CN116459268A - Solution composition containing tilmicosin and preparation method thereof - Google Patents
Solution composition containing tilmicosin and preparation method thereof Download PDFInfo
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- CN116459268A CN116459268A CN202310344523.7A CN202310344523A CN116459268A CN 116459268 A CN116459268 A CN 116459268A CN 202310344523 A CN202310344523 A CN 202310344523A CN 116459268 A CN116459268 A CN 116459268A
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- tilmicosin
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- citric acid
- polysorbate
- ethanol
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- 229960000223 tilmicosin Drugs 0.000 title claims abstract description 143
- JTSDBFGMPLKDCD-XVFHVFLVSA-N tilmicosin Chemical compound O([C@@H]1[C@@H](C)[C@H](O)CC(=O)O[C@@H]([C@H](/C=C(\C)/C=C/C(=O)[C@H](C)C[C@@H]1CCN1C[C@H](C)C[C@H](C)C1)CO[C@H]1[C@@H]([C@H](OC)[C@H](O)[C@@H](C)O1)OC)CC)[C@@H]1O[C@H](C)[C@@H](O)[C@H](N(C)C)[C@H]1O JTSDBFGMPLKDCD-XVFHVFLVSA-N 0.000 title claims abstract description 143
- 239000000203 mixture Substances 0.000 title claims abstract description 86
- 238000002360 preparation method Methods 0.000 title claims abstract description 29
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims abstract description 168
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 72
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 55
- 238000007873 sieving Methods 0.000 claims abstract description 42
- 229940044949 eucalyptus oil Drugs 0.000 claims abstract description 41
- 239000010642 eucalyptus oil Substances 0.000 claims abstract description 41
- 239000012153 distilled water Substances 0.000 claims abstract description 36
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- 239000002994 raw material Substances 0.000 claims abstract description 22
- 229960004106 citric acid Drugs 0.000 claims abstract description 15
- 229960004756 ethanol Drugs 0.000 claims abstract description 8
- 238000002156 mixing Methods 0.000 claims abstract description 8
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- 238000000034 method Methods 0.000 claims description 7
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- 229930194936 Tylosin Natural products 0.000 description 2
- 239000004182 Tylosin Substances 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
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- 238000003786 synthesis reaction Methods 0.000 description 2
- 229960004059 tylosin Drugs 0.000 description 2
- WBPYTXDJUQJLPQ-VMXQISHHSA-N tylosin Chemical compound O([C@@H]1[C@@H](C)O[C@H]([C@@H]([C@H]1N(C)C)O)O[C@@H]1[C@@H](C)[C@H](O)CC(=O)O[C@@H]([C@H](/C=C(\C)/C=C/C(=O)[C@H](C)C[C@@H]1CC=O)CO[C@H]1[C@@H]([C@H](OC)[C@H](O)[C@@H](C)O1)OC)CC)[C@H]1C[C@@](C)(O)[C@@H](O)[C@H](C)O1 WBPYTXDJUQJLPQ-VMXQISHHSA-N 0.000 description 2
- 235000019375 tylosin Nutrition 0.000 description 2
- 229940126673 western medicines Drugs 0.000 description 2
- NESIVXZOSKKUDP-ARVJLQODSA-N (4r,5s,6s,7r,9r,11e,13e,15r,16r)-6-[(2r,3r,4s,5s,6r)-4-(dimethylamino)-3,5-dihydroxy-6-methyloxan-2-yl]oxy-7-[2-[(3s,5r)-3,5-dimethylpiperidin-1-yl]ethyl]-16-ethyl-4-hydroxy-15-[[(2r,3r,4r,5r,6r)-5-hydroxy-3,4-dimethoxy-6-methyloxan-2-yl]oxymethyl]-5,9,13 Chemical compound OP(O)(O)=O.O([C@@H]1[C@@H](C)[C@H](O)CC(=O)O[C@@H]([C@H](/C=C(\C)/C=C/C(=O)[C@H](C)C[C@@H]1CCN1C[C@H](C)C[C@H](C)C1)CO[C@H]1[C@@H]([C@H](OC)[C@H](O)[C@@H](C)O1)OC)CC)[C@@H]1O[C@H](C)[C@@H](O)[C@H](N(C)C)[C@H]1O NESIVXZOSKKUDP-ARVJLQODSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- 101100468575 Arabidopsis thaliana RH25 gene Proteins 0.000 description 1
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- 229920000855 Fucoidan Polymers 0.000 description 1
- 241000288140 Gruiformes Species 0.000 description 1
- 241000606790 Haemophilus Species 0.000 description 1
- 235000006679 Mentha X verticillata Nutrition 0.000 description 1
- 235000002899 Mentha suaveolens Nutrition 0.000 description 1
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- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
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- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
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- 230000000832 effect on mycoplasma Effects 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 108010017796 epoxidase Proteins 0.000 description 1
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- 235000013305 food Nutrition 0.000 description 1
- 229920001903 high density polyethylene Polymers 0.000 description 1
- 239000004700 high-density polyethylene Substances 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
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- 239000002736 nonionic surfactant Substances 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- NOOLISFMXDJSKH-UHFFFAOYSA-N p-menthan-3-ol Chemical compound CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 1
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- 244000052769 pathogen Species 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
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- 206010037833 rales Diseases 0.000 description 1
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- 230000028327 secretion Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
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- 239000008399 tap water Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- 229960000757 tilmicosin phosphate Drugs 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 239000000273 veterinary drug Substances 0.000 description 1
Classifications
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/61—Myrtaceae (Myrtle family), e.g. teatree or eucalyptus
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- 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
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- Health & Medical Sciences (AREA)
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- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
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- General Chemical & Material Sciences (AREA)
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- Engineering & Computer Science (AREA)
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Abstract
The invention provides a solution composition containing tilmicosin and a preparation method thereof, and belongs to the technical field of veterinary medicines, wherein the solution composition comprises the following raw materials: tilmicosin, eucalyptus oil, polysorbate, citric acid, ethanol and distilled water; the preparation method of the solution composition comprises the following steps: sieving tilmicosin and citric acid for standby; taking corresponding parts by weight of distilled water, polysorbate, citric acid, ethanol and tilmicosin, uniformly mixing, then adding eucalyptus oil, and uniformly mixing to obtain a composition; the solution composition provided by the invention has the advantages of good stability, good palatability, convenient drinking water administration, obvious effect of treating mycoplasma infection of livestock and poultry, good oral absorption and high safety.
