CN101810566B - Hydrocortisone butyrate cream - Google Patents
Hydrocortisone butyrate cream Download PDFInfo
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- CN101810566B CN101810566B CN2009102287880A CN200910228788A CN101810566B CN 101810566 B CN101810566 B CN 101810566B CN 2009102287880 A CN2009102287880 A CN 2009102287880A CN 200910228788 A CN200910228788 A CN 200910228788A CN 101810566 B CN101810566 B CN 101810566B
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- Prior art keywords
- hydrocortisone butyrate
- emulsifiable paste
- citric acid
- sodium citrate
- consumption
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- BMCQMVFGOVHVNG-TUFAYURCSA-N cortisol 17-butyrate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)CO)(OC(=O)CCC)[C@@]1(C)C[C@@H]2O BMCQMVFGOVHVNG-TUFAYURCSA-N 0.000 title claims abstract description 54
- 229960001524 hydrocortisone butyrate Drugs 0.000 title claims abstract description 54
- 239000006071 cream Substances 0.000 title claims abstract description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 29
- 239000003995 emulsifying agent Substances 0.000 claims abstract description 6
- 239000007787 solid Substances 0.000 claims abstract description 5
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 72
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 45
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerol group Chemical group OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 44
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 claims description 32
- 239000001509 sodium citrate Substances 0.000 claims description 24
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 24
- 239000000839 emulsion Substances 0.000 claims description 22
- 229940057995 liquid paraffin Drugs 0.000 claims description 17
- 229920000191 poly(N-vinyl pyrrolidone) Polymers 0.000 claims description 17
- 229960001617 ethyl hydroxybenzoate Drugs 0.000 claims description 16
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 claims description 16
- GYCKQBWUSACYIF-UHFFFAOYSA-N o-hydroxybenzoic acid ethyl ester Natural products CCOC(=O)C1=CC=CC=C1O GYCKQBWUSACYIF-UHFFFAOYSA-N 0.000 claims description 16
- 239000003795 chemical substances by application Substances 0.000 claims description 14
- 239000003871 white petrolatum Substances 0.000 claims description 14
- 230000002421 anti-septic effect Effects 0.000 claims description 7
- 239000000080 wetting agent Substances 0.000 claims description 7
- 239000003607 modifier Substances 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 3
- 238000009472 formulation Methods 0.000 claims description 3
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 229940099259 vaseline Drugs 0.000 claims description 3
- 241001597008 Nomeidae Species 0.000 claims description 2
- 239000000872 buffer Substances 0.000 claims description 2
- 229940069078 citric acid / sodium citrate Drugs 0.000 claims description 2
- 239000002994 raw material Substances 0.000 claims description 2
- 229940051841 polyoxyethylene ether Drugs 0.000 claims 1
- 229920000056 polyoxyethylene ether Polymers 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 6
- 239000006174 pH buffer Substances 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 2
- 239000002131 composite material Substances 0.000 abstract 1
- 239000003906 humectant Substances 0.000 abstract 1
- 239000003755 preservative agent Substances 0.000 abstract 1
- 230000002335 preservative effect Effects 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 description 36
- 239000012071 phase Substances 0.000 description 29
- 238000003756 stirring Methods 0.000 description 23
- 238000000034 method Methods 0.000 description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 239000003921 oil Substances 0.000 description 15
- 235000019198 oils Nutrition 0.000 description 15
- 235000011187 glycerol Nutrition 0.000 description 13
- 239000002674 ointment Substances 0.000 description 13
- 239000008215 water for injection Substances 0.000 description 12
- 239000000523 sample Substances 0.000 description 11
- 238000010438 heat treatment Methods 0.000 description 9
- 239000012535 impurity Substances 0.000 description 9
- 238000005303 weighing Methods 0.000 description 9
- 239000013521 mastic Substances 0.000 description 8
- 239000011734 sodium Substances 0.000 description 8
- 239000008346 aqueous phase Substances 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 239000007864 aqueous solution Substances 0.000 description 6
- 150000002148 esters Chemical group 0.000 description 6
