000000052 comparative effect Effects 0.000 description 7
- 238000004090 dissolution Methods 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 230000007794 irritation Effects 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 230000002195 synergetic effect Effects 0.000 description 4
- 241000282887 Suidae Species 0.000 description 3
- 238000013270 controlled release Methods 0.000 description 3
- 230000002045 lasting effect Effects 0.000 description 3
- 238000005185 salting out Methods 0.000 description 3
- 241000606768 Haemophilus influenzae Species 0.000 description 2
- 241000193998 Streptococcus pneumoniae Species 0.000 description 2
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 229940047650 haemophilus influenzae Drugs 0.000 description 2
- 229940100692 oral suspension Drugs 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 2
- 229940124530 sulfonamide Drugs 0.000 description 2
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 208000003495 Coccidiosis Diseases 0.000 description 1
- 206010011509 Crystalluria Diseases 0.000 description 1
- 241000588921 Enterobacteriaceae Species 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
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- 241000588724 Escherichia coli Species 0.000 description 1
- 206010023076 Isosporiasis Diseases 0.000 description 1
- 241000588748 Klebsiella Species 0.000 description 1
- 201000009906 Meningitis Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000588771 Morganella <proteobacterium> Species 0.000 description 1
- 241000588652 Neisseria gonorrhoeae Species 0.000 description 1
- 206010033078 Otitis media Diseases 0.000 description 1
- 241000588769 Proteus <enterobacteria> Species 0.000 description 1
- 241000607142 Salmonella Species 0.000 description 1
- 241000607768 Shigella Species 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 241000194017 Streptococcus Species 0.000 description 1
- 241000193996 Streptococcus pyogenes Species 0.000 description 1
- 201000005485 Toxoplasmosis Diseases 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 230000000816 effect on animals Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
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- 150000003456 sulfonamides Chemical class 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a compound sulfadiazine suspension. The compound sulfadiazine suspension comprises sulfadiazine, trimethoprim, sodium hydroxide, a suspending aid A, a suspending aid B, a surfactant and water for injection. The preparation method comprises steps as follows: sulfadiazine and trimethoprim are ground to 400-700 nm; trimethoprim is added to the suspending aid A; the mixture is dissolved, and a first dissolved solution is obtained; the water for injection is taken and heated to 45 DEG C, sulfadiazine and the suspending aid B are added, and a second dissolved solution is obtained; the rest water for injection is taken and heated to 30 DEG C-50 DEG C, sodium hydroxide is added and dissolved, the first dissolved solution is heated to 60 DEG C-65 DEG C, the second dissolved solution is heated to 40 DEG C-50 DEG C, then the first dissolved solution and the second dissolved solution are mixed, a third dissolved solution and the surfactant are added to a batching container and uniformly stirred, and a fourth dissolved solution is obtained; the prepared fourth dissolved solution is added to a high-speed homogenizer and sheared for 10-20 minutes, and filtrate is sterilized for 30 minutes at the temperature of 100-300 DEG C and under the pressure of 0.1-0.2 Mpa. The absorptivity is improved, the acetylation rate is decreased, and few crystals are formed in urine.
Description
Technical Field
The invention relates to a sulfadiazine suspension preparation. More specifically, the invention relates to a compound sulfadiazine suspension prepared by using a suspending agent.
Background
Sulfadiazine belongs to middle-effect sulfonamides. Molecular formula C10H10N4O2S, molecular weight 250.28, chemical name: n-2-pyrimidinyl-4-aminobenzenesulfonamide.
The compound sulfadiazine is a compound preparation of sulfadiazine and trimethoprim, has synergistic antibacterial action when the sulfadiazine and trimethoprim are used together, and has good antibacterial activity on non-enzyme-producing staphylococcus aureus, streptococcus pyogenes, streptococcus pneumoniae, escherichia coli, klebsiella, salmonella, proteus, morganella, shigella and other enterobacteriaceae bacteria, neisseria gonorrhoeae, neisseria meningitidis and haemophilus influenzae. Can enter cerebrospinal fluid through blood brain barrier, and is the first choice medicine for treating meningitis of animals. Has good prevention and treatment effect on livestock and poultry bacterial infection, and has remarkable prevention and treatment effect on animal coccidiosis, toxoplasmosis and the like. In addition, the medicine can treat sensitive infections of otitis media, skin soft tissue and the like caused by haemophilus influenzae, streptococcus pneumoniae and other streptococcus.
