CN101134108A - Desonide cyclodextrin clathrate compound and method for preparing the same - Google Patents
Desonide cyclodextrin clathrate compound and method for preparing the same Download PDFInfo
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- CN101134108A CN101134108A CNA2006101141021A CN200610114102A CN101134108A CN 101134108 A CN101134108 A CN 101134108A CN A2006101141021 A CNA2006101141021 A CN A2006101141021A CN 200610114102 A CN200610114102 A CN 200610114102A CN 101134108 A CN101134108 A CN 101134108A
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Abstract
The present invention relates to cyclodextrin inclusion compound of desonide and its preparation process. The cyclodextrin inclusion compound of desonide has molecule ratio between desonide and cyclodextrin of 0.1-2. It is prepared through adding the alcohol solution of desonide into the water solution of cyclodextrin to include. Compared with common desonide preparation, the cyclodextrin included desonide preparation has obviously raised stability.
Description
Technical field:
The present invention relates to the cyclodextrin clathrate of desonide.The invention still further relates to the preparation method of described desonide clathrate and preparation thereof.
Background technology:
Desonide (desonide) is a glucocorticoid medicine, and its chemical name is 11 β, 21-dihydroxy-16 α, 17-[(1-methyl ethylidene)-dioxy] pregnant steroid-1,4-diene-3,20-diketone.
The desonide external can be treated the various skin disease.As allergic skin diseases such as contact dermatitis, eczemas; Erythroderma desquamativums such as psoriasis, pityriasis rosea, lichen planus; Dermatosis due to the physical factor; Itching skin disease; Cutaneous vasculitis etc.
But desonide easily decomposes, and decomposes especially easily under aqueous solution and the illumination condition.The external preparation drug content in the shelf-life that contains desonide descends comparatively fast, influences the stability of product.Therefore solving its easy resolution problem by the physicochemical property that changes desonide, is the key technology that guarantees the desonide preparation stability.
Summary of the invention:
The purpose of this invention is to provide the higher desonide preparation of a kind of chemical stability.
For achieving the above object, the present invention is that host molecule, desonide are guest molecule with the cyclodextrin, adopts the molecule inclusion technology, the desonide molecule inclusion is formed molecular clathrate in the cavity of cyclodextrin molecular, and make external preparation with this clathrate.The molecular proportion of desonide and cyclodextrin is 2: 1～1: 10 in the clathrate, preferred 1: 1～1: 5.
Described cyclodextrin comprises cyclodextrin and derivant thereof, is selected from alpha-cyclodextrin, beta-schardinger dextrin-, gamma-cyclodextrin, hydroxyethyl-, HP-, dihydroxypropyl-beta-schardinger dextrin-, methyl-gamma-cyclodextrin, glucose ring dextrin, maltose cyclodextrin, carboxymethyl cyclodextrin or sulfoalkyl cyclodextrin.Preferred alpha-cyclodextrin, beta-schardinger dextrin-, gamma-cyclodextrin or HP-.
Described desonide also comprises its salt, example hydrochloric acid salt, with and the acceptable form of medicine such as hydrate.
The preparation method of clathrate may further comprise the steps:
1) with the water-soluble saturated solution of making of cyclodextrin:
2), slowly join in the cyclodextrin solution with the desonide dissolve with ethanol;
3) stirring or the above-mentioned solution 30min～2h of ultrasonic enclose leach solids, use the washing with alcohol after drying.
Cyclodextrin is the cyclic oligomer sugar compounds, has circulus, and its stereochemical structure is up-narrow and down-wide both ends open ring-type hollow circle tube.Outside, cavity and porch are rich in hydrophilic, the cavity is inner to be made of carbon one hydrogen bond and ehter bond, be that CH-on C (3), the C (5) and the bonded O atomic arrangement of glucoside are inner in the cavity, be hydrophobicity, nonpolar enclosed molecule can firmly interact with hydrophobic bond in hydrophobic bond and the host molecule cavity and form clathrate.Therefore cyclodextrin can be incorporated into the pharmaceutical pack of number molecular weight suitable size in its circulus, forms " molecular capsule ", thereby can significantly change the physicochemical property of medicine, the toxic and side effects of improving pharmaceutical preparation quality, the former medicine of reduction, raising curative effect.
