Summary of the invention:
The object of the invention is to develop a kind of compound preparation containing retinoid medicine, the cicatrix causing for Acne treatment and acne or pigmentation provide the new compound pharmaceutical preparation of a kind of efficient, safety, low toxicity.
The present invention has developed the compound preparation of a kind of asiaticoside and retinoid Drug combination, has reached foregoing invention object.Technical scheme is as follows:
A pharmaceutical composition for Acne treatment and cicatrix, contains Herba Centellae total glycosides and retinoid medicine, wherein:
External preparation is containing Herba Centellae total glycosides 5 ‰~30 ‰ (W/W), retinoid medicine 0.1 ‰~5 ‰ (W/W).
Preferably in external preparation, contain Herba Centellae total glycosides 10~25 ‰ (W/W), retinoid medicine 0.15 ‰~3 ‰ (W/W);
In preferred external preparation composition, Herba Centellae total glycosides and retinoid medicine are (W/W):
Herba Centellae total glycosides 10~25 ‰, retinoic acid 0.1 ‰~0.5 ‰, or
Herba Centellae total glycosides 10~25 ‰, Viaminate 1 ‰~4 ‰, or
Herba Centellae total glycosides 10~25 ‰, tazarotene 0.15 ‰~1.5 ‰, or
Herba Centellae total glycosides 10~25 ‰, adapalene 0.2 ‰~1.5 ‰.
External preparation common every day of local use 1~4 time, its consumption is determined by clinician according to the order of severity of the different state of an illness and acne and cicatrix.
In oral drugs, Herba Centellae total glycosides with retinoid drug dose than (weight portion) is: Herba Centellae total glycosides: retinoid=1~30: 2.5~60.Preferable amount than (weight portion) is: Herba Centellae total glycosides: retinoid=6~24: 2.5~50.
In preferred oral preparation composition, Herba Centellae total glycosides is (W/W) with retinoid drug dose than (weight portion):
Herba Centellae total glycosides: retinoic acid=6~24: 2.5~15, or
Herba Centellae total glycosides: Viaminate=6~24: 10~50, or
Herba Centellae total glycosides: Accutane=6~24: 2.5~15.
Tablet or capsule preparations conventional amount used everyone each serving with 1~4 slice/, take every day 2~3 times.
Other peroral dosage form is as the drug dose of oral liquid, syrup, granule, pill, powder etc., and those skilled in the art can calculate according to the content of above-mentioned tablet or capsule.
Described Herba Centellae total glycosides is commercially available product, refers to asiaticoside (C
48h
78o
20) and asiaticoside (C
48h
78o
19) total content be not less than 40% Herba Centellae extract.With reference to national drug standards WS
3the form of presentation of-B-2596-97-2002, described in above-mentioned oral and external preparation, Herba Centellae total glycosides consumption is the consumption of Herba Centellae extract.
Described retinoid medicine comprises retinoic acid, Accutane, Viaminate, adapalene, tazarotene etc.
Formula pharmacology analysis:
That Herba Centellae total glycosides has is antibacterial, antiinflammatory, antiulcer, anti-melanin pigmentation, suppress fibroblast proliferation and the effect such as collagen is synthetic, clinical skin ulcer, hypertrophic cicatrix and the keloid of being used for the treatment of, also have treatment chloasma, acne nodosum and control Acne Scar report [referring to: Wang Wei is luxuriant etc. Jixuedaipian treatment is with acne vulgaris [J] world clinical medicine of nodular lesion, 2003,24 (8): 479; Zhang Chunmei. the medical Leader of cicatrix 48 examples [J] after asiaticoside treatment facial acne, 2007,26 (7): 782-783.].Retinoid drug main will have reconciliation statement chrotoplast Differentiation and proliferation, suppress the effects such as sebum secretion, check melanin generation, antiinflammatory, immunomodulating, inhibition skin photoage, the clinical dermatosiss such as psoriasis, acne, ichthyosis that are usually used in, also have report treatment chloasma, cicatrix etc. [referring to Li Jiayan etc. the control severe acne recurrence of thymosin associating tretinoin cream and the Chinese leprosy dermatosis of synulotic clinical observation [J] magazine, 2008,24 (1): 31], therefore, both existing coincidences of effect, also have complementary part.By Herba Centellae total glycosides and the coupling of retinoic acid prescription, the pathological process for acne: 1. 2. 3. 4. 5. cicatrix of tuberosity, cyst of pimple, pus born of the same parents of acne of hypersteatosis, can play the effect of Synergistic.The cicatrix and the pigmentation that in Acne treatment, acne are caused play preventive and therapeutic effect, have remarkable difference compared with the conventional medicine of other treatment acne, have obvious advantage.
