CN107308110A - A kind of anhydrous micellar solution of Tilmicosin and preparation method thereof - Google Patents
A kind of anhydrous micellar solution of Tilmicosin and preparation method thereof Download PDFInfo
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- CN107308110A CN107308110A CN201710447044.2A CN201710447044A CN107308110A CN 107308110 A CN107308110 A CN 107308110A CN 201710447044 A CN201710447044 A CN 201710447044A CN 107308110 A CN107308110 A CN 107308110A
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- tilmicosin
- anhydrous
- micellar solution
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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
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
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- 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
- 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
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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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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Abstract
The invention discloses a kind of anhydrous micellar solution of Tilmicosin, including following components：Tilmicosin, 1,2 propane diols, polyethylene glycol, absolute ethyl alcohol, PVP, acidity regulator；The Tilmicosin, 1,2 propane diols, polyethylene glycol, absolute ethyl alcohol, PVP, the mass ratio of acidity regulator are (10 25):(30‑50):(10‑15):(12‑15):(3‑5):(5‑8).The PVP of the present invention is used as the copolymer with hydrophilic block, with polyethylene glycol collective effect during micelle forma-tion, increase the steric repulsion of water-wet side, reduce the surface free energy of core shell structure, under the mutual restriction of interfacial tension and steric repulsion, stable micella is formed.
Description
Technical field
The present invention relates to a kind of pharmaceutic preparation for livestock, and in particular to a kind of anhydrous micellar solution of Tilmicosin and its preparation side
Method.
Background technology
Tilmicosin（Tilmicosin）It is a kind of semi-synthetic macrolides livestock and poultry special broad-spectrum antibiotic, is safe pleasure
The derivative of rhzomorph, with the similar antimicrobial spectrum of same tylosin, to gram-positive bacteria and part Gram-negative bacteria, mould shape
Body, conveyor screw etc. have inhibitory action, and especially Actinobacillus pleuropneumoniae, pasteurella haemolytica and livestock and poultry Mycoplasma are acted on
It is most strong.The first target organs of Tilmicosin are lung and breast, and drug concentration is high, therefore is mainly used in livestock and poultry respiratory tract infection and milk
The treatment of garget.But Tilmicosin is atomic is dissolved in water, solubility is low in water, and in the market primary formulation is its phosphoric acid
Salt, is easily destroyed after taking orally by hydrochloric acid in gastric juice, absorbs incomplete, bioavilability is low, and Half-life in vivo is short, it is impossible to gives full play to and is examined for rice
The antibacterial action of star.
In the prior art, in order to increase the water solubility of Tilmicosin, tilmicosin solution preparation uses a certain amount of water
As solvent, the H that Tilmicosin ionizes out in water with acid-base modifier+Or OH-React, solution preserves process for a long time
Middle medicine stability is difficult to control, and and H+Or OH-Palatability of drugs after reacting is poor, and bitter taste is big.Therefore, find a kind of
Tilmicosin micro-capsule preparation, when drinking water for animals is administered, pharmaceutical preparation can fully dissolve in drinking-water, good dispersion, and conduct
Preparation stabilization is good, and medicine is not influenceed by acid, alkali ionization in solution, it is ensured that curative effect of medication is certain.
The content of the invention
To achieve the above object, the deficiencies in the prior art are made up, the present invention provides a kind of anhydrous micellar solution of Tilmicosin
And preparation method thereof, the Tilmicosin micellar solution prepared by the method not added water can be uniformly dispersed in water, be easy to move
Thing colony drinking water administration, and anhydrous solution preparation it also avoid medicine and influenceed in aqueous by soda acid ionization, ensure medicine
The stability of thing preparation.