Description
Technical Field
The invention belongs to the technical field of veterinary medicines, and particularly relates to a solution composition containing tilmicosin and a preparation method thereof.
Background
Respiratory diseases are always limiting the development of livestock breeding industry in China. Especially, along with the economic development, the consumption level of people is improved, the requirements on the health and safety of foods are continuously improved, the traditional cultivation is changed into large-scale cultivation and intensive cultivation, and the cultivation quantity is greatly increased. Although the national industry system is continuously perfect and sound, the problems of history carry-over and antibiotics abuse and the like lead the incidence rate of respiratory diseases in livestock and poultry cultivation to be high, the cultivation cost to be continuously increased, and the method is an pain spot which is not solved by the cultivation industry in China.
Mycoplasma, a class of minimal prokaryotic type microorganisms that have no cell wall, are highly polymorphic, and are 0.1-0.3 microns in size. After mycoplasma infection, the mycoplasma is mainly attached to cilium cells of the airway epithelium, so that cilium activities are reduced, antibacterial mucus is reduced, and the organism generates airway symptoms; moreover, the probability of invasion of other pathogenic microorganisms into organisms is increased, and mixed infection of other bacteria such as colibacillosis and viruses is extremely easy to occur in mycoplasma-pathogenic chicken mycoplasmosis, mycoplasma synoviae disease, mycoplasma hyopneumoniae and the like, so that prevention and treatment of mycoplasma infection is a serious issue in cultivation.
Tilmicosin belongs to a semisynthetic macrolide antibacterial agent special for animals, has an antibacterial effect similar to tylosin, and sensitive gram-positive bacteria such as staphylococcus aureus (including penicillin-resistant staphylococcus aureus), pneumococcus, streptococcus and the like. Sensitive gram-negative bacteria include haemophilus and pasteurella, and are also effective against mycoplasma. Has stronger activity on mycoplasma avium than tylosin. However, the application range is affected by the defects of poor palatability, poor water solubility, cardiotoxicity caused by injection administration and the like, and generally, the phosphate is used for improving the water solubility and is more used on poultry.
The eucalyptus oil can inhibit the synthesis of epoxidase (inflammatory substance denoprostone synthesis rate-limiting enzyme), thereby preventing the release of inflammatory reaction medium, inhibiting the generation and secretion of mucus, exhibiting anti-inflammatory properties, promoting the regeneration of airway epithelial cells, especially the regeneration of cilia in the trachea, and preventing the entry of particulate matter and pathogens into the lower airway; relieving inflammation and cough, relieving respiratory tract symptoms, diluting sputum in respiratory tract, accelerating cilia swing, and promoting sputum discharge.
In the prior art, the problems of poor water solubility, poor palatability, easy degradation and low bioavailability of tilmicosin exist, and stable tilmicosin solution products are difficult to prepare.
Chinese patent document CN107998265A (application number: 201810037522.7) discloses a compound oral liquid of Chinese and western medicines for treating porcine respiratory diseases, and a preparation method and application thereof, wherein the preparation method of the compound oral liquid of Chinese and western medicines comprises the following steps: dissolving folium Eriobotryae extract, bulbus Fritillariae Cirrhosae extract, tilmicosin phosphate, mentholum, essence, sucrose and adjuvants, and sterilizing. Chinese patent document CN114796108A (application number: 202210753943.6) discloses a tilmicosin solution and a preparation method thereof, wherein the tilmicosin solution is prepared from the following raw materials in parts by weight: 1 to 2 parts of hydroxypropyl methylcellulose, 0.1 to 0.2 part of raw material A, 8 to 12 parts of tilmicosin and a proper amount of purified water; wherein the viscosity of the hypromellose is 3 mPa.s-2000 mPa.s; the raw material A is one of sodium alginate, alginic acid sulfate and fucoidan sodium diester. Chinese patent document CN112516085a (application number: 202011334422.4) discloses a tilmicosin solution, and a preparation method and a use method thereof, wherein the tilmicosin solution comprises the following raw materials in percentage by weight: 10 to 50 percent of tilmicosin, 4 to 10 percent of mixture, 1 to 3 percent of solubilizer, 8 to 15 percent of emulsifier, 2 to 5 percent of auxiliary emulsifier, 1 to 3 percent of flavoring agent, 0.5 to 2 percent of taste blocking agent, 8 to 20 percent of oil phase substance and the balance of water; the emulsifier consists of a natural emulsifier and a nonionic surfactant. The tilmicosin solution product disclosed in the prior art is obviously different from the technical scheme of the invention.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a solution composition containing tilmicosin and a preparation method thereof.