Medicine provided by the invention can oral or external.Can as required, make multiple dosage form according to pharmaceutical methods well known in the art, comprise emulsifiable paste, ointment, gel, aerosol, spray, liniment, capsule, soft capsule, tablet etc.
According to the different dosage form of medicine and requirement, in pharmaceutical composition of the present invention, can add the acceptable adjuvant of his medicine, adjuvant as conventional in excipient, antiseptic and medicine for external use etc.
The present invention, taking retinoic acid and asiatic centella total glycoside composition as example, has carried out pharmacodynamics and the safety testing of new compound preparation.
The relatively drug effect of new compound preparation and alone Herba Centellae total glycosides and two kinds of medicines of retinoic acid; And two kinds of medication combined medications of new compound preparation and Herba Centellae total glycosides and retinoic acid are contrasted.Multiple result of the test shows, pharmaceutical composition of the present invention to suppress acne about bacterium, antiinflammatory, alleviate cicatrix or the scar hyperplasia that cuticle thickness and Acne treatment cause and have significant curative effect (referring to embodiment 16,17).
Through safety testing, result shows, drug safety of the present invention is good, and untoward reaction rate reduces, causalgia, scratch where it itches, the local excitation symptom such as twinge and erythema obviously alleviates.(referring to embodiment 16).
Because clinical treatment wound, operation wound, burn, keloid and the scleroderma of being specifically designed to of the preparation of Herba Centellae total glycosides.Compound preparation of the present invention be except being used for the treatment of the cicatrix that acne causes thus, can also be used for the treatment reparation of the cicatrix of skin that other reason causes as wound, operation wound or burn and scald.
Detailed description of the invention
The content of the Herba Centellae total glycosides adopting in following examples is 55% (purchased from Guangzhou Han Fang Modern Chinese Traditional Medicine Research Development Co., Ltd), and retinoic acid, Accutane, Viaminate are produced by Huabang Pharmaceutical Co., Ltd., Chongqing.
Embodiment 1 compound recipe asiaticoside tretinoin cream
Herba Centellae total glycosides 25g, retinoic acid 0.25g, glycerol 50g, lanoline 20g, ethyl hydroxybenzoate 1g, triethanolamine 20g, stearic acid 130g, white vaseline 250g, distilled water adds to 1000g.
Embodiment 2 compound recipe asiaticoside tretinoin creams
Herba Centellae total glycosides 15g, retinoic acid 0.25g, oily 50g, lanoline 20g, ethyl hydroxybenzoate 1g, triethanolamine 20g, stearic acid 135g, white vaseline 250g, distilled water adds to 1000g.
Embodiment 3 compound recipe asiaticoside tretinoin creams
Herba Centellae total glycosides 25g, retinoic acid 0.15g, glycerol 50g, lanoline 20g, ethyl hydroxybenzoate 1g, triethanolamine 20g, stearic acid 125g, white vaseline 250g, distilled water adds to 1000g.
Embodiment 4 compound recipe asiaticoside tretinoin creams
Herba Centellae total glycosides 20g, retinoic acid 0.20g, glycerol 50g, lanoline 20g, ethyl hydroxybenzoate 1g, triethanolamine 20g, stearic acid 130g, white vaseline 250g, distilled water adds to 1000g.
Embodiment 5 compound recipe asiaticoside viaminate creams
Herba Centellae total glycosides 25g, Viaminate 3g, silicone oil 273g, vaseline 80g, hexadecanol 60g, glyceryl monostearate 65g, peregal 0205.5g, sorbester p18 38g, propylene glycol 45g, benzyl alcohol 10g, distilled water adds to 1000g.
Embodiment 6 compound recipe asiaticoside tretinoin gels
Herba Centellae total glycosides 25g, retinoic acid 0.25g, PEG400450g, hexanediol 80g, Tween 80 20g, carbomer 10g, triethanolamine 6ml, benzyl alcohol 10g, distilled water adds to 1000g.