The traditional compound sulfadiazine suspension has low absorption rate and high acetylation rate, the dissolution rate in urine is low, crystalluria is easy to occur, and generally, the medicine is injected into two preparations in one day, the injection amount is large, and the stimulation to the bodies of livestock is large.
Disclosure of Invention
An object of the present invention is to solve at least the above problems and/or disadvantages and to provide at least the advantages described hereinafter.
In view of the above problems, it is still another object of the present invention to provide a compound sulfadiazine suspension with good tissue compatibility.
The invention also aims to provide a preparation method of the compound sulfadiazine suspension, which adopts different temperatures to dissolve sulfadiazine and trimethoprim in different suspending agents respectively and then adopts a high-speed homogenizer to dissolve the two agents, thus improving the absorption rate of livestock to the agents and reducing the irritation of the agents to the livestock.
To achieve these objects and other advantages in accordance with the present invention, there is provided a compound sulfadiazine suspension comprising the following raw materials in parts by weight: 5-30 parts of sulfadiazine, 1-6 parts of trimethoprim, 0.3-1.5 parts of sodium hydroxide, 0.06-0.1 part of a suspending agent A, 0.005-0.03 part of a suspending agent B, 0.005-0.03 part of a surfactant and 300 parts of water for injection. Wherein,
the suspending agent A comprises xanthan gum, sorbitol with the concentration of 800-1500ppm, sodium chloride and propylene glycol which are mixed according to the mass ratio of 80-150:2-4:0.03-0.15: 50-60;
the suspending agent B is polyvinylpyrrolidone with a K value of 60-80, superoxide dismutase with a concentration of 0.2-0.8ppm, an antioxidant and secondary amine according to a mass ratio of 80-100:1-3:1-4: 4-8.
Preferably, wherein the average particle size of the sulfadiazine is 400-700 nm.
Preferably, the surfactant is any one or more of tween-80, tween-20, tween 21, tween 40 and tween 61.
Preferably, the antioxidant is any one or more of 4-methyl-7-cholestanol, ascorbic acid, tert-butyl p-hydroxyanisole and dibutyl phenol.
The object of the invention can be further realized by a preparation method of the compound sulfadiazine suspension, which comprises the following steps of adding the following raw materials in parts by weight:
the method comprises the following steps: grinding sulfadiazine and trimethoprim respectively by a colloid mill until the particle size is 400-700 nm;
step two: adding the trimethoprim treated in the step one into the suspending agent A, and stirring to fully dissolve the trimethoprim to obtain a first dissolving solution;
step three: taking 30% of the water for injection in parts by weight, heating to 45 ℃, adding the sulfadiazine treated in the step one, stirring and dissolving, adding the suspending agent B, and stirring and dissolving to obtain a second solution;
step four: heating the rest water for injection to 30-35 deg.C, adding sodium hydroxide, and stirring to dissolve completely to obtain a third solution;
step five: sequentially heating the first solution to 60-65 ℃, placing the first solution in a batching container, heating the second solution to 40-50 ℃, adding the second solution into the batching container, adding the third solution and a surfactant into the batching container, and uniformly stirring to obtain a fourth solution;
step six: and (4) adding the fourth dissolved solution prepared in the fifth step into a high-speed homogenizer, mechanically shearing for 10-20 minutes, and then sterilizing the completely sheared filtrate at the temperature of 100 ℃ and 130 ℃ and under the pressure of 0.1-0.2Mpa for 30 minutes to obtain the compound sulfadiazine suspension.