The invention develops a novel tilmicosin composition product with obvious effect on mycoplasma infection, long-acting stability and good palatability, and is suitable for popularization and application in livestock breeding industry.
The technical scheme of the invention is as follows:
a solution composition containing tilmicosin comprises the following raw materials: tilmicosin, eucalyptus oil, polysorbate, citric acid, ethanol and distilled water.
According to the invention, the solution composition comprises the following raw materials in 100 parts by weight: 10-25 parts of tilmicosin, 5-30 parts of eucalyptus oil, 10-20 parts of polysorbate, 1-3 parts of citric acid, 15-30 parts of ethanol and the balance of distilled water.
According to a preferred embodiment of the invention, the polysorbate is polysorbate 80.
The preparation method of the tilmicosin-containing solution composition comprises the following steps:
(1) Sieving tilmicosin and citric acid for standby;
(2) Taking corresponding parts by weight of distilled water, polysorbate, citric acid, ethanol and tilmicosin, uniformly mixing, then adding eucalyptus oil, and uniformly mixing to obtain the composition.
According to a preferred embodiment of the present invention, in step (1), tilmicosin is sieved through a 80 mesh sieve and citric acid is sieved through a 200 mesh sieve.
According to the invention, in the step (2), the tilmicosin, polysorbate and citric acid which are corresponding weight parts are taken, placed into a mixed solution of ethanol and distilled water, uniformly mixed, and then eucalyptus oil is added to uniformly mix, so that the composition is prepared.
According to a preferred embodiment of the present invention, in the step (2), the polysorbate is polysorbate 80.
Advantageous effects
1. The tilmicosin-containing solution composition provided by the invention has good stability in the product stability investigation period; in the water solution simulating the water blending amount for clinical use, the stability is good within 48 hours, the degradation rate is low, and the clinical application is convenient.
2. The tilmicosin-containing solution composition provided by the invention has obvious effect of treating mycoplasma infection of livestock and poultry, good oral absorption, high safety and stable effect.
3. The tilmicosin-containing solution composition provided by the invention is simple in preparation method and beneficial to popularization and application.
Drawings
FIG. 1 is a graph showing the variation of tilmicosin content in aqueous solutions for preparing compositions of examples 1-3.
FIG. 2 is a graph showing the variation of tilmicosin content in aqueous solutions of compositions prepared in comparative examples 1-7.
FIG. 3 is a liquid chromatogram of tilmicosin content of the composition prepared in example 1 stored for 2 months.
FIG. 4 is a liquid chromatogram of tilmicosin content when the composition prepared in comparative example 1 was stored for 1 month.
FIG. 5 is a liquid chromatogram of tilmicosin content in an aqueous solution at 0h of the composition prepared in example 1.
Fig. 6 is a liquid chromatogram of tilmicosin standard.
Detailed Description
The invention is further described below with reference to the drawings and the specific embodiments, but the scope of the invention is not limited thereto.
The drugs and reagents used in the examples are common products on the market unless otherwise specified, and the details not specifically described in the examples are all in accordance with the prior art.
Example 1
A solution composition containing tilmicosin, which comprises the following raw materials in 100 parts by weight: 10 parts of tilmicosin, 5 parts of eucalyptus oil, 80 parts of polysorbate, 1 part of citric acid, 15 parts of ethanol and the balance of distilled water.
The preparation method of the tilmicosin-containing solution composition comprises the following steps:
(1) Sieving: sieving tilmicosin in the formula with 80 mesh sieve for standby, and sieving citric acid with 200 mesh sieve for standby;
(2) Dissolving: and (3) placing the tilmicosin with the formula amount, the polysorbate 80 with the formula amount and the citric acid with the formula amount into a mixed solution of ethanol with the formula amount and distilled water with the formula amount, stirring, adding eucalyptus oil with the formula amount after the tilmicosin is dissolved until the tilmicosin is clarified, and stirring until the tilmicosin is clarified, thus obtaining the composition.
Example 2
A solution composition containing tilmicosin, which comprises the following raw materials in 100 parts by weight: 25 parts of tilmicosin, 15 parts of eucalyptus oil, 15 parts of polysorbate, 3 parts of citric acid, 30 parts of ethanol and the balance of distilled water.
