CN1555802A

CN1555802A - Cinnarizone self micro emulsified soft capsule and its preparation method

Info

Publication number: CN1555802A
Application number: CNA2004100210063A
Authority: CN
Inventors: 何仲贵; 殷静; 唐星; 张天虹
Original assignee: Shenyang Pharmaceutical University
Current assignee: Shenyang Pharmaceutical University
Priority date: 2004-01-05
Filing date: 2004-01-05
Publication date: 2004-12-22
Anticipated expiration: 2024-01-05
Also published as: CN100556407C

Abstract

A self-microemulsified softgel of cinnarizine for treating cerebral infarction, cerebral arteriosclerosis, cerebral trauma sequelae, etc is prepared from cannarizine, coemulsifier, emulsifier and an oil phase through proportionally mixing, and stirring while self emulsifying. Its advantage is high biological utilization rate.

Description

Cinnarizine self-emulsification soft capsules and preparation method thereof

Technical field:

The present invention relates to medical technical field, exactly it is a kind of cinnarizine self-emulsification soft capsules and preparation method thereof.

Background technology:

Cinnarizine is the piperazines calcium channel blocker, can block the interior stream of calcium of vascular smooth muscle, causes vasodilation, can improve cerebral circulation and following of arteria coronaria by significance, and cerebrovascular is had certain selectively acting, removes cerebral vasospasm.Acting duration is also very long.Be mainly used in cerebral arteriosclerosis, cerebral infarction, hypertensive encephalopathy, cerebral thrombosis, cerebral hemorrhage convalescent period and subarachnoid hemorrhage convalescent period, cerebral trauma sequela, auditory vertigo and peripheral angiopathy such as raynaud disease etc.Also be used for tinnitus, dizziness and dysacousis.

Cinnarizine has antihistamine, medmain, anti-kassinin kinin is active and suppress complement C ₄Activatory effect.Anaphylaxis dermatosis such as chronic urticaria, eczema, neurodermatitis, prurigo nodularis, senile prurigo and hereditary angioedema there is certain curative effect.

Oral cinnarizine reached Cmax, t in 3～7 hours _1/2Be 3～24 hours, excrement drained 66% through homaluria 23% in 72 hours.But cerebral blood flow increasing is about 10%～29% after the medication; Quiet notes 2～7 minutes, can make cerebral blood flow increase by 10%.

Existing cinnarizine oral formulations has preparations such as tablet, hard capsule, according to foreign literature, the bioavailability of cinnarizine depends on its meltage under one's belt, and people's gastric acidity often changes owing to be subjected to the influence of food or physiologic factor, particularly the use object of cinnarizine preparation old people normally, mostly suffers from achlorhydria, medicine meltage is under one's belt reduced, cause bioavailability to reduce, thereby make the bioavailability of cinnarizine have tangible individual difference.

Summary of the invention:

The purpose of this invention is to provide a kind of cinnarizine self-emulsification soft capsules and preparation method thereof, it adopts the self-emulsifying microemulsion technology to be made into the self-emulsifying microemulsion capsule, can form microemulsion rapidly under one's belt after oral, significantly improved the dissolution of cinnarizine, thereby improved the few patient's of gastric acid secretion bioavailability, greatly reduced cinnarizine at the intravital individual difference of patient.Self-emulsifying drug delivery system (Self-Emulsifying DrugDelivery System, SEDDS) be the solution of the transparent and homogeneous that forms by oil phase, emulsifying agent and co-emulsifier, under the condition of stirring of ambient temperature (being often referred to about 37 ℃) and gentleness, because the existence of emulsifying agent, spontaneous emulsification forms the Emulsion of particle about 5 microns.Along with increasing of emulsifying agent consumption, this self-emulsifying drug delivery systems can be in gastrointestinal tract spontaneous formation microemulsion, be referred to as the self-emulsifying microemulsion drug delivery system (Self-Microemulsifying Drug Delivery System, SMEDDS).Medicine is present in these tiny oil droplets, is distributed in fast in the whole gastrointestinal tract, and medicine distributes between oil/water is biphase, and the stripping that relies on the huge specific surface area of tiny oil droplet to improve water-insoluble drug has greatly improved bioavailability of medicament.

