CN101422425B - Etretinate type medicine solid dispersion - Google Patents
Etretinate type medicine solid dispersion Download PDFInfo
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- CN101422425B CN101422425B CN2007101764629A CN200710176462A CN101422425B CN 101422425 B CN101422425 B CN 101422425B CN 2007101764629 A CN2007101764629 A CN 2007101764629A CN 200710176462 A CN200710176462 A CN 200710176462A CN 101422425 B CN101422425 B CN 101422425B
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Abstract
The invention relates to an aromatic tretinoin medicament compound, in particular to a solid dispersoid which can improve the dissolution rate and the dissolution degree of aromatic tretinoin as well as the amine salt and ester medicaments thereof. The invention takes a strongly hydrophilic high molecular compound, a surface active agent or an organic acid compound as a dispersing vector to prepare the aromatic tretinoin medicament into the solid dispersoid. The dispersoid can be prepared into a plurality of preparations which can be used on clinic. Test approves that the prepared solid dispersoid can effectively improve the dissolution rate and the external dissolution degree of the aromatic tretinoin medicament.
Description
Technical field:
The present invention relates to a kind of Etretinate type medicine compositions, be specifically related to improve etretinnate and amine salt thereof, the dissolution rate of esters medicine and the solid dispersion of dissolution.
Background technology:
Etretinate type medicine is used for various dermatosiss and tumor treatment, has developed into the third generation at present, and since the seventies in 20th century, synthetic Etretinate type medicine has kind more than 1500.
The water solublity of etretinnate and esters thereof and salt is lower; As the beginning of the eighties in last century synthetic etretinnate ethyl ester be exactly representative drugs (arotinoid ethyl ester, RO 13-6298) wherein; Though in vitro tests, show better therapeutic effect; But since water solublity than limit use clinically, do not have the Related product listing so far.
In order effectively to improve the water solublity of medicine, prior art adopts following two kinds of methods usually: the one, and structure is modified, transformed, in chemical constitution, introduce the water miscible group of enhancing, like hands sections such as employing salifies; The 2nd, the employing preparation technique improves the water solublity of medicine, as adding surfactant, medicine being carried out cyclodextrin inclusion compound, medicine is processed liposome etc.
Chinese patent CN 1197839C reported raising 4-[(E)-2-(5,6,7; 8-tetrahydrochysene-5,5,8; 8-tetramethyl-2-naphthyl) acrylic] the water miscible method of benzoic acid (being etretinnate), this patent adopts salifiable mode that its structure is transformed, and is made into organic amine salt.Though water solublity has improved several times than former chemical compound; But still belong to water-fast material; If adopt common preparation means to be made into solid orally ingestible; Dissolution in vitro test shows that medicine almost can't stripping, by " dissolution in vitro when dissolution determination method is measured tablet or capsule 60 minutes in the Chinese pharmacopoeia (version in 2005) is no more than 5%.
For slightly water-soluble Etretinate type class medicines such as etretinnate, etretinnate ethyl ester, etretinnate organic amine salts; Adopt above-mentioned interpolation surfactant, medicine is carried out cyclodextrin inclusion compound, medicine process preparation techniques such as liposome and can not improve equally that it is insoluble, improve its external dissolution.
Therefore, the dissolution rate and the dissolution in vitro that effectively improve Etretinate type medicine are problem demanding prompt solutions in such pharmaceutical preparation research.
Summary of the invention:
The objective of the invention is to improve and improve the water solublity of slightly solubility Etretinate type medicine, for improving the absorption of this type of medicine, and then improve drug bioavailability and lay the foundation.
For achieving the above object, the present invention adopts the solid dispersion technology of preparing, and slightly solubility Etretinate type material and strongly hydrophilic dispersible carrier are processed solid dispersion.
Said etretinnate is the chemical compound that has as shown in the formula the I chemical constitution:
Formula I
Said Etretinate type medicine comprises above-mentioned formula I chemical compound and pharmaceutically useful organic amine salt or ester.
Said organic amine salt is selected from meglumine salt, lysinate, ethylenediamine salt, piperazine salt, hexahydropyridine salt, amino butanetriol salt, dimethyl ethanol amine salt.
