CN1883444A - Application of paeonol in preparation of whitening and freckle-removing cosmetic or pigmentation disease-treating medicine - Google Patents
Application of paeonol in preparation of whitening and freckle-removing cosmetic or pigmentation disease-treating medicine Download PDFInfo
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Abstract
The invention relates to application of paeonol in preparation of cosmetic for eliminating macula and whitening skin or in preparation of medicament for whitening skin or curing pigment deposition ailment. The cosmetic and medicament are both external use. The mass concentration of said paeonol is 0.01-5 %, optimization scheme is 5-10%. The paeonol and ground substance carrier are mixed to form tincture, spirit, cataplasm, ointment, cream, emulsion, oil agent, face mask, gel, film coating agent, aerosol and solution agent to which other component such as light screening agent and/or antioxidant and/or component for eliminating macula and whitening skin except paeonol can be added. The mechanism of paeonol directly restraining tyrosine enzyme activity, melanin generation and transport is various. The application of paeonol in cosmetic or medicament has unambiguous effect on skin whitening and curing pigment deposition ailment.
Description
Technical field
The present invention relates to a kind of new purposes of material, be specifically related to a kind of paeonol, perhaps the application on the medicine of preparation skin-whitening and treatment pigmentation disease at preparation skin-whitening and cosmetics.
Background technology
Mainly by melanic colour developing decision, the pigment anomaly disease is the common beauty treatment dermatoses of a class to the human body skin color.Treat the medicine of this type of disease at present, as hydroquinone, Arbutin etc., great majority play certain curative effect in actual applications at the melanocyte building-up process, but general effect can not be satisfactory, and its reason may be because the model defectiveness of these medicines of screening.The in-vitro screening model of this respect mainly comprises synthetic mensuration of extracellular Mushroom Tyrosinase determination of activity, cell tyrosinase activity and melanocyte and whole animal model at present.These models can only detect the melanocyte building-up process, can't detect other link of melanin pigmentation, as the melanocyte transport process, equally can't analogue body in keratinocyte for the synthetic influence process of melanocyte; Aspect drug screening, there is certain deficiency, might causes Lou sieve or false positive results appearance.
Synthetic and be that carrier is transported to from melanocyte and makes the skin colour developing in the keratinocyte with the melanosome in the melanosome of melanin in melanocyte.In epidermis, epidermal melanin unit of the common composition of a melanocyte and about 36 keratinocytes, the melanocyte process color carries out in many such epidermal melanin units, and in epidermal melanin unit, keratinocyte plays a leading role relatively; The melanocyte process color relates to that melanocyte is synthetic, melanocyte transportation and transhipment, melanocyte metabolism too many levels.Each link is to the final crucial effect of melanocyte colour developing all plaing.
For this reason, the present inventor has set up keratinocyte-melanocyte co-culture model at home first, and utilize multiple model to the active screening of the anti-pigment of some chemical compounds, found that, the Chinese medicine monomer paeonol removes restraint of tyrosinase activity significantly, can suppress the synthetic link that reaches multiple melanin pigmentations such as melanocyte transhipment of melanocyte simultaneously significantly.Be used for skin-whitening and treat cutaneous pigmentation disease aspect to have very big market prospect.
Paeonol is used for the treatment of anaphylaxis dermatosis at present, and it is not appearing in the newspapers aspect skin-whitening and the treatment pigment anomaly calmness disease.
Summary of the invention
The present invention will provide a kind of new purposes of paeonol: paeonol is in preparation skin-whitening and cosmetics or the application on the medicine of preparation skin-whitening and treatment pigmentation disease.No matter from the composition of material still from the mechanism aspect of effect, " cosmetics of preparation skin-whitening and speckle dispelling " are same technical scheme with " medicine of preparation skin-whitening and treatment pigmentation disease ", be the realization of this scheme on different commodity field, so technical spirit is same invention.
Technical scheme of the present invention is: paeonol contains paeonol in preparation skin-whitening and cosmetics or the application on the medicine of preparation skin-whitening and treatment pigmentation disease in the medium carrier of prepared cosmetics or medicine; External.