When cyclodextrin and derivant thereof formed clathrate with the medicine organic molecule in aqueous solution, the higher cyclodextrin hydrophobic cavity of cloud density produced to the medicine enclosed molecule that electron cloud is little to be held together, and makes the ultra-violet absorption spectrum spectral peak shift or the enhancing of object.The relative variation of uv absorption promptly reflects the enclose situation of medicine object and cyclodextrin.See embodiment 1 for details.
Can prepare dermopathic medicines such as treatment allergy, erythema squama, infectivity, heredity and keratinization with desonide cyclodextrin clathrate provided by the invention.
The desonide cyclodextrin clathrate relatively has the following advantages with the desonide of enclose not:
1. desonide clathrate stability improves
The desonide clathrate through the strong illumination stability test, is investigated and do not seen after 10 days that medicament contg descends, decomposes the solid appearance no change.See embodiment 8 for details.
2. the preparation stability of desonide clathrate improves
The external preparation of the different content that the desonide clathrate is made compares experiment with the corresponding preparations that the desonide of enclose is not made.Under 30 ± 2 ℃, humidity 65% ± 5% accelerated test condition, accelerated tests is in the time of 6 months, and the emulsifiable paste Chinese medicine that clathrate is made does not see that almost content descends and decomposes rotten; And enclose desonide emulsifiable paste Chinese medicine content has not descended 11.5%, and catabolite has increased by 2.7 times.See embodiment 14 for details.
Description of drawings
Fig. 1 is a desonide crude drug ultraviolet absorpting spectrum;
Fig. 2 is the beta-schardinger dextrin-ultraviolet absorpting spectrum;
Fig. 3 is beta-schardinger dextrin-and desonide clathrate ultraviolet absorpting spectrum;
Fig. 4 is beta-schardinger dextrin-and desonide physical mixture ultraviolet absorpting spectrum.
The specific embodiment
The prescription of the following examples only is used to illustrate the present invention, and does not limit the present invention in any way.
The system of embodiment 1 desonide/beta-schardinger dextrin-(molecular proportion: 2: 1) clathrate respectively
(β-CD) 1.36g adding 73.5ml water is made into saturated solution, and dissolving is clear and bright under stirring with beta-schardinger dextrin-; Other gets desonide crude drug 1g, after ethanol 5m1 dissolving, stirs slow down the adding in β-CD saturated solution, finishes ultrasonic 60 minutes; Leave standstill, filter the precipitate of gained, and use washing with alcohol, gained precipitate in 70 ℃ of baking ovens dry 6 hours must cyclodextrin clathrate, and outward appearance is a white solid.Drug content and envelop rate see Table 2 in the clathrate.
The detection of cyclodextrin clathrate
1) uv absorption experiment
Desonide solution UV scanning is obtained uv-spectrogram; According to clathrate content, calculate the content of desonide in the clathrate, be mixed with and contain the principal agent concentration solution identical, UV scanning, uv-spectrogram that must clathrate with the desonide solution concentration; Preparation only contains the solution of host molecule β-cyclodextrin, UV scanning, the ultraviolet absorpting spectrum of host molecule cyclodextrin; The ratio of medicine and cyclodextrin during according to the preparation clathrate, the physical mixture of preparation principal agent and cyclodextrin is mixed with the solution identical with clathrate concentration again, and UV scanning gets host molecule and enclosed molecule physical mixture ultraviolet absorpting spectrum.Each ultraviolet absorpting spectrum is seen accompanying drawing.
2) desonide assay
Measure with high performance liquid chromatography (two appendix VD of Chinese Pharmacopoeia version in 2000).
Chromatographic condition and system suitability test are filler with octadecylsilane chemically bonded silica, with acetonitrile-methanol-water (33: 17: 50) is mobile phase, the detection wavelength is 245nm, regulate the mutual-assistance number of theoretical plate that flows and should be not less than 3000 with the calculating of desonide peak, adjacent impurity peaks and main peak separating degree should meet the requirements.
3) the desonide related substance detects
High performance liquid chromatography (two appendix VD of Chinese Pharmacopoeia version in 2000) is measured.With octadecylsilane chemically bonded silica is filler; With acetonitrile-methanol-water (33: 17: 50) is mobile phase; The detection wavelength is 245nm; Number of theoretical plate calculates by the desonide peak should be not less than 3000, and the separating degree of adjacent impurity peaks and main peak should meet the requirements.
