CN101422435A - Tilmicosin liposome preparation and preparation method thereof - Google Patents
Tilmicosin liposome preparation and preparation method thereof Download PDFInfo
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- CN101422435A CN101422435A CNA2008101629265A CN200810162926A CN101422435A CN 101422435 A CN101422435 A CN 101422435A CN A2008101629265 A CNA2008101629265 A CN A2008101629265A CN 200810162926 A CN200810162926 A CN 200810162926A CN 101422435 A CN101422435 A CN 101422435A
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Abstract
The invention relates to a Tilmicosin lipidosome preparation and a preparation method. The Tilmicosin lipidosome preparation consists of the Tilmicosin lipidosome and the acceptable vector of a medicament; wherein, the Tilmicosin lipidosome contains Tilmicosin, phospholipid and cholesterin with the weight ratio of 1 : 2 to100 : 1 to 15; the acceptable vector of the medicament comprises an internal buffer system, alkali used for regulating pH, and a frozen-dried supporting agent; the adding amount of the frozen-dried supporting agent calculated according to the weight ratio of the phospholipid is as follows: 0.2 to 4 portions of the frozen-dried supporting agent is added into one portion of the phospholipid; the adding amount of the internal buffer system is 5 to 15mL. The invention has the advantages that: the Tilmicosin content in the unit volume of the Tilmicosin lipidosome preparation is high; the envelop rate is high; the stability is good; moreover, the medicament-loading rate is stable. The medicament in the lipidosome is continuously released, thus remarkably improving the concentration of blood medicament and prolonging the circulating time of the medicament in the blood. The Tilmicosin lipidosome preparation improves the curative effect of the medicament and enhances the clinic usability of the medicament.
Description
Technical field
The present invention relates to a kind of Liposomal formulation and preparation method, mainly is a kind of tilmicosin liposome preparation and preparation method.
Background technology
Tilmicosin (tilmiosin) is the macrolide antibiotics by the semisynthetic animal specific of tylosin, is to be succeeded in developing by Lilly Co., Eli. at first.Because its unique antibacterial activity and special characteristics of pharmacokinetics have abroad been ratified to be used for animals such as pig, fowl, cattle, sheep by the microbial infectious disease of sensitivity, particularly livestock and poultry respiratory tract infection at present.Though tilmicosin curative effect aspect livestock and birds respiratory disease is very definite, as a kind of new synthetic chemicals its relative toxic and side effects is arranged, may produce cardiac toxicity and Toxicity of Kidney.Think that according to relevant research tilmicosin mainly is because the cardiovascular of animal body itself etc. have damage to cardiovascular damage, perhaps excessive, the dosing mode of dosage is reasons such as quiet notes or instillation.Therefore need seek a kind of effective method, can be under the situation that does not increase drug dose, the half-life of prolong drug, the antibacterial effect of raising medicine, the toxic and side effects of minimizing medicine strengthens the clinical practice of medicine.
Liposome is a kind of targeted drug carrier, belongs to a kind of novel form of targeting drug delivery system.Medicine with liposome after, can targeting in diseased region, thereby improve the therapeutic index of medicine, can also reduce the therapeutic dose of medicine simultaneously, reduce systemic adverse reactions, improve drug safety.
Summary of the invention
The present invention is according to the characteristic of liposome vectors properties of materials and tilmicosin product itself, and a kind of Liposomal formulation and preparation method of macrolide antibiotics tilmicosin are provided.
Tilmicosin liposome preparation of the present invention is a kind of preparations for oral administration, the present invention has found through screening and can make the liposome Chinese medicine continue to discharge raising blood drug level, prolong drug circulation time in blood, improve bioavailability of medicament, can reduce simultaneously the toxic and side effects of medicine again, strengthen the effective pharmaceutical formulation of the compliance of poultry.
Tilmicosin liposome preparation of the present invention is made up of the liposome and the medicine acceptable carrier of tilmicosin, and wherein tilmicosin liposome contains tilmicosin, phospholipid, cholesterol, and their weight ratio is: 1: 2～100: 1～15; The medicine acceptable carrier comprises the internal damping system, regulates pH alkali and frozen-dried supporting agent, the addition of freeze drying protectant, and the by phospholipase weight ratio is calculated, and 1 part of phospholipid adds 0.2～4 part of frozen-dried supporting agent; The addition of internal damping system is 5-15mL.
