CN114931553B - Coated enrofloxacin soluble powder and preparation method thereof - Google Patents

Coated enrofloxacin soluble powder and preparation method thereof Download PDF

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CN114931553B
CN114931553B CN202210650715.6A CN202210650715A CN114931553B CN 114931553 B CN114931553 B CN 114931553B CN 202210650715 A CN202210650715 A CN 202210650715A CN 114931553 B CN114931553 B CN 114931553B
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enrofloxacin
soluble powder
coated
parts
water
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CN114931553A (en
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孔庆强
吴章治
朱育玮
姜亚洁
孔令敏
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Shandong Baisheng Pharmaceutical Co ltd
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Shandong Baisheng Pharmaceutical Co ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • 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
    • Y02A40/00—Adaptation technologies in agriculture, forestry, livestock or agroalimentary production
    • Y02A40/70—Adaptation technologies in agriculture, forestry, livestock or agroalimentary production in livestock or poultry
    • 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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  • Health & Medical Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
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  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
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Abstract

The invention discloses coated enrofloxacin soluble powder and a preparation method thereof, wherein the coated enrofloxacin soluble powder comprises the following raw materials: enrofloxacin, coating agent, dispersing agent, solubilizer, flavoring agent and adhesive; the invention prepares a polymer by reacting methyl betacyclodextrin and diphenyl carbonate, then adopts beta-sitosterol and capsicum oleoresin to carry out homogeneous mixing, and adds trichloroacetic acid and lecithin to carry out centrifugal reaction to obtain a coating agent; carrying out high-temperature shearing reaction on hydrolyzed wheat protein, camellia oil, palm oil and polyglycerol-3 polyricinoleate under a neutral environment to obtain an adhesive; and then the enrofloxacin-coated soluble powder is obtained by a conventional soluble powder preparation process. Compared with the prior art, the enrofloxacin-coated soluble powder prepared by the invention can improve the coating rate, cover up the bitter taste of enrofloxacin, respond to gastric acid in intestinal tracts to release medicines, improve the dissolution rate, reduce adverse oxidation reaction and meet the national quality standard in various indexes.

Description

Coated enrofloxacin soluble powder and preparation method thereof
Technical Field
The invention relates to the technical field of veterinary medicine preparations, in particular to coated enrofloxacin soluble powder and a preparation method thereof.
Background
Enrofloxacin is yellowish or yellowish crystalline powder, bitter in taste, insoluble in water and also the first fluoroquinolone special for livestock and poultry. Has special effect on bacterial diseases and mycoplasma infection. Although enrofloxacin has a plurality of advantages, the enrofloxacin is insoluble in water, and the common enrofloxacin preparation has bitter taste, seriously affects the feed intake and the absorption effect of pigs, has limited use mode and has poor bioavailability.
Enrofloxacin is prepared into inclusion compound by adopting a special means, so that the solubility of the medicine can be increased to improve the bioavailability of the medicine. However, the existing inclusion compound has the defects of poor drug absorption, large damage to animal intestines and stomach caused by the inclusion compound and complex preparation process. The existing bitter masking process by soluble powder is complex, and parameters in all aspects are difficult to reach national standards; low economic benefit and environmental pollution.
The cyclodextrin is used for preparing the inclusion compound in a common mode, but the inclusion compound has limitation, is easy to dilute and separate, and has high requirements on the molecular weight and water solubility of drug molecules. In addition, cyclodextrin has limited water solubility due to strong intermolecular hydrogen bonding in the crystalline state.
The invention patent CN107837235A discloses a preparation method of coated enrofloxacin soluble powder, which comprises the steps of mixing and stirring a high polymer and enrofloxacin uniformly, forming a solid under the conditions of critical temperature and high pressure, crushing the solid into coated enrofloxacin by nano-scale, adding auxiliary materials, stirring uniformly and sub-packaging. According to the invention, after the high polymer and the enrofloxacin are uniformly mixed, the mixture is crushed to the nano level by adopting the nano crushing technology, so that the enrofloxacin can be uniformly distributed in water, in addition, the anhydrous glucose is adopted as an auxiliary material, so that the dissolution rate of the enrofloxacin in water can be improved, animals can eat uniformly, the medicine consumption can not be wasted, and the cultivation cost can be reduced; the prepared enrofloxacin-coated soluble powder can completely solve the problems of solubility and palatability (bitter taste) of the medicine, and can completely meet the national quality standard requirements; the invention has the advantages of few raw material types, simple whole preparation steps, low cost and suitability for large-scale production. However, the coated enrofloxacin soluble powder prepared by the invention is difficult to release in intestinal tracts, and has low drug loading capacity and stability.