Embodiment 7 compound recipe asiaticoside Viaminate gels
Herba Centellae total glycosides 20g, Viaminate 1.5g, PEG400452g, ethylene glycol 80g, Tween 80 20g, carbomer 10g, triethanolamine 6ml, benzyl alcohol 10g, distilled water adds to 1000g.
Embodiment 8 compound recipe asiaticoside retinoic acid capsules
Herba Centellae total glycosides 12g, retinoic acid 5g, starch 78g, makes 1000.
Embodiment 9 compound recipe asiaticoside Viaminate soft capsules
Herba Centellae total glycosides 24g, Viaminate 50g, soybean oil 100g, gelatin 50g, glycerol 15g, water 48g, 1000.
Embodiment 10 compound recipe asiaticoside Accutane soft capsules
Herba Centellae total glycosides 6g, Accutane 2.5g, PEG400 150g, gelatin 50g, glycerol 17g, water 63g, makes 1000.
Embodiment 11 compound recipe asiaticoside retinoic acid sheets
Herba Centellae total glycosides 24g, retinoic acid 10g, microcrystalline Cellulose 60g, starch 10g, micropowder silica gel 7g, Pulvis Talci 5g, magnesium stearate 4g, makes 1000.
Embodiment 12 compound recipe asiaticoside Tazarotene gels
Herba Centellae total glycosides 15g, tazarotene 0.5g, carbomer 12.5g, EDTA-2Na0.5g, PEG-400250g, polysorbate40 4g, Vc 0.5g, propylene glycol 20g, benzyl alcohol 10g, three ethanol 8g, distilled water adds to 1000g.
Embodiment 13 compound recipe asiaticoside adapalene gels
Herba Centellae total glycosides 20g, adapalene 1g, PEG400 350g, ethylene glycol 40g, Tween 80 20g, carbomer 12g, triethanolamine 7ml, benzyl alcohol 10g, distilled water adds to 1000g.
Embodiment 14 compound recipe asiaticoside Viaminate soft capsules
Herba Centellae total glycosides 12g, Viaminate 25g, soybean oil 100g, gelatin 50g, glycerol 15g, water 48g, 1000.
Embodiment 15 compound recipe asiaticoside Accutane sheets
Herba Centellae total glycosides 12g, Accutane 10g, microcrystalline Cellulose 55g, starch 15g, micropowder silica gel 7g, Pulvis Talci 5g, magnesium stearate 4g, makes 1000.
Two kinds of active component content catalogs in table 1 embodiment 1~15 preparation
* the content of Herba Centellae total glycosides is 55% (W/W)
*
[1]tazarotene,
[2]adapalene,
[3]accutane
Embodiment 16 compound recipe of the present invention (ointment) and two kinds of single medicine pharmacodynamics contrast tests
One, Experimental agents: totally 6 kinds of emulsifiable pastes:
1. the pharmaceutical composition of embodiment 1: (containing Herba Centellae total glycosides 2.5%, retinoic acid 0.025%)
2. the pharmaceutical composition of embodiment 2: (containing Herba Centellae total glycosides 1.5%, retinoic acid 0.025%)
3. the pharmaceutical composition of embodiment 3: (containing Herba Centellae total glycosides 2.5%, retinoic acid 0.015%)
4. the pharmaceutical composition of embodiment 4: (containing Herba Centellae total glycosides 2.0%, retinoic acid 0.020%)
5.0.025% tretinoin cream (Huabang Pharmaceutical Co., Ltd., Chongqing)
6.2.5% asiaticoside ointment (Shanghai Hyundai Pharmacy stock Co., Ltd)
Two, test method and investigation content
1, each medicine to propionibacterium acnes, staphylococcus epidermidis, staphylococcus aureus bacteriostasis comparison
Extracorporeal bacteria inhibitor test, measures MIC value: take the each 50g of above each Experimental agents, distilled water dissolves 50ml volumetric flask standardize solution, obtains 1000mg/ml suspension solution, pours infusion bottle into, lid thin film, moulding plug and aluminium lid, autoclaving.When test, get the doubly dilutions such as suspension 0.5ml meat soup work, concentration is respectively: 500,250,125,62.5,31.25,15.625,7.82,3.91mg/ml (1: 1,1: 2,1: 4,1: 8,1: 16,1: 32,1: 64,1: 128), minimal inhibitory concentration (MIC) is measured and is adopted test tube doubling dilution, the every pipe dosage of test organisms liquid 0.5ml, former medicine final concentration 250,125,62.5,31.25,15.625,7.82,3.91,1.96mg/ml.Mix, on request test tube is placed in respectively to aerobic and anaerobic environment 37 DEG C of cultivation 24h (aerobic) and 48h (anaerobism), in the satisfactory situation of control tube, (all blank pipe, medicine negative control pipe culture medium are clarified) observes each test tube one by one, measure the MIC of each medicine, the inhibitory action of observation experiment medicine to the relevant pathogenic bacterium propionibacterium acnes of acne, golden Portugal bacterium, form staph.