- 230000004927 fusion Effects 0.000 description 6
- 238000003860 storage Methods 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 4
- 239000013558 reference substance Substances 0.000 description 4
- MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 description 3
- YZNQMPPBWQTLFJ-TUFAYURCSA-N [2-[(8s,9s,10r,11s,13s,14s,17r)-11,17-dihydroxy-10,13-dimethyl-3-oxo-2,6,7,8,9,11,12,14,15,16-decahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-oxoethyl] butanoate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)CCC)(O)[C@@]1(C)C[C@@H]2O YZNQMPPBWQTLFJ-TUFAYURCSA-N 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 230000003637 steroidlike Effects 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229960000890 hydrocortisone Drugs 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000005457 optimization Methods 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 239000012488 sample solution Substances 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 206010006784 Burning sensation Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 206010015150 Erythema Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 208000003251 Pruritus Diseases 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229940087511 calcium disodium versenate Drugs 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 231100000321 erythema Toxicity 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 238000010931 ester hydrolysis Methods 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 230000001932 seasonal effect Effects 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 150000003509 tertiary alcohols Chemical class 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- -1 vaseline Natural products 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
Abstract
Hydrocortisone butyrate cream comprises accessories such as a solid as an oil phase composite, a consistency regulator, a humectant, an emulsifier, a pH buffer, a preservative and the balance of water which are used as medicines, and the pH value of cream is 5.2-5.8.
Description
Technical field
The present invention relates to a kind of steroidal 17-hydroxy-11-dehydrocorticosterone emulsifiable paste, especially relate to a kind of emulsion of hydrocortisone butyrate.
Background technology
Hydrocortisone butyrate (Hydrocortisone-17-butyrate; CAS:13609-67-1) be a kind of of steroidal 17-hydroxy-11-dehydrocorticosterone; Can suppress the reaction of inflammation and allergic skin; Also suppress simultaneously to add the related reaction of rapid regeneration and cause symptom with cell, for example erythema, edema, thickization of skin, skin surface is coarse goes down, and alleviates problems such as pruritus, burning sensation and pain.Owing on the hydrocortisone molecule, introduced the 17-butyrate; Make the fat-soluble better of hydrocortisone butyrate; Thereby when external is treated, can reach better therapeutic, keep the lighter advantage of side effect of hydrocortisone simultaneously, be a kind of external steroidal 17-hydroxy-11-dehydrocorticosterone that can be used for the child.The existing main emulsion of hydrocortisone butyrate of external preparation (trade name: hydrocortisone butyrate; Tianjin Pharmaceutical Group Corp., Ltd produces; 1994 in China's listing); The adjuvant that in the description (http://www.kingyork.biz/2009/0312/446.html) of emulsion of hydrocortisone butyrate, discloses its use is glycerol, propylene glycol, vaseline, octadecanol, liquid Paraffin, peregal A-20, citric acid, sodium citrate, ethyl hydroxybenzoate (antiseptic), purified water.
Testing the impurity that in storage process, is produced in the discovery emulsion of hydrocortisone butyrate through us mainly is the 21-hydrocortisone butyrate; The main cause that produces this impurity is that hydrolysis has taken place in storage process 17 ester groups, and similar ester exchange reaction takes place and become hydrocortisone-21-butyrate with 21 hydroxyls.Hydrocortisone-21-butyrate (HCB-21) that main impurity ester exchange produces in the experiment of hydrocortisone butyrate preparation stability is also disclosed in U.S. Patent application US20040152682A1 description second page table 3; Existing preparation process and prescription are down; The rapid speed that ester exchange reaction takes place; The impurity that produces is more, and the stability of product is produced the interference that strengthens, simultaneously because the generation of impurity has also produced certain influence to the curative effect of product.