Said ester is selected from methyl ester, ethyl ester, propyl ester, butyl ester, isobutyl ester.
Said strongly hydrophilic dispersible carrier comprises macromolecular compound, surfactant or the organic acid chemical compound etc. with strongly hydrophilic; Said dispersible carrier can be selected for use a kind of, also can select two or more complex carrier for use.The weight ratio of solid dispersion Chinese medicine active component and dispersible carrier is 1: 50～800.
Said macromolecular compound is selected from polyvinylpyrrolidone (mean molecule quantity is 29000-32000), Polyethylene Glycol, polyacrylic resin class, hypromellose etc.;
Said surfactant is selected from poloxamer, sodium lauryl sulphate, sodium cholate, tween, fatty alcohol-polyoxyethylene ether or Myrj 45, and wherein the Myrj 45 molecular weight is 1000-3000, for example polyoxyethylene stearate (40) ester etc.;
Said organic acid chemical compound is selected from stearic acid, mountain Yu acid, maleic acid, fumaric acid, citric acid, malic acid or succinic acid etc.
Can also contain stabilizing agent in the solid dispersion in addition.Said stabilizing agent is selected from vitamin E, tertiarybutylhydroquinone, propyl gallate, 2,6-di-tert-butyl-4-methy phenol, butylated hydroxyarisol.The consumption of stabilizing agent is: the formula I chemical compound of 1 weight portion or its pharmaceutically useful organic amine salt or ester, the stabilizing agent of 0.5-20 weight portion.
Etretinate type medicine solid dispersion can make through following method for preparing:
(1), solvent method, active component Etretinate type medicine and dispersible carrier are dissolved in certain solvent jointly, remove through volatilization and desolvate, dried residue promptly gets dispersion.Be prepared into useful clinically preparation after again dispersion further being pulverized.
(2), fusion method, active component Etretinate type medicine and dispersible carrier are melted in water-bath or oil bath, IQF is again got frozen material and is pulverized and to process useful clinically preparation.
(3), spray drying method, active component Etretinate type medicine and carrier are dissolved in certain solvent jointly, adopt the spray drying mode to obtain dispersion again, further be prepared into useful clinically preparation again.
Saidly process useful clinically preparation and be meant; The Etretinate type medicine solid dispersion of gained of the present invention can directly adopt the ordinary preparation technology that it is prepared into the pharmaceutical dosage form that is suitable for clinical practice, comprises dosage forms such as tablet, capsule, granule, oral (suspendible) liquid, dry suspension.
Method of the present invention can be dispersed in the strongly hydrophilic carrier by messenger drug object height degree, has increased the surface area of medicine greatly, and the strongly hydrophilic carrier can make medicine have good wettability simultaneously.Therefore accelerate the dissolution rate of medicine, improved the dissolubility of medicine.Through measuring, the dissolution in vitro of the resulting solid dispersion of the present invention in the time of 30 minutes can reach more than 50%, is higher than 5% dissolution of Chinese patent CN 1197839C far away.
The specific embodiment
Following embodiment only is used to illustrate the present invention, but also limits prescription of the present invention never in any form.
Embodiment 1: etretinnate solid dispersion ()
Etretinnate 1g
Polyvinylpyrrolidone K30 50g
Dehydrated alcohol 50ml
Get the 1g etretinnate and 50g polyvinylpyrrolidone K30 puts in the beaker, add the 50ml dehydrated alcohol, under 60 ℃ of water bath condition, be stirred to dissolving fully.Keep 60 ℃ of water-bath states, with Rotary Evaporators with solvent evaporates.Be transferred to and continue dry 12 hours (40 ℃) in the vacuum desiccator, take out, pulverize, cross 80 mesh sieves, promptly get.
Embodiment 2: etretinnate amino butanetriol salt solid dispersion ()
Etretinnate amino butanetriol salt 0.1g
Poloxamer 188 25g
Tertiarybutylhydroquinone 0.05g
Dehydrated alcohol 60ml
Get 0.1g etretinnate acid amino butanetriol salt and 50g poloxamer 188 and put in the beaker, add the 60ml dehydrated alcohol, under 60 ℃ of water bath condition, be stirred to dissolving fully.Keep 60 ℃ of water-bath states, with Rotary Evaporators with solvent evaporates.Be transferred to and continue dry 12 hours (40 ℃) in the vacuum desiccator, take out, pulverize, cross 80 mesh sieves, promptly get.
