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WO1998048775A9 - Serine protease et compositions retinoides topiques - Google Patents

Serine protease et compositions retinoides topiques

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Publication number
WO1998048775A9
WO1998048775A9 PCT/US1998/002618 US9802618W WO9848775A9 WO 1998048775 A9 WO1998048775 A9 WO 1998048775A9 US 9802618 W US9802618 W US 9802618W WO 9848775 A9 WO9848775 A9 WO 9848775A9
Authority
WO
WIPO (PCT)
Prior art keywords
topically active
active agent
pharmaceutical
trypsin
composition
Prior art date
Application number
PCT/US1998/002618
Other languages
English (en)
Other versions
WO1998048775A1 (fr
Filing date
Publication date
Priority to IL13132298A priority Critical patent/IL131322A0/xx
Priority to JP54694698A priority patent/JP2002515903A/ja
Priority to MXPA99007442A priority patent/MXPA99007442A/es
Priority to DE19882420T priority patent/DE19882420T1/de
Priority to FI992177A priority patent/FI19992177L/fi
Priority to CA002280747A priority patent/CA2280747A1/fr
Application filed filed Critical
Priority to BR9812996-1A priority patent/BR9812996A/pt
Priority to AU65345/98A priority patent/AU749215B2/en
Publication of WO1998048775A1 publication Critical patent/WO1998048775A1/fr
Publication of WO1998048775A9 publication Critical patent/WO1998048775A9/fr
Priority to DK199901456A priority patent/DK199901456A/da
Priority to SE9904059A priority patent/SE9904059D0/xx