(horse military camp as everyone knows; The type of carboxyester hydrolysis and influence factor; " Xinyang Normal College's journal: natural science edition "; 1998 11 4 phases of volume, 417-421) tertiary alcohol ester hydrocortisone butyrate can be hydrolyzed under acidity or alkali condition, but because different pH values can produce bigger influence to the ester hydrolysis rate.
In addition; Emulsion of hydrocortisone butyrate all has sale in China various places, because China's Various Seasonal, different regions room temperature gap big (10-30 ℃), when commercially available emulsion of hydrocortisone butyrate changes greatly in different room temperatures; Stickiness changes greatly, brings inconvenience easily in use.
Summary of the invention
For overcoming the problems of the prior art; The invention provides a kind of emulsion of hydrocortisone butyrate of new prescription,, suppressing dissociating simultaneously of 17-ester through the pH scope of preferred gained preparation and the ionic strength of pH buffer agent; The carrying out that has also suppressed ester exchange reaction; The stickiness of more unexpected is preparation changes less when different room temperatures change greatly, thereby has improved stability of formulation, has reduced the inconvenience in patient's use.
A kind of emulsion of hydrocortisone butyrate that the invention provides; Pharmaceutically useful adjuvants such as water by as solid, consistency modifiers, wetting agent, emulsifying agent, pH buffer agent, antiseptic and the surplus of oil-phase component constitute, it is characterized in that said ointment pH value be 5.2-5.8.
The hydrocortisone butyrate 0.05-0.2% that contains in the said ointment as active component; Preferred 0.1%.
The solid consumption as oil-phase component that contains in the said ointment is 3%～20%, is selected from the higher alcohol (monohydric alcohol of 16-22 carbon atom) one or more, and said higher alcohol selects excellent hexadecanol and/or octadecanol;
The consistency modifiers that contains in the said ointment, consumption are 5%～20%.Be selected from vaseline, liquid paraffin, the vegetable oil one or more,
The consumption of the wetting agent that contains in the said ointment is 3%～10%, is selected from multicomponent alcoholics compound, preferably glycerine and/or propylene glycol;
Said wetting agent can also be as the solvent that disperses the hydrocortisone butyrate crude drug.
The emulsifying agent consumption that contains in the said ointment is 1-10%, optional selfpolyoxyethylene ether derivant, preferred peregal A-20;
The antiseptic consumption that contains in the said ointment is 0.05-0.2%, is selected from the parabens antiseptic, preferred ethyl hydroxybenzoate, described pH regulator agent optimization citric acid/sodium citrate buffer agent;
Can also add stabilizing agent in the said emulsifiable paste, preferred but be not limited only to Calcium Disodium Versenate, the consumption of stabilizing agent is 0.05%～0.3%;
The emulsion of hydrocortisone butyrate that the invention provides, its formula optimization is made up of following raw materials by weight percent: hydrocortisone butyrate 0.1%, white vaseline 3-10%; Octadecanol 3-10%, liquid paraffin 3-10%, peregal A-201%～5%; Glycerol 1-5%, propylene glycol 1-5%,, ethyl hydroxybenzoate 0.1%; Citric acid and sodium citrate amount to 1-3%, and surplus is a water, citric acid (C
6H
8O
7H
2O): sodium citrate (Na
3C
6H
5O
72H
2O)=1: 1.5-1: 2.0 (weight ratios).
The citric acid that uses in the technical scheme of the present invention is C
6H
8O
7H
2O, sodium citrate Na
3C
6H
5O
72H
2O
Percentage ratio in the technical scheme of the present invention is the percentage by weight that accounts for emulsifiable paste weight.
Described higher alcohol also plays influence of surfactant simultaneously in substrate.
The compound method that the invention provides a kind of emulsion of hydrocortisone butyrate is following:
(1) oil phase preparation: solid, consistency modifiers, the emulsifying agent heating and melting of taking in oil phase substrate become solution, and temperature remains on 70-90 ℃;
(2) water preparation: the water that will regulate pH value mixes, heating, and the temperature that stirs remains on 70-90 ℃; The hydrocortisone butyrate micropowder is dispersed in the wetting agent as solvent, adds in the entry then and stir.Temperature remains on 70-90 ℃;
(3) close phase: the oil phase of step (1) preparation is slowly added the aqueous phase that step (2) is prepared, stir, maintain the temperature at 70-90 ℃, stir 10-30min, be cooled to cream.