The mass fraction (w/w) of oil phase in SEDDS is generally 20%～70%, oil phase as SEDDS, requirement can be with the medicine of less consumption dissolving recipe quantity, and does not also have medicine separate out under the cryopreservation condition, meets simultaneously behind the water easily by the emulsifying agent emulsifying in the prescription.The oil that SEDDS uses the earliest is crude vegetal, but the ability and the automatic emulsifying performance of these oil dissolving fat-soluble medicines are not strong.In the presence of non-ionic surface active agent that can be oral, easily form SEDDS through the vegetable oil after structure of modification and the hydrolysis, as soybean oil, Oleum Arachidis hypogaeae semen, safflower oil, the Fructus Canarii albi wet goods after the improvement.The flowability of fatty acid ester, dissolubility and self emulsifying are better, especially the medium chain fatty glyceride (medium-chainglyceride of chain length between C8～C10, be called for short MCT), be everlasting and preferentially used among the SEDDS, its safety, stable, can make Emulsion under different temperatures with multiple composition, MCT also can promote the little intestinal absorption of medicine.At present often adopt long-chain and medium-chainly have in various degree that the triglyceride oils of saturation designs the self emulsifying dosage form.Except that vegetable oil that can be oral commonly used, following oils is good to the insoluble drug dissolubility, and automatic emulsifying performance is good:

Arlacel 80 (HLB=4.3) oleic acid sorbitol ester

Arlacel 86 (HLB=2.8) olein: propylene glycol (90: 10)

Capmul MCM (HLB=5.5～6.0) Oleum Cocois C8/C10 monoglyceride or dibasic acid esters

Captex 200 (oil) Oleum Cocois C8/C10 propylene glycol dibasic acid esters

Captex 355 (oil) Oleum Cocois C8/C10 triglyceride

Miglyol 812 (oil) Oleum Cocois C8/C10 triglyceride

The acetylizad monoglyceride of Myvacet (oil) purification

Myverol 18-92 (HLB=3～7) purification Oleum helianthi monoglyceride (containing 90% glyceryl linoleate)

Soybean oil mainly is the triglyceride that contains oleic acid (25%) and linoleic acid (54%)

Peceol (HLB=3) olein

Maisine (HLB=3) glyceryl linoleate

Gelucire 44/14 (HLB=14) Polyethylene Glycol glyceryl laurate ester

The general nonionic emulsifier that adopts high HLB of emulsifying agent among the SEDDS.Nonionic emulsifier is lower than ionic emulsifying agent toxicity, and they only cause that the infiltrative reversibility of gastrointestinal tract wall changes.The strongly hydrophilic of high HLB emulsifying agent is to form oil-in-water emulsion droplet and self emulsifying liquid immediately to spread necessaryly in aqueous environment, and it can make the self emulsifying process faster.Emulsifying agent is amphiphatic, and they itself also can dissolve a large amount of relatively hydrophobic drugs, can prevent that medicine from depositing in gastrointestinal tract and the dissolved state of prolong drug molecule, and this is extremely important to effective absorption.When the emulsifier content height arrives to a certain degree, will cause the formation of self-emulsifying microemulsion system.Different types of liquid or solid ethyoxyl polyoxyethylene glyceride, polyoxyethylene oleate, Tween80 are the most frequently used emulsifying agents.In order to reach good emulsifying effectiveness, adopt the emulsifying agent more than 30% usually.Below be preparation self-emulsifiable preparation some emulsifier commonly used:

Ophase 31 (HLB=4.0) liquid egg phospholipid

Cremophor EL (HLB=13.5) polyoxyethylene castor oil

Labrafac CM10 (HLB=10) Oleum Cocois C8/C10 polyethyleneglycol glyceride

Labrafil M1944 CSD (HLB=3～4) mainly is an almond oil acid polyethylene glycol glyceride