Embodiment 3: etretinnate ethyl ester solid dispersion
Etretinnate ethyl ester 0.1g
Polyoxyethylene (23) lauryl alcohol 60g
Vitamin E 0.25g
Dehydrated alcohol 60ml
Get 0.1g etretinnate ethyl ester, 50g polyoxyethylene stearate (40) ester and 0.25g vitamin E and put in the beaker, add the 60ml dehydrated alcohol, under 80 ℃ of water bath condition, be stirred to dissolving fully.Keep 60 ℃ of water-bath states, with Rotary Evaporators with solvent evaporates.Be transferred to and continue dry 12 hours (40 ℃) in the vacuum desiccator, take out, pulverize, cross 80 mesh sieves, promptly get.
Embodiment 4: etretinnate lysinate solid dispersion
Etretinnate lysinate 0.1g
Polyethylene glycol 6000 75g
Propyl gallate 2g
Dehydrated alcohol 30ml
Get the 75g polyethylene glycol 6000 in beaker, put in 80 ℃ of water-baths, fusion fully.Etretinnate lysinate, 2g propyl gallate are dissolved in the 30ml anhydrous alcohol solution, add in the Polyethylene Glycol fused solution, mixing makes its clarification.After flinging to ethanol, pour out, 40 ℃ of vacuum dryings are adopted in cooling rapidly, promptly get.
Embodiment 5: etretinnate solid dispersion (two)
Etretinnate 0.1g
Polyoxyethylene stearate (40) ester 80g
Tertiarybutylhydroquinone 1g
Dehydrated alcohol 30ml
Get the 0.1g etretinnate and 20g polyoxyethylene stearate (40) ester is put in the beaker, mixing adds dehydrated alcohol, stirs and makes dissolving.Spray drying obtains solid dispersion.
Embodiment 6: etretinnate amino butanetriol salt solid dispersion (two)
Etretinnate amino butanetriol salt 0.1g
Polyoxyethylene stearate (40) ester 20g
Polyvinylpyrrolidone K30 10g
Propyl gallate 0.4g
Dehydrated alcohol 30ml
Get 0.1g etretinnate amino butanetriol salt and 20g polyoxyethylene stearate (40) ester is put in the beaker, mixing adds dehydrated alcohol, stirs and makes dissolving.Spray drying obtains solid dispersion.
Embodiment 7: etretinnate amino butanetriol salt solid dispersion (three)
Etretinnate amino butanetriol salt 0.1g
Citric acid 15g
Dehydrated alcohol 30ml
Get 0.1g etretinnate amino butanetriol salt and 20g polyoxyethylene stearate (40) ester is put in the beaker, mixing adds dehydrated alcohol, stirs and makes dissolving.Spray drying obtains solid dispersion.
Embodiment 8: the preparation of etretinnate solid dispersion tablet
Composition consumption (mg/ sheet)
Solid dispersion (embodiment 1) 1.02 (being equivalent to etretinnate 20 μ g)
Lactose 74
Polyvinylpyrrolidone 0.58
Low-substituted hydroxypropyl cellulose 4
Magnesium stearate 0.4
Detailed process: above-mentioned composition is mixed the back adopt common wet granulation with water-wet except that magnesium stearate, adding the magnesium stearate mix homogeneously behind the particle drying is that the shallow arc punch die of 5.5mm tabletting promptly gets with the diameter.
Embodiment 9: the preparation of etretinnate amino butanetriol salt solid dispersion tablet
Composition consumption (mg/ sheet)
Solid dispersion (embodiment 2) 6.78 (containing etretinnate 20 μ g)
Microcrystalline Cellulose 24
Starch 50
Polyvinylpyrrolidone 0.58
Carboxymethyl starch sodium 4
Magnesium stearate 0.4
Tablet manufacture is with embodiment 8.