The preparation method of the tilmicosin-containing solution composition comprises the following steps:
(1) Sieving: sieving tilmicosin in the formula with an 80-mesh sieve for standby, and sieving citric acid with a 200-mesh sieve for standby;
(2) Dissolving: and (3) placing the tilmicosin with the formula amount, the polysorbate 80 with the formula amount and the citric acid with the formula amount into a mixed solution of ethanol with the formula amount and distilled water with the formula amount, stirring, adding eucalyptus oil with the formula amount after the tilmicosin is dissolved until the tilmicosin is clarified, and stirring until the tilmicosin is clarified, thus obtaining the composition.
Example 3
A solution composition containing tilmicosin, which comprises the following raw materials in 100 parts by weight: 10 parts of tilmicosin, 30 parts of eucalyptus oil, 20 parts of polysorbate, 1 part of citric acid, 20 parts of ethanol and the balance of distilled water.
The preparation method of the tilmicosin-containing solution composition comprises the following steps:
(1) Sieving: sieving tilmicosin in the formula with an 80-mesh sieve for standby, and sieving citric acid with a 200-mesh sieve for standby;
(2) Dissolving: and (3) placing the tilmicosin with the formula amount, the polysorbate 80 with the formula amount and the citric acid with the formula amount into a mixed solution of ethanol with the formula amount and distilled water with the formula amount, stirring, adding eucalyptus oil with the formula amount after the tilmicosin is dissolved until the tilmicosin is clarified, and stirring until the tilmicosin is clarified, thus obtaining the composition.
Comparative example 1
A composition, which comprises the following raw materials in 100 parts by weight: 10 parts of tilmicosin, 2.5 parts of eucalyptus oil, 2.5 parts of peppermint essential oil, 80 parts of polysorbate, 1 part of citric acid, 15 parts of ethanol and the balance of distilled water.
The difference from example 1 is that 2.5 parts of eucalyptus oil, 2.5 parts of peppermint essential oil are all the same.
The preparation method of the composition comprises the following steps:
(1) Sieving: sieving tilmicosin in the formula with an 80-mesh sieve for standby, and sieving citric acid with a 200-mesh sieve for standby;
(2) Dissolving: and (3) placing the tilmicosin, polysorbate 80 and citric acid in a mixed solution of ethanol and distilled water in a formula amount, stirring, adding eucalyptus oil and peppermint essential oil in the formula amount after the tilmicosin is dissolved until the tilmicosin is clarified, and stirring until the tilmicosin is clarified, thus obtaining the composition.
Comparative example 2
A composition, which comprises the following raw materials in 100 parts by weight: 10 parts of tilmicosin, 5 parts of mint essential oil, 80 parts of polysorbate, 1 part of citric acid, 15 parts of ethanol and the balance of distilled water.
The difference from example 1 is that the eucalyptus oil is 0 part, the peppermint essential oil is 5 parts, and the other parts are the same.
The preparation method of the composition comprises the following steps:
(1) Sieving: sieving tilmicosin in the formula with an 80-mesh sieve for standby, and sieving citric acid with a 200-mesh sieve for standby;
(2) Dissolving: and (3) taking the formula amount of tilmicosin, the formula amount of polysorbate 80 and the formula amount of citric acid, placing the tilmicosin, the formula amount of polysorbate 80 and the formula amount of citric acid into a mixed solution of the formula amount of ethanol and the formula amount of distilled water, stirring, adding the formula amount of peppermint essential oil after the tilmicosin is dissolved until the tilmicosin is clarified, and stirring until the tilmicosin is clarified, thus obtaining the composition.
Comparative example 3
A composition, which comprises the following raw materials in 100 parts by weight: 10 parts of tilmicosin, 5 parts of eucalyptus oil, 5 parts of polysorbate, 5 parts of polyoxyethylene castor oil, 1 part of citric acid, 15 parts of ethanol and the balance of distilled water.
The difference from example 1 is that the polysorbate is 5 parts, the polyoxyethylated castor oil is 5 parts, all other things being equal.
The preparation method of the composition comprises the following steps:
(1) Sieving: sieving tilmicosin in the formula with an 80-mesh sieve for standby, and sieving citric acid with a 200-mesh sieve for standby;
(2) Dissolving: and (3) placing the tilmicosin, the polysorbate 80, the polyoxyethylene castor oil and the citric acid in a mixed solution of the ethanol and the distilled water in the formula amount, stirring, adding the eucalyptus oil in the formula amount after the tilmicosin is dissolved until the tilmicosin is clarified, and stirring until the tilmicosin is clarified, thus obtaining the composition.
Comparative example 4
A composition, which comprises the following raw materials in 100 parts by weight: 10 parts of tilmicosin, 5 parts of eucalyptus oil, 10 parts of polyoxyethylene castor oil, 1 part of citric acid, 15 parts of ethanol and the balance of distilled water.
The difference from example 1 is that polysorbate 80 parts, polyoxyethylated castor oil 10 parts, all other things being equal.
The preparation method of the composition comprises the following steps:
(1) Sieving: sieving tilmicosin in the formula with an 80-mesh sieve for standby, and sieving citric acid with a 200-mesh sieve for standby;
(2) Dissolving: and (3) placing the tilmicosin, the polyoxyethylene castor oil and the citric acid in the formula amount into a mixed solution of the ethanol in the formula amount and the distilled water in the formula amount, stirring, adding the eucalyptus oil in the formula amount after the tilmicosin is dissolved until the tilmicosin is clarified, and stirring until the tilmicosin is clarified, thus obtaining the composition.