The patent CN107412189B discloses a taste-masking enrofloxacin soluble powder and a preparation method thereof, wherein the taste-masking enrofloxacin soluble powder comprises the following components in mass percent: 10 to 15 parts of enrofloxacin, 75.5 to 84.5 parts of inclusion agent, 3 to 5 parts of cosolvent, 0.5 to 1.5 parts of corrigent and 2 to 3 parts of film-forming slow-release agent. The enrofloxacin soluble powder disclosed by the invention achieves a good masking effect on the bitter taste of enrofloxacin through a molecular inclusion and spray-coating slow-release double taste masking technology, can be stirred and dissolved in water, and can be used for detecting the content according to national standard requirements. Solves the problem of poor palatability of animals fed by mixing materials at the breeding terminal, solves the problem of drinking water of poultry, improves the bioavailability of the medicine and has remarkable social and economic benefits. However, the taste-masking enrofloxacin soluble powder prepared by the method is easy to separate out in saliva, and the taste is affected.
According to the invention, through analyzing intestinal digestive juice, the coating material with the sponge structure is designed, so that the coating material has the characteristic of high capacity, hydrophilic and hydrophobic substances can be combined together, and the coating agent and the adhesive prepared by the invention have good coating effect, can regulate gastric acid in intestinal tracts to release medicines, and reduce adverse oxidation reaction.
Disclosure of Invention
In view of the defects of poor palatability, easy decomposition and deterioration and low release rate in intestinal tracts of enrofloxacin soluble powder in the prior art, the invention aims to provide coated enrofloxacin soluble powder which has good palatability and stability and can respond to gastric acid in intestinal tracts to release medicines.
In order to achieve the above object, the present invention adopts the following technical scheme:
a coated enrofloxacin soluble powder comprising the following components: enrofloxacin, coating agent, dispersing agent, solubilizer, flavoring agent and binder.
Preferably, the enrofloxacin-coated soluble powder comprises the following components in percentage by weight: 5 to 15 percent of enrofloxacin, 70 to 80 percent of coating agent, 5 to 8 percent of dispersing agent, 1 to 2 percent of solubilizer, 0.2 to 1 percent of flavoring agent and 1 to 5 percent of adhesive.
Most preferably, the enrofloxacin-coated soluble powder comprises the following components in percentage by weight: 10% of enrofloxacin, 80% of coating agent, 6% of dispersing agent, 1.5% of solubilizer, 0.5% of flavoring agent and 2% of adhesive.
Preferably, the dispersing agent is at least one of polyvinyl alcohol, microcrystalline cellulose, sucrose fatty acid ester or isomaltooligosaccharide.
Preferably, the solubilizer is at least one of Tween 80, tween 20 and propylene glycol.
Preferably, the flavoring agent is at least one of maltose, erythritol, vanillin, steviol glycoside.
The preparation method of the coated enrofloxacin soluble powder comprises the following steps: uniformly stirring and mixing enrofloxacin and an adhesive according to the formula amount, and then adding a coating agent and water, wherein the liquid-to-material ratio of the coating agent to the water is 1.5-3: 1g/mL, regulating the water temperature to 80-85 ℃, and stirring and mixing uniformly; adding dispersing agent, flavoring agent and solubilizing agent at constant temperature, stirring and mixing uniformly, preserving heat for 1-3 h, centrifuging, spray drying, controlling particle diameter to 100-300 μm, centrifuging, spray drying parameters to inlet air temperature to 175-180 ℃, outlet air temperature to 80-85 ℃, and atomizing disc rotating speed to 4000-5000 r/min to obtain enrofloxacin soluble powder.