Above-described cosmetics or the medicine that contains paeonol can be two or more skin whitening, speckle dispelling and the compound recipe formed of the medicine of treatment chromatopathy that comprises paeonol; Also can be folk prescription (here " folk prescription " is meant: paeonol wherein is unique skin whitening, speckle dispelling and the medicine for the treatment of chromatopathy, and other components are dressing or are added with opacifier or/and antioxidant).Be external, be used for skin whitening, speckle dispelling and treatment chromatopathy (as chloasma etc.).
The mass concentration of paeonol can be 0.1%～20% in above cosmetics or the medicine;
The mass concentration of paeonol is in the prioritization scheme that the application recommends: 3% to 10%.
The dosage form of above-described cosmetics that contain paeonol or medicine is meant that paeonol mixes with medium carrier and forms tincture or spirit or paste or ointment or ointment or oil preparation or facial film or liniment or gel or aerosol or solution (comprising lotion, liniment).
Other components that in above-mentioned dosage form, can add as: opacifier or/and antioxidant or/and other (beyond the paeonol) whitening and speckle dispelling compositions.
Antioxidant wherein is as vitamin C or vitamin E and their derivant thereof or other antioxidants, their consumption adopts conventional amount used of the prior art (for example: vitamin E 0.1～2%, vitamin E Nicotinate 0.1～2%, or vitamin C phosplate magnesium 1～8%);
Opacifier wherein is as titanium dioxide 1～10%, cinnamate derivative 1～15%, amino benzoic Acid esters 1～8%, benzophenone 1～15%, melatonin 1～5% or other UV absorbent.
Whitening and speckle dispelling composition beyond the described paeonol is as arbutin 1～5%, melatonin 1～5%, hydroquinone 1～4%, or other whitening and speckle dispelling compositions.
Described opacifier, antioxidant, other whitening and speckle dispelling compositions all can adopt wherein one or more.
The application specifically recommends to adopt following prioritization scheme, and the prescription of described cosmetics or medicine is:
The mass concentration of paeonol is 5%, and dosage form is an ointment, contains titanium dioxide 8% and vitamin e1 %, and medium carrier is an emulsifiable paste matrix of the prior art.Also can be in compound recipe, to contain this prescription.
Action effect and the test of such scheme aspect the treatment chloasma, specific as follows:
One. Basic Experiment Study:
One) paeonol is to melanogenic influence.
1. the preparation of medicine:
Paeonol: available from, purity＞98% adopts DMSO (dimethyl sulfoxide) dissolving, and storage concentration is 1M/L, is diluted to required final concentration during experiment, and DMSO concentration is 0.1% among its highest final concentration 1mM/L.
2. the foundation of various screening models:
1) cultivate Mus B16F10 melanoma cells:
Culture medium is 1640 basal mediums+10% heat-inactivated fetal bovine serum+1% antibiotic/antifungal solution), the exponential phase cell is used for experiment.
2) cultivate former generation Chinese epidermal melanophore:
Take from the peritomize foreskin of postoperative of Chinese teenager, the melanocyte of getting for 2 to 3 generations is used for test.
3) cultivate former generation Chinese epidermal keratinocytes:
Take from the peritomize foreskin of postoperative of Chinese teenager, the keratinocyte of getting for 2 to 3 generations is used for test.
4) set up the external model that Chinese's epidermal melanophore and keratinocyte are cultivated altogether,
Melanocyte and keratinocyte are cultivated altogether: cultured melanocyte and keratinocyte were mixed inoculation according to 1: 2, and co-cultivation, its culture medium are that melanocyte culture medium and keratinocyte culture medium get by mixing in 1: 2.
3. experimental technique:
1) B16F10 cell, people's epidermal melanophore, human epidermic keratinocyte and co-cultured cell appreciation rate influence determination experiment (MTT experiment): data are represented with x ± s, relatively adopt the t check of independent sample between two groups.
2) melanin content determination experiment: data are represented with x ± s, relatively adopt the t check of independent sample between two groups.
3) tyrosinase activity determination experiment: data are represented with x ± s, relatively adopt the t check of independent sample between two groups.
4) sxemiquantitative RT-PCR detects people's epidermal melanophore tryrosinase mRNA: data are represented with x ± s, relatively adopt the t check of independent sample between two groups.