Labrafil M2125 CS (HLB=3～4) mainly is an almond oil acid polyethylene glycol glyceride

Tagat TO (HLB=11.3) polyoxyethylene (25) triolein

Tween 80 (HLB=11.0) polyoxyethylene (20) sorbitan oleate

Labrasol (HLB=14) Polyethylene Glycol-8-glycerol is sad/decanoin

Co-emulsifier agent among the SEDDS, its existing hydrophilic also has lipophile.Co-emulsifier helps active component to form uniform Emulsion and keeps the stability of Emulsion in storage process.Spendable cosurfactant has ethanol, propylene glycol, Polyethylene Glycol (molecular weight is at 200-600), propylene carbonate (propylene carbonate), ethylene glycol monomethyl ether (transcutol), glycerol furfural, dimethyl Soquad or above mixture in this invention.

Advantage of the present invention is: the present invention can significantly improve the individual bioavailability of cinnarizine, and it is very little that stripping is influenced by PH, can reduce the individual difference of bioavailability, thereby improved the curative effect of medicine.

Description of drawings:

Fig. 1 is cinnarizine self-emulsifying microemulsion capsule of the present invention and marketed tablet, capsular dissolution curve chart.

The specific embodiment:

Embodiment 1:

It is composed as follows to write out a prescription: (g)

Cinnarizine 25

Dimethyl Soquad 100

Oleic acid 50

Tween?80 185

Vitamin E 5

Make 1000 soft capsules altogether

Preparation technology: cinnarizine self-emulsifying microemulsion capsule preparation method thereof: take by weighing an amount of cinnarizine, the dimethyl Soquad, Tween 80, the oleic acid that add recipe quantity, at 40C, vibration made its dissolving in about 1.5 hours during 100 rev/mins of constant temperature vibrations were bathed, adding antioxidant again stirs, after treating that medicinal liquid is reduced to room temperature, be pressed into capsule.

The cinnarizine self-emulsifying microemulsion capsule and marketed tablet, the capsule dissolution that make according to embodiment 1 compare: the uniform solution that makes is packed in the hard capsule by recipe quantity, commercially available cinnarizine tablet, capsule are carried out the dissolution test, the results are shown in accompanying drawing 1.

Dissolution determination method: get this product, according to dissolution method (two appendix XC first methods of Chinese Pharmacopoeia version in 2000), respectively with distilled water, 0.1mol/L hydrochloric acid, pH6.8 buffer salt solution 900mL is a solvent, rotating speed is 100r/min, operation in accordance with the law, respectively 5,10,20,30,45, during 60min, get solution an amount of (replenishing the fresh medium of equality of temperature simultaneously) with volume, filter, get subsequent filtrate 8ml, therefrom take out 5ml again and be diluted to 10ml,, measure peak area at the wavelength place of 253nm according to high performance liquid chromatography (two appendix VD of Chinese Pharmacopoeia version in 2000) with mobile phase, it is an amount of that other gets the cinnarizine reference substance, be made into the cinnarizine solution that concentration is about 15 μ g/mL with mobile phase, measure, calculate the accumulation stripping quantity of every capsules with method.

By accompanying drawing 1 as seen, homemade cinnarizine SMEDDS capsule obviously improves than commercially available cinnarizine tablet, capsule dissolution in water, simulated intestinal fluid medium.

Embodiment 2:

It is composed as follows to write out a prescription: (g)

Cinnarizine 25

Dimethyl Soquad 130

Oleic acid 55

Tween?80 185

Vitamin E 5

Make 1000 soft capsules altogether

Preparation technology is with example 1.

Embodiment 3:

It is composed as follows to write out a prescription: (g)

Cinnarizine 25

Dimethyl Soquad 150

Oleic acid 38

Tween?80 190

Vitamin E 5

Make 1000 soft capsules altogether

Embodiment 4:

It is composed as follows to write out a prescription: (g)

Cinnarizine 25

Dimethyl Soquad 85

Miglyol?812 17

Oleic acid 51

Tween?80 170

Vitamin E 5

Make 1000 soft capsules altogether

Preparation technology is with example 1.