The present invention is achieved through the following technical solutions：
A kind of anhydrous micellar solution of Tilmicosin, it is characterized in that：Including following components：Tilmicosin, 1,2- propane diols,
Polyethylene glycol, absolute ethyl alcohol, PVP, acidity regulator；The Tilmicosin, 1,2- propane diols, polyethylene glycol,
Absolute ethyl alcohol, PVP, the mass ratio of acidity regulator are (10-25):(30-50):(10-15): (12-15):
(3-5):(5-8).The present invention PVP as the copolymer with hydrophilic block, during micelle forma-tion with
Polyethylene glycol collective effect, increases the steric repulsion of water-wet side, reduces the surface free energy of core shell structure, in interfacial tension and
Under the mutual restriction of steric repulsion, stable micella is formed.
Further, the anhydrous micellar solution of Tilmicosin of the invention, the polyethylene glycol is polyethylene glycol -200, poly- second
One or both of glycol -400.
Further, the anhydrous micellar solution of Tilmicosin of the invention, the PVP is polyvinyl pyrrole
Alkanone-K30.
Further, the anhydrous micellar solution of Tilmicosin of the invention, the acidity regulator is citric acid, citric acid
One kind in potassium, sodium citrate, tartaric acid, lactic acid, malic acid, preferably uses citric acid.
The anhydrous micellar solution of Tilmicosin of the present invention, the Tilmicosin, 1,2-PD, polyethylene glycol, anhydrous second
It is (15-20) that alcohol, PVP, the mass ratio of acidity regulator, which are preferably,:(35-45):(11-14):(12-15):
(3-5):(6-8)。
The preparation method of the anhydrous micellar solution of Tilmicosin of the present invention, comprises the following steps：
（1）, Tilmicosin raw material and acidity regulator be added in absolute ethyl alcohol be sufficiently stirred for dissolving；
（2）, when PVP and polyethylene glycol are heated into 30-40 DEG C, be slowly added into step（1）Drug solution
In, stirring makes it fully mix；
（3）, by step（2）Gained admixing medical solutions are slowly added into 1,2-PD, and fully dissolving produces final decoction.
The preparation method of the anhydrous micellar solution of Tilmicosin of the present invention, step（3）The pH of the final decoction of gained is 7-8.
The beneficial effects of the invention are as follows：Organic solvent is used in the Tilmicosin micellar solution preparation process of the present invention, no
The addition of water is needed, simple to operate, the organic solvent of selection is medicinal solvent, is had no toxic side effect, and obtained drug solution is steady
It is qualitative good, it is uniformly dispersed in water, overcoming medicine and being ionized in aqueous by soda acid is influenceed, and improves the agreeable to the taste of medicine
Property, it is more suitable for animal clinical drinking water administration.
Embodiment
With reference to embodiment, the present invention is further detailed explanation, to help those skilled in the art
Inventive concept, technical scheme to the present invention have more complete, accurate and deep understanding, and protection scope of the present invention is included but not
It is limited to following examples, any details to technical scheme on the premise of without departing from spirit and scope
Each fallen within the modification that form is made in protection scope of the present invention.
Embodiment 1
Drug concentration is 10% tilmicosin solution
Preparation method is as follows：
（1）, 10.2g Tilmicosin raw materials（Material content 98%）, citric acid 5g, add 14ml absolute ethyl alcohols in stir 15min,
Fully it is dissolved to solution clear.
（2）, by 5g polyvinylpyrrolidones-K30 add 10ml PEG-4000s in, be stirred and heated to 40 DEG C, most
End form is into settled solution.
（3）, by step（2）Resulting solution is slowly added to step（1）15min is sufficiently stirred in solution, it is all well mixed.
（4）, by step（3）Gained decoction is added fully to be mixed in 1,2- propane diols, is finally settled to 1,2 propane diols
100ml, obtains the anhydrous micellar solution of 10% Tilmicosin, and micellar solution pH value is 7.85.
Embodiment 2
Drug concentration is 15% tilmicosin solution
Preparation method is as follows：
（1）, 15.3g Tilmicosin raw materials（Material content 98%）, citric acid 6g, add 18ml absolute ethyl alcohols in stir 15min,
Fully it is dissolved to solution clear.