Preferably, the preparation method of the suspending agent A comprises the following steps:
step a: adding xanthan gum with the mass ratio into an aqueous solution of sorbitol with the concentration of 800-1500ppm, stirring for 10-30min at the temperature of 30-35 ℃, and adding sodium hydroxide to adjust the pH value to 8.5-9;
step b: adding sodium chloride in the mass ratio into the solution obtained in the step a, stirring until the sodium chloride is completely dissolved, adding propylene glycol in the mass ratio, and stirring at 20-30 ℃ until filiform substances are completely separated out;
step c: drying the filiform substance at 50-70 deg.C until the water content is 70% -90%, to obtain the suspending agent A.
Preferably, the preparation method of the suspending agent B comprises the following steps:
step 1: sterilizing the polyvinylpyrrolidone at low temperature for 2-3 hours, adding the antioxidant and secondary amine into the sterilized polyvinylpyrrolidone under the protection of nitrogen, and uniformly mixing;
step 2: heating the mixture in the step 1 to 50-70 ℃, and reacting for 4-6 hours;
and step 3: and (3) adding the superoxide dismutase into the substance which is reacted in the step (2), thus obtaining the suspending agent B.
The invention has the following beneficial effects:
(1) when the compound sulfadiazine suspension is prepared, the compound sulfadiazine suspension generally comprises a main drug, a surfactant, a suspending agent and an antioxidant, the formula of the suspending agent is improved, the compound sulfadiazine suspension of the main drug is respectively dissolved in the suspending agent A and the suspending agent B, the main drug is specifically dissolved, and the dissolution rate of the main drug is improved;
(2) the suspending agent A is prepared from xanthan gum, sorbitol with the concentration of 800-;
(3) the suspending agent B is dissolved by polyvinylpyrrolidone with K value of 60-80, superoxide dismutase with concentration of 0.2-0.8ppm, antioxidant and secondary amine, so that when the trimethoprim is dissolved in the suspending agent B, the content of insoluble substances is low, and the thermal stability is high; the thermal stability and the stability in an oxygen-containing medium are both obviously improved, and the absorption rate of the compound sulfadiazine suspension in the livestock body is favorably improved;
(4) the medicament has targeting property and slow release property, high and durable medicament utilization rate, and can quickly lock the diseases caused by sensitive pathogenic bacteria, such as salmonella choleraesuis, neisseria meningitidis, pneumococcus and the like, and release active ingredients;
(5) the antibacterial effect can be enhanced by nearly ten times by adding trimethoprim in sulfadiazine;
(6) the pH value of the suspension is 8.5-9, so that the suspension can meet the adaptability of livestock bodies, accelerate the absorption of the livestock bodies to the drugs and reduce the local stimulation of the drugs to the livestock, and the xanthan gum and the polyvinylpyrrolidone can maintain the stability and the maximum antibacterial activity of the sulfadiazine and the trimethoprim.
Detailed Description
The present invention is further described in detail below with reference to examples so that those skilled in the art can practice the invention with reference to the description.
Example 1
The compound sulfadiazine suspension is prepared from the following raw materials in parts by weight: 5 parts of sulfadiazine, 1 part of trimethoprim, 0.3 part of sodium hydroxide, 0.06 part of a suspending agent A, 0.005 part of a suspending agent B, 0.005 part of a surfactant and 100 parts of water for injection. The antibacterial effect can be enhanced by nearly ten times by adding trimethoprim into sulfadiazine. Wherein,
the suspending agent A is prepared by mixing xanthan gum, sorbitol with the concentration of 800ppm, sodium chloride and propylene glycol according to the mass ratio of 80:2:0.03: 50. The suspending agent A is prepared from xanthan gum, sorbitol with the concentration of 800-1500ppm, sodium chloride and propylene glycol according to a certain proportion, the xanthan gum is an excellent drug controlled release carrier, the duration in a livestock body is lasting, the initial release speed of the drug can be inhibited, the irritation of the livestock body is reduced, the sorbitol and the propylene glycol are added to act together, the xanthan gum is dissolved more fully, the caking phenomenon is prevented, the salting-out is promoted due to the synergistic effect of the sodium chloride and the propylene glycol after the sodium chloride is added, and high-quality filaments can be obtained, so that the viscosity of the xanthan gum is higher.