Embodiment 10: the preparation of etretinnate ethyl ester solid dispersion capsule
Composition consumption (mg/ grain)
Solid dispersion (embodiment 3) 13.05 (containing etretinnate 20 μ g)
Mannitol 148.82
Magnesium stearate 0.4
Preparation process: No. 3 capsules of packing into after the above-mentioned composition mixing are promptly got.
Embodiment 11: the preparation of etretinnate lysine solid dispersion capsule
Composition consumption (mg/ grain)
Solid dispersion (embodiment 4) 21.92 (containing etretinnate 20 μ g)
Glucose 150.49
Polyvinylpyrrolidone 0.58
Magnesium stearate 0.4
The preparation process: after adding the suitable quantity of water moistening behind other composition mix homogeneously of magnesium stearate, carry out preparation of granules with common wet granulation with above-mentioned, dry back adds the magnesium stearate mix homogeneously, and No. 3 capsules of packing into promptly get.
Embodiment 12: the preparation of etretinnate solid dispersion granule
Composition consumption (mg/ bag)
Solid dispersion (embodiment 5) 16.22 (containing etretinnate 20 μ g)
Icing Sugar 150.49
Starch 200
Polyvinylpyrrolidone 1
Micropowder rule glue 0.5
Magnesium stearate 0.4
The preparation process: after adding the suitable quantity of water moistening behind above-mentioned other composition mix homogeneously except that magnesium stearate and micropowder silica gel, carry out preparation of granules with common wet granulation, dry back adds magnesium stearate and micropowder silica gel mix homogeneously, and two aluminium plastic bags of packing into promptly get.
Embodiment 13: the preparation of etretinnate amino butanetriol salt solid dispersion capsule
Composition consumption (mg/ grain)
Solid dispersion (embodiment 6) 8.23 (containing etretinnate 20 μ g)
Lactose 154
Micropowder silica gel 0.37
Magnesium stearate 0.4
The preparation process: after adding the suitable quantity of water moistening behind above-mentioned other composition mix homogeneously except that magnesium stearate and micropowder silica gel, carry out preparation of granules with common wet granulation, dry back adds the magnesium stearate mix homogeneously, and No. 3 capsules of packing into promptly get.
Embodiment 14: the preparation of etretinnate amino butanetriol salt solid dispersion oral liquid
Composition consumption (mg/ props up)
Solid dispersion (embodiment 7) 4.08 (containing etretinnate 20 μ g)
Sucrose 60
Propylene glycol 0.5ml
Water adds to 5ml
Preparation process: on dispersion being added in the mixed solvent of the propylene glycol be dissolved with recipe quantity sucrose and water, in the 10ml oral liquid bottle of packing into, sterilize and promptly got in 30 minutes for damp and hot 121 ℃.
Comparative Examples 1: the preparation of etretinnate conventional tablet
Composition consumption (mg/ grain)
Etretinnate 20 μ g
Lactose 79
Low-substituted hydroxypropyl cellulose 0.4
Dehydrated alcohol is an amount of
Magnesium stearate 0.5
The preparation process: get etretinnate and add dehydrated alcohol, stir and make dissolving, add the lactose mix homogeneously, by common wet granulation, dry back adds the magnesium stearate mixing and promptly gets with the shallow arc of 5.5mm punching press system.
Comparative Examples 2: the preparation of etretinnate conventional capsule agent
Composition consumption (mg/ grain)
Etretinnate 20 μ g
Lactose 160
Dehydrated alcohol is an amount of
Magnesium stearate 0.5
The preparation process: get etretinnate and add dehydrated alcohol, stir and make dissolving, add the lactose mix homogeneously, by common wet granulation, dry back adds magnesium stearate mixing No. 3 capsules of packing into and promptly gets.