Links

Definitions

  • This invention is related to methods for treating Acne Vulgaris and/or for producing anti-aging effects on the skin of a mammal, and compositions effective for the same. More specifically, the present invention is directed to the use of serine proteases, either alone or in combination with a retinoid compound in a pharmaceutical or cosmetic composition.
  • Acne Vulgaris is a disorder of the pilosebaceous unit that effects nearly all adolescents to some degree, as well as many adults.
  • the initial lesion of the disease is believed to be due to hypercornification and hyperkeratinization of the infundibulum, a process that helps to transform the sebaceous follicle into a comedone.
  • This disorganization of the epithelium may give rise to inflammatory lesions, as the infundibulum ruptures and sebum is introduced into the dermis.
  • Topical retinoids are considered to be one of the most effective closes of comedolytic agents for the treatment of Acne Vulgaris, however their clinical efficacy is limited by their irritant effects. Topical retinoids have also been used to produce anti-aging effects on the surface of mammalian skin. While they .are known in the art as one of the most effective topical treatments available, these compounds are limited by their irritant effects.
  • a method for treating Acne Vulgaris and/or for producing anti-aging effects on the skin of a mammal comprising, consisting essentially of, or consisting of topically applying to the skin of a mammal an effective amount of a first topically active agent comprising a protease.
  • a method for treating Acne Vulgaris and/or for producing anti-aging effects on the skin of a mammal comprising, consisting essentially of, or consisting of topically applying to the skin of a mammal an effective amount of a first topically active agent comprising a protease in combination with a second topically active agent comprising a retinoid.
  • a pharmaceutical or cosmetic composition comprising, consisting essentially of, or consisting of: a) a first topically active agent comprising a protease; and b) a second topically active agent comprising a retinoid.
  • compositions and methods of this invention provide a unique, convenient means for treating Acne Vulgaris and/or for producing anti-aging effects on the skin of a mammal.
  • FIG. 1(a) is a representation which illustrates a cross-sectional view of the skin of a Rhino mouse one hour after treatment with fluorescently labeled trypsin.
  • FIG. 1(b) is a representation which illustrates a cross-sectional view of the skin of a Rhino mouse four hours after treatment with fluorescently labeled trypsin.
  • FIG (c) is a representation which illustrates a cross-sectional view of the skin of a Rhino mouse four hours .after treatment with fluorescently labeled trypsin, following 5 days of daily treatment with 1% (w/v) trypsin.
  • FIGS. 2(a) and 2(b) are representations which illustrate the histology of Rhino mouse skins processed with H&E stmning, (a) untreated, and (b) treated daily with
  • FIGS. 3(a) and 3(b) are color representations which illustrate the cross- sectional view of Rhino mouse skins which were processed for paraffin sections and stained for elastin.
  • FIG. 3(a) is vehicle treated
  • FIG. 3(b) is trypsin treated.
  • FIGS. 3(a) is vehicle treated
  • FIG. 3(b) is trypsin treated.
  • 3(c) and 3(d) are representations which illustrate the cross-sectional view of C57B1/6 mouse skins which were processed for paraffin sections and stained for elastin.
  • FIG. 1
  • FIGS. 4(a-c) are representations which illustrate the histology of Rhino mouse skins processed with H&E staining, (a) treated with 0.0005% (w/v) all-trans retinoic acid, (b) treated with 0.005% (w/v) trypsin, and (c) treated with both 0.0005% (w/v) all-trans retinoic acid and 0.005% (w/v) trypsin.
  • FIGS. 5(a) and 5(b) are representations which illustrate the cross-sectional view of the TUNEL-stained skin tissue of a vehicle treated Rhino mouse.
  • ⁇ and 5(d) .are representations which illustrate the cross-sectional view of the TUNEL- stained skin tissue of a Rhino mouse treated with trypsin.
  • FIG. 6 is a representation which illustrates the profile of gene expression of trypsin treated Rhino mouse skins at various concentrations of trypsin as detected by Reverse Transcription-Polymerase Chain Reaction ("RT-PCR").
  • topically active agents suitable for use in the compositions of the present invention as the first topically active agent include proteases, which include, but are not limited to, serine proteases.
  • the first topically active agent is selected from trypsin, carboxypeptidase-Y, protease IV, subtilysin, or mixtures thereof.
  • the protease of choice is trypsin.
  • the protease is present in an amount, based upon the total volume of the composition of the present invention, of from about 0%
  • the first topically active agent of the present invention treats the hyperkeratinization associated with Acne Vulgaris and/or produces anti-aging effects on the skin.