The suspending agent B is polyvinylpyrrolidone with a K value of 60, superoxide dismutase with a concentration of 0.2ppm, an antioxidant and secondary amine according to a mass ratio of 80:1:1: 4. The suspending agent B is dissolved by polyvinylpyrrolidone with K value of 60-80, superoxide dismutase with concentration of 0.2-0.8ppm, antioxidant and secondary amine, so that when the trimethoprim is dissolved in the suspending agent B, the content of insoluble substances is low, and the thermal stability is high; the thermal stability and the stability in an oxygen-containing medium are both obviously improved, and the absorption rate of the compound sulfadiazine suspension in livestock is favorably improved.
Wherein the average particle size of the sulfadiazine is 400 nm.
Wherein the surfactant is tween-80.
Wherein the antioxidant is ascorbic acid, tert-butyl p-hydroxyanisole and dibutyl phenol.
The preparation method of the compound sulfadiazine suspension comprises the following steps of adding the following raw materials in parts by weight:
the method comprises the following steps: grinding sulfadiazine and trimethoprim respectively by a colloid mill until the particle size is 400 nm;
step two: adding the trimethoprim treated in the step one into the suspending agent A, and stirring to fully dissolve the trimethoprim to obtain a first dissolving solution;
step three: taking 30% of the water for injection in parts by weight, heating to 45 ℃, adding the sulfadiazine treated in the step one, stirring and dissolving, adding the suspending agent B, and stirring and dissolving to obtain a second solution;
step four: heating the rest water for injection to 30 ℃, adding sodium hydroxide, and stirring until the sodium hydroxide is fully dissolved to obtain a third dissolved solution;
step five: sequentially heating the first solution to 60 ℃, placing the first solution into a batching container, heating the second solution to 40 ℃, adding the second solution into the batching container, adding the third solution and a surfactant into the batching container, and uniformly stirring to obtain a fourth solution;
step six: and (4) adding the fourth dissolved solution prepared in the fifth step into a high-speed homogenizer, mechanically shearing for 10 minutes, and then sterilizing the completely sheared filtrate at 100 ℃ and under 0.1Mpa for 30 minutes to obtain the compound sulfadiazine suspension.
The preparation method of the suspending agent A comprises the following steps:
step a: adding xanthan gum with the mass ratio into an aqueous solution of sorbitol with the concentration of 800ppm, stirring for 10min at 30 ℃, and adding sodium hydroxide to adjust the pH to 8.5;
step b: adding sodium chloride in the mass ratio into the solution obtained in the step a, stirring until the sodium chloride is completely dissolved, adding propylene glycol in the mass ratio, and stirring at 20 ℃ until filaments are completely separated out;
step c: drying the filiform substance at 50 deg.C until the water content is 70% to obtain the suspending agent A.
The preparation method of the suspending agent B comprises the following steps:
step 1: sterilizing the polyvinylpyrrolidone at low temperature for 2 hours, adding the antioxidant and the secondary amine into the sterilized polyvinylpyrrolidone under the protection of nitrogen, and uniformly mixing;
step 2: heating the mixture in the step 1 to 50 ℃, and reacting for 4 hours;
and step 3: and (3) adding the superoxide dismutase into the substance which is reacted in the step (2), thus obtaining the suspending agent B.
When the compound sulfadiazine suspension is prepared, the compound sulfadiazine suspension generally comprises a main drug, a surfactant, a suspending agent and an antioxidant, the formula of the suspending agent is improved, the compound sulfadiazine suspension of the main drug is respectively dissolved in the suspending agent A and the suspending agent B, the main drug is specifically dissolved, and the dissolution rate of the main drug is improved.