5) Western-blot, chemoluminescence method detection reaction band, the gel imaging instrument carries out photodensitometry
6) melanocyte transhipment research experiment: difference single culture people's epidermal melanophore and keratinocyte, dye melanocyte with CFDA-ester, two kinds of co-culture of cells (according to the front describing method), analyze down in flow cytometer, melanocyte has only the CFDA positive, have by the come keratinocyte equal positive of CFDA and phycoerythrin then of melanosome of melanocyte transhipment, statistical disposition post analysis result.
4. experimental result:
1) the MTT experimental result of paeonol shows: choose three experimental concentration according to the result: 50 μ mol/L, 100 μ mol/L and 200 μ mol/L.
2) various experimental results are as follows:
①
Table 1 paeonol to tyrosinase activity in the co-cultured cell, the synthetic influence of melanocyte (x ± s, %)
| Paeonol concentration | Tyrosinase activity (n=4) | Melanin content (n=4) |
| High in low | 86.13±5.32 # 70.24±4.15 ## 57.31±5.25 ## | 74.41±7.68 # 62.50±17.18 # 56.55±14.17 ## |
The matched group analog value is made as 100%, compares with matched group,
#P＜0.05,
##P＜0.01
Table 2 paeonol to tyrosinase activity in people's epidermal melanophore, the synthetic influence of melanocyte (x ± s, %)
| Paeonol concentration | Tyrosinase activity (n=4) | Melanin content (n=4) |
| High in low | 75.13±12.62# 52.72±8.55## 41.75±7.49## | 61.47±4.63## 45.90±9.18## 33.72±6.15## |
The matched group analog value is made as 100%, compares with matched group,
#P＜0.05,
##P＜0.01
Table 3 paeonol to tyrosinase activity in the B16F10 cell, the synthetic influence of melanocyte (x ± s, %)
| Paeonol concentration | Tyrosinase activity (n=4) | Melanin content (n=4) |
| High in low | 72.21±14.64# 49.56±4.72## 43.92±8.36## | 60.15±7.65## 48.11±5.24## 39.37±4.31## |
The matched group analog value is made as 100%, compares with matched group,
#P＜0.05,
##P＜0.01
2. paeonol is for the influence of tryrosinase mRNA in people's epidermal melanophore
Table 4 paeonol to the influence of tryrosinase mRNA in people's epidermal melanophore (x ± s, %)
| Paeonol concentration (μ mol/L) | mRNA(Tyr/β-actin) | The p value |
| 200 100 50 Control | 0.32±0.02 0.51±0.06 1.21±0.16 1.66±0.17 | ＜0.01 ＜0.01 ＜0.05 |
3. paeonol is for the synthetic influence of tyrosinase protein in people's epidermal melanophore
The influence that table 5 paeonol is expressed tyrosinase protein in people's epidermal melanophore (x ± s, %)
| Paeonol concentration (μ mol/L) | Albumen (Tyr) | The p value |
| 200 100 | 166.67±12.06 233.67±10.60 | ＜0.01 ＜0.05 |
| 50 Control | 251.33±2.52 252.00±3.61 |
4. paeonol is to the influence of co-cultured cell melanocyte transhipment
Table 6 paeonol is to the influence of co-cultured cell melanocyte transhipment
| Keratinocyte (contrast) | Cultivate altogether (50 μ M paeonol) | Cultivate altogether (100 μ M paeonol) | Cultivate altogether (200 μ M paeonol) | Cultivate altogether (nicotiamide) | |
| Fluorescence intensity suppression ratio (%) | 0.216 | 6.73 0 | 5.47 19.3 | 4.91 27.9 | 3.16 54.8 |
Two. clinical experimental study
The applicant makes 10% paeonol frost, compares with substrate, whiten and the practical function for the treatment of chloasma is studied for paeonol, before the treatment after tested, 10% paeonol frost vacuum response.Have 6 volunteers and participate in the test of whitening, 3 patient with chloasma participation therapeutic tests, male 2 people wherein, women 7 people; Every equal defendant's of volunteer the external every day 10% paeonol frost morning and evening, respectively once sun-proof, (the left hand test group was wiped 10% paeonol frost outward to the volunteer right-hand man's own control of whitening; Right hand matched group is wiped substrate outward), the chloasma group is chosen adjacent two chloasma, a matched group, a test group, test is February altogether, during must not external other influence the medicine of the colour of skin, follow up a case by regular visits to three (beginnings, after January, after February) the record analysis result is following (uses colour of skin measuring instrument test result, repeat 3 times at every turn, after January and result and initial results after February carry out statistical analysis t and check, p＜0.05 is a difference)
One) group of whitening: after January, all volunteer's matched group N and the equal zero difference of e-value, test group 1 people's e-value is variant, matched group N and e-value zero difference still after February, everyone e-value of test group is all variant, and 3 people N values are variant, and concrete data see Table 7.