  • the first topically active agent can be used as the sole active ingredient in a composition for the treatment of Acne Vulgaris and/or to produce anti-aging effects on the skin, to more thoroughly treat Acne Vulgaris, the first topically active agent of the present invention can be combined with a second topically active agent.
  • said second topically active agent treats both the hyperkeratinization and the obstruction of the sebaceous follicle associated with Acne Vulgaris, while also producing anti-aging effects on the skin which are comparable to those produced by the first topically active agent.
  • the first feature of combining said first and second topically active agents is that the resulting treatment attacks at least two of the pathological processes associated with Acne Vulgaris, while not sacrificing the anti-aging benefits of the first topically active agent.
  • Example 4 shows that combining said first topically active agent with said second topically active agent mitigates the irritant effect associated with said second topically active agent.
  • the efficacy of treatment of Acne Vulgaris and/or signs of anti-aging effects on the skin are approximately the same with the treatments of the present invention as compared with treatments involving the second topically active agent alone, but the irritant effect normally associated with said second topically active agent is substantially reduced.
  • Example 7 shows that combining said first topically active agent with said second topically active agent substantially reduces the time necessary for product efficacy as compared to the use of the second topically active agent alone.
  • the efficacy of treatment remains approximately the same as compared with treatments utilizing the second topically active agent alone, but the length of time required to see results normally associated with said second topically active agent is substantially reduced by combining said second topically active agent with said first topically active agent.
  • Topically active agents suitable for use in the compositions of the present invention as the second topically active agent include those compounds in the class of retinoids, which include, but .are not limited to, retinoic acids, vitamin A alcohol, vitamin A aldehyde, retinyl acetate, retinyl palmitate, or other derivatives, analogs or mixtures thereof.
  • the retinoid of choice is all-trans retinoic acid.
  • the retinoid is present in an amount, based upon the total volume of the composition of the present invention, of from about 0.0001% (w/v) to about 0.5% (w/v), and more preferably from about 0.001% (w/v) to about 0.025% (w/v).
  • the pharmaceutical or cosmetic compositions of the present invention may preferably be further comprised of a pharmaceutically or cosmetically acceptable vehicle capable of functioning as a delivery system to enable the penetration of the topically active agent into the utriculus. While any commercially available vehicle for delivering the first topically active agent to the appropriate skin appendage, which in this case is the utriculus, is suitable for use as the pharmaceutically or cosmetically acceptable vehicle, liposomes are preferred.
  • the liposomes are more preferably non-ionic and comprised of: (a) glycerol dilaurate or glycerol distearate; (b) compounds having the steroid backbone found in cholesterol; and (c) fatty acid ethers having from about 12 to about
  • Liposomes comprised of glycerol dilaurate / cholesterol / polyoxyethylene-10-stearyl ether ("GDL") are most preferred.
  • GDL polyoxyethylene-10-stearyl ether
  • the liposomes are present in an amount, based upon the total volume of the composition, of from about 10 mg/mL to about 100 mg/mL, and more preferably from about 25 mg/mL to about 50 mg/mL. A ratio of about 58:15:27, respectively, is most preferred.
  • Suitable liposomes may preferably be prepared in accordance with the protocol set forth in Example 2, though other methods commonly used in the art are also acceptable.
  • the above described liposomal composition may be prepared by combining the desired components in a suitable container and mixing them under ambient conditions in any conventional high shear mixing means well known in the art for non-ionic liposomes preparations, such as those disclosed in Niemiec et al., "Influence of Nonionic Liposomal
  • the pharmaceutical or cosmetic composition of the present invention may be optionally combined with other ingredients such as moisturizers, cosmetic adjuvants, anti-oxidants, surfactants, foaming agents, conditioners, humectants, fragrances, viscosifiers, buffering agents, sunscreens, colorants, preservatives, and the like in an amount which will not destroy the liposomal structure, if present, in order to produce cosmetic or pharmaceutical products.
  • the first and second topically active agents of the present invention can be applied to the skin of a mammal either simultaneously or at different times.
