CN117695217B - Preparation method of enrofloxacin oral solution - Google Patents
Preparation method of enrofloxacin oral solution Download PDFInfo
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- CN117695217B CN117695217B CN202410149222.3A CN202410149222A CN117695217B CN 117695217 B CN117695217 B CN 117695217B CN 202410149222 A CN202410149222 A CN 202410149222A CN 117695217 B CN117695217 B CN 117695217B
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- SPFYMRJSYKOXGV-UHFFFAOYSA-N Baytril Chemical compound C1CN(CC)CCN1C(C(=C1)F)=CC2=C1C(=O)C(C(O)=O)=CN2C1CC1 SPFYMRJSYKOXGV-UHFFFAOYSA-N 0.000 title claims abstract description 61
- 229960000740 enrofloxacin Drugs 0.000 title claims abstract description 61
- 229940100688 oral solution Drugs 0.000 title claims abstract description 45
- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- 238000002156 mixing Methods 0.000 claims abstract description 31
- 238000010008 shearing Methods 0.000 claims abstract description 27
- 239000000463 material Substances 0.000 claims abstract description 11
- 229920001491 Lentinan Polymers 0.000 claims description 72
- 229940115286 lentinan Drugs 0.000 claims description 72
- 238000003756 stirring Methods 0.000 claims description 64
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 33
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 29
- 230000001276 controlling effect Effects 0.000 claims description 29
- 239000011259 mixed solution Substances 0.000 claims description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- 239000008215 water for injection Substances 0.000 claims description 18
- 239000007788 liquid Substances 0.000 claims description 17
- 229920000161 Locust bean gum Polymers 0.000 claims description 15
- 238000005538 encapsulation Methods 0.000 claims description 15
- 235000010420 locust bean gum Nutrition 0.000 claims description 15
- 239000000711 locust bean gum Substances 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 12
- 239000008055 phosphate buffer solution Substances 0.000 claims description 11
- 230000001105 regulatory effect Effects 0.000 claims description 11
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 10
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 10
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 claims description 10
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 claims description 10
- 230000001954 sterilising effect Effects 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- 238000010306 acid treatment Methods 0.000 claims description 5
- 238000004108 freeze drying Methods 0.000 claims description 5
- 239000002244 precipitate Substances 0.000 claims description 5
- 230000001376 precipitating effect Effects 0.000 claims description 5
- 239000003814 drug Substances 0.000 abstract description 21
- 238000002474 experimental method Methods 0.000 abstract description 16
- 238000002425 crystallisation Methods 0.000 abstract description 11
- 230000008025 crystallization Effects 0.000 abstract description 11
- 229940079593 drug Drugs 0.000 abstract description 5
- 238000003860 storage Methods 0.000 abstract description 3
- 238000001816 cooling Methods 0.000 abstract description 2
- 239000013078 crystal Substances 0.000 abstract description 2
- 239000013081 microcrystal Substances 0.000 abstract description 2
- 235000021050 feed intake Nutrition 0.000 description 12
- 241001465754 Metazoa Species 0.000 description 11
- 241000282887 Suidae Species 0.000 description 11
- 235000019629 palatability Nutrition 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- 230000000052 comparative effect Effects 0.000 description 9
- 230000002354 daily effect Effects 0.000 description 6
- 230000001133 acceleration Effects 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000008363 phosphate buffer Substances 0.000 description 4
- 235000019658 bitter taste Nutrition 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000011049 filling Methods 0.000 description 3
- 238000004659 sterilization and disinfection Methods 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 230000007012 clinical effect Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
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- 239000011521 glass Substances 0.000 description 2
- 150000004676 glycans Chemical class 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 238000010255 intramuscular injection Methods 0.000 description 2
- 239000007927 intramuscular injection Substances 0.000 description 2
- 229920001282 polysaccharide Polymers 0.000 description 2
- 239000005017 polysaccharide Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 241000588724 Escherichia coli Species 0.000 description 1
- 240000008620 Fagopyrum esculentum Species 0.000 description 1
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- 241000606790 Haemophilus Species 0.000 description 1