Two) chloasma treatment group: after January, all volunteer's matched group N and the equal zero difference of e-value, test group 1 people N value is variant, matched group N and e-value zero difference still after February, everyone N of test group and e-value are all variant, the results are shown in Table 8.
Through the evidence in February paeonol for whitening and to treat pigmentation disease (as chloasma) all effective.
Three. paeonol merges the research that other composition is used to whiten and treats pigmentation disease
Through research, we find that emulsifiable paste that external contains paeonol can obviously reduce the pigmentation of skin, can be used for skin-whitening and treatment chromatopathy disease.As in the paeonol emulsifiable paste, adding a certain amount of opacifier (UV absorbent), then help improving stability of drug and curative effect as aminobenzoic acids, cinnamate derivative, amino benzoic Acid esters, benzophenone, melatonin and/or antioxidant such as vitamin E, vitamin C or their derivant; In addition, the tincture of paeonol, spirit, paste, ointment, Emulsion, oil preparation, facial film, gel, liniment, aerosol, solution all have good curative effect after deliberation.
To sum up, the applicant discovers that melanocyte generates paeonol and the transhipment of melanocyte can suppressing, and its mechanism is many-sided, both direct restraint of tyrosinase activity, simultaneously can suppress its transport process, so the effect of paeonol Pear Power and treatment pigmentation disease.Paeonol is applied on the medicine of preparation skin-whitening and cosmetics or skin-whitening and treatment pigmentation disease, can reaches whitening effect, aspect the treatment pigmentation disease clear and definite effect is being arranged also.
The specific embodiment
Below the nonrestrictive part embodiment that the present invention relates to that exemplified.
Embodiment 1, and the application of paeonol on preparation skin-whitening and cosmetics or treatment pigmentation disease medicine contains paeonol in prepared cosmetics or the medicine; Be used to whiten and treat pigmentation disease (as chloasma), effective mass concentration is 5%.Dosage form is a tincture; Medium carrier tincture substrate.Contain antioxidant vitamin E Nicotinate 0.5% and opacifier cinnamate derivative 15% simultaneously.This medicine or cosmetics external are used for skin-whitening, speckle dispelling and treatment chromatopathy.
Embodiment 2, and is substantially the same manner as Example 1, but the mass concentration of paeonol is 10%.Dosage form is a spirit; Medium carrier is a spirit substrate.Contain antioxidant vitamin E2 % and opacifier titanium dioxide 5% simultaneously.
Embodiment 3, and is substantially the same manner as Example 1, but the mass concentration of paeonol is 5%.Dosage form is a spirit; Medium carrier is a spirit substrate.Antioxidant is vitamin E Nicotinate 0.5%; Opacifier is an amino benzoic Acid esters 8%.
Embodiment 4, and is substantially the same manner as Example 1, but the mass concentration of paeonol is 8%.Dosage form is a paste, and carrier matrix is a paste substrate; Antioxidant is that antioxidant is vitamin E Nicotinate 1%, also contains opacifier titanium dioxide 6%.
Embodiment 5, and is substantially the same manner as Example 1, but the mass concentration of paeonol is 10%.Dosage form is an ointment, and carrier matrix is an ointment base; Also contain opacifier cinnamate 1%.
Embodiment 6, and is substantially the same manner as Example 1, but the mass concentration of paeonol is 5%.Dosage form is an ointment, and carrier matrix is an emulsifiable paste matrix; Also contain titanium dioxide 8% and vitamin e1 %.
Embodiment 7, and is substantially the same manner as Example 1, but the mass concentration of paeonol is 10%.Dosage form is an oil preparation, and carrier matrix is an oil preparation substrate; Also contain opacifier benzophenone 8% and vitamin e1 %.
Embodiment 8, and is substantially the same manner as Example 1, but the mass concentration of paeonol is 5%.Dosage form is a liniment, and carrier matrix is a membrane substrate.Also contain melatonin 1%.
