CN102397237A - Tilmicosin micelle preparation and preparation method thereof - Google Patents
Tilmicosin micelle preparation and preparation method thereof Download PDFInfo
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- CN102397237A CN102397237A CN2011103745309A CN201110374530A CN102397237A CN 102397237 A CN102397237 A CN 102397237A CN 2011103745309 A CN2011103745309 A CN 2011103745309A CN 201110374530 A CN201110374530 A CN 201110374530A CN 102397237 A CN102397237 A CN 102397237A
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Abstract
The invention belongs to the technical field of medicinal preparations and relates to a tilmicosin micelle preparation and a preparation method thereof. The tilmicosin micelle preparation comprises the following components in part by weight: 3 to 5 parts of tilmicosin, 5.0 to 15.5 parts of pharmaceutically acceptable carrier materials, 52 to 68 parts of poly(butylene succinate) (PBS ), 0 to 8 parts of additive and a pH modifier, wherein the pH value of the pH modifier is 5 to 7. In the tilmicosin micelle preparation, poloxamer 188 serves as the main micelle component. The poloxamer 188 is an asymmetric amphiphilic block copolymer and can automatically form the micelle in aqueous solution, wherein the hydrophobic block of the micelle gathers inwards and the hydrophilic block gathers outwards. Because the formed micelle is relatively smaller low in particle size, the micelle is higher in retention capability to an inflammatory part and stable onto heat and is not easy to oxidize. The entrapment rate and the drug loading capacity of the tilmicosin micelle preparation are high.
Description
Technical field
The invention belongs to technical field of medicine, relate to a kind of tilmicosin micellar preparation and preparation method thereof.
Background technology
Tilmicosin (Tilmicosin) is a kind of animal specific macrolide antibiotics of the Britain Elanco company exploitation eighties in 20th century, and the nineties is in China's approval listing.It is white or light yellow crystalline powder, in methanol, acetonitrile, acetone, is prone to dissolve, and in ethanol, dissolves, and is almost insoluble in n-hexane.
Tilmicosin has special antibacterial activity and materia medica characteristic; And gram positive bacteria and part Gram-negative, Mycoplasma, spirillum etc. all there are inhibitory action, especially pleuropneumonia actinomycetes, pasteurella haemolytica, pasteurella multocida and livestock and poultry mycoplasma are had the antibacterial activity lighter than tylosin; Its pharmacokinetics carried out research animals such as milch cow, milk goat, sheep, pig, chickens; No matter be for oral administration or subcutaneous injection administration; It is good all to have tissue penetration, and infiltration rate is rapid, eliminates long half time; Apparent volume of distribution is big, and Ruzhong, lung Chinese medicine concentration are high and eliminate characteristic slowly.Be usually used in animal infectious diseases, particularly livestock and birds respiratory disease such as cattle, sheep, pig, chicken, the clinical treatment of Actinobacillus property breast mould pneumonia, pasteurellosis bacillus, mycoplasma infection and mastitis.
At present, existing both at home and abroad relevant report to tilmicosin drinking agent, tablet and normal injection agent.Lanzhou veterinary drug institute was once studied the drug effect of homemade tilmicosin drinking agent.Select 180 of healthy chickens for use; Be divided into 6 groups at random, 1-5 group chicken with the Pasteurella multocida C48-2 bacterium liquid of 1 minimum lethal dose (bacteria containing amount be about 6/ml), get 0.6ml 2h behind the chest muscle injection inoculation; 1-4 group chicken begins to drink and adds liquid medicine successive administration 5d; Test continues to observe the 15d to the inoculation back, and the 1-3 group is drunk agent 100mg/L, 200mg/L, 300mg/L to tilmicosin respectively, gives tylosin drinking agent 500mg/L for the 4th group; Only inoculate not administration for the 5th group, do not inoculate also not administration for the 6th group.The result shows that this has the good curing effect to the chicken pasteurellosis bacillus that the artificial challenge causes, can reduce mortality rate, improves survival rate, reduces the pathology damage that the artificial challenge causes; After using 3-5d continuously, tilmicosin height, middle dosage treatment group and tylosin treatment group all have tangible gaining effect to chicken, but both gaining effect difference effects are not remarkable.Adopting continuously, drinking-water administration suggestion using dosage is 200mg/L.Tilmicosin compares with tylosin that to have a consumption few, the significant advantage of infection.