（2）, by 8g polyvinylpyrrolidones-K30 add 15ml PEG-4000s in, be stirred and heated to 35 DEG C, most
End form is into settled solution.
（3）, by step（2）Resulting solution is slowly added to step（1）15min is sufficiently stirred in solution, it is all well mixed.
（4）, by step（3）Gained decoction is added fully to be mixed in 1,2- propane diols, is finally settled to 1,2 propane diols
100ml, obtains the anhydrous micellar solution of 15% Tilmicosin.
Embodiment 3
Drug concentration is 20% tilmicosin solution
Preparation method is as follows：
（1）, 20.4g Tilmicosin raw materials（Material content 98%）, citric acid 7g, add 18ml absolute ethyl alcohols in stir 15min,
Fully it is dissolved to solution clear.
（2）, 8g polyvinylpyrrolidones-K30 added in 18ml polyethylene glycol -200, be stirred and heated to 30 DEG C, most
End form is into settled solution.
（3）, by step（2）Resulting solution is slowly added to step（1）15min is sufficiently stirred in solution, it is all well mixed.
（4）, by step（3）Gained decoction is added fully to be mixed in 1,2- propane diols, is finally settled to 1,2 propane diols
100ml, obtains the anhydrous micellar solution of 20% Tilmicosin.
Embodiment 4
Drug concentration is 25% tilmicosin solution
Preparation method is as follows：
（1）, 25.5g Tilmicosin raw materials（Material content 98%）, malic acid 8g, add 20ml absolute ethyl alcohols in stir 15min,
Fully it is dissolved to solution clear.
（2）, 8g polyvinylpyrrolidones-K30 added in 20ml polyethylene glycol -200, be stirred and heated to 40 DEG C, most
End form is into settled solution.
（3）, by step（2）Resulting solution is slowly added to step（1）15min is sufficiently stirred in solution, it is all well mixed.
（4）, by step（3）Gained decoction is added fully to be mixed in 1,2- propane diols, is finally settled to 1,2 propane diols
100ml, obtains the anhydrous micellar solution of 25% Tilmicosin.
Stability test
The outward appearance of the anhydrous micellar solution of obtained Tilmicosin of the invention is yellow clear liquid, without muddy, cotton-shaped, layering
Etc. phenomenon；After 10000 r/min centrifugations 20min, it is still the homogeneous liquid of faint yellow clear, shows that product stability is good.
According to《Chinese veterinary pharmacopoeia》The detection method of tilmicosin solution carries out assay, and 10%, 25% tilmicosin solution meets《In
State's veterinary drug allusion quotation》Relevant regulations.To the reserved sample observing of embodiment 1, stability test is carried out, test result is as follows：
The above results show that the anhydrous micellar solution of Tilmicosin is placed for a long time at different temperatures, can keep appearance transparent equal
One and pH is stable.
Claims (7)
1. a kind of anhydrous micellar solution of Tilmicosin, it is characterised in that：Including following components：It is Tilmicosin, 1,2- propane diols, poly-
Ethylene glycol, absolute ethyl alcohol, PVP, acidity regulator；The Tilmicosin, 1,2- propane diols, polyethylene glycol, nothing
Water-ethanol, PVP, the mass ratio of acidity regulator are (10-25):(30-50):(10-15): (12-15):
(3-5):(5-8)。
2. the anhydrous micellar solution of a kind of Tilmicosin according to claim 1, it is characterised in that：The polyethylene glycol is poly-
One or both of ethylene glycol -200, PEG-4000.
3. the anhydrous micellar solution of a kind of Tilmicosin according to claim 1, it is characterised in that：The polyethylene ratio coughs up alkane
Ketone is polyvinylpyrrolidone-K30.
4. the anhydrous micellar solution of a kind of Tilmicosin according to claim 1, it is characterised in that：The acidity regulator is
One kind in citric acid, potassium citrate, sodium citrate, tartaric acid, lactic acid, malic acid.
