CN104352439A - Tiamulin lipidosome, preparation method and application thereof - Google Patents

Abstract

The invention belongs to the technical field of pharmaceutics, and provides a tiamulin lipidosome. The tiamulin lipidosome comprises the following constituents in percentage by weight: 0.01-5% of tiamulin, 2-18% of lecithin, 0.1-5% of an emulsifying agent, 2-15% of a co-emulsifier, 0-1% of an antioxidant, and the balance of deionized water. The preparation method comprises the following steps: (1) mixing tiamulin, lecithin, the emulsifying agent, the co-emulsifier and the antioxidant, heating the substances to 30-60 DEG C, and stirring uniformly; (2) adding the deionized water at the temperature of 30-60 DEG C to the hot mixed liquid obtained in the step (1), and stirring for 3-30 minutes at a stirring rate of 200-800 revolutions per minute; (3) cooling the mixture to a room temperature, and namely obtaining the tiamulin lipidosome. The tiamulin lipidosome disclosed by the invention is strong in permeability, good in curative effect, long in half-life period, and capable of being used for preparing a veterinary injection.

Description

Taimulin liposome and its production and use

Technical field

The invention belongs to pharmaceutical technology sectors, be specifically related to a kind of taimulin liposome, also relate to preparation method and the purposes of this liposome simultaneously.

Background technology

Taimulin (Tiamulin), molecular formula: C ₂₈h ₄₇nO ₄sC ₄h ₄o ₄, be by higher fungus basidiomycetes pleurotus pleurotus mutilusafter fermentation obtains pleuromutilin, then obtaining hydrogenation fumarate through chemosynthesis, is the special antibiotic of a kind of di-terpene class poultry.Nineteen fifty-one is proposed first by Australian Kavangh, starts extensive research the sixties, is one of large veterinary antibiotic in the world ten.This product is easily molten, water-soluble in methanol or ethanol, slightly molten in acetone.The antimicrobial spectrum of taimulin is similar to macrolide antibiotics, main resisting gram-positive bacteria, stronger inhibitory action is had, the strong and Macrolide to the effect of mycoplasma to staphylococcus aureus, streptococcus, mycoplasma, actinobacillus pleuropneumoniae, pig treponema dysentery etc.To gram negative bacteria, especially intestinal effect is more weak.

Liposome (liposome) is that British scholar Bangham and Standish found in nineteen sixty-five; 1971, the people such as Lai Men started liposome to be used for pharmaceutical carrier.Liposome is made up of phospholipid and additives, and phospholipid is amphiprotic substance, and its structure has hydrophilic and lipophilic group, and conventional has lecithin, fabaceous lecithin etc.The hydrophilic stem forming the lipoid of bilayer forms the surfaces externally and internally of film, and lipophilic end section is in the centre of film, and wall thickness is about 5 ~ 7nm, and the diameter of capsule is generally between 25 ~ 50nm.Based on this structural property of liposome, it can simultaneously as the carrier of hydrophobicity (hydrophobic) and hydrophilic (hydrophilic) medicine, hydrophobicity medicine can embed in lipid bilayer, and hydrophilic medicine then can be coated in the aqueous layer in micro-fat body.

The present invention using liposome as carrier loaded taimulin, to improving dissolubility and the bioavailability of taimulin further.

Summary of the invention

The object of the invention is to provide a kind of taimulin liposome and preparation method thereof, the purposes providing it new is then another object of the present invention.

Based on above-mentioned purpose, this invention takes following technical scheme: taimulin liposome, in described liposome, the percentage by weight of each composition is: taimulin 0.01 ~ 5%, lecithin 2 ~ 18%, emulsifying agent 0.1 ~ 5%, co-emulsifier 2 ~ 15%, antioxidant 0 ~ 1%, and all the other are deionized water.

In described liposome, the percentage by weight of each composition is: taimulin 0.1 ~ 2%, lecithin 2 ~ 16%, emulsifying agent 0.2 ~ 5%, co-emulsifier 2 ~ 5%, antioxidant 0.2 ~ 0.8%, and all the other are deionized water.

Described emulsifying agent is selected from polysorbas20, polysorbate60 and Tween 80.

Described co-emulsifier is propylene glycol.

Described lecithin is Ovum Gallus domesticus Flavus lecithin and/or soybean lecithin.

Described antioxidant is Vitamin E acetate.

The preparation method of described taimulin liposome, comprises the following steps:

(1) get taimulin, lecithin, emulsifying agent, co-emulsifier, antioxidant mixing, be heated to 30 ~ 60 DEG C and stir;

(2) in the hot mixed liquor of step (1) gained, add the deionized water that temperature is 30 ~ 60 DEG C, under the stir speed (S.S.) of 200r/min ~ 800r/min, stir 3 ~ 30min;

(3) be cooled to room temperature, obtain taimulin liposome.