2, the inhibitory action comparison of antiinflammatory action---each trial drug to mice auricle swelling
Set up mice caused by dimethylbenzene xylene auricle edema model, 105 male mices are divided into blank group and experimental group at random, respectively at auris dextra administration 3d, each 0.5g, 30min after experiment was administered once the same day again, in the wide two-sided painting dimethylbenzene 0.05ml of every Mus auris dextra, puts to death animal after 1h, with the card punch of diameter 8mm, take off the auricle of ears with position, weigh, calculate auricle swelling degree and suppression ratio, each administration group and matched group comparison, and carry out the antiinflammatory action of t survey Experimental agents compositions.
3, each trial drug is on the cuticular impact of rabbit ear Acne Model
Set up coal tar and cause the wide Acne Model of the rabbit ear, 64 rabbits are divided into after matched group and experimental group at random, on the focus skin of 6 experimental grouies, embrocate respectively above Experimental agents compositions, every day 1 time, 0.5g/ time, totally 3 weeks, observe the impact on cuticle thickness.
4. the incidence rate of cicatrix inhibitory action comparison---each trial drug to rabbit ear cicatrix and the effect of scar hyperplasia index
Set up rabbits hypertrophic scars model, making auricular vein with 30g/L pentobarbital sodium (30mg/kg) anaesthetizes, under strict aseptic technique, avoid visible vessels at rabbit ear veutro along major axis, make 1cm × 1cm size wound surface, more than wound surface interval 1cm, remove rabbit ear holostrome skin and perichondrium, edge of wound burns with flatiron, and every rabbit ear is made 6 identical wound surface.Postoperative wound surface exposes, and treats that wound surface heals voluntarily.At the rabbit ear postoperative the 6th day, after wound surface is dry, rabbit is divided into matched group and experimental group (every group of 4 rabbits, 6 wound surface of each rabbit ear) at random, in wound surface kitchen range, embrocate respectively above Experimental agents compositions, every day 1 time, totally 4 weeks, the incidence rate of the 28th day statistics rabbit ear cicatrix, and in anesthesia situation, put to death rabbit, cut scar tissue specimen, measure the scar hyperplasia index ratio of normal skin height (the cicatrix height with).
Three, experimental result
1. bacteriostasis
Minimal inhibitory concentration (MIC) measurement result (mg/ml) of the each trial drug of table 2
Group |
Propionibacterium acnes |
Staphylococcus aureus |
Staphylococcus epidermidis |
Embodiment 1 emulsifiable paste |
31.25 |
31.25 |
15.625 |
Embodiment 2 emulsifiable pastes |
125 |
125 |
62.5 |
Embodiment 3 emulsifiable pastes |
31.25 |
31.25 |
15.625 |
Embodiment 4 emulsifiable pastes |
62.5 |
31.25 |
15.625 |
0.025% tretinoin cream |
- |
- |
- |
2.5% asiaticoside ointment |
62.5 |
31.25 |
15.625 |
From upper table, the tretinoin cream except 0.025% is to three kinds of pathogenic bacterias without obvious bacteriostasis, and all the other have certain inhibitory action.Embodiment 1 is more or less the same with embodiment 3 effects, organizes compared with other.