  • the first topically active agent can be administered in the morning and the second topically active agent can be administered in the afternoon.
  • the second topically active agent can be administered in the morning and the first topically active agent can be administered in the afternoon.
  • the first and second topically active agents can be administered together.
  • the first and second topically active agents can be administered on alternate days.
  • the treatments with the first and second topically active agents do not have to be given in a one-to-one dosage, so the first topically active agent can be administered for two days, while the second topically active agent is administered on the third day and so on.
  • the previous five examples are provided only to illustrate some of the many different treatment regimens possible with the methods of the present invention. It should be understood that these examples are not limiting in any way to the treatment methods of the present invention, and that many other treatment regimens are possible.
  • the pharmaceutical or cosmetic composition should be applied in an amount effective to treat Acne Vulgaris and/or produce anti-aging effects on the skin.
  • amount effective shall mean an amount sufficient to cover the region of skin surface where treatment of Acne Vulgaris and/or production of anti-aging effects is desired.
  • the composition is applied to the skin surface such that, based upon a square cm of skin surface, from about 2 ⁇ l/cm 2 to about 8 ⁇ l/cm 2 of topically active agent is present when treatment of Acne Vulgaris and or production of anti- aging effects on the skin is desired.
  • the invention illustratively disclosed herein suitably may be practiced in the absence of any component, ingredient, or .step which is not specifically disclosed herein. Several examples are set forth below to further illustrate the nature of the invention and the manner of carrying it out. However, the invention should not be considered as being limited to the details thereof.
  • Rhino mouse has been used as an experimental acne model to screen topically active comedolytic and antikeratinizing agents as described in Sundberg, J.P., "The Hairless and Rhino Mutations, Chromosome 14," Handbook of Mouse Mutations
  • a recessive mutation on chromosome 14 results in a mouse with wrinkled skin devoid of body hair by age 25 days.
  • the end of the first hair cycle the follicular papillae fail to follow the regressing hair follicles and become isolated in the dermis.
  • the papillae do not reassociate with the follicular epithelium to initiate a new hair follicle cycle.
  • the upper remnants of the hair follicle are filled with sloughed, cornified cells and form utriculi with a small sebaceous gland at their base, resembling an open comedone.
  • the rhino skin becomes progressively loose, forming folds and ridges, due to the expansion of the surface, secondary to abortive hair follicles filling with cornified debris.
  • the utriculi progressively enlarge, forming pilary cists (pseudocomedones), which are dilated follicular infundibula filled with cornified debris.
  • glycerol dilaurate was available from International Specialty Products Van Dyke (Belleville, New Jersey) under the tradename "Emulsynt GDL.”
  • the cholesterol was available from Croda, Inc. (Parsippany, New Jersey) under the tradename "Cholesterol VSP/NF.”
  • the polyoxyethylene-10-stearyl ether was available from ICI Surfactants Americas (Wilmington, Delaware) under the tradename "Brij 76.”
  • Retinoic acid compositions contained an ethanol propylene glycol vehicle which comprised 70% (w/v) ethanol (ethyl alcohol, 200 proof) which was obtained from Quantum Chemicals Corporation (Tuscola, Illinois) and 30% (w/v) propylene glycol which was obtained from Fisher Scientific (Pittsburgh, Pennsylvania).
  • EXAMPLE 3 Delivery of Trypsin into Hair Follicles About 100 ⁇ L of the topically active trypsin composition of Example 2 was applied to the dorsal side of each Rhino mouse of Example 1. The trypsin used in this composition was fluorescently-labeled with a protein fluorescent labeling kit available from Molecular Probes, Inc. in accordance with its accompanying protocol (1996).
  • This Example shows that the application of a topically active composition containing trypsin to the skin surface of Rhino mice resulted in the delivery of the trypsin primarily to the utriculi and sebaceous glands, both after short term and long term use.
  • EXAMPLE 4 Trypsin Treatment Reduces the Size of Utriculi but Does Not Induce Dermal Irritation Rhino mice of Example 1 were topically treated with the trypsin compositions
  • Example 2 (0.001% (w/v) - 1% (w/v)) of Example 2 once daily for five days. Animals were sacrificed at day 8 and image analysis was used to quantify the reduction in utriculi size. For image analysis, whole mount epidermis was processed and microscopic measurements were taken according to the methods described in Mezick as well as Bernerd et al., "The Rhino Mouse Model: The Effects of Topically Applied All-Trans