- 241000588748 Klebsiella Species 0.000 description 1
- 241000204031 Mycoplasma Species 0.000 description 1
- 241000606856 Pasteurella multocida Species 0.000 description 1
- HDSBZMRLPLPFLQ-UHFFFAOYSA-N Propylene glycol alginate Chemical compound OC1C(O)C(OC)OC(C(O)=O)C1OC1C(O)C(O)C(C)C(C(=O)OCC(C)O)O1 HDSBZMRLPLPFLQ-UHFFFAOYSA-N 0.000 description 1
- 241000588769 Proteus <enterobacteria> Species 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- 241000607142 Salmonella Species 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 241000194017 Streptococcus Species 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
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- 235000019789 appetite Nutrition 0.000 description 1
- 239000003899 bactericide agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229940051027 pasteurella multocida Drugs 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
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- 235000010409 propane-1,2-diol alginate Nutrition 0.000 description 1
- 239000000770 propane-1,2-diol alginate Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
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- 238000012795 verification Methods 0.000 description 1
Classifications
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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Abstract
The invention discloses a preparation method of enrofloxacin oral solution, belonging to the field of veterinary medical preparations. The preparation method comprises the steps of preparing an encapsulating material, mixing and shearing, and preparing a preparation. After long-time storage, the enrofloxacin oral solution prepared by the invention is difficult to crystallize, after being placed in a drug stability experiment box with the temperature of 40 ℃ and the relative humidity of 75% and the illuminance of 4500LUX for 12 months, the enrofloxacin oral solution is taken out and observed, micro crystals can be observed in the bottle, after observation, the enrofloxacin oral solution is placed in an oven with the temperature of 55 ℃ for 60 minutes, and after cooling to room temperature, the crystallization and redissolution are observed, and no precipitated crystals are observed.
Description
Technical Field
The invention relates to a preparation method of enrofloxacin oral solution, belonging to the field of veterinary medical preparations.
Background
Enrofloxacin, also called ethyl ciprofloxacin and enrofloxacin, is yellowish or yellowish crystalline powder, has bitter taste, is insoluble in water, belongs to a broad-spectrum bactericide, has special effects on mycoplasma, and has bactericidal effects on escherichia coli, klebsiella, salmonella, proteus, pseudomonas aeruginosa, haemophilus, pasteurella multocida, staphylococcus aureus, streptococcus and the like.
The oral administration and intramuscular injection of enrofloxacin are rapidly and completely absorbed, the blood concentration reaches a peak within 0.5-2 hours, and the concentration of the medicine in almost all tissues except the central nervous system is higher than that of blood plasma, so that the treatment of systemic infection and deep tissue infection is facilitated, wherein the intramuscular injection administration mode greatly improves the labor cost in large-scale animal cultivation, the oral administration mode has high bioavailability, small toxic and side effects and convenient large-scale administration, so that the oral administration is more suitable for large-scale cultivation, but the enrofloxacin has bitter taste, poor palatability and unwilling to eat by animals, so that the treatment concentration of the medicine is not reached, and the clinical effect is poor.
CN111821258a discloses a compound enrofloxacin oral liquid and a preparation method thereof, propylene glycol alginate and buckwheat protein polysaccharide are added to make enrofloxacin Sha Xingxing become capsules, so that the bitter taste of the medicine is eliminated to a certain extent, the palatability of the medicine is improved, but the palatability is improved to a poor extent, the compound enrofloxacin oral liquid can be only diluted by a large amount of water and then is administrated by drinking water of animals, and after a feed mixing administration mode is adopted, the appetite of the animals is reduced, and the feed intake of the feed is reduced.
As the verification of improving the palatability effect in the technology adopts a method of trial eating by people, an animal feeding test is not adopted, and experiments show that the feed intake of animals is reduced in the feeding test after oral liquid is mixed with feed, if the administration mode of mixing with feed is adopted, the treatment concentration of the medicine still cannot reach the standard, and the clinical effect is deteriorated.
