CN113750049A - Soluble powder of antibacterial composition and preparation method thereof - Google Patents

Soluble powder of antibacterial composition and preparation method thereof Download PDF

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CN113750049A
CN113750049A CN202111170108.1A CN202111170108A CN113750049A CN 113750049 A CN113750049 A CN 113750049A CN 202111170108 A CN202111170108 A CN 202111170108A CN 113750049 A CN113750049 A CN 113750049A
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soluble powder
antibacterial
antibacterial composition
linking agent
surfactant
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CN113750049B (en
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李克钦
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Shandong Huimin Desaike Biotechnology Co ltd
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Shandong Huimin Desaike Biotechnology 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
    • A61K9/145—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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
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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
    • A61K9/143—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 inorganic compounds
    • 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
    • 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

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Abstract

The invention belongs to the field of antibacterial drugs, and particularly relates to soluble powder of an antibacterial composition and a preparation method thereof. The invention provides soluble powder of an antibacterial composition, which comprises the following preparation raw materials: an antibacterial component, a cross-linking agent, a surfactant, a pH regulator, a bitterness blocker and a filler; the antibacterial component comprises tiamulin fumarate, tylosin tartrate or tilmicosin; the cross-linking agent comprises one or more of water-soluble carrageenan, glucan and chitin; the surfactant comprises polyvinylpyrrolidone. The antibacterial composition provided by the invention is high in water solubility and good in odor covering property.

Description

Soluble powder of antibacterial composition and preparation method thereof
Technical Field
The invention belongs to the field of antibacterial drugs, and particularly relates to soluble powder of an antibacterial composition and a preparation method thereof.
Background
Veterinary antibiotics are a general term for a class of drugs used for treating or preventing the occurrence of diseases in livestock or for increasing economic benefits by accelerating the growth of animals. However, some drugs in veterinary antibiotics, such as tiamulin, tavermectin, tylosin and the like, have strong pungent odor, so that the animal compliance is poor, and great inconvenience is brought to disease control. In the prior art, a protective layer is formed on the surface of an antibacterial component by adopting a coating agent to reduce odor, however, the odor masking effect is not good by adopting a coating technology. In addition, the medicine has the problem of poor water solubility, and is not beneficial to animals to take.
Disclosure of Invention
In view of the above, the invention provides soluble powder of an antibacterial composition, which has high water solubility and good odor covering property.
In order to achieve the above purpose, the invention provides the following technical scheme:
the invention provides soluble powder of an antibacterial composition, which is characterized by comprising the following preparation raw materials: an antibacterial component, a cross-linking agent, a surfactant, a pH regulator, a bitterness blocker and a filler;
the antibacterial component comprises tiamulin fumarate, tylosin tartrate or tilmicosin;
the cross-linking agent comprises one or more of water-soluble carrageenan, glucan and chitin;
the surfactant comprises polyvinylpyrrolidone.
Preferably, when the antibacterial component is tiamulin fumarate, the antibacterial component comprises the following preparation raw materials in percentage by mass:
Figure BDA0003292626220000011
preferably, when the antibacterial component is tylosin tartrate, the antibacterial component comprises the following preparation raw materials in percentage by mass:
Figure BDA0003292626220000021
preferably, when the antibacterial component is tilmicosin, the antibacterial component comprises the following preparation raw materials in percentage by mass:
Figure BDA0003292626220000022
preferably, the pH adjusting agent comprises tartaric acid.
Preferably, the bitter taste blocker comprises one or more of adenosine phosphate, guanosine phosphate and monosodium glutamate.
Preferably, the filler comprises soluble starch and/or sodium hexametaphosphate.
The invention also provides a preparation method of the soluble powder of the antibacterial composition, which comprises the following steps:
first mixing a cross-linking agent, a surfactant, a bitter blocker and water to obtain a first solution;
carrying out second mixing on the first solution and the antibacterial component to obtain a primary mixed wet material;
thirdly mixing the primary mixed feed liquid with a pH regulator and a filling agent to obtain a granulation wet material;
and sequentially granulating, drying and finishing the granulated wet material to obtain the soluble powder of the antibacterial composition.
Preferably, the temperature of the first mixing is 40-60 ℃ and the time is 15-30 min.
Preferably, the drying mode is boiling drying, and the drying temperature is 45-60 ℃.