Tilmicosin drinking agent, tablet, normal injection agent etc. are the same with most of conventional formulation, and the release of its medicine is all undertaken by first order kinetics, and blood Chinese medicine composition fluctuations changes greatly; Normal " peak valley " phenomenon that occurs; At the bottom of its minimum poisoning concentration, and the effective haemoconcentration weak point of holding time, often need repeatedly repeat administration just can reach effective therapeutic purposes and reduce side effect; Increase cost; And the dosage form repeat administration that has is bigger to the stimulation of animal, and stress is obvious, is unfavorable for the healthy growth of animal.
The safety issue of tilmicosin injection, like the Corii Bovis seu Bubali injected, every 1kg body weight 50mg can cause myocardial toxicity, 150mg can cause death; The pig intramuscular injection, every 1kg body weight 10mg causes accelerated breathing, vomiting and convulsions, 20mg can make most of test pig dead; Therefore limited the application of tilmicosin injection; And thereby present most veterinary drug enterprise has developed the safety issue that nano-emulsion, the Liposomal formulation of tilmicosin have solved injection, but liposome phospholipid commonly used in the preparation, cholesterol etc., these adjuvants have thermo-labile; Be prone to the shortcoming of oxidation deterioration, thereby be difficult to long-term placement.And patent CN101422435A has carried out the lyophilizing processing with the Liposomal formulation that is prepared into, though solved the unsettled shortcoming of Liposomal formulation, has increased industrialized cost, is difficult in market for animals promote.
Poloxamer is polyoxyethylene and polyoxypropylene ether block copolymers, can receive pharmacy expert and scholar's extensive concern over past ten years from forming the micelle carrier system in aqueous solution.Polymeric micelle obtains applied research widely at aspect drug release, the genophore and a lot of aspects such as diagnostic preparation.Compare with the other drug carrier, polymer micelle is special advantages especially: have anti-dilution property, Stability Analysis of Structures; Have the renal metabolism of avoiding, hinder the opsonic action of multiple composition in the blood plasma, reduce engulfing of reticuloendothelium system, extension body circulation time, the characteristic of raising cancer therapy drug chemotherapeutic index; Carrier micelle has low particle diameter, can hide the removing of reticuloendothelial system RES and mononuclear phagocyte system MPS, gives micelle macrocyclic performance.
Summary of the invention
The object of the present invention is to provide a kind of tilmicosin micellar preparation and preparation method thereof.
For realizing above-mentioned purpose, the technical scheme that the present invention takes is following:
A kind of tilmicosin micellar preparation, in weight portion, it consists of: 3 ~ 5 parts of tilmicosins, 5.0 ~ 15.5 parts of pharmaceutically acceptable carrier materials, 52 ~ 68 parts of PBS buffer, 0 ~ 8 part of additives and with the pH regulator agent, pH 5 ~ 7 is transferred in the pH regulator agent.
For obtaining high envelop rate, the preferred poloxamer 188 of pharmaceutically acceptable carrier material.
Said additives and pH regulator agent are conventional the selection.The preferred glucose of additives, pH regulator agent optimization citric acid.
Said PBS buffer is the general buffer in this area, the PBS prescription of 1L, pH7.4: potassium dihydrogen phosphate (KH
2PO
4): 0.27g, sodium hydrogen phosphate (Na
2HPO
4): 1.42g, sodium chloride (NaCl): 8g, potassium chloride (KCl) 0.2g, add the abundant stirring and dissolving of the about 800mL of deionized water, add concentrated hydrochloric acid then and transfer pH to 7.4, last standardize solution is to 1L, room temperature preservation behind the autoclave sterilization.
A kind of method for preparing of tilmicosin micellar preparation; Step is following: pharmaceutically acceptable carrier material is added organic solvent dissolution; Film forming behind the pressure reducing and steaming organic solvent in the water-bath adds the PBS buffer that contains tilmicosin and additives, stirs aquation; Regulate pH with the pH regulator agent, membrane filtration promptly gets then.
Preferably, said organic solvent is ethyl acetate, dehydrated alcohol or acetonitrile.
Preferably, bath temperature is 45 ~ 55 ℃, and hydration time is 2 ~ 3h.
Preferably, the filter membrane aperture is 0.45 micron.