The coating agent is prepared by the following steps of:
step 1, adding 0.5 to 2 parts of methyl betacyclodextrin and 3 to 5 parts of diphenyl carbonate into 200 to 300 parts of water, uniformly stirring, performing ultrasonic reaction in a water bath at the ultrasonic power of 200 to 400W and the water bath temperature of 90 to 100 ℃ for 3 to 8 hours, cooling the reaction mixture at normal temperature, washing with 40 to 80 parts of water, collecting solids, washing with 80 to 150 parts of absolute ethyl alcohol, and collecting solids to obtain a polymer;
step 2, adding 5 to 8 parts of beta-sitosterol, 0.1 to 0.5 part of capsicum oleoresin and 15 to 30 parts of the polymer prepared in the step 1 into 200 to 300 parts of water, mixing and homogenizing for 10 to 30 minutes at the temperature of between 80 and 100 ℃; cooling to 10-28 deg.c, adding 0.2-1 portion of lecithin, centrifuging at 2000-4000 rpm for 5-20 min, flushing precipitate with 80-150 portions of 60-85 wt% concentration alcohol water solution, and freeze drying to obtain the coating agent.
The invention prepares a polymer by diphenyl carbonate through ultrasonic-assisted crosslinking reaction with methyl betacyclodextrin, then adopts beta-sitosterol and capsicum oleoresin to carry out homogeneous mixing, and adds trichloroacetic acid and lecithin for centrifugal reaction to obtain the coating agent. Carbonyl functional groups of diphenyl carbonate are crosslinked with methyl betacyclodextrin molecules, and hydroxyl groups are helpful for forming a nano sponge structure, so that the coating performance of the methyl betacyclodextrin can be improved. The porous structure of the nano-sponge is beneficial for the drug to enter the interpenetrating network of the nano-sponge, and the drug can be dispersed in the nano-sponge structure. Further lecithin may promote the encapsulation of beta-sitosterol and polymer by capsicum oleoresin. The beta-sitosterol can react and combine with the polymer to form the coating agent with stable physical structure.
The adhesive is prepared by the following steps of: 10 to 20 parts of hydrolyzed wheat protein is dissolved in 80 to 100 parts of water, the pH is regulated to 6.0 to 8.0 by adopting 3 to 8mmol/L phosphate buffer, then 1.5 to 2.5 parts of camellia oil, 1.5 to 2.5 parts of palm oil and 0.1 to 0.3 part of polyglycerol-3 polyricinoleate are added, and the mixture is sheared for 10 to 20 minutes in a water bath at the temperature of between 60 and 80 ℃ and the shearing rate of 6000 to 10000rpm, so that the adhesive is obtained.
The enrofloxacin-coated soluble powder is prepared by combining the enrofloxacin-coated soluble powder with an adhesive, complexing the medicament and the coating agent through carbonyl bonds and hydrogen bonds, and carrying out interaction coordination between groups. The adhesive prepared by hydrolyzing the wheat protein can be adsorbed on an oil-water interface, and the refractive index and the dielectric constant of water drops are changed, so that the magnitude of van der Waals attraction between the water drops is influenced. In addition, the adhesive can be adsorbed on the surface of water drops and replace an original emulsifier to change the interface thickness and the charge, so that the space and electrostatic interaction between the water drops are changed, the oil-water interface tension is reduced, the attraction interaction between the water drops is increased, the water drops are tightly gathered together, and the adhesive can show stronger viscosity and higher structural strength when the environment is changed.
Furthermore, the binder reduces the peroxide value during storage. This is probably because peroxide present in the original oil phase is partly converted into secondary reaction products, and new primary reaction products are rarely formed. The adhesive also acts as a free radical scavenger, inhibiting the formation of hydroperoxides. In addition, transition metal ions, which are pro-oxidative adjuvants in emulsions, can be chelated and deactivated. The shelf life of the drug during storage is increased by inhibiting adverse oxidation reactions. The coated enrofloxacin soluble powder thus prepared has good storage stability.