The invention provides soluble powder of an antibacterial composition, which comprises the following preparation raw materials: an antibacterial component, a cross-linking agent, a surfactant, a pH regulator, a bitterness blocker and a filler; the antibacterial component comprises tiamulin fumarate, tylosin tartrate or tilmicosin; the cross-linking agent comprises one or more of water-soluble carrageenan, glucan or chitin. The cross-linking agent selected by the invention is a linear molecule, the cross-linking agent is mixed with the surfactant, the surfactant enables the linear cross-linking agent to form series connection and form a criss-cross grid structure, then, the antibacterial component and the cross-linking agent have affinity action, and after the antibacterial component and the cross-linking agent are mixed, the antibacterial component and the cross-linking agent are trapped in the grid structure formed by the cross-linking agent and the surfactant due to the affinity action and then are combined together. Meanwhile, the cross-linking agent can be dissolved in water, so that the antibacterial component combined with the cross-linking agent can be stably distributed in the water, and the water solubility of the antibacterial component is enhanced. Meanwhile, when the antibacterial component soluble powder combined by the cross-linking agent is dissolved in water for use, the antibacterial component is easily locked in the water, so that the smell is not easily volatilized into the air, and the water solubility of the antibacterial composition is also improved by virtue of the hydrophilic characteristic of the surfactant.
Further, the soluble powder of the antibacterial composition comprises the following preparation raw materials in percentage by mass: 46% of tiamulin fumarate, 10-16% of cross-linking agent, 10-16% of surfactant, 1-5% of pH regulator, 3-6% of bitter blocker and 11-30% of filler. When the antibacterial component is tiamulin fumarate, the cross-linking agent, the surfactant and the tiamulin fumarate are mutually acted, so that the tiamulin fumarate is favorably trapped in a grid structure formed by the cross-linking agent and the surfactant, and is easily locked in water when being dissolved in water, and the smell is not easily volatilized into the air. In addition, the cross-linking agent in the above amount can stabilize the stable distribution of the antibacterial component in water and enhance the water solubility. In addition, the cross-linking agent disclosed by the invention is low in viscosity, and the viscosity is not increased and the processability is good after the cross-linking agent is cross-linked with tiamulin fumarate with high viscosity.
The data of the embodiment shows that the soluble powder of the antibacterial composition containing tiamulin fumarate provided by the invention has good water solubility, 1g of the product is dissolved in 50mL of purified water, and the solution is clear and transparent; furthermore, the odor of the product is well masked and the dose taken per animal can be completed within 2 hours at the clinical dose.
Further, the soluble powder of the antibacterial composition comprises the following preparation raw materials in percentage by mass: 31.3% of tylosin tartrate, 20-35% of cross-linking agent, 10-15% of surfactant, 2-5% of pH regulator, 3-6% of bitter blocker and 7.7-33.7% of filler. When the antibacterial component is tylosin tartrate, the crosslinking agent, the surfactant and the tylosin tartrate in the above amounts are adopted to interact, so that the tylosin fumarate is favorably trapped in a grid structure formed by the crosslinking agent and the surfactant, and then the tylosin tartrate is combined together. Meanwhile, the cross-linking agent with the dosage stabilizes the stable distribution of the tylosin tartrate in water, and the tylosin tartrate is not crystallized and separated out in normal-temperature water, so that the solubility of the tylosin tartrate in the normal-temperature water is improved. Moreover, the hydrophilic effect can be better exerted by setting the dosage of the surfactant to be in the range, the hydrophilicity of the tylosin tartrate in normal-temperature water is increased, and the solubility of the tylosin tartrate is improved.
The data of the examples show that the solubility of the tylosin tartrate-containing soluble powder in water at 5 ℃ reaches 50000ppm, the solubility of the tylosin tartrate-containing soluble powder in water at 22 ℃ reaches 10000ppm, and the obtained solution is clear and transparent. The product provided by the invention has good animal palatability, and the dose taken by each animal can be finished within 2 hours under the clinical use dose.
Further, the soluble powder of the antibacterial composition comprises the following preparation raw materials in percentage by mass: 37.5% of tilmicosin, 15-20% of cross-linking agent, 15-20% of surfactant, 5-12% of pH regulator, 1-5% of bitter blocking agent and 3-24% of filler. According to the invention, the cross-linking agent with the dosage is combined with the tilmicosin, so that the distribution of the tilmicosin in water can be better stabilized, and the tilmicosin can be uniformly distributed in the aqueous solution. The combined tilmicosin has stronger hydrophilicity under the action of a surfactant, so that the tilmicosin has very strong water solubility.
The data of the embodiment show that the soluble powder of the antibacterial composition containing tilmicosin provided by the invention has good water solubility, 40g of the soluble powder is dissolved in 100mL of purified water, the solution is clear and transparent.
The invention also provides a preparation method of the soluble powder of the antibacterial composition, which comprises the following steps: first mixing a cross-linking agent, a surfactant, a bitter blocker and water to obtain a first solution; carrying out second mixing on the first solution and the antibacterial component to obtain primary mixed feed liquid; thirdly mixing the primary mixed feed liquid with a pH regulator and a filling agent to obtain mixed feed liquid; and sequentially granulating and drying the mixed material liquid to obtain the soluble powder of the antibacterial composition. According to the invention, a first solution is obtained by mixing a cross-linking agent, a surfactant, a bitter blocking agent and water, a mixed aqueous solution is formed by utilizing the characteristics of the cross-linking agent, the surfactant and the hydrophilic property of the water, and then the mixed aqueous solution is mixed with an antibacterial component, so that the cross-linking agent can be uniformly dispersed in the antibacterial component, and the antibacterial component can be better trapped in a grid structure formed by the cross-linking agent and the surfactant. The cross-linking agent and the surfactant can be easily dissolved in water, so that the cross-linking agent and the surfactant in the combined product can play a role of a bridge so as to enhance the solubility of the cross-linked product in water.