Preferred weight ratio is: 1 part of tilmicosin, 0～40 part of phosphatidase 11,2.5～10 parts in cholesterol.
Wherein said phospholipid is soybean phospholipid, lecithin or synthetic phospholipid.
Described medicine acceptable carrier is preferably and comprises internal damping system, adjusting pH alkali, frozen-dried supporting agent, antioxidant and antiseptic.
Described internal damping system is selected from phosphatebuffer buffer system, citrate buffer system or carbonate buffer system system, and citrate buffer system wherein is citric acid-sodium citrate buffer solution of 0.05-0.5M.
Described adjusting pH is selected from sodium hydroxide, sodium hydrogen phosphate, sodium carbonate with alkali, and controlling its pH value is 5.5-8.0.
Described frozen-dried supporting agent is selected from: dextrorotation acid anhydride sugar, monosaccharide, disaccharidase or polysaccharide, and wherein monosaccharide is mannitol or glucose, and disaccharidase is lactose or sucrose, and polysaccharide is a trehalose.
Described antioxidant is vitamin E, vitamin-e ester, sodium sulfite, sodium sulfite, sodium pyrosulfite or sodium thiosulfate; Antiseptic is methyl parahydroxybenzoate, ethylparaben, propyl p-hydroxybenzoate, butyl p-hydroxybenzoate, benzoic acid, sodium benzoate or sorbic acid.
Tilmicosin liposome preparation of the present invention, can adopt following method preparation:
1) by weight phosphatidase 12-100 part,, is dissolved in the organic solvent mix homogeneously with cholesterol 1-15 part;
2) Pei Zhi internal damping system, the addition of internal damping system is 5-15mL, the internal damping system is the phosphate buffer of configuration pH6～8, also can adopt the citrate buffer of pH4.0;
3) with step 1) solution and step 2) solution mixes, emulsifying, organic solvent is removed in decompression on the membrane evaporator again; Get blank liposome turbid liquor;
4) gained blank liposome suspension is carried out high pressure breast even or Ultrasonic Pulverization or microjet, reduce particle diameter, 1 part of tilmicosin is dissolved in 20-200 part blank liposome suspension, regulates the outer water pH to 5.5-8.0 of liposome with regulating pH with alkali, 10min-60min is hatched in 30～50 ℃ of water-baths;
5) frozen-dried supporting agent is dissolved in the liposome, aseptic filtration, the addition of freeze drying protectant, the by phospholipase weight ratio is calculated, and 1 part of phospholipid adds 0.2～4 part of frozen-dried supporting agent; Described preparation is when mixing use with suitable solvent with proper proportion, its envelop rate is 60～99%, and particle diameter is 100nm-1000nm.
6) be up to the standards, bottling, capping, lyophilizing or spray drying get product, and spray-dired inlet temperature is 100-150 ℃.
Preferred manufacturing procedure is as follows
Method one:
1) get 1 part of tilmicosin, 0～40 part of phosphatidase 11 by weight,, be dissolved in organic solvent with 2.5～10 parts in cholesterol, mix all with;
2) dispose the phosphate buffer of pH6～8 by writing out a prescription;
3) with step 1) solution and step 2) solution mixes, emulsifying, organic solvent is removed in decompression on membrane evaporator; Get liposome turbid liquor;
4) the gained liposome turbid liquor is carried out the even or microjet of high pressure breast, reduce particle diameter.The lyophilizing holder of an amount of recipe quantity is dissolved in the liposome aseptic filtration;
5) be up to the standards, bottling, capping, lyophilizing or spray drying get product.
Method two:
1) by weight phosphatidase 12～100 part,, be dissolved in the organic solvent with 1～15 part in cholesterol, mix all with;
2) dispose the citrate buffer of pH4.0 by writing out a prescription;
3) with step 1) solution and step 2) solution mixes, emulsifying, organic solvent is removed in decompression on the membrane evaporator again; Get blank liposome turbid liquor;
4) gained blank liposome suspension is carried out the even or microjet of high pressure breast, reduce particle diameter, 1 part of tilmicosin is dissolved in the blank liposome, sodium hydroxide solution or phosphate buffer are transferred liposome pH to 6～8.10～60min is hatched in 30～50 ℃ of water-baths;
5) the lyophilizing holder with an amount of recipe quantity is dissolved in the liposome aseptic filtration;
6) be up to the standards, bottling, capping, lyophilizing or spray drying get product.