The coated enrofloxacin soluble powder has the shell structure of the coating agent replaced by a large amount of free gastric acid molecules in the presence of gastric acid to form a soluble gastric acid/coating agent complex, and the release of capsicum oleoresin is caused by the dissolution of the coating structure, but only a small amount of capsicum oleoresin is released, and the irritation of the stomach wall can be inhibited by the formation of the soluble gastric acid/coating agent complex. Finally the gastric acid/coating agent complex is free to dissolve and be absorbed through the intestinal tract. Therefore, in the beta-sitosterol particles coated by the capsicum oleoresin, gastric acid molecules can promote the rapid dissolution and absorption of the capsicum oleoresin.
The outer bag body complex gradually dissolves in the gastric acid, resulting in the release of enrofloxacin into the dissolution medium. The enrofloxacin soluble powder has a bitter taste, and the enrofloxacin dose is progressive with the bitter taste. Because the enrofloxacin soluble powder is diluted by saliva in the oral cavity, a very small part of enrofloxacin flows out from the liquid drops, is trapped in the liquid drops after flowing out, has a layer of oil around the liquid drops, and is not easy to reach taste buds on the tongue. Reducing the perception of bitter taste in the mouth. The encapsulated enrofloxacin is released in gastric juice by the action of gastric acid, is partially hydrolyzed by proteases in the small intestinal fluid and is absorbed by intestinal cells. Thus, coated enrofloxacin soluble powder is a novel enteric controlled release material which is capable of releasing drugs in response to gastric acid in the intestine. This enteric release is not affected by pH, unlike conventional enteric coatings with pH sensitive acidic polymers. The individual difference of the drug in small intestine dissolution is small. The soluble powder can be widely applied to medicines with poor stability and palatability.
Compared with the prior art, the invention has the beneficial effects that:
1) The methyl betacyclodextrin and diphenyl carbonate react to prepare a polymer, then beta-sitosterol and capsicum oleoresin are adopted for homogeneous mixing, trichloroacetic acid and lecithin are added for centrifugal reaction to obtain a coating agent, so that the bitter taste of enrofloxacin can be covered, the dissolution rate is improved, and finally the oral bioavailability is improved;
2) The hydrolyzed wheat protein and camellia oil, palm oil and polyglycerol-3 polyricinoleate are subjected to high-temperature shearing reaction in a neutral environment to obtain the adhesive, so that the shearing modulus and viscosity can be increased, the coating rate can be improved, a synergistic effect can be generated with a coating agent, medicines are released in response to gastric acid in intestinal tracts, adverse oxidation reactions are reduced, and the shelf life of the medicines is prolonged;
3) The preparation process is simple, meets the national quality standard, is suitable for large-scale production, and provides an effective scheme for solving the problems of the dissolution rate and palatability of enrofloxacin.
Detailed Description
Example 1
The enrofloxacin-coated soluble powder is prepared by the following method: uniformly stirring and mixing 10kg of enrofloxacin and 2kg of adhesive, then adding 80kg of coating agent and 184kg of water, adjusting the water temperature to 82 ℃, and uniformly stirring and mixing; adding 6kg of microcrystalline cellulose, 0.5kg of maltose and 1.5kg of Tween 80 at the maintaining temperature, stirring and mixing uniformly, preserving heat for 2 hours, adopting centrifugal spray drying, controlling the particle size to be 100-300 mu m, controlling the centrifugal spray drying parameters to be the air inlet temperature of 180 ℃, the air outlet temperature of 82 ℃, and the rotating speed of an atomizing disk to be 4500r/min, thus obtaining the coated enrofloxacin soluble powder.
The coating agent is prepared by the following method:
step 1, adding 1kg of methyl betacyclodextrin and 4kg of diphenyl carbonate into 250kg of water, uniformly stirring, performing ultrasonic reaction in a water bath with the ultrasonic power of 300W and the water bath temperature of 100 ℃ for 5 hours, cooling the reaction mixture at normal temperature, washing with 50kg of water, collecting solids, washing with 100kg of absolute ethyl alcohol, and collecting solids to obtain a polymer;
step 2, adding 6.0kg of beta-sitosterol, 0.2kg of capsicum oleoresin and 20kg of the polymer prepared in the step 1 into 220kg of water, mixing and homogenizing for 20 minutes at 90 ℃ by using a homogenizer; after cooling to 25 ℃, 0.4kg of lecithin was added, the reaction was carried out by centrifugation at 3000rpm for 10min, the precipitate was washed with 100kg of 75wt% aqueous ethanol solution, and the coating agent was obtained by freeze-drying.
