CN101513419A - Application of 11-hydroxy-oleanane-28-acid-2,12-diene in preparing medicament for treating skin diseases - Google Patents
Application of 11-hydroxy-oleanane-28-acid-2,12-diene in preparing medicament for treating skin diseases Download PDFInfo
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- CN101513419A CN101513419A CNA2008101545414A CN200810154541A CN101513419A CN 101513419 A CN101513419 A CN 101513419A CN A2008101545414 A CNA2008101545414 A CN A2008101545414A CN 200810154541 A CN200810154541 A CN 200810154541A CN 101513419 A CN101513419 A CN 101513419A
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Abstract
The invention discloses application of 11-hydroxy-oleanane-28-acid-2,12-diene in preparing a medicament for treating skin diseases, and a pharmaceutical composition. The pharmaceutical composition is characterized by comprising the 11-hydroxy-oleanane-28-acid-2,12-diene (I) which is taken as an active component and one or more medicinal accessories. In the pharmaceutical composition provided by the invention, the medicinal accessories are all administrative accessories which are suitable for the skin or mucosa.
Description
Technical field:
The present invention designs the application of a kind of pentacyclic triterpenoid in preparation treatment dermatosis treating medicine.
Background technology:
Pentacyclic triterpenoid such as oleanolic acid (Oleanolic acid, OA), it is a kind of natural product chemistry composition, extensively be present in the plants such as Herba Hedyotidis Diffusae, Fructus Crataegi, Flos Caryophylli, Fructus Jujubae, Fructus Ligustri Lucidi, Folium Eriobotryae, Quercus acutissima Carr., Spica Prunellae since the seventies in 20th century, this medicine was used for the treatment of hepatitis first with form free or that be combined into glycosides, researcheres are constantly found its new pharmacological action, and have carried out further investigation it is used widely clinically.(the pharmacological research overview of oleanolic acid, CHINA JOURNAL OF CHINESE MATERIA MEDICA, 2002.12 such as Tian Liting; 884-885) disclose the various uses of oleanolic acid on the pharmacology, mainly contained hepatoprotective, separate liver toxicity, blood sugar lowering, effect for reducing fat, antivirus action, antiallergic, antiinflammatory action, and anticancer, antimutagenic effect.Chinese patent application CN200710194191.X discloses a kind of 11-hydroxyl-oleanane-28-acid-2 of oleanolic acid having been carried out structure of modification, 12-diene (I), and disclose this chemical compound xylol and cause the mice ear model inhibitory action is arranged, but compound (I) xylol of not coming into the open in this application causes the concrete therapeutic effect of mice ear model, also unexposed its application when the treatment disease specific.
Summary of the invention:
Our surprised discovery under study for action, 11-hydroxyl-oleanane-28-acid-2,12-diene (I) have special effect when treatment people or mammal skin disease
The invention provides 11-hydroxyl-oleanane-28-acid-2, the application of 12-diene (I) in preparation treatment dermatosis medicine.
The present invention also provides a kind of pharmaceutical composition, it is characterized in that containing the 11-hydroxyl-oleanane-28-acid-2 as active component, 12-diene (I) and one or more pharmaceutically useful adjuvants.
In the pharmaceutical composition provided by the invention, described pharmaceutically useful adjuvant is all adjuvants that are applicable to skin or mucosa delivery, preferably makes in ointment, ointment, gel, the paste one or more.Special preferred for preparation becomes ointment, gel.
11-hydroxyl-oleanane in the described pharmaceutical composition-28-acid-2, the content of 12-diene (I) is 0.01%～2%, is preferably 0.05%～0.5%.
When described pharmaceutical composition was made ointment, described pharmaceutically useful adjuvant included but are not limited to oil-phase component, emulsifying agent, water, and as in the antioxidant of additives, antiseptic, pH buffer agent, the wetting agent one or more.