By 4 batches of emulsifiable pastes (according to embodiment 1) that the present invention joined, regulate down according to according to " two methods of Chinese pharmacopoeia version in 2005 are measured dynamic viscosity, adopt NDJ-1 type Rotary Viscosimeter, and with No. 4 rotors, rotating speed is per minute 6 commentaries on classics in different temperatures respectively.Test result such as table 1:
Two kinds of emulsion of hydrocortisone butyrate viscositys of table 1 test result
(uniform Design is inquired into the viscosity of moulding of average O emulsifiable paste matrix to Zhen Shaoli, 2009 the 21st the 1st phases of volume of Strait Pharmaceutical Journal, 29-30) thinks; The viscosity that is fit to of ointment is 3200mPa.S; The result shows, compares with existing emulsion of hydrocortisone butyrate, and the viscosity of the emulsifiable paste that embodiment of the present invention provides under 10-30 ℃ is more near ideal ointment viscosity; And littler with variations in temperature with viscosity, character is more stable.This suitable stickiness is the assurance that emulsifiable paste is not stratified, principal agent is not separated out.10-30 ℃ is China resident indoor temperature scope; Also be that medicine preparation storage can employable temperature range, compare that ointment provided by the invention is in this temperature range with existing emulsifiable paste; Viscosity changes less; More can keep original coating performance basically, more can in bigger temperature range, keep good coating performance, thereby more can adapt to the temperature range in China resident room.Thereby be more conducive to store and use.
Brand-new emulsion of hydrocortisone butyrate provided by the invention is compared with commercially available emulsion of hydrocortisone butyrate, and quality stability will be got well.We are according to " the study on the stability method of the ointment formulation that Chinese pharmacopoeia version in 2005 is two ones has been carried out long-term and the study on the stability that quickens to homemade brand-new emulsion of hydrocortisone butyrate and commercial goods, and sample is from embodiment 1～4; (lot number is that 200603154 Tianjin Pharmaceutical Group Corp., Ltd produce to the commercially available emulsifiable paste of emulsifiable paste that each embodiment makes and new production, and the date of manufacture: on JIUYUE 13rd, 2006) compare, every group of sample size is 45; Specification is that 10g/ props up; The plastic-aluminum tube packaging mainly detects liquid content and HCB-21 content, and (the HPLC method is measured hydrocortisone butyrate in the hydrocortisone butyrate ointment to detection method according to Zhong Weigao; (Huai-Hai medicine; The 24th the 5th phase of volume of JIUYUE in 2006,428-429) disclosed method detects, and each sampling amount is 5.
Detecting instrument: day island proper Tianjin LC-IOA high performance liquid chromatograph; The SPD-10A UV-detector
Chromatographic condition: chromatographic column, Tianjin, island CIS-ODS post (150mm * 4.6mm, 5 μ m); Mobile phase, methanol: water: ether (62: 38: 2); Flow velocity 1.0ml/min; Sample size, 20 μ L; Column temperature, room temperature; Detect wavelength, UV240nm.Theoretical cam curve is calculated by hydrocortisone butyrate should be not less than 2000.The peak of hydrocortisone butyrate and the separating degree of adjacent impurity peaks meet the requirements.
The preparation of reference substance solution, precision take by weighing the hydrocortisone butyrate reference substance, and ((assay usefulness, the calibrating of Chinese biological goods provides) 12.0mg with the mobile phase dissolving, and is settled to 100ml, shakes up.Promptly be that concentration is the solution that every 1ml contains 0.120mg approximately.