The adhesive is prepared by the following method: 15kg of hydrolyzed wheat protein is dissolved in 85kg of water, the pH is adjusted to 7.0 by using 5mmol/L of phosphate buffer, then 1.9kg of camellia oil, 1.9kg of palm oil and 0.2kg of polyglycerol-3 polyricinoleate are added, and the mixture is sheared for 15 minutes in a water bath at 70 ℃ with a shearing rate of 8000rpm, so that the adhesive is obtained.
Example 2
The process for preparing coated enrofloxacin soluble powder is essentially the same as in example 1, the only difference being that: the preparation method of the coating agent is inconsistent.
The preparation steps of the coating agent are as follows:
step 1, adding 1kg of methyl betacyclodextrin into 250kg of water, uniformly stirring, performing ultrasonic reaction in a water bath with the ultrasonic power of 300W and the water bath temperature of 100 ℃ for 5 hours, cooling the reaction mixture at normal temperature, washing with 50kg of water, collecting solids, washing with 100kg of absolute ethyl alcohol, and collecting solids to obtain a polymer;
step 2, adding 6.0kg of beta-sitosterol, 0.2kg of capsicum oleoresin and 20kg of the polymer prepared in the step 1 into 220kg of water, mixing and homogenizing for 20 minutes at 90 ℃ by using a homogenizer; after cooling to 25 ℃, 0.4kg of lecithin was added, the reaction was carried out by centrifugation at 3000rpm for 10min, the precipitate was washed with 100kg of 75wt% aqueous ethanol solution, and the coating agent was obtained by freeze-drying.
The adhesive was the same as in example 1.
Example 3
The process for preparing coated enrofloxacin soluble powder is essentially the same as in example 1, the only difference being that: the preparation method of the coating agent is inconsistent.
The preparation steps of the coating agent are as follows:
step 1, adding 1kg of methyl betacyclodextrin and 4kg of diphenyl carbonate into 250kg of water, uniformly stirring, performing ultrasonic reaction in a water bath with the ultrasonic power of 300W and the water bath temperature of 100 ℃ for 5 hours, cooling the reaction mixture at normal temperature, washing with 50kg of water, collecting solids, washing with 100kg of absolute ethyl alcohol, and collecting solids to obtain a polymer;
step 2, adding 0.2kg of capsicum oleoresin and 20kg of the polymer prepared in the step 1 into 220kg of water, mixing and homogenizing for 20 minutes at 90 ℃ by using a homogenizer; after cooling to 25 ℃, 0.4kg of lecithin was added, the reaction was carried out by centrifugation at 3000rpm for 10min, the precipitate was rinsed with 100kg of 75wt% aqueous ethanol solution, and the resulting coating was freeze-dried.
The adhesive was the same as in example 1.
Example 4
The process for preparing coated enrofloxacin soluble powder is essentially the same as in example 1, the only difference being that: the preparation method of the coating agent is inconsistent.
The preparation steps of the coating agent are as follows:
step 1, adding 1kg of methyl betacyclodextrin and 4kg of diphenyl carbonate into 250kg of water, uniformly stirring, performing ultrasonic reaction in a water bath with the ultrasonic power of 300W and the water bath temperature of 100 ℃ for 5 hours, cooling the reaction mixture at normal temperature, washing with 50kg of water, collecting solids, washing with 100kg of absolute ethyl alcohol, and collecting solids to obtain a polymer;
step 2, adding 6.0kg of beta-sitosterol, 0.2kg of capsicum oleoresin and 20kg of the polymer prepared in the step 1 into 220kg of water, mixing and homogenizing for 20 minutes at 90 ℃ by using a homogenizer; after cooling to 25 ℃, centrifugal reaction is carried out for 10min at 3000rpm, 100kg of 75wt% ethanol aqueous solution is used for washing the precipitate, and the coating agent is obtained after freeze drying.
