CN1969861A - Sustained release system of clozapine solid liposome microparticle - Google Patents
Sustained release system of clozapine solid liposome microparticle Download PDFInfo
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- CN1969861A CN1969861A CNA2006101239087A CN200610123908A CN1969861A CN 1969861 A CN1969861 A CN 1969861A CN A2006101239087 A CNA2006101239087 A CN A2006101239087A CN 200610123908 A CN200610123908 A CN 200610123908A CN 1969861 A CN1969861 A CN 1969861A
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- clozapine
- fatty acid
- alkyl chain
- saturated alkyl
- solid lipid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
- A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
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Abstract
The invention discloses a clozapine solid liposome microparticle control slow-release system, which is characterized by the following: adopting high-fusing point and biological compatible solid liposome as carrier material such as fatty acid ester, fatty acid, fatty alcohol or their two composition; making surface activator or macromolecule as stabilizer such as lecithin, poloxamer series, polysorbate series, cholate and so on.
Description
Technical field
The present invention relates to a kind of schizoid controlled drug delivery system that is used for the treatment of, specifically a kind of sustained release system of clozapine solid liposome microparticle.
Background technology
Clozapine (clozapine) is a kind of atypical antipsychotic, is one of schizoid common drug of present state's internal therapy, and schizophrenia positive or negative symptom is all had clinical efficacy preferably.
Clozapine is a kind of flaxen crystalline powder, although clozapine produces EPS hardly under lower daily dose, but because clozapine very easily dissolving in acid solution, by very fast absorption, its bioavailability is lower at stomach for the oral back of its conventional tablet.And clozapine (neutral environment) in water is almost insoluble, and it in the release at intestinal position but seldom.Therefore, when using the treatment of clozapine conventional tablet in order to guarantee effective blood drug level, must every day multiple dosing, thereby cause blood concentration fluctuation big.Poisoning may take place or than serious adverse effects, as headache, lethargy, nauseating, vomiting, occur arrhythmia or respiration inhibition etc. when serious in excessive concentration; Concentration is low excessively, can not produce effective curative effect.Simultaneously, the psychotic has certain difficulty when taking medicine, and need again to take for a long time, therefore, the slow-releasing agent of exploitation clozapine is highly significant, not only can keep the effective blood drug level of clozapine in the long time, reduces patient's medicining times, but also can improve the bioavailability of clozapine, reduce side effects of pharmaceutical drugs.
The patent of domestic disclosed relevant clozapine control slow release formulation is few.Patent " pill for tranquilizing and curing mania and preparation method thereof " (ZL9710478.5), " a kind of Ningshen medicinal composition of anti-spirit " (ZL95117410.X) and the disclosed pharmaceutical formulation of " 'Anshenyangxin ' and preparation method thereof " (application number 200410024524) be Chinese patent medicine based on Chinese medicine, combined with westem clozapine, its advantage is that side effect is little.But clozapine shared content in tablet is lower, and still need repeatedly take medicine every day, and be difficult to effectively bring into play the efficacy of a drug of clozapine.Patent " a kind of clozapine oral slow, controlled-release solid formulations " (application number 02134550) is to be the adjuvant and the inserts of skeleton with starch, hypromellose, ethyl cellulose, magnesium stearate, Pulvis Talci etc., strikes out common oral tablet.Mention this tablet in the patent specification and have certain sustained release property, but releasing effect is not obvious.
Summary of the invention
The object of the present invention is to provide a kind of sustained release system of clozapine solid liposome microparticle, almost insoluble at clozapine (neutral environment) in water, very easily dissolving in acid solution, the fluctuation of concentration of the oral back of its conventional tablet in the blood medicine is big, and the deficiency that need repeatedly take in 1st, the present invention is loaded in the clozapine bag in the solid lipid carrier, make subparticle, can effectively control the release performance of clozapine, slow down the rate of release of clozapine in sour environment, and improve its release at neutral environment.Can as required microparticle further be processed into different dosage forms, as capsule, suspension etc.