Detailed Description
The soluble powder of the antibacterial composition provided by the invention comprises the following preparation raw materials: an antibacterial component, a cross-linking agent, a surfactant, a pH regulator, a bitterness blocker and a filler;
the antibacterial component comprises tiamulin fumarate, tylosin tartrate or tilmicosin;
the cross-linking agent comprises one or more of water-soluble carrageenan, glucan and chitin;
the surfactant comprises polyvinylpyrrolidone.
In the present invention, unless otherwise specified, all the starting materials required for the preparation are commercially available products well known to those skilled in the art.
The raw materials for preparing the soluble powder of the antibacterial composition comprise a cross-linking agent, wherein the cross-linking agent comprises one or more of water-soluble carrageenan, glucan and chitin, and preferably the water-soluble carrageenan, the glucan or the chitin.
The raw materials for preparing the soluble powder of the antibacterial composition comprise a surfactant, wherein the surfactant preferably comprises polyvinylpyrrolidone; the binder preferably comprises one or more of polyvinylpyrrolidone K15, polyvinylpyrrolidone K17, polyvinylpyrrolidone K30, polyvinylpyrrolidone K60 or polyvinylpyrrolidone K90, and more preferably a mixture of polyvinylpyrrolidone K15 and polyvinylpyrrolidone K30, a mixture of polyvinylpyrrolidone K17 and polyvinylpyrrolidone K60 or a mixture of polyvinylpyrrolidone K17 and polyvinylpyrrolidone K90.
The raw materials for preparing the soluble powder of the antibacterial composition comprise a pH regulator. In the present invention, the pH adjuster preferably includes tartaric acid.
The raw materials for preparing the soluble powder of the antibacterial composition comprise a bitter blocker; the bitter taste blocker preferably comprises one or more of adenosine phosphate, guanosine phosphate and monosodium glutamate, and is further preferably adenosine phosphate, guanosine phosphate or monosodium glutamate.
The raw materials for preparing the soluble powder of the antibacterial composition comprise a filling agent, and the filling agent preferably comprises soluble starch and/or sodium hexametaphosphate.
In the present invention, when the antibacterial component is preferably tiamulin fumarate; the soluble powder of the antibacterial composition preferably comprises the following preparation raw materials in percentage by mass: 46% of tiamulin fumarate, 10-16% of cross-linking agent, 10-16% of surfactant, 1-5% of pH regulator, 3-6% of bitter blocker and 11-30% of filler.
Hereinafter, the antibacterial composition soluble powder having the antibacterial component of tiamulin fumarate will be described in detail, and when described, the antibacterial composition soluble powder having the antibacterial component of tiamulin fumarate is referred to as tiamulin fumarate-containing antibacterial composition soluble powder.
The antibacterial composition soluble powder containing tiamulin fumarate provided by the invention comprises 46% of tiamulin fumarate in percentage by mass.
Based on the mass percentage of the tiamulin fumarate, the antibacterial composition soluble powder containing the tiamulin fumarate comprises 10-16% of a cross-linking agent by mass percentage, and is further preferably 12-16%.
The antibacterial composition soluble powder containing tiamulin fumarate comprises 10-16% by mass of a surfactant, and is further preferably 13-16% by mass of tiamulin fumarate.
The antibacterial composition soluble powder containing tiamulin fumarate comprises 1-5% by mass of a pH regulator, and preferably 2-3% by mass of tiamulin fumarate.
The antibacterial composition soluble powder containing tiamulin fumarate comprises 3-6% by mass of bitter blocker, and preferably 5-6% by mass of tiamulin fumarate. .
The antibacterial composition soluble powder containing tiamulin fumarate comprises 11-30% by mass of a filler, and preferably 14-20% by mass of tiamulin fumarate.
In the present invention, when the antibacterial component is preferably tylosin tartrate; the soluble powder of the antibacterial composition preferably comprises the following preparation raw materials in percentage by mass: 31.3% of tylosin tartrate, 20-35% of cross-linking agent, 10-15% of surfactant, 2-5% of pH regulator, 3-6% of bitter blocker and 7.7-33.7% of filler. Hereinafter, the soluble powder of the antibacterial composition having the antibacterial component of tylosin tartrate will be described in detail, and when described, the soluble powder of the antibacterial composition having the antibacterial component of tylosin tartrate will be referred to as a soluble powder of the antibacterial composition containing tylosin tartrate.
The antibacterial composition soluble powder containing tiamulin fumarate provided by the invention comprises 31.3% of tiamulin tartrate by mass.