Comparative example 5
A composition, which comprises the following raw materials in 100 parts by weight: 10 parts of tilmicosin, 32 parts of eucalyptus oil, 8010 parts of polysorbate, 1 part of citric acid, 15 parts of ethanol and the balance of distilled water.
The difference from example 1 is that 32 parts of eucalyptus oil are identical to each other.
The preparation method of the composition comprises the following steps:
(1) Sieving: sieving tilmicosin in the formula with 80 mesh sieve for standby, and sieving citric acid with 200 mesh sieve for standby;
(2) Dissolving: and (3) placing the tilmicosin with the formula amount, the polysorbate 80 with the formula amount and the citric acid with the formula amount into a mixed solution of ethanol with the formula amount and distilled water with the formula amount, stirring, adding eucalyptus oil with the formula amount after the tilmicosin is dissolved until the tilmicosin is clarified, and stirring until the tilmicosin is clarified, thus obtaining the composition.
Comparative example 6
A composition, which comprises the following raw materials in 100 parts by weight: 10 parts of tilmicosin, 3 parts of eucalyptus oil, 80 parts of polysorbate, 1 part of citric acid, 15 parts of ethanol and the balance of distilled water.
The difference from example 1 is that 3 parts of eucalyptus oil are identical to each other.
The preparation method of the composition comprises the following steps:
(1) Sieving: sieving tilmicosin in the formula with 80 mesh sieve for standby, and sieving citric acid with 200 mesh sieve for standby;
(2) Dissolving: and (3) placing the tilmicosin with the formula amount, the polysorbate 80 with the formula amount and the citric acid with the formula amount into a mixed solution of ethanol with the formula amount and distilled water with the formula amount, stirring, adding eucalyptus oil with the formula amount after the tilmicosin is dissolved until the tilmicosin is clarified, and stirring until the tilmicosin is clarified, thus obtaining the composition.
Comparative example 7
A composition, which comprises the following raw materials in 100 parts by weight: 10 parts of tilmicosin, 80 parts of polysorbate, 1 part of citric acid, 15 parts of ethanol and the balance of distilled water.
The difference from example 1 is that the eucalyptus oil is 0 part, all other things being equal.
The preparation method of the composition comprises the following steps:
(1) Sieving: sieving tilmicosin in the formula with 80 mesh sieve for standby, and sieving citric acid with 200 mesh sieve for standby;
(2) Dissolving: and (3) taking the formula amount of tilmicosin, the formula amount of polysorbate 80 and the formula amount of citric acid, placing the tilmicosin, the formula amount of polysorbate 80 and the formula amount of citric acid into a mixed solution of the formula amount of ethanol and the formula amount of distilled water, stirring, and obtaining the composition after the tilmicosin is dissolved until the tilmicosin is clear.
Comparative example 8
A composition, which comprises the following raw materials in 100 parts by weight: 10 parts of tilmicosin, 5 parts of eucalyptus oil, 80 parts of polysorbate, 1 part of citric acid, 15 parts of ethanol and the balance of distilled water.
The difference from example 1 is that the polysorbate 80 is 23 parts, all other things being equal.
The preparation method of the composition comprises the following steps:
(1) Sieving: sieving tilmicosin in the formula with 80 mesh sieve for standby, and sieving citric acid with 200 mesh sieve for standby;
(2) Dissolving: and (3) placing the tilmicosin, polysorbate 80 and citric acid in a mixed solution of ethanol and distilled water in a formula amount, stirring, adding eucalyptus oil in a formula amount after the tilmicosin is dissolved to be clear, and stirring until turbidity is not clear.
Therefore, when polysorbate 80 is used in excess of parts by weight, a uniform and stable clear solution cannot be obtained.
Comparative example 9
A composition, which comprises the following raw materials in 100 parts by weight: 10 parts of tilmicosin, 5 parts of eucalyptus oil, 5 parts of polysorbate, 1 part of citric acid, 15 parts of ethanol and the balance of distilled water.
The difference from example 1 is that the polysorbate 80 is 5 parts, all other things being equal.
The preparation method of the composition comprises the following steps:
(1) Sieving: sieving tilmicosin in the formula with 80 mesh sieve for standby, and sieving citric acid with 200 mesh sieve for standby;
(2) Dissolving: and (3) placing the tilmicosin, polysorbate 80 and citric acid in a mixed solution of ethanol and distilled water in a formula amount, stirring, adding eucalyptus oil in a formula amount after the tilmicosin is dissolved until the tilmicosin is clear, and stirring until the solution is slightly turbid and not clear.
Therefore, when polysorbate 80 is used below parts by weight, a uniform and stable clear solution cannot be obtained.
Comparative example 10
A composition, which comprises the following raw materials in 100 parts by weight: 10 parts of tilmicosin, 5 parts of eucalyptus oil, 1 part of citric acid, 15 parts of ethanol and the balance of distilled water.
The difference from example 1 is that the polysorbate 80 is 0 part, all other things being equal.