The adhesive was the same as in example 1.
Comparative example 1
The process for preparing coated enrofloxacin soluble powder is essentially the same as in example 1, the only difference being that: the preparation method of the coating agent is inconsistent.
The preparation steps of the coating agent are as follows:
step 1, adding 1kg of methyl betacyclodextrin into 250kg of water, uniformly stirring, performing ultrasonic reaction in a water bath with the ultrasonic power of 300W and the water bath temperature of 100 ℃ for 5 hours, cooling the reaction mixture at normal temperature, washing with 50kg of water, collecting solids, washing with 100kg of absolute ethyl alcohol, and collecting solids to obtain a polymer;
step 2, adding 0.2kg of capsicum oleoresin and 20kg of the polymer prepared in the step 1 into 220kg of water, mixing and homogenizing for 20 minutes at 90 ℃ by using a homogenizer; after cooling to 25 ℃, centrifugal reaction is carried out for 10min at 3000rpm, 100kg of 75wt% ethanol aqueous solution is used for washing the precipitate, and the coating agent is obtained after freeze drying.
The adhesive was the same as in example 1.
Comparative example 2
The process for preparing coated enrofloxacin soluble powder is essentially the same as in example 1, the only difference being that: the preparation method of the coated enrofloxacin soluble powder is free from adding coating agent.
Comparative example 3
The process for preparing coated enrofloxacin soluble powder is essentially the same as in example 1, the only difference being that: the preparation method of the enrofloxacin soluble powder is free from adding adhesives.
Test example 1
Stability test
Uniformly spreading 100g of enrofloxacin soluble powder prepared in the examples and the comparative examples in a transparent polyester container, wherein the upper part of the container is opened; the temperature was set to 35℃and the transparent polyester bag was continuously irradiated from the top with a 30W ultraviolet light source, and after 21 days irradiation, the sample was observed for color change and caking, weighed, and tested three times for each group, and an average value was obtained.
The test results are shown in Table 1
Table 1: stability test results
Scheme for the production of a semiconductor device Color of Caking condition Rate of mass change
Example 1 White powder No caking -0.27％
Example 2 Pale yellow powder Small amount of caking -0.67％
Example 3 Pale yellow powder Very little caking -0.52％
Example 4 Pale yellow powder Very little caking -0.59％
Comparative example 1 Yellow powder Medium caking -1.19％
Comparative example 2 Yellow powder Medium caking -1.31％
Comparative example 3 Yellow powder Medium caking -1.72％
As can be seen from the test results of Table 1, the coated enrofloxacin soluble powder prepared in example 1 has the best stability, probably because diphenyl carbonate is used for preparing a polymer through ultrasonic-assisted crosslinking reaction with methyl betacyclodextrin, beta-sitosterol and capsicum oleoresin are used for carrying out homogenization mixing, trichloroacetic acid and lecithin are added for centrifugal reaction, and the coating agent is obtained. Carbonyl functional groups of diphenyl carbonate are crosslinked with methyl betacyclodextrin molecules, and hydroxyl groups are helpful for forming a nano sponge structure, so that the coating performance of the methyl betacyclodextrin is improved. The porous structure of the nano-sponge is beneficial for the drug to enter the interpenetrating network of the nano-sponge, and the drug can be dispersed in the nano-sponge structure. Further lecithin may promote the encapsulation of beta-sitosterol and polymer by capsicum oleoresin. The beta-sitosterol can react and combine with the polymer to form the coating agent with stable physical structure.
The enrofloxacin-coated soluble powder is prepared by combining the enrofloxacin-coated soluble powder with an adhesive, complexing the medicament and the coating agent through carbonyl bonds and hydrogen bonds, and carrying out interaction coordination between groups. The adhesive prepared by hydrolyzing the wheat protein can be adsorbed on an oil-water interface, and the refractive index and the dielectric constant of water drops are changed, so that the magnitude of van der Waals attraction between the water drops is influenced. In addition, the adhesive can be adsorbed on the surface of water drops and replace an original emulsifier to change the interface thickness and the charge, so that the space and electrostatic interaction between the water drops are changed, the oil-water interface tension is reduced, the attraction interaction between the water drops is increased, the water drops are tightly gathered together, and the adhesive can show stronger viscosity and higher structural strength when the environment is changed.