The antibacterial composition soluble powder containing the tylosin tartrate preferably comprises 20-35% of a cross-linking agent, and more preferably 28-35% of the antibacterial composition soluble powder containing the tylosin tartrate.
In the invention, the antibacterial composition soluble powder containing the tylosin tartrate preferably comprises 10-15% of surfactant, and more preferably 13-15% of surfactant.
The antibacterial composition soluble powder containing the tylosin tartrate preferably comprises 2-5% of a pH regulator, and more preferably 4-5% of the antibacterial composition soluble powder based on the percentage of the tylosin tartrate.
In the invention, the antibacterial composition soluble powder containing the tylosin tartrate preferably comprises 3-6% of bitter blocker, and more preferably 3-6% of the bitter blocker.
In the invention, the antibacterial composition soluble powder containing the tylosin tartrate preferably comprises 7.7-33.7% of a filler, and more preferably 15-25% of the filler.
In the present invention, when the antibacterial component is preferably tilmicosin; the soluble powder of the antibacterial composition preferably comprises the following preparation raw materials in percentage by mass: tilmicosin 37.5%; 15-20% of a cross-linking agent; 15-20% of a surfactant; 5-12% of a pH regulator; 1-5% of a bitter blocker; and 3-24% of filling. Hereinafter, the soluble powder of the antibacterial composition having an antibacterial component of tilmicosin will be described in detail, and when the soluble powder of the antibacterial composition having an antibacterial component of tilmicosin is described, it is referred to as the soluble powder of the antibacterial composition containing tilmicosin.
The antibacterial composition soluble powder containing tiamulin fumarate provided by the invention comprises 37.5% of tilmicosin in percentage by mass.
The antibacterial composition soluble powder containing tylosin tartrate preferably comprises 15-20% of cross-linking agent, and more preferably 15-20% of the antibacterial composition soluble powder based on the percentage content of tilmicosin.
The antibacterial composition soluble powder containing the tylosin tartrate preferably comprises 15-20% of surfactant, and more preferably 14-17% of the surfactant in percentage by weight of tilmicosin.
The antibacterial composition soluble powder containing the tylosin tartrate preferably comprises 5-12% of pH regulator, and more preferably 4-5% of the antibacterial composition soluble powder based on the percentage content of tilmicosin.
The antibacterial composition soluble powder containing tylosin tartrate preferably comprises 1-5% of bitter blocker, and more preferably 2-5% of bitter blocker in percentage by weight of tilmicosin.
The antibacterial composition soluble powder containing the tylosin tartrate preferably comprises 3-24% of a filling agent, and more preferably 15-20% of the filling agent in percentage by weight of tilmicosin.
The invention also provides a preparation method of the soluble powder of the antibacterial composition, which comprises the following steps:
first mixing a cross-linking agent, a surfactant, a bitter blocker and water to obtain a first solution;
carrying out second mixing on the first solution and the antibacterial component to obtain a primary mixed wet material;
thirdly mixing the primary mixed feed liquid with a pH regulator and a filling agent to obtain a granulation wet material;
and sequentially granulating, drying and finishing the granulated wet material to obtain the soluble powder of the antibacterial composition.
The present invention first mixes a cross-linking agent, a surfactant, a bitter blocker, and water to obtain a first solution.
In the present invention, the water is preferably purified water.
In the present invention, the first mixing mode is preferably stirring, and the rotation speed of the stirring is preferably 20 to 60rpm, and more preferably 30 to 40 rpm. In the invention, the temperature of the first mixing is preferably 40-60 ℃, more preferably 50-60 ℃, and the time of the first mixing is preferably 15-30 min.
After the first solution is obtained, the first solution and the antibacterial component are subjected to second mixing to obtain a primary mixed wet material.
In the invention, the second mixing is preferably to spray the first solution to the antibacterial component, the temperature of the second mixing is preferably 40-60 ℃, and more preferably 50-60 ℃, the second mixing is preferably to stir, and the rotation speed of the stirring is preferably 30-50 rpm; the time is preferably 10-20 min.
After the primary mixed wet material is obtained, the primary mixed material liquid, the pH regulator and the filler are subjected to third mixing to obtain the granulation wet material.
In the present invention, the third mixing is preferably wet mixing; the wet mixing is preferably carried out under the condition of stirring, and the rotation speed of the stirring is preferably 20-60 rpm, and more preferably 30-50 rpm; the time for the third mixing is preferably 15-20 min. In the present invention, the wet mixing apparatus is preferably a wet mixer.
And sequentially granulating, drying and finishing the granulated wet material to obtain the soluble powder of the antibacterial composition.
In the invention, the granulation is preferably wet granulation, and the equipment for wet granulation is preferably a wet granulator.
In the present invention, the drying is preferably boiling drying; the drying temperature is preferably 45-60 ℃, the drying time is not particularly limited, and the moisture percentage content in the dried material is 1.5-2.5%.
In the present invention, the granulating device is preferably a granulator. In the invention, the particle size of the soluble powder of the antibacterial composition is preferably 20-80 meshes, and more preferably 40-70 meshes.