Experimental example 1: solid dispersion preparation (tablet, capsule) compares with the dissolution of ordinary preparation
1, experiment medicine
1) experiment sample be solid dispersion preparation: embodiment 8 tablets, embodiment 9 tablets, embodiment 10 capsules,
Embodiment 11 capsules, embodiment 13 capsule samples;
2) check sample: Comparative Examples 1 conventional tablet and Comparative Examples 2 conventional capsule agent samples
2, experimental apparatus
ZRS-8 intelligence dissolution appearance (University Of Tianjin) dissolution medium: pH6.8 phosphate buffer 1 00ml dissolution medium temperature: 37+0.5 ℃ of rotating speed: 100rpm
3, experimental technique
Measure and adopt " the dissolution cuvette algoscopy of Chinese pharmacopoeia (version in 2005) regulation.Analytical method: adopt the HPLC method to measure.Chromatographic condition: liquid-phase chromatographic column Cosmosil C18 (150mm * 4.6mm; Nacalai Tecque, Japan), methanol-water (96: 4) is a mobile phase, sample size 20 μ l, flow velocity 1.0ml/min, detector UV304
4, experimental result: see table 1,2
Table 1 tablet dissolution comparing result
Table 2 capsule dissolution comparing result
Conclusion: the result of extraction that experimental data shows the etretinnate that adopts the solid dispersions technique preparation and analog solid dispersion is effective far beyond the technological preparing product of ordinary preparation.
Claims (9)
1. the solid dispersion of formula I chemical compound is characterized by the surfactant or the organic acid of the formula I chemical compound that contains 1 weight portion or its pharmaceutically useful organic amine salt, 50～800 weight portions;
Said organic amine salt is selected from meglumine salt, lysinate, ethylenediamine salt, piperazine salt, hexahydropyridine salt, amino butanetriol salt or dimethyl ethanol amine salt;
Said surfactant is selected from poloxamer, sodium lauryl sulphate, sodium cholate, fatty alcohol-polyoxyethylene ether, Myrj 45 or tween; Said organic acid is selected from stearic acid, mountain Yu acid, maleic acid, fumaric acid, citric acid, malic acid or succinic acid;
2. solid dispersion according to claim 1, said surfactant are selected from poloxamer, polyoxyethylene stearate (40) ester or polyoxyethylene (23) lauryl alcohol.
3. solid dispersion according to claim 1, said organic acid is selected from stearic acid or citric acid.
4. according to arbitrary described solid dispersion in the claim 1～3, contain and be selected from vitamin E, tertiarybutylhydroquinone, propyl gallate, 2, the stabilizing agent of 6-di-tert-butyl-4-methy phenol or butylated hydroxyarisol; The consumption of stabilizing agent is: the formula I chemical compound of 1 weight portion or its pharmaceutically useful organic amine salt, the stabilizing agent of 0.5-20 weight portion.
5. solid dispersion according to claim 4, said stabilizing agent is selected from vitamin E, tertiarybutylhydroquinone, propyl gallate.
6. the pharmaceutical preparation of processing with the described solid dispersion of claim 1 comprises tablet, capsule, granule, solution, suspension, dry suspension.
7. the pharmaceutical preparation of processing with the described solid dispersion of claim 4 comprises tablet, capsule, granule, solution, suspension, dry suspension.
8. the Etretinate type medicine compositions is characterized in that containing the described solid dispersion of claim 1.
9. the Etretinate type medicine compositions is characterized in that containing the described solid dispersion of claim 4.
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| Application Number | Priority Date | Filing Date | Title |
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| CN2007101764629A CN101422425B (en) | 2007-10-29 | 2007-10-29 | Etretinate type medicine solid dispersion |
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| CN2007101764629A CN101422425B (en) | 2007-10-29 | 2007-10-29 | Etretinate type medicine solid dispersion |
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| CN101422425B true CN101422425B (en) | 2012-11-21 |
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Non-Patent Citations (2)
| Title |
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| 忻祥法.芳香维A酸及其乙酯研究进展.《上海医药情报研究》.1996,(第4期总43期),第6－8页. * |
| 洪涛等.固体分散体的载体选择及质量评价的新进展.《黑龙江畜牧兽医》.2004,(第9期),84-86. * |
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Owner name: CHONGQING HUAPONT PHARMACEUTICAL CO., LTD. Free format text: FORMER OWNER: HUABANG PHARMACEUTICAL CO., LTD., CHONGQING Effective date: 20130219 |
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