Described organic solvent is ether or chloroform.
Tilmicosin liposome preparation of the present invention, when mixing use with suitable solvent with proper proportion, its envelop rate is 60～90%, particle diameter is 100nm～1 μ m.
In the liposome of the present invention, contain 1～10mg tilmicosin in every ml liposome turbid liquor.
Liposome of the present invention can be used prior art for preparing such as film dispersion method, reverse phase evaporation, multi-emulsion method and pH gradient method.
The effect of benefit of the present invention: tilmicosin liposome preparation of the present invention, the tilmicosin content height in its unit volume, the envelop rate height, good stability has stable drug loading again.The liposome Chinese medicine continues to discharge, and has significantly improved blood drug level, the circulation time of prolong drug in blood.Tilmicosin liposome preparation of the present invention has improved curative effect of medication, has strengthened the clinical usability of medicine.
The specific embodiment
Further specify this explanation by the following examples, but not as limitation of the present invention.
Embodiment 1
Taking by weighing 10mg tilmicosin, 200mg soybean phospholipid (purity〉76% phosphatidylcholine) and 50mg cholesterol is dissolved in the ether, mix all with, this solution is placed the ground round-bottomed flask, and under the condition of 100rpm and decompression, boil off organic solvent with Rotary Evaporators in 35 ℃ of waters bath with thermostatic control and make filmogen such as phospholipid form an even lipid membrane at drag; Add the 20ml ether dissolution in above-mentioned adipose membrane, other adds 10ml pH7.4 phosphate buffer, and the ultrasonic one-tenth breast of water-bath is removed organic solvent at 35 ℃ with Rotary Evaporators, and until becoming the milky liposome turbid liquor, the high pressure breast spares or microjet reduces particle diameter promptly.The 100mg trehalose is dissolved in the liposome, and (membrane filter aperture 0.2 μ m) will finally disperse thing to be divided in the cillin bottle, then lyophilization or spray drying after the aseptic filtration.
Embodiment 2
Taking by weighing 20mg tilmicosin, 400mg soybean phospholipid (purity〉76% phosphatidylcholine) and 100mg cholesterol is dissolved in the ether, mix all with, this solution is placed the ground round-bottomed flask, and under the condition of 100rpm and decompression, boil off organic solvent with Rotary Evaporators in 35 ℃ of waters bath with thermostatic control and make filmogen such as phospholipid form an even lipid membrane at drag; Add the 20ml ether dissolution in above-mentioned adipose membrane, other adds 10ml pH7.4 phosphate buffer, and the ultrasonic one-tenth breast of water-bath is removed organic solvent at 35 ℃ with Rotary Evaporators, and until becoming the milky liposome turbid liquor, the high pressure breast spares or microjet reduces particle diameter promptly.The 200mg trehalose is dissolved in the liposome, and (membrane filter aperture 0.2 μ m) will finally disperse thing to be divided in the cillin bottle, then lyophilization or spray drying after the aseptic filtration.
Embodiment 3
Taking by weighing 30mg tilmicosin, 600mg soybean phospholipid (purity〉76% phosphatidylcholine) and 150mg cholesterol is dissolved in the ether, mix all with, this solution is placed the ground round-bottomed flask, and under the condition of 100rpm and decompression, boil off organic solvent with Rotary Evaporators in 35 ℃ of waters bath with thermostatic control and make filmogen such as phospholipid form an even lipid membrane at drag; Add the 20ml ether dissolution in above-mentioned adipose membrane, other adds 10ml pH7.4 phosphate buffer, and the ultrasonic one-tenth breast of water-bath is removed organic solvent at 35 ℃ with Rotary Evaporators, and until becoming the milky liposome turbid liquor, the high pressure breast spares or microjet reduces particle diameter promptly.The 300mg trehalose is dissolved in the liposome, and (membrane filter aperture 0.2 μ m) will finally disperse thing to be divided in the cillin bottle, then lyophilization or spray drying after the aseptic filtration.