2. antiinflammatory action
The impact (X ± S) of the each trial drug of table 3 on mice auricle swelling
Group |
Animal number of elements/n |
Swelling/mg |
Suppression ratio/% |
Blank group |
15 |
16.86±4.483 |
|
Embodiment 1 emulsifiable paste |
15 |
8.14±3.055 |
51.72** |
Embodiment 2 emulsifiable pastes |
15 |
10.07±2.960 |
40.27** |
Embodiment 3 emulsifiable pastes |
15 |
8.96±3.041 |
46.86** |
Embodiment 4 emulsifiable pastes |
15 |
9.46±3.056 |
43.89** |
0.025% tretinoin cream |
15 |
14.16±3.086 |
16.01* |
2.5% asiaticoside ointment |
15 |
10.42±2.183 |
38.2** |
Note: with the comparison of blank group, * * P < 0.01, * P < 0.05
All medicines all have the effect that alleviates suppurative inflammation, and wherein embodiment 1 and embodiment 3 act on more obviously, and for the rat auricle Acne Model of setting up, both all can obviously alleviate its swelling.Tissue slice and model group are relatively without purulent lesion, and cell infiltration obviously reduces, and organizational structure is more complete.The effect of its expression is followed successively by: the tretinoin cream of the asiaticoside ointment > 0.025% of embodiment 1 > embodiment 3 > embodiment 4 > embodiment 2 > 2.5%;
3. pair cuticular effect:
The each trial drug of table 4 is on the cuticular impact of rabbit ear Acne Model (X ± S)
Group |
Animal number of elements (n) |
Dosage (g emulsifiable paste × d) |
(μ m) for cuticle thickness |
Blank group |
8 |
Substrate |
15.43±1.99** |
Model group |
8 |
Substrate |
20.79±6.12 |
Embodiment 1 emulsifiable paste |
8 |
0.5×20 |
14.48±1.81** |
Embodiment 2 emulsifiable pastes |
8 |
0.5×20 |
14.67±1.98** |
Embodiment 3 emulsifiable pastes |
8 |
0.5×20 |
17.23±2.88** |
Embodiment 4 emulsifiable pastes |
8 |
0.5×20 |
15.64±2.27** |
0.025% tretinoin cream |
8 |
0.5×20 |
16.27±3.17** |
2.5% asiaticoside ointment |
8 |
0.5×20 |
19.65±4.86 |
Note: each group and model group comparison, * p < 0.05, * * p < 0.01
Except 2.5% asiaticoside ointment, other respectively organize medicine all has and comparatively significantly suppresses dyskeratosis effect the rabbit ear Acne Model of setting up.After administration surrounding, each administration group all shows and necessarily alleviates cuticle thickness effect, wherein embodiment 1, embodiment 2, embodiment 4 and 0.025% tretinoin cream effect are more obvious, rabbit ear deliquescing, attenuation, hair follicle pimple disappears substantially, and without desquamation crust, surface skin is more level and smooth.Each group expressional function is the asiaticoside ointment of tretinoin cream > embodiment 3 > 2.5% of embodiment 1 ≈ embodiment 2 > embodiment 4 > 0.025%;
4. the inhibitory action of pair cicatrix:
The incidence rate (n=48, %) of the postoperative 28d rabbit ear of table 5 cicatrix
Group |
Matched group |
Embodiment 1 |
Embodiment 2 |
Embodiment 3 |
Incidence rate |
91.7(44/48) |
25 (12/48)** |
58.3 (28/48)** |
29.2 (14/48)** |
Group |
Embodiment 4 |
0.025% tretinoin cream |
2.5% asiaticoside ointment |
|
Incidence rate |
41.7 (20/48)** |
81.3 (39/48)* |
35.4 (17/48)** |
|
The hypertrophy index (X ± S, n=48) of the postoperative 28d rabbit ear of table 6 cicatrix
Group |
Matched group |
Embodiment 1 |
Embodiment 2 |
Embodiment 3 |
Hypertrophy index |
4.20±0.83 |
2.85±0.47** |
3.52±0.51* |
2.98±0.43** |
Group |
Embodiment 4 |
0.025% tretinoin cream |
2.5% asiaticoside ointment |
|
Hypertrophy index |
3.21±0.47** |
4.01±0.63 |
3.05±0.37** |
|
Note: each group and matched group comparison, * p < 0.05, * * p < 0.01
From upper table, except 0.025% tretinoin cream, all the other several groups have inhibitory action in various degree: embodiment 1 > embodiment 3 > 2.5% asiaticoside ointment > embodiment 4 > embodiment 2 to cicatrix
The curative effect comparison of embodiment 17 asiaticoside retinoic acid compound recipes and asiaticoside and retinoic acid drug combination
One, Experimental agents
1. the compound cream of embodiment 1 (containing Herba Centellae total glycosides 2.5%, retinoic acid 0.025%)
2. drug combination group:
0.025% tretinoin cream (Huabang Pharmaceutical Co., Ltd., Chongqing)
2.5% asiaticoside ointment (Shanghai Hyundai Pharmacy stock Co., Ltd)
Two, experimental technique
1. antiinflammatory action---mice auricle swelling rejection ratio
Set up mice caused by dimethylbenzene xylene auricle edema model, mice is divided into model control group, 1 group of embodiment and coupling group at random, respectively at auris dextra administration 3d, the each 0.5g of embodiment group, coupling group is first coated with 0.025% retinoic acid 0.5g, repastes the asiaticoside frost ointment 0.5g that wipes 2.5%.30min after experiment was administered once the same day again, in the wide two-sided painting dimethylbenzene 0.05ml of every Mus auris dextra, puts to death animal after 1h, with the card punch of diameter 8mm, take off the auricle of ears with position, weighs, and calculates auricle swelling degree and suppression ratio.