In actual production, encapsulated components can be tried to be changed, or other polysaccharides are used for preparing solution, the problem of palatability can be better solved, after the solution is mixed with feed and administered, the feed intake of animals can not be obviously changed, the solution is favorable for achieving therapeutic concentration, the therapeutic effect of the enrofloxacin oral solution is improved to a great extent, the enrofloxacin is insoluble in water, the prepared oral solution is easy to crystallize after being stored for a period of time, the preparation after crystallization is tried to be heated, the crystallization re-dissolution degree is small after the solution is heated for a period of time, and the problem of crystallization can not be well solved.
In summary, enrofloxacin oral solution in the prior art is generally encapsulated, so that the palatability of the drug is improved, and the enrofloxacin oral solution is suitable for being mixed with feed for administration, but the prepared solution can be subjected to crystallization after being stored for a period of time, and the crystallized preparation is heated, so that the crystallization can not be obviously redissolved.
Disclosure of Invention
The invention aims to overcome the defects in the prior art, and the preparation is further prepared by preparing the encapsulating material to obtain the enrofloxacin oral solution, so that the palatability of the medicine is improved, and the crystallization phenomenon after long-time storage is reduced.
In order to solve the technical problems, the invention adopts the following technical scheme:
a method for preparing enrofloxacin oral solution, which comprises the steps of preparing an encapsulating material, mixing and shearing, and preparing a preparation.
The following is a further improvement of the above technical scheme:
The step of preparing the encapsulating material includes dissolving, sulfonic acid treatment;
mixing lentinan with a phosphate buffer solution, stirring until the lentinan is dissolved to obtain a lentinan mixed solution, then controlling the temperature to be 81-83 ℃, continuing stirring until the viscosity of the lentinan mixed solution is obviously reduced, and preserving heat;
the mass ratio of the lentinan to the phosphate buffer solution is 1:43-47;
The lentinan has a molecular weight of 1.2-3.5X10 6;
the pH of the phosphate buffer was 6.2;
Adding sulfamic acid, N-hydroxysuccinimide and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride into the heat-preserving lentinan mixed solution, uniformly stirring, controlling the temperature to be 81-83 ℃, stirring for 17-19 hours, precipitating lentinan by using absolute ethyl alcohol after stirring is completed, and freeze-drying the precipitate to obtain the lentinan treated by sulfonic acid;
The mass ratio of the lentinan mixed solution to sulfamic acid to N-hydroxysuccinimide to 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride is 450-550:14-16:10-14:0.8-1.2;
Mixing the lentinan treated by sulfonic acid, locust bean gum and water for injection, regulating the pH to 6.5 by acetic acid, controlling the temperature to 81-83 ℃, stirring until the lentinan treated by sulfonic acid and the locust bean gum are completely dissolved, feeding the dissolved mixed solution into a high-speed shearing machine, controlling the shearing speed to 7250-7750r/min, shearing for 14-18min, and obtaining the encapsulation liquid after shearing;
The mass ratio of the lentinan treated by the sulfonic acid to the locust bean gum to the water for injection is 11-13:8.5-9.5:525-575.
The preparation method comprises the steps of premixing and constant volume;
The premixing method comprises the steps of mixing 800mg of enrofloxacin and 65-75mL of encapsulation liquid, controlling the stirring speed to be 1200-1500r/min, stirring for 135-160min, and regulating the pH to 6.5 by acetic acid after stirring to obtain a premixed liquid;
the method for fixing the volume comprises the steps of fixing the volume of the premix to 100mL by using water for injection, controlling the stirring speed to be 700-800r/min, stirring for 55-65min, sterilizing and bottling after stirring to obtain enrofloxacin oral solution;
The concentration of the enrofloxacin oral solution is 8mg/mL.