The clozapine crystal is very low at the rate of dissolution of neutral environment (pH is in 7.2 the phosphate buffer solution), and its release belongs to dissolving control, and the rate of dissolution of clozapine has determined release rate of drugs.The clozapine bag is loaded among the SLM, and the clozapine crystalline size reduces greatly, and perhaps clozapine is distributed in the carrier with molecule or amorphous state, has improved the dissolution velocity of clozapine, thereby improves its release performance.In sour environment (hydrochloric acid solution of 0.1mol/L), the clozapine crystal is just dissolving fully about two hours, and its release belongs to DIFFUSION CONTROLLED, and solid lipid microparticle carrier material will effectively be controlled the diffusion of clozapine, prolong its release time.
Solid lipid microparticle (SLM) is a solid fat higher with fusing point, good biocompatibility, as polyunsaturated fatty acid ester, fatty acid, aliphatic alcohol, mixed ester or two or more the mixture in them is carrier material, with surfactants such as lecithin, poloxamer series, polysorbate series, cholic acid salt or polymer substance is stabilizing agent, a kind of newtype drug control slow release transmission system of formation.Mainly be applicable to lipophilic drugs encapsulation, also hydrophilic medicament can be made refabrication SLM behind the fat-soluble strong prerequisite medicine by methods such as esterifications.SLM has following advantage: can effectively control the release of medicine; The good biocompatibility of carrier material reduces greatly to the toxic danger of organism; Can realize the solid state of liquid towards medicine, strengthen stability of drug; Avoided using deleterious organic solvent in the preparation process, can residual deleterious organic solvent in the medicament.
The present invention can adopt existing fusion-cooling method to prepare the solid lipid microparticle.At first, the mixing in anhydrous ethanol solvent with clozapine and carrier at a certain temperature, solvent is reclaimed in evaporation then; Molten mixture is scattered under the magnetic agitation effect in the aqueous solution that same temperature contains stabilizing agent; The reuse high-shearing dispersion emulsifying machine was handled about 15 minutes, formed the O/W type emulsion of high degree of dispersion; At last emulsion is placed psychrolusia, fat phase crystallisation by cooling is separated out, obtain the suspension of particle diameter at the clozapine solid lipid subparticle of 5-20 μ m.Suspension can carry out drying by lyophilization or spray-dired method, obtains dried granules.
A kind of clozapine solid lipid microparticle control delivery provided by the invention, make by following mass fraction component:
Clozapine 1～10
Stabilizing agent 10～50.
Preferably:
Clozapine 2～8
Stabilizing agent 20～40.
One or more mixture in described solid lipid preferred fat acid esters, fatty acid, the aliphatic alcohol.
The molecular structural formula of described fatty acid ester is R
1COOR
2, wherein, R
1Be C
8～C
24The saturated alkyl chain, R
2Be C
1～C
24The saturated alkyl chain; Perhaps be
R
3COOR
4-, wherein, R
3Be C
8～C
24The saturated alkyl chain, R
4Be C
1～C
24The saturated alkyl chain; Perhaps be
R
5COOR
6-, wherein, R
5And R
6Be C
8～C
24The saturated alkyl chain.
The molecular structural formula of described fatty acid is R
7COOH, wherein, R
7Be C
11～C
24The saturated alkyl chain.
The molecular structural formula of described aliphatic alcohol is R
8OH, wherein, R
8Be C
11～C
24The saturated alkyl chain.
Described fatty acid ester is the mixture of fatty glyceride, and its mass fraction is composed as follows:
Glycerine monofatty ester 10～70
Fatty acid double glyceride 10～70
Fatty acid glyceryl ester 10～70.
Fatty acid in the described fatty glyceride is C
8～C
24Satisfied fatty acid.
Stabilizing agent is selected from surfactant or the polymer substances such as one or more mixture in lecithin, PVA, poloxamer series, polysorbate series, the cholate, can effectively stop the SLM gathering and keep it stable.
The extracorporeal releasing experiment of clozapine solid lipid microparticle carries out in simulation intestinal environment (pH is 7.2 phosphate buffer solution) and simulation gastric environment (hydrochloric acid solution of 0.1mol/L) respectively among the present invention, experimental temperature is 374 ± 0.5 ℃, does not consider the effect of enzyme.Carry out according to the slurry method in the dissolution method among the Chinese Pharmacopoeia 2000 appendix XD.Get 5.00g SLM sample and place in the bag filter, in the reception liquid of 900ml, discharge.The rotating speed of stirring arm is 100 rev/mins.Sample in certain time interval is got the 5ml reception tank with the concentration of ultraviolet spectrophotometry at 242nm wavelength mensuration acceptable solution Chinese medicine, calculates the percentage ratio of drug release.Each sampling back replenishes the fresh reception liquid of equivalent.