Embodiment 5:

It is composed as follows to write out a prescription: (g)

Cinnarizine 25

Dimethyl Soquad 110

Oleic acid 38

Ethyl oleate 37

Tween?80 190

Vitamin E 5

Make 1000 soft capsules altogether

Preparation technology is with example 1.

Embodiment 6:

It is composed as follows to write out a prescription: (g)

Cinnarizine 25

Dimethyl Soquad 180

Oleic acid 45

Ethyl oleate 45

Tween?80 185

Vitamin E 5

Make 1000 soft capsules altogether

Embodiment 7:

It is composed as follows to write out a prescription: (g)

Cinnarizine 25

Dimethyl Soquad 150

Oleic acid 38

Tween?80 190

Vitamin E 5

Make 1000 soft capsules altogether

Claims

1, cinnarizine self-emulsification capsule, it is characterized in that: it is the solution of the transparent and homogeneous that formed by oil phase, emulsifying agent and co-emulsifier, under the condition of stirring of ambient temperature and gentleness, because the existence of emulsifying agent, spontaneous emulsification forms the Emulsion of particle about 5 microns, and wherein the ratio of cinnarizine, co-emulsifier, emulsifying agent and a kind of oil phase is 1: 1～10: 1～20: 0.5～5; The ratio of cinnarizine, co-emulsifier, emulsifying agent and two kinds of oil phases is 1: 1～10: 1～20: 0.5～5: 0.5～5.

2, cinnarizine self-emulsification capsule according to claim 1, it is characterized in that: the co-emulsifier in the self-emulsifying microemulsion drug delivery system is that existing hydrophilic also has oil loving co-emulsifier, co-emulsifier helps active component to form the medicinal liquid of transparent and homogeneous and keeps the stability of medicinal liquid in storage process, and spendable co-emulsifier has ethanol, propylene glycol, molecular weight Polyethylene Glycol, propylene carbonate, ethylene glycol monomethyl ether, glycerol furfural, dimethyl Soquad or the above-mentioned mixture at 200-600.

3, cinnarizine self-emulsification capsule according to claim 1 is characterized in that: the oil phase in the self-emulsifying microemulsion drug delivery system can be after crude vegetal or process structure of modification and the hydrolysis or soybean oil, Oleum Arachidis hypogaeae semen, safflower oil, Fructus Canarii albi wet goods after the improvement.

4, cinnarizine self-emulsification capsule according to claim 3, it is characterized in that: oil phase can be the medium chain fatty glyceride of chain length between C8～C10, spendable oil phase has Arlacel 80, Arlacel86, Capmul MCM, Captex 200 (oil), Captex 355 (oil), Miglyol 812 (oil), Myvacet (oil), Myverol 18-92, olein, glyceryl linoleate, the Polyethylene Glycol glyceryl laurate ester, ethyl oleate, Ethyl linoleate etc., wherein Miglyol 812 or ethyl oleate must be united with oleic acid and used or oleic acid uses as oil phase separately.

5, cinnarizine self-emulsification capsule according to claim 1, it is characterized in that: the emulsifying agent in the self-emulsifying microemulsion drug delivery system adopts the nonionic emulsifier of high HLB, and spendable emulsifying agent has liquid egg phospholipid, hydrogenation polyoxyethylene, Oleum Ricini, Labrafac CM 10, Labrafil M 1944 CSD, Labrafil M2125 CS, Tagat TO, Tween 80, Labrasol etc.

6, a kind of preparation method of cinnarizine self-emulsification capsule as claimed in claim 1, it is characterized in that: cinnarizine self-emulsifying microemulsion capsule preparation method thereof: take by weighing an amount of cinnarizine, the oil phase, co-emulsifier, the emulsifying agent that add recipe quantity, at 40 ℃, vibration made its dissolving in about 1.5 hours during 100 rev/mins of constant temperature vibrations were bathed, add antioxidant again and stir, treat that medicinal liquid is reduced to room temperature after, be pressed into capsule.