  • the mean utriculus diameter ( ⁇ ) and the mean sebaceous gland size ( ⁇ 2 ) were calculated for each treatment group (3 Rhino mice), using 5 random fields, two measurements per field, per animal. Percent reduction in utriculi diameter was calculated in accordance with the methods described in Finney, D. J., "Parallel Line Assays, Statistical Method in Biological Assay," Charles Griffen & Company Ltd. 69-104 (1978) which is incorporated herein by reference in its entirety. As shown in Table 1, trypsin induced a dose dependent reduction in utriculus size that reached a plateau at ⁇ 0.1% (w/v) trypsin.
  • a further increase in trypsin concentration did not result in more than 55% reduction of utriculus size relative to liposomal control.
  • a small reduction in utriculus diameter was observed in the liposome vehicle alone.
  • a single trypsin (1% (w/v)) treatment had no effect on utriculus size reduction when analyzed seven days later (not shown).
  • TEWL transepidermal water loss
  • TEWL increased in a dose dependent manner, with a plateau reached at -0.05% (w/v) trypsin. This is approximately the same concentration for the maximal reduction in utriculi diameter. There was no correlation between TEWL increase and visual irritation. The minor scaling and erythema observed throughout these experiments were not dose dependent and remained low even at 1% (w/v) trypsin. Furthermore, the TEWL for trypsin treated mice was lower than that for retinoid treatment given alone.
  • the trypsin treated epidermis was hyperplastic with .an increase in the number of cell layers of both the follicular epithelium and the epidermis when compared with the untreated epidermis shown in FIG. 2(a). Changes were observed mainly at the granular layer and the stratum corneum resulting in restored desquamation and improved skin structure. These epidermal changes are well- characterized markers for retinoid activity in vivo, and are associated with potential clinical efficacy. To further support the assertion that trypsin is unrelated to dermal irritation, FIG.2(b) shows no inflammatory cells, which would normally be present in an irritation situation.
  • This example shows that trypsin causes a dose dependent reduction in the size of utriculi. A reduction in the size of the utriculi is associated with potential clinical efficacy of compositions for treating Acne Vulgaris. Therefore, this example further shows that trypsin is effective in the treatment of Acne Vulgaris. This example further shows that topical trypsin treatments do not induce skin irritation.
  • Rhino mice of Example 1 which were treated with the trypsin composition of Example 2 showed a noticeable effect in skin elasticity. To quantitate this effect, a cutometer analysis was performed. We used a cutometer available from Acaderm
  • FIGS. 3(c) and (d), the untreated and trypsin treated skins, respectively, show the results of elastin staining.
  • Table 3 below shows the increase in skin mechanical parameters following the trypsin treatment.
  • This example shows that topical treatment with trypsin increases the elasticity of C57B1/6 and Rhino mouse skins. Skin elasticity is a property associated with anti- aging. Therefore, this example further shows that trypsin imparts anti-aging effects to the surface of the skin.
  • a first set of Rhino mice of Example 1 were treated with suboptimal doses of the trypsin composition of Example 2.
  • “suboptimal” is defined as levels of trypsin concentration below the optimum for utriculi size reduction as demonstrated in Example 4.
  • a second set of Rhino mice of Example 1 were treated with suboptimal concentrations of the all-trans retinoic acid composition of Example 2.
  • a third set of Rhino mice of Example 1 were treated with both suboptimal doses of the trypsin composition of Example 2 and the all-trans retinoic acid composition of
  • Example 2 In this third set of Rhino mice, the trypsin and all-trans retinoic acid treatments were each administered daily, but at different times (i.e. trypsin in the morning and all-trans retinoic acid in the afternoon). Mice were sacrificed and their skins were examined histologically with the procedure set forth in Example 3. As shown in FIG. 4(c), Rhino mice treated with both the trypsin and all-trans retinoic acid compositions showed much improved desquamation when compared to the trypsin and all-trans retinoic acid treatments given alone (FIGS. 4(a&b)), though the treatments given alone showed marked inprovement over the untreated skin (FIG. 2(a)).
  • the histological analysis revealed far fewer open utriculi in the surface of treated skins than either treatment given alone.
  • This example shows that a combined treatment of trypsin and all-trans retinoic acid produces an additive effect on skin surface characteristics such as the number of open utriculi, which means that these compositions are effective in the treatment of Acne Vulgaris.
  • Rhino mice of Example 1 were treated daily with a 0.1% (w/v) trypsin composition of Example 2 for five days and sacrificed at day eight.