The preferred distilled water of described water
The preferred ethylenediaminetetraacetic acid (EDTA) of described antioxidant and/or its alkali metal salt, ascorbic acid, alpha-tocopherol and 2,6-ditertbutylparacresol (BHT), sodium pyrosulfite, preferred ethylenediaminetetraacetic acid (EDTA) and/or its alkali metal salt and/or alpha-tocopherol, the consumption of described antioxidant is preferably 0.05%～0.3%.
Described antibiotic antiseptic can include but are not limited to benzoic acid, benzyl alcohol, p-Hydroxybenzoate (nipalgin), comprise in methyl hydroxybenzoate, ethyl hydroxybenzoate, the propylparaben one or more,, described antibiotic antiseptic consumption is preferably 0.01～0.2%.
Described pH buffer agent can comprise phosphoric acid/phosphate buffer, acetic acid/acetate buffer, citric acid/citrate buffer agent, boric acid/borate buffer, the phosphoric acid/phosphate or the citric acid/citrate buffer agent of preferred pH=4～7.
Described wetting agent includes but are not limited to glycerol, propylene glycol, sorbitol.
Described wetting agent consumption preferred 4%～10%.
Described oil-phase component comprises one or more in solid in the oil-phase component, consistency modifiers, the emulsifying agent.
Solid in the described oil-phase component includes but are not limited to one or more of stearic acid, paraffin, Cera Flava, higher alcohol, and described higher alcohol is the monohydric alcohol of 16～22 carbon atoms, preferred higher alcohol, and described oil-phase component consumption is 1%～15%.
Described consistency modifiers includes but are not limited to one or more in vaseline, liquid paraffin, the vegetable oil, preferred vaseline and/or liquid Paraffin, and the consumption of described consistency modifiers is 5%～20%.
Described emulsifying agent, include but are not limited to the derivant of soap class emulsifying agent, polyoxyethylene ether, preferably as the glyceryl monostearate of soap class emulsifying agent and/or as the peregal A-20 of polyoxy ether class emulsifying agent, total consumption of described emulsifying agent is 1～18%, preferred soap class emulsifying agent consumption is 0.5%～10%, and polyoxy ether class emulsifying agent consumption is 0.5%～8%.
Described higher alcohol also plays the effect of surfactant simultaneously in emulsifiable paste.Percentage ratio of the present invention is the percentage by weight of relative pharmaceutical composition.
It is described that the composition of described oil-phase component is not limited only to technical solution of the present invention, also comprise any oil-phase component composition that can be used to prepare ointment substrate, the composition of described substrate can be with reference to disclosed scheme in " pharmaceutics " (the 5th edition, Cui Fude published in 2003).
Described ointment can adopt following method preparation:
The preparation of oil phase
That gets recipe quantity is heated to fusing (60 ℃～90 ℃) as oil-phase component, to be dissolved in the 11-hydroxyl-oleanane-28-acid-2 of propylene glycol, (available in case of necessity an amount of organic solvent dissolution stirs while adding to evenly promptly the described antibiotic antiseptic of 12-diene (I).
The preparation of emulsifiable paste
Distilled water is heated to 60～90 ℃, the wetting agent that is heated to same temperature is added to the water, mixing, the oil-phase component that will be heated to 60～90 ℃ again joins in the water quality, stir while adding evenly to condensation promptly.
When described pharmaceutical composition was made gel, described pharmaceutically useful adjuvant included but are not limited to one or more in carbomer, cellulose derivative, wetting agent, solvent, antiseptic, surfactant, the pH regulator agent, and the water of surplus.
Described carbomer is selected from carbomer 934, Acritamer 940, and a kind of in the Carbopol 941, described carbomer consumption is 0.2%～2% of a pharmaceutical composition, preferred 0.5%～1.5%.
Described cellulose derivative includes but are not limited to one or more in sodium carboxymethyl cellulose, methylcellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, the hydroxyethyl-cellulose, the consumption of described cellulose derivative is 0.2%～2% of a pharmaceutical composition, preferred 0.5%～1.5%
Described solvent is selected from water and/or organic solvent, one or more among described organic solvent preferred alcohol, propylene glycol, DMF, the DMSO.The carbomer or the dissolved minimum of cellulose derivative of recipe quantity can be as the criterion.