Embodiment 9, and is substantially the same manner as Example 1, but the mass concentration of paeonol is 8%.Dosage form is agent, and carrier matrix is an aerosol substrate.Also contain vitamin C 0.5% and vitamin E2 %.
Embodiment 10, and is substantially the same manner as Example 1, but the mass concentration of paeonol is 5%.Dosage form is a gel, and carrier matrix is a gel-type vehicle; Also contain opacifier p-aminobenzoate 8% and vitamin C 1%.
Embodiment 11, and is substantially the same manner as Example 1, but the mass concentration of paeonol is 5%.Dosage form is a facial film, and carrier matrix is a facial film substrate; Also contain opacifier p-aminobenzoate 8% and vitamin E Nicotinate 8%.
Embodiment 12, and is substantially the same manner as Example 1, but the mass concentration of paeonol is 5%.Dosage form is a solution, and adjuvant is a solution substrate; The opacifier cinnamate is 1%; Vitamin E Nicotinate is 0.1%.
Embodiment 13, and is substantially the same manner as Example 1, but the mass concentration of paeonol is 5%.Outside adjuvant and embodiment 12 are identical, also can immerse in the carrier non-woven fabrics, also contain opacifier p-aminobenzoate 5%, o-aminobenzoa 3% and vitamin E2 %.
Embodiment 14, and is substantially the same manner as Example 6, but the mass concentration of paeonol is 10%.
Embodiment 15, and is substantially the same manner as Example 6, but the mass concentration of paeonol is 3%.Also contain arbutin 5%
Embodiment 16, and is substantially the same manner as Example 13, but used carrier is a gauze.
Embodiment 17, and the mass concentration of paeonol is 5%.Dosage form is an ointment.Carrier matrix is an emulsifiable paste matrix.
Embodiment 18, and is substantially the same manner as Example 17, but the mass concentration of paeonol is 0.1%.
Embodiment 19, and is substantially the same manner as Example 17, but the mass concentration of paeonol is 0.01%.
Embodiment 20, and is substantially the same manner as Example 6, but the mass concentration of paeonol is 3%; Titanium dioxide is 1%.
Embodiment 21, and is substantially the same manner as Example 6, but the mass concentration of paeonol is 20%; Titanium dioxide is 1%.
Embodiment 22, and is substantially the same manner as Example 6, but the mass concentration of paeonol is 8%; Titanium dioxide is 10%.
Embodiment 23, and is substantially the same manner as Example 10, but p-aminobenzoate is 1%.
Embodiment 24, and is substantially the same manner as Example 8, but melatonin is 5%.
Embodiment 25, and is substantially the same manner as Example 7, but benzophenone is 1%.
Embodiment 26, and is substantially the same manner as Example 7, but benzophenone is 15%.
Embodiment 28, and is substantially the same manner as Example 1, but is added with vitamin C phosplate magnesium 1%.
Embodiment 29, and is substantially the same manner as Example 1, but is added with vitamin C phosplate magnesium 8%.
Embodiment 30, and is substantially the same manner as Example 1, but is added with arbutin 1%.
Embodiment 31, and is substantially the same manner as Example 1, but is added with arbutin 5%.
Embodiment 32, and is substantially the same manner as Example 1, but is added with hydroquinone 1%.
Embodiment 33, and is substantially the same manner as Example 1, but is added with hydroquinone 4%.
Embodiment 34, and is substantially the same manner as Example 1, but is added with arbutin 1%, melatonin 1% and hydroquinone 1%.
Embodiment 35, and is substantially the same manner as Example 1, but only contains paeonol 5%, do not contain opacifier and antioxidant.