The present invention compared with prior art has following advantage:
1, clozapine solid lipid microparticle provided by the present invention can effectively be controlled the release performance of clozapine, can slow down the rate of release of clozapine in sour environment, improves its release at neutral environment.
2, the good biocompatibility of the carrier material that adopts among the present invention, low price; Preparation process is simple to operate, and the stable dispersion of stabilizing agent is effective, uniform particles; Avoided using deleterious organic solvent in the preparation process.
Description of drawings
Fig. 1 is the microscope figure with a kind of clozapine solid lipid microparticle provided by the invention.
Fig. 2 is the particle size distribution figure of the clozapine solid lipid microparticle among Fig. 1.
Fig. 3 is clozapine crystal and the clozapine solid lipid microparticle provided by the invention release in vitro curve of (pH is 7.2 phosphate buffer solution) under neutral environment.
Fig. 4 is clozapine crystal and the clozapine solid lipid microparticle provided by the invention release in vitro curve of (hydrochloric acid solution of 0.1mol/L) under sour environment.
The specific embodiment
With the stearin of 5% (W/W is a benchmark with emulsion, and is together following) and clozapine mixing in anhydrous ethanol solvent of 0.5%, solvent is reclaimed in evaporation then under 85 ℃; Molten mixture is scattered under the magnetic agitation effect in the aqueous solution that same temperature contains lecithin/bovine bile stabilizing agent of 2%; The high-shearing dispersion emulsifying machine that reuse is 8000 rev/mins was handled about 15 minutes, formed the O/W type emulsion of high degree of dispersion; At last emulsion is placed 5 ℃ psychrolusia, fat phase crystallisation by cooling is separated out, obtaining mean diameter is the suspension of the clozapine solid lipid subparticle of 8 μ m.In temperature-50 ℃, lyophilization 24h under the pressure 5.0Pa obtains exsiccant microparticle.
With 5% stearin and the mixing in anhydrous ethanol solvent of 0.5% clozapine, solvent is reclaimed in evaporation then under 85 ℃; Molten mixture is scattered under the magnetic agitation effect in the aqueous solution that same temperature contains 2% PVA (MW=13000-23000) stabilizing agent; The high-shearing dispersion emulsifying machine that reuse is 10000 rev/mins was handled about 15 minutes, formed the O/W type emulsion of high degree of dispersion; At last emulsion is placed 5 ℃ psychrolusia, fat phase crystallisation by cooling is separated out, obtaining mean diameter is the suspension of the solid lipid microparticle of sealing clozapine of 5 μ m.Temperature-50 ℃, lyophilization 24h under the pressure 5.0Pa obtains exsiccant microparticle.
With 5% mixed ester (glycerol monostearate 17%, stearic acid double glyceride 54%, glycerol stearate 29%) and clozapine mixing in anhydrous ethanol solvent of 0.5%, make solvent evaporate fully, reclaim then under 85 ℃; Molten mixture is scattered under the magnetic agitation effect in the aqueous solution that same temperature contains 2% PVA (MW=13000-23000) stabilizing agent; The high-shearing dispersion emulsifying machine that reuse is 8000 rev/mins was handled about 15 minutes, formed the O/W type emulsion of high degree of dispersion; At last emulsion is placed 5 ℃ psychrolusia, fat phase crystallisation by cooling is separated out, obtaining mean diameter is the suspension of the clozapine solid lipid subparticle of 5 μ m.In temperature-50 ℃, lyophilization 24h under the pressure 5.0Pa obtains exsiccant microparticle.
With 8% hexadecanol and clozapine mixing in anhydrous ethanol solvent of 0.5%, make solvent evaporate fully, reclaim then under 85 ℃; Molten mixture is scattered under the magnetic agitation effect in the aqueous solution that same temperature contains 2% PVA (MW=31000-50000) stabilizing agent; The high-shearing dispersion emulsifying machine that reuse is 8000 rev/mins was handled about 15 minutes, formed the O/W type emulsion of high degree of dispersion; At last emulsion is placed 5 ℃ psychrolusia, fat phase crystallisation by cooling is separated out, obtaining mean diameter is the suspension of the clozapine solid lipid subparticle of 6 μ m.In temperature-50 ℃, lyophilization 24h under the pressure 5.0Pa obtains exsiccant microparticle.