Furthermore, the binder reduces the peroxide value during storage. This is probably because peroxide present in the original oil phase is partly converted into secondary reaction products, and new primary reaction products are rarely formed. The adhesive also acts as a free radical scavenger, inhibiting the formation of hydroperoxides. In addition, transition metal ions, which are pro-oxidative adjuvants in emulsions, can be chelated and deactivated. The shelf life of the drug during storage is increased by inhibiting adverse oxidation reactions. The coated enrofloxacin soluble powder thus prepared has good storage stability.
Test example 2
Determination of drug release rate
Reference paper (preparation of mequindox taste masking nano-pro-drug and in vitro release, authors: bao Guangming, university of agriculture in Jiangxi, 2019).
Artificial gastric juice: taking 16.4mL of concentrated hydrochloric acid, adding 800mL of water and 10g of pepsin, shaking uniformly, adding water to dilute into 1000mL, and regulating to obtain the artificial gastric juice.
Accurately weighing 100mg of enrofloxacin-coated soluble powder, dispersing in 100mL of artificial gastric juice, magnetically stirring, taking the artificial gastric juice after stirring for 30 seconds, filtering with 450nm water-based filter membranes respectively, uniformly shaking the filtrate, and measuring the enrofloxacin concentration at 271nm by an absorbance method to evaluate the drug release rate. The measurement was performed three times to obtain an average value. The test results are shown in Table 2.
Test example 3
Taste masking effect test
Selecting 80 healthy pork pigs of 50-60 kg, randomly dividing the healthy pork pigs into 8 groups of 10 pork pigs; the enrofloxacin soluble powder coated in 24g is mixed with conventional pig feed to obtain 240kg of feed, and 30kg of non-drug conventional pig feed is prepared; each group is respectively used for isolating 30kg of feed which is fed and configured, the control group is used for feeding non-drug feed, the feeding trough is cleaned after 1.5 hours, the weight of the residual feed is weighed, and the feeding effect is evaluated by calculating the feeding amount; the above test was repeated 1 time in the next week, and the average of three tests was taken. The test results are shown in Table 2.
Table 2: drug release rate and feed intake test results
Test protocol Drug release rate (%) Average feed intake (%)
Example 1 68.9 86.5
Example 2 54.2 71.4
Example 3 57.2 71.2
Example 4 59.1 70.5
Comparative example 1 51.3 53.5
Comparative example 2 48.5 49.7
Comparative example 3 68.6 50.2
Control group - 87.3
As can be seen from the test results of table 2, the drug release rate of example 1 is highest, and the average feed intake is the greatest in examples and comparative examples, probably because the coated enrofloxacin soluble powder prepared in the present invention, in the presence of gastric acid, the shell structure of the coating agent is replaced by a large amount of free gastric acid molecules to form a soluble gastric acid/coating agent complex, and the release of capsicum oleoresin is caused by the dissolution of the coating structure, but only a small amount of capsicum oleoresin is released, and the irritation to the stomach wall can be suppressed by the formation of the soluble gastric acid/coating agent complex. Finally the gastric acid/coating agent complex is free to dissolve and be absorbed through the intestinal tract. Thus, in the capsicum oleoresin coated beta-sitosterol particles, gastric acid molecules promote rapid dissolution of capsicum oleoresin.
The outer bag body complex gradually dissolves in the gastric acid, resulting in the release of enrofloxacin into the dissolution medium. The enrofloxacin soluble powder has a bitter taste, and the enrofloxacin dose is progressive with the bitter taste. In example 1, pigs had the greatest feed intake, probably because a very small portion of enrofloxacin was released from the drops after the enrofloxacin soluble powder was diluted in the mouth with saliva, and was trapped in the drops after the release, and there was a layer of oil around the drops, which was not likely to reach the taste buds on the tongue. Reducing the perception of bitter taste in the mouth. The encapsulated enrofloxacin is released in gastric juice by the action of gastric acid, is partially hydrolyzed by proteases in the small intestinal fluid and is absorbed by intestinal cells. Thus, coated enrofloxacin soluble powder is a novel enteric controlled release material which is capable of releasing drugs in response to gastric acid in the intestine. This enteric release is not affected by pH, unlike conventional enteric coatings with pH sensitive acidic polymers. The individual difference of the drug in small intestine dissolution is small. The soluble powder can be widely applied to medicines with poor stability and palatability.