2. the effect comparison of pair cicatrix
Set up rabbits hypertrophic scars model, at the rabbit ear postoperative the 6th day, after wound surface is dry, rabbit is divided into model control group, 1 group of embodiment and coupling group (every group of 4 rabbits at random, 6 wound surface of every rabbit ear), embodiment 1 forms the pharmaceutical composition of embrocating embodiment 1 in face kitchen range, every day 1 time, each 0.5g, totally 4 weeks, coupling group is embrocated 0.025% tretinoin cream evening, embrocate 2.5% asiaticoside frost ointment simultaneously, carry out drug combination, every day 1 time, each every kind of 0.5g, totally 4 weeks.The incidence rate of the 28th day statistics rabbit ear cicatrix and measure the scar hyperplasia index ratio of normal skin height (the cicatrix height with).
Three, experimental result
1, antiinflammatory action
The impact of table 7 on mice auricle swelling
Group |
Animal number of elements (n) |
Swelling/mg |
Suppression ratio/% |
Blank group |
15 |
16.79±4.113 |
|
1 group of embodiment |
15 |
7.66±3.107 |
54.38** |
Coupling group |
15 |
9.82±2.984 |
41.51** |
Note: each group and matched group comparison, * p < 0.05, * * p < 0.01
From upper table, 1 group of embodiment has obvious antiinflammatory action with coupling group, but the pharmaceutical composition of 1 group of embodiment is better than coupling group.
2, cicatrix inhibitory action
The incidence rate (n=48, %) of the postoperative 28d rabbit ear of table 8 cicatrix
Group |
Matched group |
Embodiment 1 |
Coupling group |
Incidence rate |
90(43/48) |
23 (11/48)** |
33.3 (16/48)** |
The hypertrophy index (X ± S, n=48) of the postoperative 28d rabbit ear of table 9 cicatrix
Group |
Matched group |
Embodiment 1 |
Coupling group |
Hypertrophy index |
4.11±0.79 |
2.63±0.55** |
3.05±0.47** |
Note: each group and matched group comparison, * p < 0.05, * * p < 0.01
1 group of embodiment is low compared with matched group with the cicatrix incidence rate of coupling group, and all there were significant differences, but 1 group of successful of embodiment is better than coupling group.1 group of cicatrix obtaining with coupling group of embodiment contrasts all and has clear improvement in subjective symptom, and flushing goes down, and matter is soft, more flat, but from scar hyperplasia index, 1 group of effect of embodiment is better than coupling group.Known by this Comparison of therapeutic, pharmaceutical composition to the inhibitory action of cicatrix than asiaticoside and retinoic acid drug combination better effects if.
Suppress two tests of pesticide effectiveness by antiinflammatory and cicatrix and show, pharmaceutical composition is than simple retinoic acid and asiaticoside drug combination better effects if.
Embodiment 18 untoward reaction comparisons
Compare with independent medication (2.5% asiaticoside ointment and 0.025% tretinoin cream), the adverse reaction rate of the pharmaceutical composition of embodiment 1 has remarkable reduction compared with 0.025% tretinoin cream, causalgia, scratch where it itches, the local excitation symptom such as twinge and erythema obviously alleviates (incidence rate of three's untoward reaction successively: 2.5% asiaticoside ointment 2%, embodiment 1 pharmaceutical composition 10%, 0.025% tretinoin cream 38%).