Compared with the prior art, the invention has the following beneficial effects:
The enrofloxacin oral solution prepared by the invention has good palatability, and can keep good feed intake of animals by both administration by pouring and feed mixing, when administration by pouring is adopted, 50kg of pigs have feed intake of 1.955-1.974kg on the same day as that of pouring, 1.981-2.057kg on the same day as that of pouring, 1.994-2.058kg on the same day as that of pouring, 2.055-2.107kg on the same day as that of pouring, 1.893-1.972kg on the same day as that of 50kg of pigs, 1.935-2.012kg on the same day as that of feeding, 2.026-2.032kg on the same day as that of feeding, and 2.018-2.044kg on the same day as that of feeding;
After long-time storage, the enrofloxacin oral solution prepared by the invention is difficult to crystallize, after being placed in a drug stability experiment box with the temperature of 40 ℃ and the relative humidity of 75% and the illuminance of 4500LUX for 12 months, the enrofloxacin oral solution is taken out and observed, micro-crystals can be observed in the bottle, the drug bottle is placed in a baking oven with the temperature of 55 ℃ for 60 minutes after observation, and after cooling to room temperature, the crystallization and redissolution conditions are observed, and the precipitated crystals are not observed;
The enrofloxacin oral solution prepared by the invention has good stability, and is subjected to high-temperature high-humidity strong light acceleration experiments according to a pharmaceutical stability experiment method in 2020 edition of Chinese animal pharmacopoeia, the high-temperature high-humidity strong light acceleration experiments are carried out in a pharmaceutical stability experiment box with the temperature of 40 ℃ and the relative humidity of 75% and the illuminance of 4500LUX, the samples are taken once at the bottoms of 1 st month, 2 nd month, 3 rd month and 6 th month in the experiment period, the pH value and the content of the enrofloxacin oral solution are detected, the pH value is 6.5 in 0 month, the pH value is 6.5 in 1 month, the pH value is 6.5 in 2 months, the pH value is 6.4-6.5 in 3 months, the pH value is 6.4 in 6 months, the pH value is 6.4 in 0 month, the content is 100.0% in 1 month and 99.9% in 2 months, the content is 99.8% in 3 months and the content is 99.5-99.7% in 6 months and 99.3-99.5%.
Detailed Description
Example 1
(1) Preparation of encapsulation materials
A. dissolving
Mixing lentinan with phosphate buffer solution, stirring until lentinan is dissolved to obtain lentinan mixed solution, controlling the temperature to be 82 ℃, continuing stirring until the viscosity of the lentinan mixed solution is obviously reduced, and preserving heat;
the mass ratio of the lentinan to the phosphate buffer solution is 1:45;
The lentinan has a molecular weight of 1.2X10 6;
the pH of the phosphate buffer was 6.2;
b. Sulfonic acid treatment
Adding sulfamic acid, N-hydroxysuccinimide and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride into the heat-preserving lentinan mixed solution, uniformly stirring, controlling the temperature to be 82 ℃, stirring for 18 hours, precipitating lentinan by using absolute ethyl alcohol after stirring is completed, and freeze-drying the precipitate to obtain the lentinan treated by sulfonic acid;
The mass ratio of the lentinan mixed solution to sulfamic acid to N-hydroxysuccinimide to 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride is 500:15:12:1;
(2) Mixing and shearing
Mixing the lentinan treated by sulfonic acid, locust bean gum and water for injection, regulating the pH to 6.5 with acetic acid, controlling the temperature to 82 ℃, stirring until the lentinan treated by sulfonic acid and the locust bean gum are completely dissolved, feeding the dissolved mixed solution into a high-speed shearing machine, controlling the shearing speed to 7500r/min, shearing for 15min, and shearing to obtain the encapsulation liquid;
the mass ratio of the lentinan treated by sulfonic acid to the locust bean gum to the water for injection is 12:9:550.