Described wetting agent includes but are not limited to glycerol, propylene glycol, sorbitol.Consumption is 4%～10%
The optional kind of antiseptic is identical with concentration range in described antiseptic and the ointment.
Described gel can adopt following method preparation:
Get the 11-hydroxyl-oleanane-28-acid-2 of recipe quantity, 12-diene (I) is dissolved in organic solvent, heating for dissolving, add again the cellulose derivative of recipe quantity or carbomer class or, stir homogenize.
Compared with prior art, the invention provides with 11-hydroxyl-oleanane-28-acid-2,12-diene (I) be active component the dermal drug compositions technical scheme, and determined to contain the concentration of the available chemical compound (I) of compositions when the treatment scytitis of chemical compound (I) by pharmacological evaluation, thereby provide a kind of anti-inflammatory pharmaceutical compositions with excellent curative treatment scytitis.And provide the application of chemical compound (I) in preparation treatment dermatosis medicine.In addition, because chemical compound (I) is not a 17-hydroxy-11-dehydrocorticosterone,, there is not the side effect of common 17-hydroxy-11-dehydrocorticosterone preparation, as local telangiectasis realizing the antiphlogistic while.Thinning of skin and the systemic side effects that causes by Transdermal absorption.
The specific embodiment:
Embodiment 1
The preparation of ointment
11-hydroxyl-oleanane-28-acid-2,12-diene (I) 5g is dissolved in the propylene glycol.
Ethyl hydroxybenzoate 1g,
Oil-phase component
Octadecanol 30g, liquid Paraffin 30g, white vaseline 30g peregal A-20 40g
Water-phase component
Glycerol 50g, distilled water is to 1000g
The preparation of oil phase
The oil-phase component of recipe quantity is heated to fusing (60 ℃～90 ℃), to be dissolved in the 11-hydroxyl-oleanane-28-acid-2 of propylene glycol, (available in case of necessity an amount of organic solvent dissolution stirs while adding to evenly promptly the described antibiotic antiseptic of 12-diene (I)
The preparation of emulsifiable paste
Distilled water is heated to 60～90 ℃, the glycerol that is heated to same temperature is added to the water, mixing, the oil-phase component that will be heated to 60～90 ℃ again joins in the water quality, stir while adding evenly to condensation promptly.
Embodiment 2
The preparation of gel
11-hydroxyl-oleanane-28-acid-2,12-diene (I) 5g is dissolved in the ethanol
Carbopol 940 10g ethanol 50g glycerol 50g polyoxyethylene sorbitan monoleate 2g
Ethyl hydroxybenzoate 1g sodium hydroxide 4g distilled water adds to 1000g
Carbopol is mixed with polyoxyethylene sorbitan monoleate and 300ml distilled water, and sodium hydroxide is dissolved in adding behind the 100ml water to be gone up liquid and stirs evenly, and ethyl hydroxybenzoate and chemical compound (I) is dissolved in adding gradually behind the ethanol again stirring evenly, and promptly gets clear gel.
The treatment of pharmacology embodiment 1 xylol induced mice auricle edema
The foundation of auricle edema model: respectively drip scorching laboratory animal grouping of 10 μ l caused by dimethylbenzene xylene and administration at the mouse right ear tow sides with microsyringe: 80 of male mice in kunming, body weight 24-26g, is divided into 8 groups by 10 every group.Cause the 30min administration of scorching back, after administration, took off cervical vertebra in 2 hours to put to death animal.Take off with the card punch of the diameter 9mm auricle with the same position of ears, accurately weighing with left and right sides auricle weight difference is the swelling degree, calculates inhibitory rate of intumesce with following formula: inhibitory rate of intumesce=(1-swelling degree/matched group 1 swelling degree weight) * 100%.The experimental group administration is prepared the emulsifiable paste or the gel of different chemical compounds (I) content respectively according to the method for embodiment 1,2.
