CN1072482C

CN1072482C - Low-molecular heparin liposome spray preparation and its preparation

Info

Publication number: CN1072482C
Application number: CN96116044A
Authority: CN
Inventors: 邹立家; 张天民; 翟光喜; 姬胜利
Original assignee: SHANDONG MEDICAL UNIV
Current assignee: SHANDONG MEDICAL UNIV
Priority date: 1996-11-08
Filing date: 1996-11-08
Publication date: 2001-10-10
Anticipated expiration: 2016-11-08
Also published as: CN1181929A

Abstract

Low molecular heparin is a new drug which developed in the recent ten years for resisting thrombus, and the clinical application at present is only low molecular heparin injections. The present invention relates to a low molecular heparin liposome spraying preparation which takes low molecular heparin as the main medicine and precursor liposome as the carrier, and is prepared by adding and triturating vitamin E as the anti-oxidant, ethylparaben and propanediol as the preservative, buffer solution, etc. The preparation can promote the transdermal absorption of low molecular heparin and obviously restrain the formation of thrombus. In addition, the present invention has the advantages of convenient clinical application and obviously enhanced drug action time.

Description

Low-molecular heparin liposome spray preparation and preparation technology

The invention belongs to a kind of biochemical pharmaceutics, relate to a kind of biochemical drug low-molecular heparin liposome spray preparation (liposomal low-molecular-weight heparinspray gel) and preparation method thereof (technology) of antithrombotic embolism class diseases.

Low molecular heparin is a class antithrombotic new drug that grows up the nearly more than ten years, and it has 1, anticoagulation Xa factor activity; 2, impel vascular endothelial cell to discharge the endogenous aminopolysaccharide of tool anti-thrombus activity; 3, impel activator of plasminogen to discharge, help the fibrinolytic effect; 4, blood viscosity lowering, promoting blood flow increases the hemocyte surface negative charge, prevents that hemocyte gathering etc. from preventing the thrombosis effect.Successfully be applied to prevent and treat embolism class diseases such as dvt, pulmonary infarction, disseminated inravascular coagulation clinically.The dosage form of using has only injection at present.Injection onset time is fast, but action time is shorter, uses inconveniently, is unfavorable for life-time service.Therefore need a kind of safe and reliable, pharmaceutical preparation that effect is lasting, easy to use clinically.

The objective of the invention is to develop a kind of lasting medicine, Low molecular heparin liposome spray glue preparation easy to use.By part spraying medication Transdermal absorption, reach the purpose of control thrombotic disease.

The present invention is a principal agent with the Low molecular heparin, is carrier with the pro-liposome, adds an amount of antioxidant, antiseptic and buffer etc. and makes the spray colloid.Low molecular heparin can be selected Low molecular heparin crude drug (for existing commodity) for use; Pro-liposome adopts German Natipide blank liposome (to be existing commodity, the Phospholipon by 20% ^Zero80,14%～18% ethanol and 62%～66% deionized water are formed).This liposome can with the effect of keratodermatitis lipid, reduce cuticular barrier action, promote the Transdermal absorption of medicine; Its stable in properties to the skin nonirritant, and has good moistening protective effect.Antioxidant is selected vitamin E, ascorbic acid and derivant thereof for use, can both protect in the phospholipid of liposome unsaturated fatty acid not oxidized.Because vitamin E is harmless, and has the effect of protecting skin, so selected.Antiseptic is selected parabens and propylene glycol for use.With ethyl hydroxybenzoate and propylene glycol use in conjunction, can improve antiseptic power.Certain density propylene glycol can promote the Transdermal absorption of medicine simultaneously.Selecting phosphate buffer for use is that buffer capacity is strong because of its stable in properties, and to the skin nonirritant, and raw material is easy to get.Why pH elects as in 6～8 scopes, is that this scope is to the application on human skin nonirritant simultaneously because the phospholipid composition of liposome is the most stable in this scope.

Each composition proportion of low-molecular heparin liposome spray preparation of the present invention is calculated by weight with Low molecular heparin: pro-liposome: vitamin E: ethyl hydroxybenzoate: propylene glycol counts 2～5: 30～50: 0.2～0.4: 0.3～0.5: 5～7, and pH6～8 phosphate buffers account for 42.1～62.5% of gross weight.

The preparation method of low-molecular heparin liposome spray preparation is: 1, get a certain amount of Low molecular heparin earlier by above proportioning, place milling apparatus, add an amount of pH6～8 phosphate buffer furnishing pasty states, add an amount of pro-liposome and grind after 30～60 minutes, left standstill 30～60 minutes; Add stir behind the appropriate vitamin E mixture; 2, an amount of ethyl hydroxybenzoate is dissolved in an amount of propylene glycol, joins in the said mixture, stir, add capacity pH6～8 phosphate buffers again, stir, be end product low-molecular heparin liposome spray preparation of the present invention, Colloidal fluid is creamy white.It is packed into has in the brown withstand voltage vial of valve system and immersion pipe, seals standby.