In order to further illustrate the present invention, the following examples are given to describe the soluble powder of the antibacterial composition and the preparation method thereof in detail, but they should not be construed as limiting the scope of the present invention.
The reagents used in the following examples are all commercially available.
Reagents used in the examples: tiamulin fumarate: supplied by Xinjiang Zhejiang sunshine Biotechnology, Inc.; tylosin tartrate: supplied by grazing biopharmaceutical industry ltd in inner mongolia; tilmicosin: supplied by Ningxia Tairui pharmaceuticals, Inc.; polyvinylpyrrolidone (PVP) K15, polyvinylpyrrolidone (PVP) K17, polyvinylpyrrolidone (PVP) K30, polyvinylpyrrolidone (PVP) K60, polyvinylpyrrolidone (PVP) K90: supplied by Hubeixin Rundchemical Co., Ltd; water-soluble carrageenan: dextran, supplied by nicotineamed rong marine biologies, inc, was supplied by xuzhou saich biotechnology, inc; chitin: from Qingdao cloud Zey corporation; tartaric acid was provided by Suzhou friend high-definition industries, Inc.; adenosine phosphate (AMP): supplied by Zhengzhou spring and autumn chemical Co., Ltd; guanosine phosphate (GMP): supplied by Zhengzhou spring and autumn chemical Co., Ltd; monosodium glutamate is provided by Sanjiu monosodium glutamate Co., Ltd, Shandong; soluble starch: provided by the emerging chemical company of Qinyang city; sodium hexametaphosphate: provided by Weifang Hai Tongli chemical Limited company.
Example 1
The antibacterial composition soluble powder containing tiamulin fumarate is prepared from the following raw materials:
Figure BDA0003292626220000091
Figure BDA0003292626220000101
the preparation method comprises the following steps:
adding crosslinking agent, surfactant, and bitter blocker into purified water 15% of the total weight of the preparation, heating to 60 deg.C, stirring at 30rpm for 20min to obtain a first solution.
And putting the tiamulin fumarate into a wet mixer, starting the mixer, spraying the first solution onto the tiamulin fumarate, and mixing at the rotation speed of 50rpm for 20min to obtain a primary mixed feed liquid.
After the pH regulator and the filler were put into the wet mixer, the mixer was started and mixed at 50rpm for 20min to obtain a mixed feed liquid.
And adding the uniformly mixed feed liquid into a wet granulator for wet granulation, sucking the obtained granular antibacterial composition into a boiling drying tower in vacuum, and carrying out boiling drying at the temperature of 50 ℃ for 35min to ensure that the moisture of the material is 1.5-2.5%.
And (4) granulating the dried material by a granulator to obtain 45% tiamulin fumarate soluble powder of 20-80 meshes.
Example 2
The antibacterial composition soluble powder containing tiamulin fumarate is prepared from the following raw materials:
Figure BDA0003292626220000102
the preparation method is different from the preparation method of example 1 only in the replacement of the formula, and the rest operations and parameters are the same and are not described again.
Example 3
The antibacterial composition soluble powder containing tiamulin fumarate is prepared from the following raw materials:
Figure BDA0003292626220000111
the preparation method is different from the preparation method of example 1 only in the replacement of the formula, and the rest operations and parameters are the same and are not described again.
The performance test of the soluble powder of the antibacterial composition containing tiamulin fumarate disclosed in the embodiment 1-3 is carried out, and the test results are shown in table 1.
The detection method is tested according to the related regulation of tiamulin fumarate soluble powder in the first part of the pharmacopoeia of the people's republic of China 2020 edition. The specific performance test method is as follows:
[ PROPERTIES ] the product is white or off-white powder.
[ SOLUBILITY ] 1.0g of this product was taken, 50mL of water was added, and shaken to dissolve all the product.
[ acidity ] 0.1g of this product is taken, 10mL of water is added, and the product is dissolved, and the pH value is 3.0-6.5 according to law (appendix 0631).
[ IDENTIFICATION ] in the chromatogram recorded under the item [ CONTENT DETERMINATION ], the retention time of two main peaks of the test solution should be consistent with that of two corresponding main peaks of the reference solution.
[ RELATED MATERIALS ] taking appropriate amount of the product, dissolving with mobile phase (the mobile phase specified in the chromatographic conditions and system applicability test) and diluting to obtain solution containing 4mg per 1mL as test solution; an appropriate amount was precisely measured and quantitatively diluted with a mobile phase to prepare a solution containing 0.04mg per 1mL as a control solution. According to the chromatographic conditions under the item of content determination, 20 mu L of each of the reference solution and the test solution is precisely measured and injected into a liquid chromatograph, and the chromatogram is recorded until the retention time of the main component is 3 times. If an impurity peak exists in a chromatogram of the test solution, the area of a single impurity peak is not larger than the main peak area (1.0%) of the control solution, and the sum of the areas of the impurity peaks is not larger than 3 times (3.0%) of the main peak area of the control solution.