  • TUNEL TdT-mediated dUTP-biotin nick end labeling
  • FIGS. 5(a-d) show a histological analysis wherein the stain has a peroxidase end point (brown) and a methyl green counter-stain. The resulting representations of this are provided in FIGS. 5(a&b) which are vehicle treated and FIGS. 5(c&d) which are trypsin treated.
  • the TUNEL-stained samples defined apoptotic cells by both morphology (condensed or fragmented nuclei and cytoplasm or apoptotic bodies) and by the color of its stain (fragmented DNA within the condensed nuclei were stained brown).
  • TUNEL staining revealed an unusually high level of apoptotic bodies in the follicular epithelium. Trypsin treatment resulted in the elimination of all the apoptotic bodies within the follicular epithelium and the restoration of programmed cell death ("PCD") at the granular layer (FIGS. 5(c&d)) as epidermal differentiation was restored.
  • PCD programmed cell death
  • This example suggests that trypsin could restore the balance between cell death and proliferation within the follicular epithelium and within the epidermis.
  • One of the contributing pathological processes of Acne Vulgaris is hyperkeratinization, which may result from a shift in this balance. Therefore, this example further shows that the ability of trypsin to restore the proper balance in epithelial cell death and proliferation may be a factor in its ability to treat Acne Vulgaris.
  • Rhino mice of Example 1 were treated daily with trypsin compositions (0% (w/v), 0.0001% (w/v), 0.001% (w/v), and 0.01% (w/v)), as prepared in Example 2, for five days and sacrificed at day eight.
  • the skins of vehicle treated mice and trypsin- treated mice were obtained as described in Example 3, then their total RNAs were extracted using "RNA Stat-60" reagent available from Tel-Test "B,” Inc. as described in Chomczymski, "Single Step Method of RNA Isolation By Acid Guanidinium Thiocyanate-phenol-chloroform extraction," 162 Anal. Biochem. 156-59 (1987) which is incorporated herein by reference in its entirety.
  • RT products were then amplified via a polymerase chain reaction ("PCR") using about a 0.5 unit (per 100 ⁇ l reaction) of a thermostable DNA polymerase which is commercially available from Perkin-Elmer-Cetus Corporation under the tradename "Taq polymerase," and about 0.1 ⁇ mol reaction of mouse glyceraldehyde-3-phosphate-dehydrogenase (G3PDH) primers available from Clontech Laboratories, Inc. (“Clontech”), or primers as set forth in Table 4 (using the conditions in Table 4 or in accordance with the procedures set forth in the protocol accompanying the primers from Clontech).
  • PCR polymerase chain reaction
  • Table 5 illustrates some of the DNA primers used, the amount of MgCl 2 required for the PCR reaction, and the length of the PCR cycle. Involucrin primers were as described in Marthinuss, et al., "Apoptosis in Pam212, an Epidermal
  • Keratinocyte Cell Line A Possible Role for bcl-2 in Epidermal Differentiation", 6 Cell Growth Diff. 239-250 (1995) which is incorporated herein by reference in its entirety.
  • Table 4 DNA Primers Utilized in RT-PCR Assay
  • RNA sample from the skin of a Rhino mouse that was not reverse-transcribed was used as a negative control for each PCR amplification.
  • An RNA sample from the skin of a six month old Rhino mouse was used as a positive control when positive controls were not commercially available. The results of the gel analysis showed that the migration of the RT-PCR products on the gels was always identical to that of the positive controls, and to that of the reported amplimer sizes.
  • Transglutaminase an enzyme involved in the cross linking and formation of apoptotic bodies, displayed high mRNA levels in control animals, and was reduced to below detection level with increasing concentrations of trypsin. This shows that trypsin restored utriculi homeostasis and eliminated abnormally high levels of apoptosis in the follicular epithelium.
  • Elastin mRNA increased following treatment with increasing concentrations of trypsin. Therefore, new elastin is expressed following trypsin treatment which results in increased skin elasticity, as described in Example 5.
  • the level of involucrin a marker of epidermal differentiation, was increased following trypsin treatment in a dose dependent manner. This indicates that normal epidermal turnover and differentiation were restored. Thus, trypsin restores the balance of epidermal differentiation as shown in Example 8.
  • Glycerol dilaurate cholesterol/polyoxyethylene-10-stearyl ether liposomes are prepared in accordance with the procedures set forth in Niemiec, wherein the constituent compounds of the liposomes are in a ratio of about 58: 15:27, respectively.
  • a second composition which comprises l.Og trypsin disolved in a 0.05M Hepes buffer, at pH 7.4 (q.s. to 100ml), is added to the liposome composition in a ratio of about 1 part of the second composition for every 8 parts of the liposome composition.
  • This final composition is suitable for immediate topical application.