The used Low molecular heparin of preparation technology, pro-liposome, antioxidant, antiseptic and buffer be all in advance through method degerming such as film processing, and operate in the air cleaning environment.

Embodiment 1:

Take by weighing Low molecular heparin 3g, the phosphate buffer that adds a small amount of pH6.8 makes into pasty state, adds pro-liposome 40g, ground 30 minutes, placed 30 minutes, and added vitamin E 0.2g, stirring is dissolved in ethyl hydroxybenzoate 0.5g among the propylene glycol 5g, under constantly stirring, it is slowly joined in the above-mentioned mixture that contains Low molecular heparin, and the buffer that adds pH6.8 again stirs to 100g, the milky Colloidal fluid that obtains is low-molecular heparin liposome spray preparation of the present invention.Then it being packed into has in the brown withstand voltage vial of valve system and immersion pipe, seals standby.

Embodiment 2:

Take by weighing Low molecular heparin 4g, the phosphate buffer that adds a small amount of pH7.0 makes into pasty state, adds pro-liposome 50g, grinds 40 minutes, places 60 minutes; Adding vitamin E 0.3g stirs evenly; Ethyl hydroxybenzoate 0.5g is dissolved among the propylene glycol 6g, under constantly stirring, it is slowly joined in the above-mentioned mixture that contains Low molecular heparin, add the pH7.0 phosphate buffer again to 100g, stir, promptly obtain end product of the present invention, it is packed into has in the brown withstand voltage vial of valve system and immersion pipe then, seals standby.

Embodiment 3:

Get low-molecular heparin liposome spray preparation 4～5g, be sprayed on the new zealand rabbit back depilation skin, area is 14 * 14cm.Respectively at before the medication and after the medication 6 hours, with disposable syringe heart puncturing extracting blood 1.8ml, inject fast in the silication rotating ring of extracorporeal thrombosis forming device, with the rotation of 17 rev/mins rotating speeds, take out after 15 minutes.Blood in the pipe is poured on the filter paper together with thrombosis, blots thrombosis surface blood, measure thrombosis length and wet weight of thrombus.The result shows, and compares before the medication, and medication is after 6 hours, thrombosis contraction in length 1.94 ± 1.12cm (P＜0.05, n=5), wet weight of thrombus reduce by 52.28 ± 27.23mg (P＜0.05, n=5).Show that low-molecular heparin liposome spray preparation has significant inhibitory effect to the formation of experimental thrombosis.

Studies show that low-molecular heparin liposome spray preparation can promote the Transdermal absorption of Low molecular heparin, the significant prolongation blood coagulation time significantly suppresses the formation of experimental thrombosis.Said preparation has avoided the oral administration gastrointestinal tract to the decomposition of medicine and the first pass effect of liver with open transdermal administration, has improved bioavailability of medicament, and effect is better than the injection Low molecular heparin; Avoided drug administration by injection to bring patient's inconvenience simultaneously, made things convenient for patient's medication, and, helped prolonged application, realized purpose of the present invention fully owing to effect has reduced administration number of times lastingly.This product preparation technology's novelty, simple and easy to do, be suitable for to promote and produce, good social benefit and economic benefit will be arranged.

Claims

1, a kind of low-molecular heparin liposome spray preparation, it is characterized in that this spray colloid is is principal agent with the Low molecular heparin, pro-liposome is a carrier, adds the spray glue type external preparation that an amount of antioxidant, antiseptic and buffer are made, and described pro-liposome is by 20% Phospholipon ^Zero80,14%～18% ethanol and 62%～66% deionized water are formed.

2, low-molecular heparin liposome spray preparation according to claim 1 is characterized in that described antioxidant selects vitamin E for use, and antiseptic is made up of parabens and propylene glycol, and buffer is selected pH6～8 phosphate buffers for use; Its proportioning: the weight ratio of Low molecular heparin, pro-liposome, antioxidant, ethyl hydroxybenzoate, propylene glycol, buffer is: 2～5: 30～50: 0.2～0.4: 0.3～0.5: 5～7: 42.1～62.5.

3, the preparation technology of claim 1 or 2 described low-molecular heparin liposome spray preparations, the preparation technology who it is characterized in that this spray colloid is: earlier with the principal agent Low molecular heparin with a small amount of buffer furnishing pasty state, adding pro-liposome ground 30～60 minutes, left standstill 30～60 minutes, add anti-agent stir mixture; The antiseptic parabens is dissolved in the propylene glycol, adds in the said mixture, stir, add buffer again, stir,, be end product low-molecular heparin liposome spray preparation of the present invention to the jelly that is creamy white.

4, spray colloid preparation technology according to claim 3 is characterized in that the used Low molecular heparin of this technology, pro-liposome, antioxidant, antiseptic and buffer, all carries out degerming through membrane processing method in advance, and operates in the air cleaning environment.