The present invention uses poloxamer 188 to be main micelle component, and poloxamer 188 is a kind of amphipathic nature block polymers, in aqueous solution, can spontaneous formation hydrophobic section inwardly assemble, and hydrophilic section is micelle outwards.Because the micelle particle diameter that forms is less, there is stronger retentivity at the inflammatory position, and to thermally-stabilised, is difficult for oxidation.Tilmicosin micellar preparation envelop rate of the present invention and carrying drug ratio are high.
The specific embodiment
Embodiment 1
A kind of tilmicosin micellar preparation, it consists of: tilmicosin 3g, poloxamer 188 5g, PBS buffer 52g, glucose 3.0g and citric acid 0.7g.
Method for preparing is following:
(1) poloxamer 188 is placed eggplant-shape bottle, add the acetic acid ethyl dissolution of meltage, film forming behind the pressure reducing and steaming organic solvent in 45 ℃ of water-baths.
(2) tilmicosin and glucose are dissolved with the PBS buffer.
(3) (2) are added in (1), stir aquation 2h,, use the 0.45um membrane filtration then, promptly get with Fructus Citri Limoniae acid for adjusting pH to 5.
Envelop rate and the drug loading of measuring tilmicosin are respectively 85.5% and 15%.
Embodiment 2
A kind of tilmicosin micellar preparation, it consists of: tilmicosin 3.5g, poloxamer 118 12.5g, PBS buffer 58g, glucose 4g and citric acid 1.0g.
Method for preparing is following:
(1) poloxamer 188 is placed eggplant-shape bottle, add the anhydrous alcohol solution of meltage, film forming behind the pressure reducing and steaming organic solvent in 50 ℃ of water-baths.
(2) tilmicosin and glucose are dissolved with the PBS buffer.
(3) (2) are added in (1), stir aquation 2.5h,, use 0.45 um membrane filtration then, promptly get with Fructus Citri Limoniae acid for adjusting pH to 6.
Envelop rate and the drug loading of measuring tilmicosin are respectively 88% and 17%.
Embodiment 3
A kind of tilmicosin micellar preparation, it consists of: tilmicosin 5.0g, poloxamer 188 15.5g, PBS buffer 68g, glucose 8.0g, citric acid 1.1g.
Method for preparing is following:
(1) poloxamer 188 is placed eggplant-shape bottle, add the acetonitrile dissolving of meltage, film forming behind the pressure reducing and steaming organic solvent in 55 ℃ of water-baths.
(2) tilmicosin and glucose are dissolved with the PBS buffer.
(3) (2) are added in (1), stir aquation 3h,, use the 0.45um membrane filtration then, promptly get with Fructus Citri Limoniae acid for adjusting pH to 7.
Envelop rate and the drug loading of measuring tilmicosin are respectively 80% and 14%.
Embodiment 4
A kind of tilmicosin micellar preparation, it consists of: tilmicosin 4.0g, poloxamer 188 14.5g, PBS buffer 60g, citric acid 1.0g.
Method for preparing is following:
(1) poloxamer 188 is placed eggplant-shape bottle, add the acetic acid ethyl dissolution of meltage, film forming behind the pressure reducing and steaming organic solvent in 50 ℃ of water-baths.
(2) tilmicosin is dissolved with the PBS buffer.
(3) (2) are added in (1), stir aquation 2.5h,, use the 0.45um membrane filtration then, promptly get with Fructus Citri Limoniae acid for adjusting pH to 6.
Envelop rate and the drug loading of measuring tilmicosin are respectively 80% and 10%.
Claims (8)
1. tilmicosin micellar preparation; It is characterized in that in weight portion; It consists of: 3 ~ 5 parts of tilmicosins, 5.0 ~ 15.5 parts of pharmaceutically acceptable carrier materials, 52 ~ 68 parts of PBS buffer, 0 ~ 8 part of additives and pH regulator agent, pH 5 ~ 7 is transferred in the pH regulator agent.
2. tilmicosin micellar preparation as claimed in claim 1 is characterized in that: said pharmaceutically acceptable carrier material is a poloxamer 188.
3. tilmicosin micellar preparation as claimed in claim 1 is characterized in that: said additives are glucose.
4. tilmicosin micellar preparation as claimed in claim 1 is characterized in that: said pH regulator agent is a citric acid.