The preparation method of the composition comprises the following steps:
(1) Sieving: sieving tilmicosin in the formula with 80 mesh sieve for standby, and sieving citric acid with 200 mesh sieve for standby;
(2) Dissolving: and (3) placing the tilmicosin with the formula amount and the citric acid with the formula amount into a mixed solution of ethanol with the formula amount and distilled water with the formula amount, stirring, adding the eucalyptus oil with the formula amount after the tilmicosin is dissolved until the tilmicosin is clarified, stirring until the tilmicosin is slightly turbid, and standing until layering occurs.
Thus, when the present invention rejects polysorbate 80, a uniform and stable clear solution is not obtained.
Effect example
Test example 1 stability test of inventive and comparative preparation compositions
Test samples prepared in examples 1-3 and samples prepared in comparative examples 1-7 were selected, marketed package (oral liquid pharmaceutical high density polyethylene bottle) was simulated, stored for 6 months in an environment of 40 ℃ ± 2 ℃ and RH25% ± 5%, sampled at the end of the 0 th, 1, 2, 3 and 6 months of the test period, and the tilmicosin content was detected (according to the classical veterinary drug standard, the limit of detection was 90% -110% of the indicated amount), and compared with the detection result of the 0 th month, and the results are shown in table 1.
TABLE 1 stability test results for compositions prepared in examples and comparative examples of the present invention
Note that: tilmicosin content is a percentage of the indicated amount.
As is clear from Table 1, the degradation rates of examples 1 to 3 were 3.8%, 3.7% and 3.8% respectively, and the degradation rates of comparative examples 1 to 7 were 6.8%, 7.8%, 6.5%, 7.3%, 8.7%, 8.4% and 9.0% respectively, although the detection results at month 6 were all within the limits of the detection limit. According to the technical guidelines of research on the stability of veterinary chemical drugs, the content of the samples in examples 1-3 is not more than 5%, and the stability is good; the content of the samples in comparative examples 1-7 is changed by more than 5%, and the stability is not qualified.
The composition prepared in example 1 is stored for 2 months, and a liquid chromatogram of tilmicosin content is shown in fig. 3; the composition prepared in comparative example 1 is stored for 1 month, and a liquid chromatogram of tilmicosin content is shown in fig. 4; the liquid chromatogram of tilmicosin standard is shown in figure 6.
Test example 2 stability test of aqueous solutions of the compositions prepared in examples and comparative examples of the present invention
The samples prepared in examples 1-3 and the samples prepared in comparative examples 1-7 were selected for aqueous solution stability test; examples 1, 3 and comparative examples 1 to 7 were dissolved in 500ml of purified water respectively according to the water addition amount of 0.75ml/L, example 2 was dissolved in 0.3ml/L of purified water respectively, the samples were taken as the 0 th hour after mixing, and then the samples were taken from the top and bottom of the standing solution at the 1 st hour, 2h, 3h, 6h, 12h, 24h and 48h respectively, and the tilmicosin content was measured, and the results were shown in FIG. 1 and FIG. 2; the degradation rate of 48h compared with 0h was calculated and the results are shown in Table 2.
TABLE 2 results of 48h degradation rate in aqueous solution stability test of compositions prepared in examples and comparative examples of the present invention
Note that: in comparison with the 0h of the same group, * (P<0.05), ** (P<0.01 A) is provided; compared to the same set of 48h top sampling points, △ (P<0.05), △△ (P<0.01)。
as can be seen from fig. 1 and 2, the comparative examples 1 to 7 have a large variation in tilmicosin degradation rate as compared with the examples 1 to 3.
As can be seen from Table 2, there was no significant difference (p > 0.05) between the top and bottom contents of the groups of examples 1 to 3, indicating that the aqueous solutions of the groups of examples 1 to 3 were uniform and stable for 48 hours. Compared with 0h, 48h shows that the degradation rates of the different sampling points of the tilmicosin content groups of examples 1-3 are all within 0.5%, and have no significant difference (p > 0.05), and the degradation rates of the different sampling points of the comparison examples 1-7 are all above 2%, and have significant difference (p < 0.05) or very significant difference (p < 0.01). Therefore, the aqueous solutions of examples 1 to 3 are stable within 48 hours compared with the aqueous solutions of comparative examples 1 to 7, are convenient for clinical application, and are suitable for popularization.
The composition prepared in example 1 has a liquid chromatogram of tilmicosin content in the aqueous solution at 0h as shown in FIG. 5; the liquid chromatogram of tilmicosin standard is shown in figure 6.
Test example 3 comparative test of the effects of the compositions prepared in the examples and comparative examples of the present invention on treatment of Mycoplasma gallisepticum
Test the samples prepared in examples 1-3 and comparative examples 1-7 were selected for testing.