With 10% mixed ester (glycerol monostearate 17%, stearic acid double glyceride 54%, glycerol stearate 29%) and the mixing in anhydrous ethanol solvent of 0.8% clozapine, solvent is reclaimed in evaporation then under 85 ℃; Molten mixture is scattered under the magnetic agitation effect in the aqueous solution that same temperature contains 2% PVA (MW=13000-23000) stabilizing agent; The high-shearing dispersion emulsifying machine that reuse is 8000 rev/mins was handled about 15 minutes, formed the O/W type emulsion of high degree of dispersion; At last emulsion is placed 5 ℃ psychrolusia, fat phase crystallisation by cooling is separated out, obtaining mean diameter is the suspension of the clozapine solid lipid subparticle of 10 μ m.In temperature-50 ℃, lyophilization 24h under the pressure 5.0Pa obtains exsiccant microparticle.
With 5% mixed ester (glycerol monostearate 17%, stearic acid double glyceride 54%, glycerol stearate 29%) and clozapine mixing in anhydrous ethanol solvent of 0.5%, solvent is reclaimed in evaporation then under 85 ℃; Molten mixture is scattered under the magnetic agitation effect in the aqueous solution that same temperature contains 5% poloxamer-407 stabilizing agent; The high-shearing dispersion emulsifying machine that reuse is 8000 rev/mins was handled about 15 minutes, formed the O/W type emulsion of high degree of dispersion; At last emulsion is placed 5 ℃ psychrolusia, fat phase crystallisation by cooling is separated out, obtaining mean diameter is the suspension of the clozapine solid lipid subparticle of 10 μ m.In temperature-50 ℃, lyophilization 24h under the pressure 5.0Pa obtains exsiccant microparticle.
With 5% mixed ester (glycerol monostearate 25%, stearic acid double glyceride 40%, glycerol stearate 35%) and clozapine mixing in anhydrous ethanol solvent of 0.5%, solvent is reclaimed in evaporation then under 85 ℃; Molten mixture is scattered under the magnetic agitation effect in the aqueous solution that same temperature contains 2% PVA (MW=13000-23000) stabilizing agent; The high-shearing dispersion emulsifying machine that reuse is 8000 rev/mins was handled about 15 minutes, formed the O/W type emulsion of high degree of dispersion; At last emulsion is placed 5 ℃ psychrolusia, fat phase crystallisation by cooling is separated out, obtaining mean diameter is the suspension of the clozapine solid lipid subparticle of 6 μ m.In temperature-50 ℃, lyophilization 24h under the pressure 5.0Pa obtains exsiccant microparticle.
With 5% stearic acid and clozapine mixing in anhydrous ethanol solvent of 0.25%, solvent is evaporated fully under 85 ℃; Molten mixture is scattered under the magnetic agitation effect in the aqueous solution that same temperature contains 3% poloxamer-407 stabilizing agent; The high-shearing dispersion emulsifying machine that reuse is 8000 rev/mins was handled about 15 minutes, formed the O/W type emulsion of high degree of dispersion; At last emulsion is placed 5 ℃ psychrolusia, fat phase crystallisation by cooling is separated out, obtaining mean diameter is the suspension of the clozapine solid lipid subparticle of 8 μ m.In temperature-50 ℃, lyophilization 24h under the pressure 5.0Pa obtains exsiccant microparticle.
As depicted in figs. 1 and 2, be the micro-Electronic Speculum figure and the particle size distribution figure of the solid lipid microparticle suspension of sealing clozapine for preparing for 3 times at embodiment.Distribution of particles is even, and mean diameter is 5 μ m.
As shown in Figure 3, be the clozapine stearin microparticle of clozapine mixed ester microparticle, embodiment 2 preparations of 3 times preparations of clozapine medicine crystal (about 5 μ m), the embodiment release in vitro curve of (pH is 7.2 phosphate buffer solution) under neutral environment.The rate of dissolution of clozapine crystal in neutral environment is very low.The clozapine bag is loaded among the SLM, has improved the rate of release of clozapine.The raising of rate of release in neutral environment is better than stearin to mixed ester to clozapine.