5. the anhydrous micellar solution of a kind of Tilmicosin according to claim 1, it is characterised in that：The Tilmicosin, 1,
2- propane diols, polyethylene glycol, absolute ethyl alcohol, PVP, the mass ratio of acidity regulator are (15-20):(35-
45):(11-14): (12-15):(3-5):(6-8)。
6. a kind of preparation method of the anhydrous micellar solution of Tilmicosin according to any one of claim 1-5, its feature
It is：Comprise the following steps：
Tilmicosin raw material and acidity regulator are added in absolute ethyl alcohol and are sufficiently stirred for dissolving；
When PVP and polyethylene glycol are heated into 30-40 DEG C, step is slowly added into（1）Drug solution in,
Stirring, makes it fully mix；
By step（2）Gained admixing medical solutions are slowly added into 1,2-PD, and fully dissolving produces final decoction.
7. a kind of preparation method of the anhydrous micellar solution of Tilmicosin according to claim 6, it is characterised in that：Step
（3）The pH of the final decoction of gained is 7-8.
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| CN201710447044.2A CN107308110B (en) | 2017-06-14 | 2017-06-14 | Tilmicosin anhydrous micelle solution and preparation method thereof |
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| CN201710447044.2A CN107308110B (en) | 2017-06-14 | 2017-06-14 | Tilmicosin anhydrous micelle solution and preparation method thereof |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5958888A (en) * | 1996-07-02 | 1999-09-28 | Merial, Inc. | Water miscible macrolide solutions |
| CN101496811A (en) * | 2008-12-24 | 2009-08-05 | 天津瑞普生物技术股份有限公司 | Soluble and stable tilmicosin composition |
| CN102397237A (en) * | 2011-11-23 | 2012-04-04 | 河南牧翔动物药业有限公司 | Tilmicosin micelle preparation and preparation method thereof |
| CN102657607A (en) * | 2012-05-25 | 2012-09-12 | 鼎正动物药业（天津）有限公司 | Tilmicosin stabilizing agent and preparation method thereof |
| US20160367580A1 (en) * | 2014-02-18 | 2016-12-22 | Universidad Nacional Autonoma De Mexico | Improved extended-action tilmicosin and use thereof in treatment of bovine respiratory disease complex (brd) and in dry cow period |
-
2017
- 2017-06-14 CN CN201710447044.2A patent/CN107308110B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5958888A (en) * | 1996-07-02 | 1999-09-28 | Merial, Inc. | Water miscible macrolide solutions |
| CN101496811A (en) * | 2008-12-24 | 2009-08-05 | 天津瑞普生物技术股份有限公司 | Soluble and stable tilmicosin composition |
| CN102397237A (en) * | 2011-11-23 | 2012-04-04 | 河南牧翔动物药业有限公司 | Tilmicosin micelle preparation and preparation method thereof |
| CN102657607A (en) * | 2012-05-25 | 2012-09-12 | 鼎正动物药业（天津）有限公司 | Tilmicosin stabilizing agent and preparation method thereof |
| US20160367580A1 (en) * | 2014-02-18 | 2016-12-22 | Universidad Nacional Autonoma De Mexico | Improved extended-action tilmicosin and use thereof in treatment of bovine respiratory disease complex (brd) and in dry cow period |
Non-Patent Citations (1)
| Title |
|---|
| YICHUN SUN ET AL.: "Issues and challenges in developing long-acting veterinary antibiotic formulations", 《ADVANCED DRUG DELIVERY REVIEWS》 * |
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Address after: Room 239, block B, block F, e-commerce Industrial Park, No. 33, Shangxi Road, Shanghe County, Jinan City, Shandong Province Patentee after: Wang Di Address before: No.210 Beiyuan street, Tianqiao District, Jinan City, Shandong Province Patentee before: Wang Di |