Table 7
| The experimenter | Contrast | Test | ||||||||||
| 0 | January | February | 0 | January | February | |||||||
| N | e | N | e | N | e | N | e | N | e | N | e | |
| 1 2 3 4 5 6 | 163.67±11.24 271.00±19.97 150.33±16.01 306.33±8.50 132.00±10.50 284.67±32.15 155.33±15.01 304.67±15.14 181.00±3.6 1254.00±8.66 # 144.33±14.57 245.67±8.96 #242.00±29.31 415.33±29.77 227.00±4.36 338.00±15.72 240.67±9.29 387.00±7.81 249.67±9.95 360.33±15.63 271.33±25.15 366.67±13.80 257.33±3.79 282.00±14.93 #186.67±10.41 249.00±16.64 178.33±18.80 248.33±9.02 203.00±20.00 277.67±31.94 227.67±11.59 290.00±39.74 214.67±3.21 250.00±10.54 199.00±7.00 # 218.00±3.00 #156.33±13.01 243.00±19.30 175.67±7.09 252.00±6.00 145.00±12.12 227.67±15.53 161.00±16.52 234.33±43.29 159.67±20.00 215.67±27.43 152.00±15.62 156.33±8.39 #142.33±4.55 178.67±5.77 127.33±6.03 158.33±5.51 131.67±7.23 166.00±11.53 143.00±10.54 197.66±34.49 142.33±11.02 141.00±47.57 112.00±7.55 # 113.33±8.02 #299.67±14.57 390.00±14.42 286.67±22.23 372.33±15.28 256.65±10.50 357.67±20.23 297.33±8.50 405.67±12.34 273.33±51.19 401.00±19.70 261.00±11.14 # 328.67±7.51 # | |||||||||||
The discrepant value of #.
Table 8
| The experimenter | Contrast | Test | ||||||||||
| 0 | January | February | 0 | January | February | |||||||
| N | e | N | e | N | e | N | e | N | e | N | e | |
| 7 8 9 | 170.33±6.66 283.00±20.07 173.33±4,73 282.00±25.98 179.00±26.06 279.00±26.51 259.00±4.38 233.67±17.90 243.33±8.74 # 200.00±22.61 205.33±22.50 # 167.33±4.51 #279.67±18.23 409.67±57.07 269.78±11.68 346.00±38.00 234.00±44.24 279.33±17.95 225.33±7.37 302.00±47.82 243.00±31.61 265.00±13.23 153.01±20.80 # 165.33±18.01 #218.00±17.35 277.00±7.00 254.67±7.77 293.33±16.04 268.56±10.26 322.00±28.16 283.00±38.04 291.33±17.21 266.67±40.42 256.00±24.43 164.67±16.04 # 244.00±6.55 # | |||||||||||
The discrepant value of #.
Claims (8)
1, the application of paeonol on preparation skin-whitening and cosmetics or skin-whitening and treatment pigmentation disease medicine contains paeonol in the prepared cosmetics or the medium carrier of medicine; External.
2, prepare application on skin-whitening and cosmetics or skin-whitening and the treatment pigmentation disease medicine according to claim 1 is described at paeonol, it is characterized in that, described cosmetics or medicine are the compound recipes that two or more skin whitening, speckle dispelling that comprises paeonol and the medicine for the treatment of chromatopathy are formed; Or contain the folk prescription of paeonol.
3, describedly prepare application on skin-whitening and cosmetics or skin-whitening and the treatment pigmentation disease medicine according to claim 1 or 2 at paeonol, it is characterized in that the mass concentration of paeonol is 0.1%～20% in described cosmetics or the medicine.
4, according to the application of the described paeonol of claim 3 on preparation skin-whitening and cosmetics or skin-whitening and treatment pigmentation disease medicine, it is characterized in that, paeonol in described cosmetics or the medicine mixes formation tincture or spirit or paste or ointment or ointment or Emulsion or oil preparation or facial film or gel or liniment or aerosol or solution with medium carrier.
5, according to the application of the described paeonol of claim 4 on preparation skin-whitening and cosmetics or skin-whitening and treatment pigmentation disease medicine, it is characterized in that, in described dosage form, also contain: one or more in opacifier and/or the antioxidant.
6, according to the application of the described paeonol of claim 5 on preparation skin-whitening and cosmetics or skin-whitening and treatment pigmentation disease medicine, it is characterized in that the mass concentration of described paeonol is 3%～10%.
7, the application on preparation skin-whitening and cosmetics or skin-whitening and treatment pigmentation disease medicine according to claim 4 or 5 or 6 described paeonol, it is characterized in that, contain in the medium carrier: mass concentration, paeonol 5%, titanium dioxide 8% and vitamin e1 %, dosage form is an ointment.
8, the application on preparation skin-whitening and cosmetics or skin-whitening and treatment pigmentation disease medicine according to claim 4 or 5 or 6 described paeonol, it is characterized in that, concrete prescription is: mass concentration, paeonol 5%, titanium dioxide 8% and vitamin e1 %, dosage form is an ointment.
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