As shown in Figure 4, be the clozapine stearin microparticle of clozapine mixed ester microparticle, embodiment 2 preparations of clozapine medicine crystal (about 5 μ m), the embodiment 3 preparations release in vitro curve of (hydrochloric acid solution of 0.1mol/L) under sour environment.The clozapine crystal is very fast dissolving, release in sour environment.The clozapine bag is loaded among the SLM, has effectively slowed down its rate of release.Mixed ester is better than stearin to clozapine slowing down of rate of release in sour environment.
Claims (9)
1, a kind of clozapine solid lipid microparticle control delivery is characterized in that being made by following mass fraction component:
Clozapine 1～10
Solid lipid 20～80
Stabilizing agent 10～50.
2, system according to claim 1 is characterized in that described constituent mass umber is preferably as follows:
Clozapine 2～8
Solid lipid 40～60
Stabilizing agent 20～40.
3, system according to claim 1 and 2 is characterized in that described solid lipid is one or more mixture in fatty acid ester, fatty acid, the aliphatic alcohol.
4, system according to claim 3, the molecular structural formula that it is characterized in that described fatty acid ester is R
1COOR
2, wherein, R
1Be C
8～C
24The saturated alkyl chain, R
2Be C
1～C
24The saturated alkyl chain; Perhaps be
R
3COOR
4-, wherein, R
3Be C
8～C
24The saturated alkyl chain, R
4Be C
1～C
24The saturated alkyl chain; Perhaps be
R
5COOR
6-, wherein, R
5And R
6Be C
8～C
24The saturated alkyl chain.
5, system according to claim 3, the molecular structural formula that it is characterized in that described fatty acid is R
7COOH, wherein, R
7Be C
11～C
24The saturated alkyl chain.
6, system according to claim 3, the molecular structural formula that it is characterized in that described aliphatic alcohol is R
8OH, wherein, R
8Be C
11～C
24The saturated alkyl chain.
7, system according to claim 3 is characterized in that described fatty acid ester is the mixture of fatty glyceride, and its mass fraction is composed as follows:
Glycerine monofatty ester 10～70
Fatty acid double glyceride 10～70
Fatty acid glyceryl ester 10～70.
8, system according to claim 7 is characterized in that the fatty acid in the described fatty glyceride is C
8～C
24Satisfied fatty acid.
9,, it is characterized in that stabilizing agent is selected from one or more mixture in lecithin, PVA, poloxamer series, polysorbate series, the cholate according to claim 1 and 2 described systems.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2006101239087A CN1969861A (en) | 2006-11-30 | 2006-11-30 | Sustained release system of clozapine solid liposome microparticle |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2006101239087A CN1969861A (en) | 2006-11-30 | 2006-11-30 | Sustained release system of clozapine solid liposome microparticle |
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| Publication Number | Publication Date |
|---|---|
| CN1969861A true CN1969861A (en) | 2007-05-30 |
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ID=38111009
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006101239087A Pending CN1969861A (en) | 2006-11-30 | 2006-11-30 | Sustained release system of clozapine solid liposome microparticle |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109686409A (en) * | 2019-02-01 | 2019-04-26 | 华南理工大学 | A kind of research of Dissipative Particle Dynamics comprising can break chemical bonds carrier micelle drug release process analogy method |
| CN115160239A (en) * | 2022-07-08 | 2022-10-11 | 山东省分析测试中心 | Preparation method of clozapine fine powder |
-
2006
- 2006-11-30 CN CNA2006101239087A patent/CN1969861A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109686409A (en) * | 2019-02-01 | 2019-04-26 | 华南理工大学 | A kind of research of Dissipative Particle Dynamics comprising can break chemical bonds carrier micelle drug release process analogy method |
| CN109686409B (en) * | 2019-02-01 | 2020-08-18 | 华南理工大学 | Simulation method of drug release process of drug-loaded micelle containing cleavable chemical bond |
| CN115160239A (en) * | 2022-07-08 | 2022-10-11 | 山东省分析测试中心 | Preparation method of clozapine fine powder |
| CN115160239B (en) * | 2022-07-08 | 2023-10-13 | 山东省分析测试中心 | Preparation method of clozapine fine powder |
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