Example 2
The compound sulfadiazine suspension is prepared from the following raw materials in parts by weight: 30 parts of sulfadiazine, 6 parts of trimethoprim, 1.5 parts of sodium hydroxide, 0.1 part of a suspending agent A, 0.03 part of a suspending agent B, 0.03 part of a surfactant and 300 parts of water for injection. The antibacterial effect can be enhanced by nearly ten times by adding trimethoprim into sulfadiazine. Wherein,
the suspending agent A is prepared by mixing xanthan gum, sorbitol with the concentration of 1500ppm, sodium chloride and propylene glycol according to the mass ratio of 150:4:0.15: 60. The suspending agent A is prepared from xanthan gum, sorbitol with the concentration of 800-1500ppm, sodium chloride and propylene glycol according to a certain proportion, the xanthan gum is an excellent drug controlled release carrier, the duration in a livestock body is lasting, the initial release speed of the drug can be inhibited, the irritation of the livestock body is reduced, the sorbitol and the propylene glycol are added to act together, the xanthan gum is dissolved more fully, the caking phenomenon is prevented, the salting-out is promoted due to the synergistic effect of the sodium chloride and the propylene glycol after the sodium chloride is added, and high-quality filaments can be obtained, so that the viscosity of the xanthan gum is higher.
The suspending agent B is polyvinylpyrrolidone with a K value of 80, superoxide dismutase with a concentration of 0.8ppm, an antioxidant and secondary amine according to a mass ratio of 100:3:4: 8. The suspending agent B is dissolved by polyvinylpyrrolidone with K value of 60-80, superoxide dismutase with concentration of 0.2-0.8ppm, antioxidant and secondary amine, so that when the trimethoprim is dissolved in the suspending agent B, the content of insoluble substances is low, and the thermal stability is high; the thermal stability and the stability in an oxygen-containing medium are both obviously improved, and the absorption rate of the compound sulfadiazine suspension in livestock is favorably improved.
Wherein the average particle size of the sulfadiazine is 700 nm.
Wherein, the surfactant is tween-20, tween 40 and tween 61.
Wherein the antioxidant is 4-methyl-7-cholestanol and ascorbic acid.
The preparation method of the compound sulfadiazine suspension comprises the following steps of adding the following raw materials in parts by weight:
the method comprises the following steps: grinding sulfadiazine and trimethoprim respectively by a colloid mill until the particle size is 700 nm;
step two: adding the trimethoprim treated in the step one into the suspending agent A, and stirring to fully dissolve the trimethoprim to obtain a first dissolving solution;
step three: taking 30% of the water for injection in parts by weight, heating to 45 ℃, adding the sulfadiazine treated in the step one, stirring and dissolving, adding the suspending agent B, and stirring and dissolving to obtain a second solution;
step four: heating the rest water for injection to 35 deg.C, adding sodium hydroxide, and stirring to dissolve completely to obtain a third solution;
step five: sequentially heating the first solution to 65 ℃, placing the first solution into a batching container, heating the second solution to 50 ℃, adding the second solution into the batching container, adding the third solution and a surfactant into the batching container, and uniformly stirring to obtain a fourth solution;
step six: and (4) adding the fourth dissolved solution prepared in the fifth step into a high-speed homogenizer, mechanically shearing for 20 minutes, and then sterilizing the completely sheared filtrate at 130 ℃ under 0.2Mpa for 30 minutes to obtain the compound sulfadiazine suspension.
The preparation method of the suspending agent A comprises the following steps:
step a: adding xanthan gum with the mass ratio into a sorbitol aqueous solution with the concentration of 1500ppm, stirring for 30min at 35 ℃, and adding sodium hydroxide to adjust the pH to 9;
step b: adding sodium chloride in the mass ratio into the solution obtained in the step a, stirring until the sodium chloride is completely dissolved, adding propylene glycol in the mass ratio, and stirring at 30 ℃ until filaments are completely separated out;
step c: drying the filiform substance at 70 deg.C until the water content is 90% to obtain the suspending agent A.
The preparation method of the suspending agent B comprises the following steps:
step 1: sterilizing the polyvinylpyrrolidone at low temperature for 3 hours, adding the antioxidant and the secondary amine into the sterilized polyvinylpyrrolidone under the protection of nitrogen, and uniformly mixing;
step 2: heating the mixture in the step 1 to 70 ℃, and reacting for 6 hours;
and step 3: and (3) adding the superoxide dismutase into the substance which is reacted in the step (2), thus obtaining the suspending agent B.