Embodiment 4
Taking by weighing 200mg soybean phospholipid (purity〉76% phosphatidylcholine) and 50mg cholesterol is dissolved in the 20mL ether, again 10mL pH4.0 citrate buffer solution is added in the phospholipid ether solution, emulsifying is carried out in the two mixing, pressure reducing and steaming organic solvent then, ultrasonic 5min of probe-type or microjet reduce particle diameter, standby, as blank liposome.In addition the 10mg tilmicosin is dissolved in the blank liposome, transfer pH to 7.4 with 1mol/L NaOH, in 37 ℃ of water-baths, hatch (20～60min) afterwards, after liposome is cooled to room temperature, the 100mg trehalose is dissolved in the liposome, (membrane filter aperture 0.2 μ m) will finally disperse thing to be divided in the cillin bottle, then lyophilization or spray drying after the aseptic filtration.
Embodiment 5
Taking by weighing 600mg soybean phospholipid (purity〉76% phosphatidylcholine) and 150mg cholesterol is dissolved in the 20mL ether, again the 10mLpH4.0 citrate buffer solution is added in the phospholipid ether solution, emulsifying is carried out in the two mixing, pressure reducing and steaming organic solvent then, ultrasonic 5min of probe-type or microjet reduce particle diameter, standby, as blank liposome.In addition the 30mg tilmicosin is dissolved in the blank liposome, transfer pH to 7.4 with 1mol/L NaOH, in 37 ℃ of water-baths, hatch (20～60min) afterwards, after liposome is cooled to room temperature, the 300mg trehalose is dissolved in the liposome, (membrane filter aperture 0.2 μ m) will finally disperse thing to be divided in the cillin bottle, then lyophilization or spray drying after the aseptic filtration.
Embodiment 6
Taking by weighing 1000mg soybean phospholipid (purity〉76% phosphatidylcholine) and 250mg cholesterol is dissolved in the 20mL ether, again the 10mLpH4.0 citrate buffer solution is added in the phospholipid ether solution, emulsifying is carried out in the two mixing, pressure reducing and steaming organic solvent then, ultrasonic 5min of probe-type or microjet reduce particle diameter, standby, as blank liposome.In addition the 50mg tilmicosin is dissolved in the blank liposome, transfer pH to 7.4 with 1mol/L NaOH, in 37 ℃ of water-baths, hatch (20～60min) afterwards, after liposome is cooled to room temperature, the 500mg trehalose is dissolved in the liposome, (membrane filter aperture 0.2 μ m) will finally disperse thing to be divided in the cillin bottle, then lyophilization or spray drying after the aseptic filtration.
Certainly; the present invention can also have other various embodiments; under the situation that does not deviate from spirit of the present invention and essence; those of ordinary skill in the art work as can make various corresponding changes and distortion according to the present invention, but these corresponding changes and distortion all should belong to the protection domain of the appended claim of the present invention.
Claims (10)
1, a kind of tilmicosin liposome preparation is characterized in that: liposome and medicine acceptable carrier by tilmicosin are formed, and wherein tilmicosin liposome contains tilmicosin, phospholipid, cholesterol, and their weight ratio is: 1: 2～100: 1～15; The medicine acceptable carrier comprises the internal damping system, regulates pH alkali and frozen-dried supporting agent, the addition of freeze drying protectant, and the by phospholipase weight ratio is calculated, and 1 part of phospholipid adds 0.2～4 part of frozen-dried supporting agent; The addition of internal damping system is 5-15mL.
2, tilmicosin liposome preparation according to claim 1 is characterized in that: described tilmicosin liposome contains 1 part of tilmicosin, 0～40 part of phosphatidase 11,2.5～10 parts in cholesterol.
3, tilmicosin liposome preparation according to claim 1 is characterized in that: described medicine acceptable carrier comprises the internal damping system, regulates pH alkali, frozen-dried supporting agent, antioxidant and antiseptic.
4, tilmicosin liposome preparation according to claim 1 and 2, it is characterized in that: described phospholipid is selected from soybean phospholipid, lecithin or synthetic phospholipid.
5, require 1 or 3 tilmicosin liposome preparation according to profit, it is characterized in that: described internal damping system is selected from phosphatebuffer buffer system, citrate buffer system or carbonate buffer system system, and citrate buffer system wherein is citric acid-sodium citrate buffer solution of 0.05-0.5M.
6, require 1 or 3 tilmicosin liposome preparation according to profit, it is characterized in that: described adjusting pH is selected from sodium hydroxide, sodium hydrogen phosphate, sodium carbonate with alkali, and controlling its pH value is 5.5-8.0.