The approximately diseased chickens were selected from the 10-day-old diseased chicken flocks naturally infected with mycoplasma gallisepticum, and randomly divided into a blank control group, an example 1 group, an example 2 group, an example 3 group, a comparative example 1 group, a comparative example 2 group, a comparative example 3 group, a comparative example 4 group, a comparative example 5 group, a comparative example 6 group and a comparative example 7 group, 100 healthy same-day-old breeds of chickens were selected as negative control groups, and the groups of chickens were bred under the same conditions in a mutually isolated manner, and the negative control groups were bred by a single person. The negative control group and the blank control group were each daily given clean tap water, and the other examples and comparative examples were given in the following amounts: the free drinking water of the dosage of 0.75ml/L is adopted in the groups of the examples 1 and 3, the free drinking water of the dosage of 0.3ml/L is adopted in the group of the example 2, and the free drinking water of the dosage of 0.75ml/L is adopted in the groups of the comparative examples 1 to 7 (the dosage of each group is calculated by tilmicosin, and the dosage is the same as that of the example 1). Other similar medicines are forbidden during the administration period, the administration is continued for 3 days, the administration is stopped, the observation is carried out for 5 days, the conditions of each group of chickens are observed every day, and the recorded results are shown in Table 3.
Curative effect judgment criteria:
invalidation: symptoms such as cough, depression, open mouth, wheeze, decreased appetite, tracheal rales, runny nose, eyelid swelling, conjunctival congestion, etc., and are more serious than before treatment; dead animals were counted as invalid;
the method is effective: the respiratory symptoms of the affected chickens are relieved compared with those before treatment, the respiratory symptoms are weak, the diet is gradually recovered, and the spirit and the activity are improved;
the effect is shown: the respiratory symptoms of the sick chickens are obviously relieved to disappear, the air flow is smooth during breathing, the sound is obviously relieved, the diet, the activity and the spirit are basically recovered, and the manifestation is active;
and (3) curing: the diet and activity of the affected chickens are not different from those of healthy chickens, and symptoms completely disappear;
the total effective rate calculation formula:
total effective rate= (cure number + significant number + effective number)/total number 100%.
TABLE 3 results of comparative experiments on the effects of compositions prepared in examples and comparative examples of the present invention on treatment of Mycoplasma gallisepticum
As can be seen from Table 3, the total effective rate of the group of example 1 was 97%; the total effective rate of the group of the example 2 is 96%; the total effective rate of the group of the example 3 is 96%; the total effective rate of comparative example 1 is 71%; comparative example 2 has a total effective rate of 66%; comparative example 3 has a total effective rate of 70%; comparative example 4 has a total effective rate of 62%; comparative example 5 has a total effective rate of 79%; comparative example 6 has a total effective rate of 70%; comparative example 7 has a total effective rate of 63%; the total effective rate of the blank group is 23% (self-healing).
As can be seen from the results in Table 3, the tilmicosin-containing solution composition provided by the invention has a far better effect on treating mycoplasma gallisepticum infection than other comparative examples.
Test example 4 comparative test of the effect of compositions prepared in examples and comparative examples of the present invention on treatment of mycoplasma hyopneumoniae infection
Test the samples prepared in examples 1-3 and comparative examples 1-7 were selected for testing.
The approximately diseased pigs 220 are selected from naturally infected pigs with mycoplasma and with age 5 months, randomly divided into blank control groups, example 1 groups, example 2 groups, example 3 groups, comparative example 1 groups, comparative example 2 groups, comparative example 3 groups, comparative example 4 groups, comparative example 5 groups, comparative example 6 groups and comparative example 7 groups, 20 healthy pigs with age 20 are selected as negative control groups, and the groups are fed under the same condition, mutually isolated and fed by a single person. The negative control group and the blank control group were not administered, and the groups of examples 1 and 3 were fed manually at a dose of 12 ml/head per day, the group of example 2 was fed manually at a dose of 4.8 ml/head per day, and the groups of comparative examples 1 to 7 were fed manually at a dose of 12 ml/head per day (the amounts of the groups were calculated as tilmicosin and the same as the amount of example 1). Other similar drugs were disabled during the administration period, and the administration was continued for 7 days, and after the withdrawal, the administration was observed for 7 days, and each group of conditions was observed and recorded every day, and the results are shown in table 4.
Curative effect judgment criteria:
the body temperature and appetite of the pig group after infection of mycoplasma hyopneumoniae have no obvious change. The early stage of the disease is mainly characterized by continuous dry cough, asthma and dyspnea (the pig breathes in abdomen) in middle and later stages, rapid emaciation, mild cyanosis of eyelids, nose ends, upper and lower lips, edema and congestion of few pig eyelids, bluish violet blood stasis spots at the root of the ear and the edge of auricle, and extremely emaciation in part and shivering of the back of the bow.
Invalidation: continuous dry cough, asthma, dyspnea (pig breathes in abdominal form), emaciation, slight cyanosis of eyelids, nose ends, upper and lower lips, eyelid edema congestion, blue-violet blood stasis spots on the root of ear and the edge of auricle, shivering of the back of the bow and other symptoms, and are serious before treatment; dead animals were counted as invalid;
the method is effective: compared with the prior treatment, the respiratory symptoms of the sick pigs are relieved, the asthma is weakened, the cyanosis and blood spots are not aggravated any more, and the spirit is improved;
the effect is shown: the symptoms of the respiratory tract of the sick pigs disappear, the air flow is smooth during breathing, the conditions of cyanosis and blood spots are obviously lightened, and the activities and the spirit are basically recovered;
and (3) curing: the diet and activity of the sick pigs are indiscriminate from those of healthy pigs, and symptoms completely disappear;
the total effective rate calculation formula:
total effective rate= (cure number + significant number + effective number)/total number 100%.