The preparation of sample solution: the about 3.0g of sample thief emulsifiable paste.The accurate title, decide, and puts in the 50ml measuring bottle.It is an amount of to add methanol, put 80 ℃ water-soluble in, the heating make dissolving, put and be chilled to room temperature, add methanol and be diluted to scale, shake up.Put and cool off 2h in the ice bath.Take out the back and filter rapidly, discard filtrating just, get subsequent filtrate as sample solution.
Confirming of linear relationship: precision takes by weighing hydrocortisone butyrate reference substance (content is 98.79%) 12.0mg, with methanol solution and process the solution that every 1ml contains 0.120mg approximately.Precision measures 4,8,10,12,16,20ml puts respectively in the 50ml measuring bottle, adds methanol and is diluted to scale, shakes up.Under above-mentioned chromatographic condition, sample introduction 20 μ L respectively, the result shows that hydrocortisone butyrate concentration and peak area in the 30-45mg/L concentration range have good linear relationship.Regression equation Y=4475.3X+422.45.r＝0.9993。
Sample determination: get each 20 μ L sample introduction of reference substance solution and need testing solution, read peak area value, calculate content by external standard method.The HCB-21 content assaying method is identical with the hydrocortisone butyrate method.
Examine stability carries out the stability test under the long-term stable experiment (25 ℃ ± 2 ℃, relative humidity 65% ± 5%) according to the open method of 176 pages of Chinese medicine preparation stabilities of 2005 editions appendix of Chinese Pharmacopoeia test direction principle.
Two kinds of emulsion of hydrocortisone butyrate long-time stability investigations of table 2 result's (content) (n=50, X ± s)
Impurity hydrocortisone 21-butyrate content changes the investigation result in time in two kinds of emulsion of hydrocortisone butyrate of table 3
" stipulate that the active component content scope is 90%-110% under 22 pages of " emulsion of hydrocortisone butyrate " projects that Chinese pharmacopoeia version in 2005 is two ones.Can find by table 2 and emulsion of hydrocortisone butyrate sample and the contrast of commercially available emulsifiable paste stability data that 3 embodiment 1～4 makes: reduce all in 10% through all experimental group medicament contgs behind 36 months the stability experiment; But the sample that the embodiment of the invention provides all is higher than commercially available emulsifiable paste at the active constituent content of different sampling time points; And be significantly higher than commercially available emulsifiable paste (P＜0.05) at experiments in 36 months active constituent content at the end; The corresponding sample that provides as the HCB-21 content embodiment of the invention of major impurity then significantly is lower than commercially available emulsifiable paste (P＜0.01), and this has proved absolutely that the emulsifiable paste that makes according to the embodiment of the invention is better than commercially available emulsifiable paste stability, and the impurity HCB-21 content that major impurity---ester exchange reaction produces is lower.In addition, layering, metachromatism all do not take place in the emulsifiable paste that makes by the present invention program in long-time stability are investigated.
Because the pH value of preferred gained ointment and the concentration of pH regulator agent; Make the ester exchange reaction of hydrocortisone butyrate obtain inhibition to a certain degree; Make brand-new emulsion of hydrocortisone butyrate provided by the invention compare with commercially available existing this like product, quality stability will be got well.In addition, under preferred pH value scope influence, emulsifiable paste viscosity provided by the invention changes less with storage temperature, more adapts to the condition of storage of China's average family, and the emulsifiable paste that therefore obtains is difficult for using inconvenience because of viscosity changes excessive causing in use.
The specific embodiment
To do further description to the present invention through embodiment below, these descriptions are not that content of the present invention is done further to limit.One skilled in the art will understand that to be equal to replacement to what technical characterictic of the present invention was done, or corresponding the improvement, still belong within protection scope of the present invention.
The emulsifiable paste that all embodiment make is all used with the PAP subpackage equipment that 10g/ props up.Used hydrocortisone butyrate is the micropowder of particle size range 5-50 μ m,
Emulsifiable paste mastic assay method is following: precision takes by weighing mastic sample 5g, adds to put cold purified water 25ml through boiling, and is heated to 40 ℃, stirs, and it is dissolved fully, is cooled to room temperature, and is fixed with the pH value instrumentation.