When the compound sulfadiazine suspension is prepared, the compound sulfadiazine suspension generally comprises a main drug, a surfactant, a suspending agent and an antioxidant, the formula of the suspending agent is improved, the compound sulfadiazine suspension of the main drug is respectively dissolved in the suspending agent A and the suspending agent B, the main drug is specifically dissolved, and the dissolution rate of the main drug is improved.
Example 3
The compound sulfadiazine suspension is prepared from the following raw materials in parts by weight: 20 parts of sulfadiazine, 4 parts of trimethoprim, 1 part of sodium hydroxide, 0.08 part of a suspending agent A, 0.015 part of a suspending agent B, 0.009 part of a surfactant and 200 parts of water for injection. The antibacterial effect can be enhanced by nearly ten times by adding trimethoprim into sulfadiazine. Wherein,
the suspending agent A is prepared by mixing xanthan gum, sorbitol with the concentration of 1200ppm, sodium chloride and propylene glycol according to the mass ratio of 100:3:0.1: 55; the suspending agent A is prepared from xanthan gum, sorbitol with the concentration of 800-1500ppm, sodium chloride and propylene glycol according to a certain proportion, the xanthan gum is an excellent drug controlled release carrier, the duration in a livestock body is lasting, the initial release speed of the drug can be inhibited, the irritation of the livestock body is reduced, the sorbitol and the propylene glycol are added to act together, the xanthan gum is dissolved more fully, the caking phenomenon is prevented, the salting-out is promoted due to the synergistic effect of the sodium chloride and the propylene glycol after the sodium chloride is added, and high-quality filaments can be obtained, so that the viscosity of the xanthan gum is higher.
The suspending agent B is polyvinylpyrrolidone with a K value of 70, superoxide dismutase with a concentration of 0.5ppm, an antioxidant and secondary amine according to a mass ratio of 90:2:2: 6. The suspending agent B is dissolved by polyvinylpyrrolidone with K value of 60-80, superoxide dismutase with concentration of 0.2-0.8ppm, antioxidant and secondary amine, so that when the trimethoprim is dissolved in the suspending agent B, the content of insoluble substances is low, and the thermal stability is high; the thermal stability and the stability in an oxygen-containing medium are both obviously improved, and the absorption rate of the compound sulfadiazine suspension in livestock is favorably improved.
Wherein the average particle size of the sulfadiazine is 650 nm.
Wherein the surfactant is tween-80.
Wherein the antioxidant is ascorbic acid.
The preparation method of the compound sulfadiazine suspension comprises the following steps of:
the method comprises the following steps: grinding sulfadiazine and trimethoprim respectively by a colloid mill until the particle size is 600 nm;
step two: adding the trimethoprim treated in the step one into the suspending agent A, and stirring to fully dissolve the trimethoprim to obtain a first dissolving solution;
step three: taking 30% of the water for injection in parts by weight, heating to 45 ℃, adding the sulfadiazine treated in the step one, stirring and dissolving, adding the suspending agent B, and stirring and dissolving to obtain a second solution;
step four: heating the rest water for injection to 32 ℃, adding sodium hydroxide, and stirring until the sodium hydroxide is fully dissolved to obtain a third dissolved solution;
step five: sequentially heating the first solution to 62 ℃, placing the first solution into a batching container, heating the second solution to 45 ℃, adding the second solution into the batching container, adding the third solution and a surfactant into the batching container, and uniformly stirring to obtain a fourth solution;
step six: and (4) adding the fourth dissolved solution prepared in the fifth step into a high-speed homogenizer, mechanically shearing for 15 minutes, and then sterilizing the completely sheared filtrate at 120 ℃ and under 0.15Mpa for 30 minutes to obtain the compound sulfadiazine suspension.