5. method for preparing like any described tilmicosin micellar preparation of claim 1 ~ 4; It is characterized in that step is following: pharmaceutically acceptable carrier material is added organic solvent dissolution; Film forming behind the pressure reducing and steaming organic solvent in the water-bath adds the PBS buffer that contains tilmicosin and additives, stirs aquation; Regulate pH with the pH regulator agent, membrane filtration promptly gets then.
6. the method for preparing of tilmicosin micellar preparation as claimed in claim 5 is characterized in that: said organic solvent is ethyl acetate, dehydrated alcohol or acetonitrile.
7. the method for preparing of tilmicosin micellar preparation as claimed in claim 6 is characterized in that: bath temperature is 45 ~ 55 ℃, and hydration time is 2 ~ 3h.
8. the method for preparing of tilmicosin micellar preparation as claimed in claim 7 is characterized in that: the filter membrane aperture is 0.45 micron.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110374530 CN102397237B (en) | 2011-11-23 | 2011-11-23 | Tilmicosin micelle preparation and preparation method thereof |
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| CN 201110374530 CN102397237B (en) | 2011-11-23 | 2011-11-23 | Tilmicosin micelle preparation and preparation method thereof |
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| CN102397237B CN102397237B (en) | 2012-11-28 |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN103446050A (en) * | 2013-09-13 | 2013-12-18 | 上海海虹实业(集团)巢湖今辰药业有限公司 | Preparation method of allyl isothiocyanate micelle preparation |
| CN106420613A (en) * | 2016-11-30 | 2017-02-22 | 河南牧翔动物药业有限公司 | Florfenicol micelle preparation and preparation method thereof |
| CN107308110A (en) * | 2017-06-14 | 2017-11-03 | 王荻 | A kind of anhydrous micellar solution of Tilmicosin and preparation method thereof |
| CN110025575A (en) * | 2019-05-24 | 2019-07-19 | 安徽奥力欣生物科技有限公司 | A kind of Tilmicosin mixed micelle soluble powder and preparation method thereof |
| CN115350153A (en) * | 2022-08-12 | 2022-11-18 | 青岛科技大学 | Pterostilbene nano micelle preparation and liver protection effect thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101238857A (en) * | 2008-01-28 | 2008-08-13 | 吴忠尚 | Antimicrobial growth-promoting premixed of feed for livestock and poultry and preparation thereof |
| CN101416978A (en) * | 2007-10-22 | 2009-04-29 | 洛阳普莱柯生物工程有限公司 | Preparation method of tilmicosin long-acting injection |
| CN101422432A (en) * | 2008-07-09 | 2009-05-06 | 西北农林科技大学 | A kind of tilmicosin nano-emulsion antibacterial drug and preparation method thereof |
-
2011
- 2011-11-23 CN CN 201110374530 patent/CN102397237B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101416978A (en) * | 2007-10-22 | 2009-04-29 | 洛阳普莱柯生物工程有限公司 | Preparation method of tilmicosin long-acting injection |
| CN101238857A (en) * | 2008-01-28 | 2008-08-13 | 吴忠尚 | Antimicrobial growth-promoting premixed of feed for livestock and poultry and preparation thereof |
| CN101422432A (en) * | 2008-07-09 | 2009-05-06 | 西北农林科技大学 | A kind of tilmicosin nano-emulsion antibacterial drug and preparation method thereof |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN103446050A (en) * | 2013-09-13 | 2013-12-18 | 上海海虹实业(集团)巢湖今辰药业有限公司 | Preparation method of allyl isothiocyanate micelle preparation |
| CN106420613A (en) * | 2016-11-30 | 2017-02-22 | 河南牧翔动物药业有限公司 | Florfenicol micelle preparation and preparation method thereof |
| CN107308110A (en) * | 2017-06-14 | 2017-11-03 | 王荻 | A kind of anhydrous micellar solution of Tilmicosin and preparation method thereof |
| CN107308110B (en) * | 2017-06-14 | 2020-07-07 | 王荻 | Tilmicosin anhydrous micelle solution and preparation method thereof |
| CN110025575A (en) * | 2019-05-24 | 2019-07-19 | 安徽奥力欣生物科技有限公司 | A kind of Tilmicosin mixed micelle soluble powder and preparation method thereof |
| CN115350153A (en) * | 2022-08-12 | 2022-11-18 | 青岛科技大学 | Pterostilbene nano micelle preparation and liver protection effect thereof |
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| CN102397237B (en) | 2012-11-28 |
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