Positive controls causes emulsifiable paste matrix among the scorching laggard embodiment of giving 1, and the inhibitory rate of intumesce of relative comparison group 2 carries out the t check.
Animal grouping and administration, see the following form with swelling inhibition situation
| Group | Use medicine | Drug concentration % | Swelling degree (mg) | Inhibitory rate of intumesce % | P |
| Matched group 1 | Positive control | 0 | 8.4±2.4 | ||
| *Matched group 2 | The dexamethasone acetate emulsifiable paste | 0.05 | 4.6±1.3 | 45.2 | |
| Test group 1 | Embodiment 1 | 0.2 | 2.5±1.5 | 70.2 | *P＜0.01 |
| Test group 2 | Embodiment 1 | 0.1 | 3.5±1.5 | 58.3 | *P＜0.05 |
| Test group 3 | Embodiment 1 | 0.05 | 4.5±1.3 | 46.4 | |
| Test group 4 | Embodiment 2 | 0.2 | 2.2±1.1 | 73.8 | *P＜0.01 |
| Test group 5 | Embodiment 2 | 0.1 | 3.0±1.4 | 64.3 | *P＜0.05 |
| Test group 6 | Embodiment 2 | 0.05 | 4.2±1.8 | 50 |
From table data as can be seen, the pharmaceutical composition that the embodiment of the invention provides suppressing to have significant effect when mice causes the ear swelling that inflammation causes because of xylol, is compared with existing 0.05% dexamethasone acetate emulsifiable paste, its antiphlogistic effects is suitable substantially.
Claims (7)
1,11-hydroxyl-oleanane-28-acid-2, the application of 12-diene (I) in preparation treatment dermatosis medicine.
2, a kind of pharmaceutical composition is characterized in that containing the 11-hydroxyl-oleanane-28-acid-2 as active component, 12-diene (I) and one or more pharmaceutically useful adjuvants.
3, pharmaceutical composition as claimed in claim 2 is characterized in that described pharmaceutical composition 11-hydroxyl-oleanane-28-acid-2, and the content of 12-diene (I) is 0.01%～2%.
4,, it is characterized in that described pharmaceutical composition preferred for preparation becomes ointment or gel as claim 2 or 3 described pharmaceutical compositions.
5, as arbitrary described pharmaceutical composition in the claim 2 to 4, when it is characterized in that described pharmaceutical composition is made ointment, described pharmaceutically useful adjuvant includes but are not limited to oil-phase component, emulsifying agent, water, and as in the antioxidant of additives, antiseptic, pH buffer agent, the wetting agent one or more.
6, pharmaceutical composition as claimed in claim 5 is characterized in that described oil-phase component comprises one or more in solid in the oil-phase component, consistency modifiers, the emulsifying agent.
7, pharmaceutical composition as claimed in claim 6 is characterized in that the preferred higher alcohol of solid in the described oil-phase component, and consumption is 1%～15%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008101545414A CN101513419A (en) | 2008-12-25 | 2008-12-25 | Application of 11-hydroxy-oleanane-28-acid-2,12-diene in preparing medicament for treating skin diseases |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008101545414A CN101513419A (en) | 2008-12-25 | 2008-12-25 | Application of 11-hydroxy-oleanane-28-acid-2,12-diene in preparing medicament for treating skin diseases |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101513419A true CN101513419A (en) | 2009-08-26 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2008101545414A Pending CN101513419A (en) | 2008-12-25 | 2008-12-25 | Application of 11-hydroxy-oleanane-28-acid-2,12-diene in preparing medicament for treating skin diseases |
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| Country | Link |
|---|---|
| CN (1) | CN101513419A (en) |
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- 2008-12-25 CN CNA2008101545414A patent/CN101513419A/en active Pending
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Open date: 20090826 |