(3) Preparation of the formulation
A. premixing
Mixing 800mg enrofloxacin and 70mL of encapsulation liquid, controlling the stirring speed to 1350r/min, stirring for 150min, and regulating the pH to 6.5 by acetic acid after stirring to obtain a premix;
b. Constant volume
The premixed solution is fixed to 100mL by using water for injection, the stirring speed is controlled to be 750r/min, the stirring is carried out for 60min, and the enrofloxacin oral solution is obtained after sterilization and bottling after the stirring;
The concentration of the enrofloxacin oral solution is 8mg/mL.
Example 2
(1) Preparation of encapsulation materials
A. dissolving
Mixing lentinan with phosphate buffer solution, stirring until lentinan is dissolved to obtain lentinan mixed solution, controlling the temperature to be 81 ℃, continuing stirring until the viscosity of the lentinan mixed solution is obviously reduced, and preserving heat;
The mass ratio of the lentinan to the phosphate buffer solution is 1:43;
The lentinan has a molecular weight of 2.7X10 6;
the pH of the phosphate buffer was 6.2;
b. Sulfonic acid treatment
Adding sulfamic acid, N-hydroxysuccinimide and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride into the heat-preserving lentinan mixed solution, uniformly stirring, controlling the temperature to be 81 ℃, stirring for 19 hours, precipitating lentinan by using absolute ethyl alcohol after stirring is completed, and freeze-drying the precipitate to obtain the lentinan treated by sulfonic acid;
The mass ratio of the lentinan mixed solution to sulfamic acid to N-hydroxysuccinimide to 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride is 450:14:10:0.8;
(2) Mixing and shearing
Mixing the lentinan treated by sulfonic acid, locust bean gum and water for injection, regulating the pH to 6.5 with acetic acid, controlling the temperature to 81 ℃, stirring until the lentinan treated by sulfonic acid and the locust bean gum are completely dissolved, feeding the dissolved mixed solution into a high-speed shearing machine, controlling the shearing speed to 7250r/min, shearing for 18min, and shearing to obtain the encapsulation liquid;
the mass ratio of the lentinan treated by sulfonic acid to the locust bean gum to the water for injection is 11:8.5:525.
(3) Preparation of the formulation
A. premixing
Mixing 800mg enrofloxacin and 65mL of encapsulation liquid, controlling the stirring speed to be 1200r/min, stirring for 160min, and regulating the pH to 6.5 by acetic acid after stirring to obtain a premix;
b. Constant volume
The premixed solution is fixed to 100mL by using water for injection, the stirring speed is controlled to be 700r/min, the stirring is carried out for 65min, and the enrofloxacin oral solution is obtained after sterilization and bottling after the stirring;
The concentration of the enrofloxacin oral solution is 8mg/mL.
Example 3
(1) Preparation of encapsulation materials
A. dissolving
Mixing lentinan with phosphate buffer solution, stirring until lentinan is dissolved to obtain lentinan mixed solution, controlling the temperature to 83 ℃, continuing stirring until the viscosity of the lentinan mixed solution is obviously reduced, and preserving heat;
the mass ratio of the lentinan to the phosphate buffer solution is 1:47;
the lentinan has a molecular weight of 3.5X10 6;
the pH of the phosphate buffer was 6.2;
b. Sulfonic acid treatment
Adding sulfamic acid, N-hydroxysuccinimide and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride into the heat-preserving lentinan mixed solution, uniformly stirring, controlling the temperature to be 83 ℃, stirring for 17 hours, precipitating lentinan by using absolute ethanol after stirring is completed, and freeze-drying the precipitate to obtain the lentinan treated by sulfonic acid;
The mass ratio of the lentinan mixed solution to sulfamic acid to N-hydroxysuccinimide to 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride is 550:16:14:1.2;
(2) Mixing and shearing
Mixing the lentinan treated by sulfonic acid, locust bean gum and water for injection, regulating the pH to 6.5 with acetic acid, controlling the temperature to 83 ℃, stirring until the lentinan treated by sulfonic acid and the locust bean gum are completely dissolved, feeding the dissolved mixed solution into a high-speed shearing machine, controlling the shearing speed to 7750r/min, shearing for 14min, and shearing to obtain the encapsulation liquid;
The mass ratio of the lentinan treated by sulfonic acid to the locust bean gum to the water for injection is 13:9.5:575.