The preparation method of the suspending agent A comprises the following steps:
step a: adding xanthan gum with the mass ratio into a sorbitol aqueous solution with the concentration of 1200ppm, stirring for 20min at 32 ℃, and adding sodium hydroxide to adjust the pH to 8.5;
step b: adding sodium chloride in the mass ratio into the solution obtained in the step a, stirring until the sodium chloride is completely dissolved, adding propylene glycol in the mass ratio, and stirring at 25 ℃ until filaments are completely separated out;
step c: drying the filiform substance at 60 deg.C until the water content is 80% to obtain the suspending agent A.
The preparation method of the suspending agent B comprises the following steps:
step 1: sterilizing the polyvinylpyrrolidone at low temperature for 3 hours, adding the antioxidant and the secondary amine into the sterilized polyvinylpyrrolidone under the protection of nitrogen, and uniformly mixing;
step 2: heating the mixture in the step 1 to 60 ℃, and reacting for 5 hours;
and step 3: and (3) adding the superoxide dismutase into the substance which is reacted in the step (2), thus obtaining the suspending agent B.
When the compound sulfadiazine suspension is prepared, the compound sulfadiazine suspension generally comprises a main drug, a surfactant, a suspending agent and an antioxidant, the formula of the suspending agent is improved, the compound sulfadiazine suspension of the main drug is respectively dissolved in the suspending agent A and the suspending agent B, the main drug is specifically dissolved, and the dissolution rate of the main drug is improved.
The pharmaceutical activity and the application thereof are further illustrated by pharmacodynamic experiments.
Experiment one: volume ratio of sedimentation
The detection method is carried out according to the oral suspension standard of Chinese veterinary pharmacopoeia: the sedimentation volume ratio of the oral suspension medicament is not less than 0.90.
The compound sulfadiazine suspension prepared in the embodiment 3 of the invention and the existing compound sulfadiazine (comparative example) of a certain brand are subjected to a sedimentation experiment, 30ml of each of the two samples is taken, after sealing, the two samples are oscillated for 2 minutes, the initial height H of the two samples is recorded, and when the two samples are kept stand for 5 hours, the final height H of the two samples is recorded1The sedimentation volume ratio of the two agents was calculated from the sedimentation volume ratio final height/initial height.
TABLE 1 sedimentation volume ratio of the invention and comparative examples
As can be seen from Table 1, the sedimentation volume ratio of the present invention is more than 0.9 and the dispersion is good, while the sedimentation volume ratio of the comparative example is gradually decreased with the increase of the sedimentation time and is finally less than 0.9 and the sedimentation rate is too high.
Experiment two: clinical treatment effects of the invention
Clinical treatment experiments are carried out on sick pigs with neisseria meningitidis and salmonella choleraesuis, the sick pigs are treated by the medicament in the embodiment 3 and the comparative medicament respectively, a control group is arranged, and no medicament is applied to the sick pigs in the control group.
TABLE 2 comparison of the effectiveness of the present invention and comparative examples in clinical treatment
| Group of | Name of disease | General case/head | Total cure/head | Percent cure rate/%) |
| The invention | Neisseria meningitidis | 100 | 95 | 95 |
| Salmonella choleraesuis | 200 | 197 | 98.5 | |
| Comparative example | Neisseria meningitidis | 100 | 73 | 73 |
| Salmonella choleraesuis | 200 | 164 | 82 | |
| Control group | Neisseria meningitidis | 20 | 3 | 15 |
| Salmonella choleraesuis | 30 | 5 | 16.7 |
The results show that the treatment effect of the compound preparation on the neisseria meningitidis and the salmonella choleraesuis is the best, compared with the comparative example, the cure rate of the neisseria meningitidis is higher by 20%, and the cure rate of the salmonella choleraesuis is higher by nearly 20%.
While embodiments of the invention have been described above, it is not limited to the applications set forth in the description and the embodiments, which are fully applicable to various fields of endeavor for which the invention may be embodied with additional modifications as would be readily apparent to those skilled in the art, and the invention is therefore not limited to the details given herein and to the embodiments shown and described without departing from the generic concept as defined by the claims and their equivalents.