[ loss on drying ] the product is dried to constant weight at 105 ℃, and the loss on weight should not exceed 4.0% (appendix 0831).
[ Others ] should comply with the regulations under the soluble powder item (appendix 0113).
[ CONTENT DETERMINATION ] A proper amount of the product is taken, precisely weighed, dissolved by a mobile phase and quantitatively diluted to prepare a solution containing 4mg of tiamulin fumarate in each 1ml, shaken up and determined according to a high performance liquid chromatography (appendix 0512).
[ chromatogram conditions and System suitability test ] uses octadecylsilane chemically bonded silica as filler; methanol-ammonium carbonate solution-acetonitrile (49: 28: 23) is used as a mobile phase, the column temperature is 30 ℃, the flow rate is 1.2mL/min, and the detection wavelength is 212 nm. Respectively taking a proper amount of tiamulin fumarate reference substance and a proper amount of benzyl sulfonyl pleuromutilin reference substance, dissolving and diluting the reference substances into mixed solutions containing 0.08mg of each 1mL of the reference substances by using a mobile phase, and taking the mixed solutions as system applicability solutions; and (3) injecting 20 mu L of the system applicability solution into a liquid chromatograph, recording a chromatogram, wherein the separation degree of tiamulin and the phenylmethanesulfonyl pleuromutilin peak is more than 2.0, and the number of theoretical plates is not less than 10000 according to the tiamulin peak.
Taking about 0.2g of the product, precisely weighing, placing in a 50mL measuring flask, dissolving with mobile phase, diluting to scale, using as test solution, precisely weighing 20 μ L, injecting into a liquid chromatograph, and recording chromatogram; taking another tiamulin fumarate reference substance for determination by the same method. Calculating according to the peak area by an external standard method to obtain the product.
Table 1 test results of soluble powder of antibacterial composition in examples 1 to 3
Figure BDA0003292626220000121
Figure BDA0003292626220000131
As can be seen from table 1: the tiamulin fumarate-containing soluble powder provided by the invention meets the internal control standards of enterprises and the part of ' pharmacopoeia of the people's republic of China ' 2020 edition.
Example 4
The antibacterial composition soluble powder containing tylosin tartrate is prepared from the following raw materials:
Figure BDA0003292626220000132
the preparation method is different from the preparation method of example 1 only in the replacement of the formula, and the rest operations and parameters are the same and are not described again.
Example 5
The antibacterial composition soluble powder containing tylosin tartrate is prepared from the following raw materials:
Figure BDA0003292626220000133
the preparation method is different from the preparation method of example 1 only in the replacement of the formula, and the rest operations and parameters are the same and are not described again.
Example 6
The antibacterial composition soluble powder containing tylosin tartrate is prepared from the following raw materials:
Figure BDA0003292626220000141
the preparation method is different from the preparation method of example 1 only in the replacement of the formula, and the rest operations and parameters are the same and are not described again.
The invention tests the performance of the antibacterial composition soluble powder containing tylosin tartrate described in the embodiment 4-6, and the test results are shown in table 2.
The detection method is used for detecting the related regulations of tylosin tartrate soluble powder according to the veterinary drug quality standard compilation of the Ministry of agriculture, namely the standards of imported veterinary drugs in 2006-2011.
The product has titer of not less than 780 tylosin unit (only 85% standard) per 1mg calculated on dry product, and contains tylosin (C)53H87NO19) Should be 92.0% -108.0% of the labeled amount.
[ PROPERTIES ] the product is white to light yellow powder.
[ IDENTIFICATION ] A proper amount (equivalent to 10mg of telavancin) of the product is taken, 2mL of acetone is added, shaking is carried out for 5min, filtering is carried out, filtrate is taken, l mL of hydrochloric acid is added, and the solution is gradually changed from light red to deep purple red.
(2) Taking a proper amount (about equivalent to 200mg of the tulathromycin) of the product, adding 5mL of water, shaking, centrifuging, taking 2mL of supernatant, adding 1mL of 0.4mol/L silver nitrate solution, standing for a moment to generate white precipitate, centrifuging, and dissolving the precipitate in nitric acid.
(3) Taking the product and a proper amount of standard substance of thebainsin, adding ethyl acetate to prepare a solution containing l mg in each 1mL, and testing according to thin-layer chromatography (appendix 33 page). Sucking the above two solutions each at 5 μ L, and spotting on the same silica gel GF254And (3) spreading ethyl acetate-diethylamine (volume ratio is 100: 1) as a developing agent on the thin-layer plate, airing, and immediately placing under an ultraviolet lamp (254nm) for inspection, wherein the position and the color of a main spot displayed by the test solution are the same as those of a main spot of the standard solution.
(4) Taking a proper amount of the product, adding water to prepare a solution containing 50 mu g of the tylosin in 1mL, and measuring by an ultraviolet-visible spectrophotometry (page 26 of appendix), wherein the solution has maximum absorption at 290 nm.