(3) Preparation of the formulation
A. premixing
Mixing 800mg enrofloxacin and 75mL of encapsulation liquid, controlling the stirring speed to be 1500r/min, stirring for 135min, and regulating the pH to 6.5 by acetic acid after stirring to obtain a premix;
b. Constant volume
The premixed solution is fixed to 100mL by using water for injection, the stirring speed is controlled to be 800r/min, the stirring is carried out for 55min, and the enrofloxacin oral solution is obtained after sterilization and bottling after the stirring;
The concentration of the enrofloxacin oral solution is 8mg/mL.
Comparative example 1
Unlike example 1, the preparation of encapsulating material was omitted, untreated lentinan was directly used as an encapsulating material, and in the mixing and shearing step, the untreated lentinan was used instead of the sulfonic acid-treated lentinan, and mixing and shearing were performed, and the rest steps were the same, to prepare enrofloxacin oral solution;
The untreated lentinan has a molecular weight of 1.2X10 6.
Comparative example 2
Unlike example 1, the mixing shear step was changed to the following operation:
Mixing the lentinan treated by sulfonic acid and water for injection, regulating the pH to 6.5 with acetic acid, controlling the temperature to 82 ℃, stirring until the lentinan treated by sulfonic acid is completely dissolved, and obtaining an encapsulation liquid;
the mass ratio of the lentinan treated by the sulfonic acid to the water for injection is 15:500.
Comparative example 3
Unlike example 1, the preparation formulation was changed to the following procedure:
Mixing 800mg enrofloxacin and 70mL of encapsulation liquid, adjusting the pH to 6.5, using water for injection to fix the volume to 100mL, controlling the stirring speed to 750r/min, stirring for 150min, sterilizing and bottling after stirring to obtain the enrofloxacin oral solution.
Example 4 palatability test
And (3) administration test by drenching:
The enrofloxacin oral solution prepared in the examples 1-3 and the comparative examples 1-3 is subjected to palatability test, 50 healthy pigs of about 50kg are selected in each example and comparative example, the enrofloxacin oral solution is fed to the pigs, the feeding mode is that the enrofloxacin oral solution is taken in a filling mode, the enrofloxacin oral solution is fed once in the morning and evening each day, the average daily feed intake of the pigs is counted after the filling, the average daily feed intake of the pigs on the same day is counted, and the average daily feed intake of the pigs on the 1-3 days after the filling is counted, a control group is arranged, the enrofloxacin oral solution is not taken in the control group, and the result of the average daily feed intake change is shown in the table 1;
TABLE 1
Feed mixing and administration test:
The enrofloxacin oral solutions prepared in examples 1-3 and comparative examples 1-3 were subjected to palatability test on pigs, 50 healthy pigs of about 50kg each were selected in each example and comparative example, the enrofloxacin oral solution was fed to the pigs by feed mixing, feeding the mixed feed once each morning and evening every day, the content of the active substances of enrofloxacin mixed in each kg of feed was 125mg, the feed intake amount of the pigs was counted, the average daily feed intake amount of the fed mixed feed on the day and the average daily feed intake of the fed mixed feed on the day 1-3 after feeding the mixed feed were counted, a control group was set, the control group was the non-fed mixed feed, and the results were shown in table 2.