Embodiment 1
Hydrocortisone butyrate 1g, white vaseline 100g, octadecanol 30g, liquid paraffin 30g, peregal A-20 50g, glycerol 50g, propylene glycol 20g, ethyl hydroxybenzoate 1g, citric acid (C
6H
8O
7H
2O) 10g, sodium citrate (Na
3C
6H
5O
72H
2O) 18g water for injection adds to 1000g
By the accurate weighing of above proportioning, the emulsifiable paste process for preparation is following:
(1) oil phase preparation: get white vaseline, octadecanol, liquid paraffin, peregal A-20 places container, is heated to fusion, and temperature remains on 90 ℃;
(2) water preparation: citric acid and sodium citrate are dissolved in the water for injection, principal agent is dispersed in glycerol, the propylene glycol, add the aqueous solution of citric acid and sodium citrate, ethyl hydroxybenzoate, heating, the temperature that stirs remains on 90 ℃;
(3) close phase: the oil phase of step (1) preparation is slowly added the aqueous phase that step (2) is prepared, stir, maintain the temperature at 80 ℃, stir 30min, be cooled to cream, obtain the 1000g emulsifiable paste, content 0.1%, recording mastic pH is 5.5.
Embodiment 2
Hydrocortisone butyrate 1g, white vaseline 30g, octadecanol 100g, liquid paraffin 100g, peregal A-20 10g, glycerol 10g, propylene glycol 50g, ethyl hydroxybenzoate 1g, citric acid (C
6H
8O
7H
2O) 4g, sodium citrate (Na
3C
6H
5O
72H
2O) 6g water for injection is to 1000g
By the accurate weighing of above proportioning, the emulsifiable paste process for preparation is following:
(1) oil phase preparation:, get white vaseline, octadecanol, liquid paraffin, peregal A-20 places container, is heated to fusion, and temperature remains on 75 ℃;
(2) water preparation: citric acid and sodium citrate are dissolved in the water for injection, principal agent is dispersed in glycerol, the propylene glycol, add the aqueous solution of citric acid and sodium citrate, ethyl hydroxybenzoate, heating, the temperature that stirs remains on 90 ℃;
(3) close phase: the oil phase of step (1) preparation is slowly added the aqueous phase that step (2) is prepared, stir, maintain the temperature at 90 ℃, stir 30min, be cooled to cream, obtain the 1000g emulsifiable paste, content 0.1%, recording mastic pH is 5.2.
Embodiment 3
Hydrocortisone butyrate 1g, white vaseline 30g, octadecanol 100g, liquid paraffin 30g, peregal A-20 30g, glycerol 50g, propylene glycol 50g, ethyl hydroxybenzoate 1g, citric acid (C
6H
8O
7H
2O) 10g, sodium citrate (Na
3C
6H
5O
72H
2O) 20g
Water for injection is to 1000g
By the accurate weighing of above proportioning, the emulsifiable paste process for preparation is following:
(1) oil phase preparation:, get white vaseline, octadecanol, liquid paraffin, peregal A-20 places container, is heated to fusion, and temperature remains on 85 ℃;
(2) water preparation: citric acid and sodium citrate are dissolved in the water for injection of recipe quantity, principal agent is dispersed in glycerol, the propylene glycol, add the aqueous solution of citric acid and sodium citrate, ethyl hydroxybenzoate, heating, the temperature that stirs remains on 80 ℃;
(3) close phase: the oil phase of step (1) preparation is slowly added the aqueous phase that step (2) is prepared, stir, maintain the temperature at 80 ℃, stir 30min, be cooled to cream, obtain the 1000g emulsifiable paste, content 0.1%, recording mastic pH is 5.2.