Claims (6)

1. The enrofloxacin-coated soluble powder is characterized by comprising the following components in percentage by weight: 5-15% of enrofloxacin, 70-80% of coating agent, 5-8% of dispersing agent, 1-2% of solubilizer, 0.2-1% of flavoring agent and 1-5% of adhesive;
the coating agent is prepared by the following steps of:
step 1, adding 0.5-2 parts of methyl betacyclodextrin and 3-5 parts of diphenyl carbonate into 200-300 parts of water, uniformly stirring, performing ultrasonic reaction in a water bath at the ultrasonic power of 200-400W and the water bath temperature of 90-100 ℃ for 3-8 hours, cooling the reaction mixture at normal temperature, washing with 40-80 parts of water, collecting solids, washing with 80-150 parts of absolute ethyl alcohol, and collecting solids to obtain a polymer;
step 2, adding 5-8 parts of beta-sitosterol, 0.1-0.5 part of capsicum oleoresin and 15-30 parts of the polymer prepared in the step 1 into 200-300 parts of water, mixing at 80-100 ℃ and homogenizing for 10-30 minutes; cooling to 10-28 ℃, adding 0.2-1 part of lecithin, centrifuging at 2000-4000 rpm for 5-20 min, flushing the precipitate with 80-150 parts of 60-85 wt% ethanol aqueous solution, and freeze-drying to obtain a coating agent;
the adhesive is prepared by the following steps of:
10-20 parts of hydrolyzed wheat protein is dissolved in 80-100 parts of water, the pH is adjusted to 6.0-8.0 by adopting 3-8 mmol/L of phosphate buffer, then 1.5-2.5 parts of camellia oil, 1.5-2.5 parts of palm oil and 0.1-0.3 part of polyglycerol-3 polyricinoleate are added, and the mixture is sheared for 10-20 minutes in a water bath at 60-80 ℃ with the shearing rate of 6000-10000 rpm, so that the adhesive is obtained.
2. The enrofloxacin-coated soluble powder of claim 1, comprising the following components in weight percent: 10% of enrofloxacin, 80% of coating agent, 6% of dispersing agent, 1.5% of solubilizer, 0.5% of flavoring agent and 2% of adhesive.
3. A coated enrofloxacin soluble powder as claimed in claim 1 or 2 wherein: the dispersing agent is at least one of polyvinyl alcohol, microcrystalline cellulose, sucrose fatty acid ester or isomaltooligosaccharide.
4. A coated enrofloxacin soluble powder as claimed in claim 1 or 2 wherein: the solubilizer is at least one of Tween 80, tween 20 and propylene glycol.
5. A coated enrofloxacin soluble powder as claimed in claim 1 or 2 wherein: the flavoring agent is at least one of maltose, erythritol, vanillin and stevioside.
6. The method for preparing the coated enrofloxacin soluble powder of any one of claims 1 to 5, comprising the steps of: uniformly stirring and mixing enrofloxacin and an adhesive according to the formula amount, and then adding a coating agent and water, wherein the liquid-to-material ratio of the coating agent to the water is 1.5-3: 1g/mL, adjusting the water temperature to 80-85 ℃, and uniformly stirring and mixing; and (3) further adding a dispersing agent, a flavoring agent and a solubilizing agent at a constant temperature, stirring and mixing uniformly, preserving heat for 1-3 hours, adopting centrifugal spray drying, controlling the particle size to be 100-300 mu m, controlling the air inlet temperature to be 175-180 ℃, the air outlet temperature to be 80-85 ℃, and controlling the rotating speed of an atomizing disc to be 4000-5000 r/min to obtain the enrofloxacin-coated soluble powder.
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