Described taimulin liposome is preparing the application in veterinary injection.

Phospholipid is biodegradable, and nontoxic, non-immunogenicity.The present invention is that loading liposomes active constituents of medicine taimulin prepared by bilayer membrane material with lecithin; the product obtained is due to self-isolation in structure; biological activity, the Drug controlled release speed of energy available protecting medicine, thus the object reaching prolong half-life, raising curative effect.In addition, liposome has class cellularity, has stronger affinity with cell membrane, can the transparency of enhanced activity thing, improves the therapeutic index of taimulin, improves curative effect, reduces its therapeutic dose, reduce the toxicity of medicine.

Meanwhile, preparation method step provided by the invention is simple, reproducible, workable, make the mean diameter of liposome between 10 ~ 120nm, good stability.

Test confirms, liposome of the present invention is used as veterinary injection and has long-acting.

Detailed description of the invention

Below in conjunction with specific embodiment, the present invention will be further described.

embodiment 1

Taimulin liposome, its raw material consists of:

Taimulin 0.1g;

Soybean lecithin 2.5g;

Polysorbate60 0.4g;

Propylene glycol 8.0g;

Vitamin E acetate 0.2g;

Deionized water 88.8g.

Above-mentioned taimulin liposome is prepared by following steps:

(1) take get taimulin, lecithin, emulsifying agent, co-emulsifier, antioxidant add in beaker and mix, be heated to 30 DEG C and stir;

(2) remove ionized water and be heated to 30 DEG C, then add in the hot mixed liquor of step (1) gained, under the stir speed (S.S.) of 800r/min, stir 30min;

(3) naturally cool to room temperature, obtain taimulin liposome.

Utilize Malvern Particle Size Analyzer to carry out grain size analysis to this liposome, recording its mean diameter is 10.38nm.

Described taimulin liposome is preparing the application in veterinary injection

embodiment 2

Taimulin liposome, its raw material consists of:

Taimulin 1.2g;

Ovum Gallus domesticus Flavus lecithin 5.0g;

Polysorbas20 1.4g;

Propylene glycol 2.8g;

Vitamin E acetate 0.6g;

Deionized water 89g.

Above-mentioned taimulin liposome is prepared by following steps:

(1) take get taimulin, lecithin, emulsifying agent, co-emulsifier, antioxidant add in beaker and mix, be heated to 50 DEG C and stir;

(2) remove ionized water and be heated to 50 DEG C, then add in the hot mixed liquor of step (1) gained, under the stir speed (S.S.) of 200r/min, stir 3min;

(3) naturally cool to room temperature, obtain taimulin liposome.

Utilize Malvern Particle Size Analyzer to carry out grain size analysis to this liposome, recording its mean diameter is 6.36nm.

Described taimulin liposome is preparing the application in veterinary injection

embodiment 3

Taimulin liposome, its raw material consists of:

Taimulin 0.8g;

Ovum Gallus domesticus Flavus lecithin 10.0g;

Tween 80 3.6g;

Propylene glycol 12.6g;

Vitamin E acetate 0.6g;

Deionized water 72.4g.

Above-mentioned taimulin liposome is prepared by following steps:

(1) take get taimulin, lecithin, emulsifying agent, co-emulsifier, antioxidant add in beaker and mix, be heated to 60 DEG C and stir;

(2) remove ionized water and be heated to 60 DEG C, then add in the hot mixed liquor of step (1) gained, under the stir speed (S.S.) of 500r/min, stir 20min;

(3) naturally cool to room temperature, obtain taimulin liposome.

Utilize Malvern Particle Size Analyzer to carry out grain size analysis to this liposome, recording its mean diameter is 0.86nm.

Described taimulin liposome is preparing the application in veterinary injection

embodiment 4

Taimulin liposome, its raw material consists of:

Taimulin 2.0g;

Soybean lecithin 16.0g;

Polysorbate60 4.5g;

Propylene glycol 15.0g;

Vitamin E acetate 0.8g;

Deionized water 61.7g.

Above-mentioned taimulin liposome is prepared by following steps:

(1) take get taimulin, lecithin, emulsifying agent, co-emulsifier, antioxidant add in beaker and mix, be heated to 50 DEG C and stir;

(2) remove ionized water and be heated to 50 DEG C, then add in the hot mixed liquor of step (1) gained, under the stir speed (S.S.) of 800r/min, stir 15min;

(3) naturally cool to room temperature, obtain taimulin liposome.