TABLE 2
EXAMPLE 5 crystallization test
The enrofloxacin oral solution prepared in examples 1-3 and comparative examples 1-3 is filled into a glass solution medicine bottle with a capacity of 100mL, then a high-temperature high-humidity strong light acceleration experiment is carried out according to a medicine stability experiment method in the 2020 edition of Chinese animal pharmacopoeia, the enrofloxacin oral solution is placed in a medicine stability experiment box with a temperature of 40 ℃ and a relative humidity of 75% and an illuminance of 4500LUX for 12 months, the enrofloxacin oral solution is taken out after the placement is completed, the crystallization condition of the medicine in the bottle is observed, the medicine bottle is placed in an oven with a temperature of 55 ℃ after the observation, the medicine bottle is placed for 60min, and then the medicine bottle is cooled to room temperature, and the crystallization re-dissolution condition is observed, wherein the result is shown in Table 3.
TABLE 3 Table 3
EXAMPLE 6 drug stability experiment
The enrofloxacin oral solution prepared in examples 1-3 and comparative examples 1-3 is filled into a glass solution medicine bottle with a capacity of 100mL, then a high-temperature high-humidity strong light acceleration experiment is carried out according to a medicine stability experiment method in the year 2020 edition of Chinese animal pharmacopoeia, the enrofloxacin oral solution is placed in a medicine stability experiment box with a temperature of 40 ℃ and a relative humidity of 75% and an illuminance of 4500LUX for 6 months, and samples are taken once at the bottoms of 1, 2, 3 and 6 months during the experiment, and the pH value and the content of the enrofloxacin oral solution are detected, so that the results are shown in Table 4.
TABLE 4 Table 4
Claims (3)
1. A preparation method of enrofloxacin oral solution, which is characterized by comprising the steps of preparing an encapsulating material, mixing, shearing and preparing a preparation;
The step of preparing the encapsulating material includes dissolving, sulfonic acid treatment;
mixing lentinan with a phosphate buffer solution, stirring until the lentinan is dissolved to obtain a lentinan mixed solution, then controlling the temperature to be 81-83 ℃, continuing stirring until the viscosity of the lentinan mixed solution is obviously reduced, and preserving heat;
the mass ratio of the lentinan to the phosphate buffer solution is 1:43-47;
Adding sulfamic acid, N-hydroxysuccinimide and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride into the heat-preserving lentinan mixed solution, uniformly stirring, controlling the temperature to be 81-83 ℃, stirring for 17-19 hours, precipitating lentinan by using absolute ethyl alcohol after stirring is completed, and freeze-drying the precipitate to obtain the lentinan treated by sulfonic acid;
The mass ratio of the lentinan mixed solution to sulfamic acid to N-hydroxysuccinimide to 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride is 450-550:14-16:10-14:0.8-1.2;
mixing the lentinan treated by sulfonic acid, locust bean gum and water for injection, regulating the pH to 6.5 by acetic acid, controlling the temperature to 81-83 ℃, stirring until the lentinan treated by sulfonic acid and the locust bean gum are completely dissolved, controlling the shearing speed to 7250-7750r/min, shearing the dissolved mixed solution for 14-18min, and obtaining the encapsulation liquid after shearing;
the mass ratio of the lentinan treated by sulfonic acid to the locust bean gum to the water for injection is 11-13:8.5-9.5:525-575;
The preparation method comprises the steps of premixing and constant volume;
The premixing method comprises the steps of mixing 800mg of enrofloxacin and 65-75mL of encapsulation liquid, controlling the stirring speed to be 1200-1500r/min, stirring for 135-160min, and regulating the pH to 6.5 by acetic acid after stirring to obtain a premixed liquid;
The method for fixing the volume comprises the steps of fixing the volume of the premix to 100mL by using water for injection, controlling the stirring speed to be 700-800r/min, stirring for 55-65min, sterilizing and bottling after stirring to obtain enrofloxacin oral solution; the concentration of the enrofloxacin oral solution is 8mg/mL.
2. The method for preparing the enrofloxacin oral solution according to claim 1, wherein: in the dissolving step, the lentinan has a molecular weight of 1.2-3.5X10 6.
3. The method for preparing the enrofloxacin oral solution according to claim 1, wherein: in the dissolving step, the pH of the phosphate buffer solution is 6.2.
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