[ ACID EXAMINATION ] the product is taken out and added with water to prepare a solution containing 25mg per 1mL, and the pH value is 3.0-5.0 according to the law (appendix, page 56).
[ tyramine examination ] A proper amount of the product (corresponding to 50mg of tylosin) was taken, 5mL of methanol was added to dissolve the product, 2mL of a 10% pyridine solution (10% means that the mass ratio of solute to solvent is 1: 10) and 2mL of a 2% ninhydrin solution (2% means that the mass ratio of solute to solvent is 1: 50) were added, the mixture was sealed with tin foil, and the sealed mixture was placed in a water bath at 85 ℃ for heating for 30 minutes, rapidly cooled, quantitatively transferred to a 25mL measuring flask, and diluted to the scale with water to obtain a test solution. A blank solution was prepared in the same manner. Another 5mL of a methanol solution containing 35. mu.g of tyramine per 1mL was prepared in the same manner as the control solution. Immediately after UV-Vis spectrophotometry (appendix 26, p.), the absorbance of the test solution must not be greater than that of the control solution, measured at a wavelength of 570 nm.
[ Tawangin related fractions ] were determined according to high performance liquid chromatography (appendix, page 36).
Octadecylsilane chemically bonded silica is used as a filler for chromatographic conditions and system applicability tests; acetonitrile-ammonium acetate solution (with the concentration of 0.15mol/L) -acetic acid (with the volume ratio of 45:45:10) is taken as a mobile phase; the detection wavelength was 280 nm. The number of theoretical plates is not less than 2000 calculated according to the Thevenin A peak.
The determination method comprises the following steps: taking a proper amount of the product, dissolving and diluting the product by using a mobile phase to prepare a solution containing about 0.5mg of the tylosin in each 1mL, filtering, precisely taking 10 mu L of subsequent filtrate, injecting the subsequent filtrate into a liquid chromatograph, recording a chromatogram, and calculating according to a peak area normalization method that the content of the tylosin A is not lower than 80%.
[ loss on drying ] the product is taken, phosphorus pentoxide is taken as a drying agent, and decompression drying is carried out for 3 hours at the temperature of 60 ℃, so that the loss on weight reduction is not more than 4.0% (page 78 of appendix).
And others: the respective specifications in the soluble powder section (page 16 of appendix) are to be met.
[ CONTENT DETERMINATION ] A proper amount of the product is precisely weighed, 70% methanol is added to prepare a solution containing 1000 units per 1mL, and the solution is diluted with a sterilized phosphate buffer solution (pH 8.0) to prepare a solution containing 2.5 to 10.0 units per 1 mL. Measured according to the antibiotic microbiological assay (appendix 121 page).
Table 2 test results of soluble powders of antibacterial compositions described in examples 4 to 6
Figure BDA0003292626220000161
As can be seen from table 2: the antibacterial composition soluble powder containing tylosin tartrate provided by the invention meets the internal control standard of enterprises and the standards of veterinary drugs imported in 2006-2011 from the standardization of veterinary drugs' quality standards of the ministry of agriculture.
The solubility performance of the antibacterial composition soluble powder containing tylosin tartrate described in the embodiments 4-6 is also tested, and the test results are shown in table 3.
Table 3 solubility testing of soluble powders of antimicrobial compositions according to examples 4-6
Figure BDA0003292626220000171
As can be seen from table 3: the antibacterial composition soluble powder containing the tylosin tartrate has higher solubility at low temperature and normal temperature.
Example 7
The antibacterial composition soluble powder containing tilmicosin is prepared from the following raw materials:
Figure BDA0003292626220000172
the preparation method is different from the preparation method of example 1 only in the replacement of the formula, and the rest operations and parameters are the same and are not described again.
Example 8
Figure BDA0003292626220000173
The preparation method is different from the preparation method of example 1 only in the replacement of the formula, and the rest operations and parameters are the same and are not described again.
Example 9
Figure BDA0003292626220000181
The preparation method is different from the preparation method of example 1 only in the replacement of the formula, and the rest operations and parameters are the same and are not described again.
The performance of the soluble powder of the antibacterial composition containing tilmicosin, which is described in the embodiment 7-9, is tested, and the test results are shown in table 4.
The detection method is used for detecting the related regulations of the tilmicosin soluble powder according to 'veterinary drug quality standard' 2017 edition of Ministry of agriculture.
[ PROPERTIES ] the product is a white-like powder.
[ IDENTIFICATION ] in the chromatogram recorded under the content determination term, the retention time of the main peak of the test solution should be consistent with that of the main peak of the control solution.
[ EXAMINATION ] solubility: an appropriate amount of the product (about 0.1g of tilmicosin) is taken, 100mL of water is added, and the mixture is stirred and is completely dissolved.
[ PH value ] 0.1g of this product is taken, 100mL of water is added, and the pH value is determined by law (appendix 0631) to be 5.5-7.5.