TABLE 4 results of comparative experiments on the effect of compositions prepared in examples and comparative examples of the present invention on treatment of mycoplasma infection in swine
| Group of | Quantity (head) | Cure (head) | Display effect (head) | Effective (head) | Invalidation (head) | Total effective rate (%) |
| Example 1 group | 20 | 15 | 2 | 3 | 0 | 100 |
| Example 2 group | 20 | 14 | 3 | 2 | 1 | 95 |
| Example 3 group | 20 | 16 | 2 | 2 | 0 | 100 |
| Comparative example 1 group | 20 | 6 | 5 | 3 | 6 | 70 |
| Comparative example 2 group | 20 | 5 | 2 | 6 | 7 | 65 |
| Comparative example 3 group | 20 | 8 | 4 | 2 | 6 | 70 |
| Comparative example 4 group | 20 | 6 | 2 | 4 | 8 | 60 |
| Comparative example 5 group | 20 | 7 | 4 | 5 | 4 | 80 |
| Comparative example 6 group | 20 | 6 | 4 | 4 | 6 | 70 |
| Comparative example 7 group | 20 | 5 | 2 | 6 | 7 | 65 |
| Blank control group | 20 | 0 | 0 | 3 (self-healing) | 17 | 15 |
| Negative control group | 20 | —— | —— | —— | —— | —— |
As can be seen from table 4, the total effective rate of the group of example 1 is 100%; the total effective rate of the group of the example 2 is 95%; the total effective rate of the group of the example 3 is 100%; the total effective rate of comparative example 1 is 70%; the total effective rate of comparative example 2 is 65%; comparative example 3 has a total effective rate of 70%; comparative example 4 has a total effective rate of 60%; comparative example 5 has a total effective rate of 80%; comparative example 6 has a total effective rate of 70%; comparative example 7 has a total effective rate of 65%; the total effective rate of the blank group is 15% (self-healing).
The results show that the effect of the solution composition containing tilmicosin for treating mycoplasma infection of pigs is far better than that of other comparative example groups.
Test example 5 palatability test of compositions prepared in examples and comparative examples of the present invention to pigs
Test the samples prepared in example 1 were selected for testing with the samples prepared in comparative example 7.
Selecting a pig farm fattening pig in Shandong province as a test object, selecting 60 test pigs with similar development states, wherein the weight of each test pig is 60-70 kg, randomly dividing the test pigs into 3 groups of 20 pigs, and feeding each group under the same condition. Example 1 group water was mixed in an amount of 1.5ml/L water; comparative example 7 group was mixed with water in an amount of 1.5ml/L water; the blank control group was not added with medicine, and each group was restricted in total water intake by 10L, and the water intake time was observed, and the results are shown in Table 5.
Table 5 palatability test results of compositions prepared in examples and comparative examples of the present invention to pigs
| Group of | Time (h) required for drinking 10L of water |
| Example 1 group | 19.2 |
| Comparative example 7 group | 37.5 |
| Blank control group | 19.5 |
The results show that the invention does not enable the taste-sensitive pigs to reduce the water intake, and the group of the embodiment 1 added with eucalyptus oil has less time than the blank control group and good palatability; in the group of comparative example 7, to which eucalyptus oil was not added, the water intake of pigs was much smaller than that of the blank group. Therefore, the eucalyptus oil can be used as a flavoring agent for tilmicosin with poor palatability.
The tilmicosin-containing solution composition provided by the invention has the advantages of good stability, good palatability, convenient drinking water administration, obvious effect on treating mycoplasma infection of livestock and poultry, good oral absorption and high safety. The tilmicosin-containing solution composition provided by the invention is simple in preparation method and beneficial to popularization and application.
Claims (7)
1. The tilmicosin-containing solution composition is characterized by comprising the following raw materials in parts by weight: tilmicosin, eucalyptus oil, polysorbate, citric acid, ethanol and distilled water.
2. The solution composition of claim 1, wherein the composition of the raw materials by weight of 100 parts is as follows: 10-25 parts of tilmicosin, 5-30 parts of eucalyptus oil, 10-20 parts of polysorbate, 1-3 parts of citric acid, 15-30 parts of ethanol and the balance of distilled water.
3. The solution composition of claim 1, wherein the polysorbate is polysorbate 80.
4. A process for the preparation of a solution composition containing tilmicosin according to any one of claims 1-2, comprising the steps of:
(1) Sieving tilmicosin and citric acid for standby;
(2) Taking corresponding parts by weight of distilled water, polysorbate, citric acid, ethanol and tilmicosin, uniformly mixing, then adding eucalyptus oil, and uniformly mixing to obtain the composition.
5. The method of claim 4, wherein in step (1), tilmicosin is sieved through a 80 mesh sieve and citric acid is sieved through a 200 mesh sieve.
6. The preparation method of claim 4, wherein in step (2), the corresponding parts by weight of tilmicosin, polysorbate and citric acid are taken and placed in a mixed solution of ethanol and distilled water, and the mixture is uniformly mixed, and then eucalyptus oil is added and uniformly mixed to prepare the composition.
7. The method of claim 4, wherein in step (2), the polysorbate is polysorbate 80.
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