Claims (7)
1. The compound sulfadiazine suspension is characterized by being prepared from the following raw materials in parts by weight: 5-30 parts of sulfadiazine, 1-6 parts of trimethoprim, 0.3-1.5 parts of sodium hydroxide, 0.06-0.1 part of a suspending agent A, 0.005-0.03 part of a suspending agent B, 0.005-0.03 part of a surfactant and 300 parts of water for injection; wherein,
the suspending agent A comprises xanthan gum, sorbitol with the concentration of 800-1500ppm, sodium chloride and propylene glycol which are mixed according to the mass ratio of 80-150:2-4:0.03-0.15: 50-60;
the suspending agent B is polyvinylpyrrolidone with a K value of 60-80, superoxide dismutase with a concentration of 0.2-0.8ppm, an antioxidant and secondary amine according to a mass ratio of 80-100:1-3:1-4: 4-8.
2. The compound sulfadiazine suspension of claim 1, wherein the sulfadiazine has an average particle size of 400-700 nm.
3. The compound sulfadiazine suspension of claim 2, wherein the surfactant is one or more of tween-80, tween-20, tween 21, tween 40 and tween 61.
4. The compound sulfadiazine suspension of claim 3, wherein the antioxidant is any one or more of 4-methyl-7-cholestanol, ascorbic acid, t-butyl p-hydroxyanisole and dibutyl phenol.
5. A method for preparing a compound sulfadiazine suspension according to any one of claims 1 to 4, comprising the following steps, wherein the following raw materials are added in parts by weight:
the method comprises the following steps: grinding sulfadiazine and trimethoprim respectively by a colloid mill until the particle size is 400-700 nm;
step two: adding the trimethoprim treated in the step one into the suspending agent A, and stirring to fully dissolve the trimethoprim to obtain a first dissolving solution;
step three: taking 30% of the water for injection in parts by weight, heating to 45 ℃, adding the sulfadiazine treated in the step one, stirring and dissolving, adding the suspending agent B, and stirring and dissolving to obtain a second solution;
step four: heating the rest water for injection to 30-35 deg.C, adding sodium hydroxide, and stirring to dissolve completely to obtain a third solution;
step five: sequentially heating the first solution to 60-65 ℃, placing the first solution in a batching container, heating the second solution to 40-50 ℃, adding the second solution into the batching container, adding the third solution and a surfactant into the batching container, and uniformly stirring to obtain a fourth solution;
step six: and (4) adding the fourth dissolved solution prepared in the fifth step into a high-speed homogenizer, mechanically shearing for 10-20 minutes, and then sterilizing the completely sheared filtrate at the temperature of 100 ℃ and 130 ℃ and under the pressure of 0.1-0.2Mpa for 30 minutes to obtain the compound sulfadiazine suspension.
6. The method of making a suspension of compound sulfadiazine according to claim 5, wherein the suspending agent A is made by the method comprising:
step a: adding xanthan gum with the mass ratio into an aqueous solution of sorbitol with the concentration of 800-1500ppm, stirring for 10-30min at the temperature of 30-35 ℃, and adding sodium hydroxide to adjust the pH value to 8.5-9;
step b: adding sodium chloride in the mass ratio into the solution obtained in the step a, stirring until the sodium chloride is completely dissolved, adding propylene glycol in the mass ratio, and stirring at 20-30 ℃ until filiform substances are completely separated out;
step c: drying the filiform substance at 50-70 deg.C until the water content is 70% -90%, to obtain the suspending agent A.
7. The method of making a suspension of compound sulfadiazine of claim 5, wherein the suspending agent B is made by the method of:
step 1: sterilizing the polyvinylpyrrolidone at low temperature for 2-3 hours, adding the antioxidant and secondary amine into the sterilized polyvinylpyrrolidone under the protection of nitrogen, and uniformly mixing;
step 2: heating the mixture in the step 1 to 50-70 ℃, and reacting for 4-6 hours;
and step 3: and (3) adding the superoxide dismutase into the substance which is reacted in the step (2), thus obtaining the suspending agent B.
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