7, require 1 or 3 tilmicosin liposome preparation according to profit, it is characterized in that: described frozen-dried supporting agent is selected from: dextrorotation acid anhydride sugar, monosaccharide, disaccharidase or polysaccharide, and wherein monosaccharide is mannitol or glucose, and disaccharidase is lactose or sucrose, and polysaccharide is a trehalose.
8, require 3 tilmicosin liposome preparation according to profit, it is characterized in that: described antioxidant is vitamin E, vitamin-e ester, sodium sulfite, sodium sulfite, sodium pyrosulfite or sodium thiosulfate; Antiseptic is methyl parahydroxybenzoate, ethylparaben, propyl p-hydroxybenzoate, butyl p-hydroxybenzoate, benzoic acid, sodium benzoate or sorbic acid.
9, a kind of method for preparing tilmicosin liposome preparation as claimed in claim 1, it is characterized in that: step is as follows:
1) by weight phosphatidase 12-100 part,, is dissolved in the organic solvent mix homogeneously with cholesterol 1-15 part;
2) configuration internal damping system, the addition of internal damping system is 5-15mL;
3) with step 1) solution and step 2) solution mixes, emulsifying, organic solvent is removed in decompression on the membrane evaporator again;
Get blank liposome turbid liquor;
4) gained blank liposome suspension is carried out the even or Ultrasonic Pulverization of high pressure breast, reduce particle diameter, 1 part of tilmicosin is dissolved in 20-200 part blank liposome suspension, regulates the outer water pH to 5.5-8.0 of liposome with regulating pH with alkali, 10min-60min is hatched in 30～50 ℃ of water-baths;
5) frozen-dried supporting agent is dissolved in the liposome, aseptic filtration, the addition of freeze drying protectant, the by phospholipase weight ratio is calculated, and 1 part of phospholipid adds 0.2～4 part of frozen-dried supporting agent;
6) be up to the standards, bottling, capping, lyophilizing or spray drying get product.
10, the preparation method of tilmicosin liposome preparation according to claim 9 is characterized in that: described organic solvent is ether or chloroform.
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| Application Number | Priority Date | Filing Date | Title |
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| CNA2008101629265A CN101422435A (en) | 2008-12-08 | 2008-12-08 | Tilmicosin liposome preparation and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CNA2008101629265A CN101422435A (en) | 2008-12-08 | 2008-12-08 | Tilmicosin liposome preparation and preparation method thereof |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102327225A (en) * | 2011-08-15 | 2012-01-25 | 马改云 | Tilmicosin liposome injection and preparation method thereof |
| CN103585108A (en) * | 2013-11-13 | 2014-02-19 | 河南牧翔动物药业有限公司 | Tylonolide liposome and preparation method thereof |
| CN104382855A (en) * | 2014-10-27 | 2015-03-04 | 郑州后羿制药有限公司 | Tylosin liposome preparation and preparation method thereof |
| CN107184553A (en) * | 2017-06-14 | 2017-09-22 | 天津佰力喜动物药业有限公司 | A kind of preparation method of tilmicosin liposome dispersant |
| CN112843011A (en) * | 2021-02-04 | 2021-05-28 | 广州市和生堂动物药业有限公司 | Tilmicosin premix and preparation method thereof |
-
2008
- 2008-12-08 CN CNA2008101629265A patent/CN101422435A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102327225A (en) * | 2011-08-15 | 2012-01-25 | 马改云 | Tilmicosin liposome injection and preparation method thereof |
| CN102327225B (en) * | 2011-08-15 | 2012-11-07 | 马改云 | Tilmicosin liposome injection and preparation method thereof |
| CN103585108A (en) * | 2013-11-13 | 2014-02-19 | 河南牧翔动物药业有限公司 | Tylonolide liposome and preparation method thereof |
| CN103585108B (en) * | 2013-11-13 | 2016-07-06 | 河南牧翔动物药业有限公司 | A kind of tylonolide liposome and preparation method thereof |
| CN104382855A (en) * | 2014-10-27 | 2015-03-04 | 郑州后羿制药有限公司 | Tylosin liposome preparation and preparation method thereof |
| CN107184553A (en) * | 2017-06-14 | 2017-09-22 | 天津佰力喜动物药业有限公司 | A kind of preparation method of tilmicosin liposome dispersant |
| CN112843011A (en) * | 2021-02-04 | 2021-05-28 | 广州市和生堂动物药业有限公司 | Tilmicosin premix and preparation method thereof |
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Open date: 20090506 |