The system of embodiment 2 desonide/beta-schardinger dextrin-(molecular proportion: 1: 1) clathrate respectively
D-cyclodextrin 2.72g is added 147ml water be made into saturated solution, all the other are with embodiment 1.
The preparation of embodiment 3 desonide/Benexate Hydrochloride (molecular proportion: 1: 2)
Beta-schardinger dextrin-5.45g is added 295ml water be made into saturated solution, all the other are with embodiment 1.
The preparation of embodiment 4 desonide/Benexate Hydrochloride (molecular proportion: 1: 5)
Get beta-schardinger dextrin-13.6g, add 735ml water and be made into saturated solution, all the other are with embodiment 1.
The preparation of embodiment 5 desonide/Benexate Hydrochloride (molecular proportion: 1: 10)
Get beta-schardinger dextrin-27.2g, add 1470ml water and be made into saturated solution, all the other are with embodiment 1.
The preparation of embodiment 6 desonide/alpha-cyclodextrin (molecular proportion: 1: 2) clathrate
(4.67g of α-CYD) adds 32ml water and is made into saturated solution, and stirring and dissolving is clear and bright to get alpha-cyclodextrin; Other gets desonide crude drug 1g, after ethanol 5ml dissolving, adds among α-CYD under stirring, and finishes and stirs 2h; Drying under reduced pressure gets clathrate.
The preparation of embodiment 7 desonide/gamma-cyclodextrin (molecular proportion: 1: 2) clathrate
Get gamma-cyclodextrin (6.23g of γ-CYD) adds 26.85ml water and is made into saturated solution, and stirring and dissolving is clear and bright: other gets desonide crude drug 1g, after ethanol 5ml dissolving, stirs down and adds among γ-CYD, finish and stir the 30min drying under reduced pressure, clathrate.
The preparation of embodiment 8 desonide/HP-(molecular proportion: 1: 2) clathrate
(5.53g of HP-β-CYD) adds 7.37ml water and is made into saturated solution, and all the other are with embodiment 6 to get HP-.
Table 1 embodiment 1-8 experimental result statistics
| The cyclodextrin kind | Desonide and cyclodextrin molecular ratio | Drug content in the clathrate (%) | Inclusion rate (%) | |
| Embodiment 1 | B-CYD | 2∶1 | 16.95 | 40 |
| Embodiment 2 | 1∶1 | 19.08 | 71 | |
| Embodiment 3 | 1∶2 | 14.42 | 93 | |
| Embodiment 4 | 1∶5 | 6.37 | 93 | |
| Embodiment 5 | 1∶10 | 3.35 | 95 | |
| Embodiment 6 | α-CYD | 1∶2 | 16.33 | 91 |
| Embodiment 7 | γ-CYD | 1∶2 | 12.58 | 91 |
| Embodiment 8 | HP-β-CYD | 1∶2 | 14.15 | 92 |
Several cyclodextrin molecular amounts of table 2
| Desonide | α-CYD | β-CYD | γ-CYD | HP-β-CYD | |
| Molecular weight | 416.52 | 973 | 1135 | 1297 | 1134.98+58.04×DS |
Annotate: DS is a substitution value, and DS is 4～9 among HP-β-CYD.
Experimental example 1 desonide clathrate strong illumination stability contrast test
Test specimen: the desonide crude drug of enclose not, and with the clathrate of the embodiment 1～7 of this feedstock production.
Experimental condition: sample is exposed in the culture dish that diameter is 120mm, spreads out≤thick-layer of 5mm, places the lighting box of 45001x ± 5001x.
The investigation time: investigate respectively at sampling in 5,10 days, detection level and related substance, experimental result sees Table 3.
Desonide and catabolite content thereof after the table 3 45001x illumination
Annotate: data are content (percentage by weight) in the table
Conclusion: investigate 10 days under 45001x ± 5001x illumination condition, after desonide adopted cyclodextrin inclusion compound, the light durability of principal agent obviously improved.