Embodiment 4
Hydrocortisone butyrate 1g, white vaseline 100g, octadecanol 60g, liquid paraffin 100g, peregal A-20 10g, glycerol 10g, propylene glycol 10g, ethyl hydroxybenzoate 1g, citric acid (C
6H
8O
7H
2O) 7g, sodium citrate (Na
3C
6H
5O
72H
2O) 13g water for injection is to 1000g
By the accurate weighing of above proportioning, the emulsifiable paste process for preparation is following:
(1) oil phase preparation: get white vaseline, octadecanol, liquid paraffin, peregal A-20 places container, is heated to fusion, and temperature remains on 75 ℃;
(2) water preparation: citric acid and sodium citrate are dissolved in the water for injection of recipe quantity, principal agent is dispersed in glycerol, the propylene glycol, add the aqueous solution of citric acid and sodium citrate, ethyl hydroxybenzoate, heating, the temperature that stirs remains on 90 ℃;
(3) close phase: the oil phase of step (1) preparation is slowly added the aqueous phase that step (2) is prepared, stir, maintain the temperature at 75 ℃, stir 30min, be cooled to cream, obtain the 1000g emulsifiable paste, content 0.1%, recording mastic pH is 5.3.
Embodiment 5
Hydrocortisone butyrate 2g, white vaseline 150g, octadecanol 30g, liquid paraffin 80g, peregal A-20 80g, glycerol 80g, ethyl hydroxybenzoate 1g, citric acid (C
6H
8O
7H
2O) 12g, sodium citrate (Na
3C
6H
5O
72H
2O) 18g water for injection is to 1000g
By the accurate weighing of above proportioning, the emulsifiable paste process for preparation is following:
(1) oil phase preparation:, get white vaseline, octadecanol, liquid paraffin, peregal A-20 places container, is heated to fusion, and temperature remains on 90 ℃;
(2) water preparation: citric acid and sodium citrate are dissolved in the water for injection of recipe quantity, principal agent is dispersed in the glycerol, add the aqueous solution of citric acid and sodium citrate, ethyl hydroxybenzoate, heating, the temperature that stirs remains on 80 ℃;
(3) close phase: the oil phase of step (1) preparation is slowly added the aqueous phase that step (2) is prepared, stir, maintain the temperature at 90 ℃, stir 30min, be cooled to cream, obtain the 1000g emulsifiable paste, content 0.2%, recording mastic pH is 5.2.
Embodiment 6
Hydrocortisone butyrate 0.5g, white vaseline 30g, hexadecanol 150g, liquid paraffin 30g, peregal A-20 10g, propylene glycol 30g, citric acid (C
6H
8O
7H
2O) 5g, sodium citrate (Na
3C
6H
5O
72H
2O) 10g
Water for injection is to 1000g
By the accurate weighing of above proportioning,, the emulsifiable paste process for preparation is following:
(1) oil phase preparation:, get white vaseline, octadecanol, liquid paraffin, peregal A-20 places container, is heated to fusion, and temperature remains on 75 ℃;
(2) water preparation: citric acid and sodium citrate are dissolved in the water for injection of recipe quantity, principal agent is dispersed in the propylene glycol, add the aqueous solution of citric acid and sodium citrate, ethyl hydroxybenzoate, heating, the temperature that stirs remains on 90 ℃;
(3) close phase: the oil phase of step (1) preparation is slowly added the aqueous phase that step (2) is prepared, stir, maintain the temperature at 70 ℃, stir 15min, be cooled to cream, obtain the 1000g emulsifiable paste, content 0.05%, recording mastic pH is 5.3.
Claims (6)
1. an emulsion of hydrocortisone butyrate is characterized in that containing the hydrocortisone butyrate 0.05-0.2% as active component, is 3%～20% as the solid consumption of oil-phase component, is selected from hexadecanol or the octadecanol one or more; Consistency modifiers, consumption is 5%～20%, is selected from vaseline, the liquid paraffin one or more; The consumption of wetting agent is 3%～10%, is selected from multicomponent alcoholics compound; The emulsifying agent consumption is 1-10%, is selected from the polyoxyethylene ether derivant; The antiseptic consumption is 0.05-0.2%, is selected from the parabens antiseptic; The pH regulator agent is selected from the citric acid/sodium citrate buffer agent; And the water of surplus; The pH value of described emulsifiable paste is 5.2-5.8.