Utilize Malvern Particle Size Analyzer to carry out grain size analysis to this liposome, recording its mean diameter is 7. 38nm.

embodiment 5

Taimulin liposome, its raw material consists of:

Taimulin 0.01g;

Soybean lecithin 2.0g;

Polysorbate60 0.1g;

Propylene glycol 2.0g;

Deionized water 95.89g.

Above-mentioned taimulin liposome is prepared by following steps:

(1) take get taimulin, lecithin, emulsifying agent, co-emulsifier, antioxidant add in beaker and mix, be heated to 50 DEG C and stir;

(2) remove ionized water and be heated to 50 DEG C, then add in the hot mixed liquor of step (1) gained, under the stir speed (S.S.) of 600r/min, stir 20min;

(3) naturally cool to room temperature, obtain taimulin liposome.

Utilize Malvern Particle Size Analyzer to carry out grain size analysis to this liposome, recording its mean diameter is 5.32nm.

embodiment 6

Taimulin liposome, its raw material consists of:

Taimulin 5.0g;

Ovum Gallus domesticus Flavus lecithin 18.0g;

Tween 80 5.0g;

Propylene glycol 5.0g;

Vitamin E acetate 1.0g;

Deionized water 66.0g.

Above-mentioned taimulin liposome is prepared by following steps:

(1) take get taimulin, lecithin, emulsifying agent, co-emulsifier, antioxidant add in beaker and mix, be heated to 60 DEG C and stir;

(2) remove ionized water and be heated to 60 DEG C, then add in the hot mixed liquor of step (1) gained, under the stir speed (S.S.) of 500r/min, stir 30min;

(3) naturally cool to room temperature, obtain taimulin liposome.

Utilize Malvern Particle Size Analyzer to carry out grain size analysis to this liposome, recording its mean diameter is 8.17nm.

embodiment 7

Reference literature [Huang Hexian, Zeng Zhenling etc. the pharmacokinetics of tiamulin suspension injection in pig body and bioavailability study, Scientia Agricultura Sinica, 2010,43(10): 2168-2173] in method carry out pharmacokinetics test and measure calf blood and eliminate half-life and Sheep Blood and eliminate the half-life.Administering mode: intramuscular injection.Dosage: 10mgkg ^-1b.w.Test medicine: the taimulin liposome of embodiment 1, drugs compared: in document give tiamulin suspension injection.Experimental result is as shown in table 1.

The removing half-life of the different preparation of table 1

	Drugs compared	Test medicine
			Calf blood eliminates the half-life	3 hours	9 hours
Sheep Blood eliminates the half-life	4.6 hour	12 hours

From table 1 data, taimulin liposome has the longer removing half-life, shows significant long-acting.

Claims (8)

1. taimulin liposome, is characterized in that, in described liposome, the percentage by weight of each composition is: taimulin 0.01 ~ 5%, lecithin 2 ~ 18%, emulsifying agent 0.1 ~ 5%, co-emulsifier 2 ~ 15%, antioxidant 0 ~ 1%, and all the other are deionized water.

2. taimulin liposome as claimed in claim 1, it is characterized in that, in described liposome, the percentage by weight of each composition is: taimulin 0.1 ~ 2%, lecithin 2 ~ 16%, emulsifying agent 0.2 ~ 5%, co-emulsifier 2 ~ 5%, antioxidant 0.2 ~ 0.8%, and all the other are deionized water.

3. taimulin liposome as claimed in claim 1 or 2, it is characterized in that, described emulsifying agent is selected from polysorbas20, polysorbate60 and Tween 80.

4. taimulin liposome as claimed in claim 3, it is characterized in that, described co-emulsifier is propylene glycol.

5. the taimulin liposome as described in claim 1 or 2 or 4, is characterized in that, described lecithin is Ovum Gallus domesticus Flavus lecithin and/or soybean lecithin.

6. taimulin liposome as claimed in claim 5, it is characterized in that, described antioxidant is Vitamin E acetate.

7. the preparation method of taimulin liposome described in claim 1 or 2 or 4 or 6, is characterized in that, comprise the following steps:

(1) get taimulin, lecithin, emulsifying agent, co-emulsifier, antioxidant mixing, be heated to 30 ~ 60 DEG C and stir;

(2) in the hot mixed liquor of step (1) gained, add the deionized water that temperature is 30 ~ 60 DEG C, under the stir speed (S.S.) of 200r/min ~ 800r/min, stir 3 ~ 30min;

(3) be cooled to room temperature, obtain taimulin liposome.

8. described in claim 1 or 2 or 4, taimulin liposome is preparing the application in veterinary injection.