The preparation of embodiment 9 desonide clathrate emulsifiable pastes (1)
Prescription: (in desonide, concentration is 0.05%)
Desonide clathrate (embodiment 3 gained) 0.693g
Vaseline 16g
Glyceryl monostearate 3g
Natural fatty alcohol 6g
Liquid paraffin 4g
Butylated hydroxyarisol 0.06g
Poly-hydrocarbon oxygen 40 stearate 5g
Glycerol 20g
Chlorobutanol 1g
Distilled water 144g
Be made into 200g
Compound method: glycerol 14g, chlorobutanol, purified water are put water-bath be heated to 75～80 ℃, insulation is as water.Vaseline, glyceryl monostearate, natural fatty alcohol, liquid paraffin, butylated hydroxyarisol, poly-hydrocarbon oxygen 40 stearates are put water-bath be heated to moltenly entirely, 75～80 ℃ of insulations are as oil phase.The desonide clathrate grinds evenly with the moistening of 4g glycerol, and is standby.Stir down and pour water into oil phase, 75～80 ℃ of following emulsifying 10 minutes is stirred at a slow speed and is added desonide cyclodextrin clathrate solution when being cooled to 50～55 ℃, and 2g glycerol rinse mortar stirs, and continues to be stirred at a slow speed to be emulsifiable paste and to get final product.
The preparation of embodiment 10 desonide clathrate emulsifiable pastes (2)
Prescription: embodiment 5 gained desonide clathrate 0.612g, all the other raw materials are made into 200g with embodiment 9, and content is 0.05% desonide clathrate emulsifiable paste.
Compound method: with embodiment 9.
The preparation of embodiment 11 desonide clathrate emulsifiable pastes (3)
Prescription: embodiment 6 gained desonide clathrate 0.795g, all the other raw materials are made into 200g with embodiment 9, and content is 0.05% desonide clathrate emulsifiable paste.
Compound method: with embodiment 9.
The preparation of embodiment 12 desonide clathrate emulsifiable pastes (4)
Prescription: embodiment 7 gained desonide clathrate 0.707g, all the other raw materials are made into 200g with embodiment 9, and content is 0.05% desonide clathrate emulsifiable paste.
Compound method: with embodiment 9.
Embodiment 13 is the preparation of enclose desonide emulsifiable paste not
Prescription: desonide crude drug 0.1g, all the other raw materials are made into 200g with embodiment 9, and content is 0.05% desonide emulsifiable paste.
Compound method: glycerol 14g, the three oxygen tert-butyl alcohols, purified water are put water-bath be heated to 75～80 ℃, insulation is as water.Vaseline, glyceryl monostearate, natural fatty alcohol, liquid paraffin, butylated hydroxyarisol, poly-hydrocarbon oxygen 40 stearates are put water-bath be heated to moltenly entirely, 75～80 ℃ of insulations are as oil phase.Desonide grinds evenly with 4g glycerol, and is standby.Stir down and pour water into oil phase, 75～80 ℃ of following emulsifying 10 minutes is stirred at a slow speed and is added desonide solution when being cooled to 50～55 ℃, and 2g glycerol rinse mortar stirs, and continues to be stirred at a slow speed to be emulsifiable paste.
Experimental example 2 desonide clathrate emulsifiable pastes stability contrast test (accelerated test)
The emulsifiable paste that laboratory sample: embodiment 9～13 makes
Experiment condition: adopt listing aluminum pipe packing, will treat that test specimen places the constant temperature and humidity incubator of 30 ± 2 ℃ of temperature, humidity 65% ± 5%.
The investigation time: respectively at 0,1,2,3, the sampling in June investigates, and, the results are shown in Table 4 with the content and the related substance of principal agent in high performance liquid chromatography (two appendix V of Chinese Pharmacopoeia version in 2000 D, embodiment 1 is seen in the concrete operations) working sample.
Experimental result: accelerated tests is in the time of 6 months, and desonide cyclodextrin emulsifiable paste (embodiment 9～12) Chinese medicine does not see that almost content descends and decomposition is rotten; And enclose desonide emulsifiable paste (embodiment 13) Chinese medicine content has not descended 11.5%, and catabolite has increased by 2.7 times.See the following form.