2. emulsifiable paste as claimed in claim 1 is characterized in that described hydrocortisone butyrate content is 0.1%.
3. emulsifiable paste as claimed in claim 1 is characterized in that said wetting agent is glycerol and/or propylene glycol.
4. emulsifiable paste as claimed in claim 1 is characterized in that said emulsifying agent is peregal A-20.
5. emulsifiable paste as claimed in claim 1 is characterized in that described antiseptic is an ethyl hydroxybenzoate.
6. like arbitrary described emulsifiable paste in the claim 1 to 5, the said cream formulation of its characteristic is made up of following raw materials by weight percent: hydrocortisone butyrate 0.1%, white vaseline 3-10%, octadecanol 3-10%; Liquid paraffin 3-10%, peregal A-20 1%～5%, ethyl hydroxybenzoate 0.1%; Citric acid and sodium citrate amount to 1-3%, and the weight ratio of citric acid and sodium citrate is 1: 1.2-1: 2.0, and wetting agent 3-10%; Glycerol 1-5% wherein, propylene glycol 1-5%, surplus is a water.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009102287880A CN101810566B (en) | 2009-11-26 | 2009-11-26 | Hydrocortisone butyrate cream |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009102287880A CN101810566B (en) | 2009-11-26 | 2009-11-26 | Hydrocortisone butyrate cream |
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| Publication Number | Publication Date |
|---|---|
| CN101810566A CN101810566A (en) | 2010-08-25 |
| CN101810566B true CN101810566B (en) | 2012-06-20 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN2009102287880A Active CN101810566B (en) | 2009-11-26 | 2009-11-26 | Hydrocortisone butyrate cream |
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Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102552283B (en) * | 2010-11-23 | 2015-03-18 | 天津金耀集团有限公司 | Transdermal absorption drug for skin prepared from hydrocortisone butyrate containing adjuvant and water containing adjuvant |
| CN103877117A (en) * | 2014-03-11 | 2014-06-25 | 天津金耀集团有限公司 | Hydrocortisone butyrate and zinc oxide medicine composition |
| CN103880906B (en) * | 2014-03-11 | 2015-10-07 | 天津金耀集团有限公司 | A kind of hydrocortisone butyrate semihydrate |
| CN103877119A (en) * | 2014-03-11 | 2014-06-25 | 天津金耀集团有限公司 | Hydrocortisone butyrate semihydrate zinc oxide pharmaceutical composition |
| CN103989627A (en) * | 2014-05-05 | 2014-08-20 | 湖北丽益医药科技有限公司 | Hydrocortisone emulsifiable paste and preparing method thereof |
| CN107519182A (en) * | 2016-06-20 | 2017-12-29 | 天津金耀集团有限公司 | Dermopharmaceutical composition using butyric acid hydrocortisone as active component |
| CN107519177A (en) * | 2016-06-20 | 2017-12-29 | 天津金耀集团有限公司 | Dermopharmaceutical composition using fluticasone propionate as active component |
| CN107519493A (en) * | 2016-06-20 | 2017-12-29 | 天津金耀集团有限公司 | Dermopharmaceutical composition containing Azulene sulfonate |
| CN111743853A (en) * | 2019-03-29 | 2020-10-09 | 天津金耀集团有限公司 | External pharmaceutical composition of near-neutral hydrocortisone butyrate |
| CN111743854A (en) * | 2019-03-29 | 2020-10-09 | 天津金耀集团有限公司 | Externally-applied pharmaceutical composition of hydrocortisone butyrate with viscosity control function |
| CN112386599A (en) * | 2019-08-15 | 2021-02-23 | 天津金耀药业有限公司 | Hydrocortisone butyrate external preparation |
| CN114504548B (en) * | 2020-11-16 | 2023-08-22 | 湖北舒邦药业有限公司 | Ointment and preparation method thereof |
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