[ loss on drying ] the product is taken, phosphorus pentoxide is taken as a drying agent, and the loss on weight is not more than 10.0% after being dried for 5 hours under reduced pressure at 60 ℃ (appendix 0831).
Others should comply with the various regulations in the soluble powder section (appendix 0113).
[ CONTENT DETERMINATION ] the determination was made according to high performance liquid chromatography (appendix 0512).
Chromatographic conditions and system applicability test: octadecylsilane chemically bonded silica (250 mm. times.4.6 mm, 5 μm) was used as a filler; taking water-acetonitrile-dibutylamine phosphate solution-tetrahydrofuran (805: 115: 25: 55) as a mobile phase; the detection wavelength was 280nm and the flow rate was 1.0mL per minute. The theoretical plate number is not less than 3000 calculated according to the cis-isomer peak of tilmicosin, and the separation degree of the cis-isomer peak and the trans-isomer peak of the tilmicosin meets the requirement. The relative retention times of the tilmicosin trans-isomer peak and cis-isomer peak were 0.9 and 1.0.
The preparation method of the water-acetonitrile-dibutylamine phosphate solution comprises the steps of taking 16.8mL of dibutylamine, adding 70mL of phosphoric acid solution (1 → 10) while stirring, cooling, adjusting the pH value to 2.5 +/-0.1 by using phosphoric acid, and adding water to 100mL to obtain the water-acetonitrile-dibutylamine phosphate solution.
The determination method comprises the steps of accurately weighing a proper amount (equivalent to 50mg of tilmicosin) of the product, placing the product in a 100mL measuring flask, adding phosphoric acid solution (5.71 g of phosphoric acid is taken, 900mL of water is added for dissolution, the pH value is adjusted to 2.5 +/-0.1 by using 12.5mol/L sodium hydroxide solution, the pH value is added to 1000mL of water for dissolution and dilution to a scale, shaking up, accurately measuring 10 mu L of the solution, injecting the solution into a liquid chromatograph, and recording a chromatogram; taking another appropriate amount of tilmicosin reference substance, and determining by the same method. And calculating according to the sum of the peak areas of the cis-isomer and the trans-isomer by an external standard method.
TABLE 4 results of the Performance test of the soluble powders of the antibacterial compositions described in examples 7 to 9 of the present invention
Figure BDA0003292626220000191
Figure BDA0003292626220000201
As can be seen from table 4: the soluble powder of the antibacterial composition containing tilmicosin provided by the invention meets the internal control standard of enterprises and 'veterinary drug quality standard' 2017 edition of Ministry of agriculture.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.

Claims (10)

1. The soluble powder of the antibacterial composition is characterized by comprising the following preparation raw materials: an antibacterial component, a cross-linking agent, a surfactant, a pH regulator, a bitterness blocker and a filler;
the antibacterial component comprises tiamulin fumarate, tylosin tartrate or tilmicosin;
the cross-linking agent comprises one or more of water-soluble carrageenan, glucan and chitin;
the surfactant comprises polyvinylpyrrolidone.
2. The soluble powder of antibacterial composition as claimed in claim 1, wherein when the antibacterial component is tiamulin fumarate, the soluble powder comprises the following preparation raw materials in percentage by mass:
Figure FDA0003292626210000011
3. the soluble powder of the antibacterial composition as claimed in claim 1, wherein when the antibacterial component is tylosin tartrate, the soluble powder comprises the following preparation raw materials in percentage by mass:
Figure FDA0003292626210000012
4. the soluble powder of the antibacterial composition according to claim 1, wherein when the antibacterial component is tilmicosin, the soluble powder comprises the following preparation raw materials in percentage by mass:
Figure FDA0003292626210000013
5. the soluble powder of an antibacterial composition according to any one of claims 1 to 4, wherein said pH regulator comprises tartaric acid.
6. The soluble powder for antibacterial composition according to any one of claims 1 to 4, wherein said bitter taste blocker comprises one or more of adenosine phosphate, guanosine phosphate and monosodium glutamate.
7. Soluble powder of an antimicrobial composition according to any one of claims 1 to 4, characterized in that the filler comprises soluble starch and/or sodium hexametaphosphate.
8. A method for preparing soluble powder of the antibacterial composition according to any one of claims 1 to 7, comprising the steps of:
first mixing a cross-linking agent, a surfactant, a bitter blocker and water to obtain a first solution;
carrying out second mixing on the first solution and the antibacterial component to obtain a primary mixed wet material;
thirdly mixing the primary mixed feed liquid with a pH regulator and a filling agent to obtain a granulation wet material;
and sequentially granulating, drying and finishing the granulated wet material to obtain the soluble powder of the antibacterial composition.
9. The method of claim 8, wherein the first mixing is performed at a temperature of 40 to 60 ℃ for 15 to 30 min.
10. The preparation method according to claim 8, wherein the drying mode is boiling drying, and the drying temperature is 45-60 ℃.
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