Table 4 desonide clathrate emulsifiable paste stability test result
| 0 month | January | February | March | June | ||||||
| Desonide | Related substance | Desonide | Related substance | Desonide | Related substance | Desonide | Related substance | Desonide | Related substance | |
| Embodiment 9 | 99.51 | 0.77 | 98.74 | 0.81 | 99.01 | 0.85 | 98.56 | 0.90 | 98.19 | 0.94 |
| Embodiment 10 | 101.4 | 0.84 | 101.0 | 0.85 | 101.8 | 0.90 | 101.3 | 0.95 | 100.7 | 1.07 |
| Embodiment 11 | 99.5 | 0.78 | 99.6 | 0.80 | 99.5 | 0.83 | 99.8 | 0.87 | 99.0 | 1.05 |
| Embodiment 12 | 100.7 | 0.74 | 100.9 | 0.79 | 100.2 | 0.84 | 99.4 | 0.87 | 100.0 | 0.98 |
| Comparative Examples 13 | 100.9 | 0.81 | 99.1 | 1.09 | 97.2 | 1.47 | 95.7 | 1.76 | 89.3 | 3.01 |
Annotate: data are content (percentage by weight) in the table.
Conclusion: desonide has strengthened chemical stability behind cyclodextrin inclusion compound.
Claims (7)
1. desonide cyclodextrin clathrate, the molecular proportion of desonide and cyclodextrin is 2: 1～1: 10.
2. the described desonide cyclodextrin clathrate of claim 1, described cyclodextrin comprises cyclodextrin and derivant thereof, is selected from alpha-cyclodextrin, beta-schardinger dextrin-, gamma-cyclodextrin, hydroxyethyl-, HP-, dihydroxypropyl-beta-schardinger dextrin-, methyl-beta-schardinger dextrin-, glucose ring dextrin, maltose cyclodextrin, carboxymethyl cyclodextrin or sulfoalkyl cyclodextrin.
3. the described desonide cyclodextrin clathrate of claim 2, described cyclodextrin is selected from alpha-cyclodextrin, beta-schardinger dextrin-, gamma-cyclodextrin or HP-.
4. the described desonide cyclodextrin clathrate of claim 1, described desonide also comprises its salt, and the desonide hydrate.
5. the described desonide cyclodextrin clathrate of claim 1, the molecular proportion of described desonide and cyclodextrin is 1: 1～1: 5.
6. each described desonide Preparation methods of cyclodextrin inclusion complexes in the claim 1～4 may further comprise the steps:
1) with the water-soluble saturated solution of making of cyclodextrin;
2), slowly join in the cyclodextrin solution with the desonide dissolve with ethanol;
3) stirring or the above-mentioned solution 30min～2h of ultrasonic enclose leach solids, use the washing with alcohol after drying.
7. treat the purposes of dermatosis treating medicines such as allergy, erythema squama, infectivity, heredity and keratinization with each described desonide cyclodextrin clathrate preparation of claim 1～5.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104095805A (en) * | 2014-01-02 | 2014-10-15 | 江苏知原药业有限公司 | Desonide emulsifiable paste and preparation method thereof |
| CN104117066A (en) * | 2014-07-16 | 2014-10-29 | 陈凌 | Preparation method of anti-thyroid ointment for external application |
| CN106290695A (en) * | 2015-06-25 | 2017-01-04 | 重庆华邦制药有限公司 | Desonide and the separation of related impurities and assay method |
| CN114324649A (en) * | 2021-12-27 | 2022-04-12 | 江苏知原药业股份有限公司 | Method for detecting impurities in desonide emulsifiable paste |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1232539C (en) * | 2002-05-10 | 2005-12-21 | 刘云清 | Match of organic medicine and beta-cyclodextrin derivative and its preparing process |
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2006
- 2006-10-27 CN CN200610114102A patent/CN101134108B/en active Active
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104095805A (en) * | 2014-01-02 | 2014-10-15 | 江苏知原药业有限公司 | Desonide emulsifiable paste and preparation method thereof |
| CN104117066A (en) * | 2014-07-16 | 2014-10-29 | 陈凌 | Preparation method of anti-thyroid ointment for external application |
| CN104117066B (en) * | 2014-07-16 | 2016-03-02 | 陈凌 | The preparation method of external-applied ointment used for treating thyropathy |
| US9820996B2 (en) | 2014-07-16 | 2017-11-21 | Ling Chen | Preparation method for antithyroid ointment for external application |
| CN106290695A (en) * | 2015-06-25 | 2017-01-04 | 重庆华邦制药有限公司 | Desonide and the separation of related impurities and assay method |
| CN114324649A (en) * | 2021-12-27 | 2022-04-12 | 江苏知原药业股份有限公司 | Method for detecting impurities in desonide emulsifiable paste |
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