Abstract

L'invention concerne des procédés de traitement de l'acné simple et/ou de production d'effets anti-vieillissement sur la peau d'un mammifère, ainsi que des compositions permettant de traiter l'acné simple et/ou de produire des effets anti-vieillissement. La présente invention concerne plus particulièrement l'utilisation de sérine protéases, en tant qu'unique actif d'une composition efficace pour traiter l'acné simple et/ou pour produire des effets anti-vieillissement sur la peau d'un mammifère, cette enzyme pouvant également être utilisée en combinaison avec un composé rétinoïde dans une composition permettant de traiter l'acné simple et/ou de produire des effets anti-vieillissement.
PCT/US1998/002618 1997-02-12 1998-02-06 Serine protease et compositions retinoides topiques WO1998048775A1 (fr)

Priority Applications (10)

Application Number Priority Date Filing Date Title
JP54694698A JP2002515903A (ja) 1997-02-12 1998-02-06 セリンプロテアーゼと局所レチノイドの組成物
MXPA99007442A MXPA99007442A (es) 1997-02-12 1998-02-06 Composiciones retinoides topicas y de serinaproteasa.
DE19882420T DE19882420T1 (de) 1997-02-12 1998-02-06 Serin Protease und örtliche Retinoid Zusammensetzungen
FI992177A FI19992177L (fi) 1997-02-12 1998-02-06 Seriiniproteaasi- ja paikallisesti käytettävä retinoidikoostumuksia
CA002280747A CA2280747A1 (fr) 1997-02-12 1998-02-06 Serine protease et compositions retinoides topiques
IL13132298A IL131322A0 (en) 1997-02-12 1998-02-06 Serine protease and topical retinoid compositions
BR9812996-1A BR9812996A (pt) 1997-02-12 1998-02-06 Protease de serina e composições de retinóide tópicas
AU65345/98A AU749215B2 (en) 1997-02-12 1998-02-06 Serine protease and topical retinoid compositions
DK199901456A DK199901456A (da) 1997-02-12 1999-10-12 Serinprotease og topiske retonoidpræparater
SE9904059A SE9904059D0 (sv) 1997-02-12 1999-11-10 Serine protease and topical retinoid compositions

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US3760597P 1997-02-12 1997-02-12
US60/037,605 1997-02-12

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WO1998048775A1 WO1998048775A1 (fr) 1998-11-05
WO1998048775A9 true WO1998048775A9 (fr) 1999-03-04

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CO (1) CO4950526A1 (fr)
DK (1) DK199901456A (fr)
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WO (1) WO1998048775A1 (fr)

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Publication number Priority date Publication date Assignee Title
CA2309373A1 (fr) * 1999-05-27 2000-11-27 Johnson & Johnson Consumer Companies, Inc. Preparations topiques nouvelles
MXPA01013246A (es) * 1999-06-18 2003-08-20 Jon Bragi Bjarnason Proteinasas serina de pescado y su uso farmaceutico y cosmetico.
EP1317246A1 (fr) * 2000-09-13 2003-06-11 The Procter & Gamble Company Traitement cosmetique
JP2004508392A (ja) * 2000-09-13 2004-03-18 ザ、プロクター、エンド、ギャンブル、カンパニー 化粧方法
AU2000274801A1 (en) * 2000-09-13 2002-03-26 The Procter And Gamble Company Cosmetic method for treatment of skin and/or hair
FR2817475B1 (fr) * 2000-12-04 2005-06-17 Rocher Yves Biolog Vegetale Utilisation d'une association proteases-source de retinol pour s'opposer au vieillissement cutane
CN107405281A (zh) * 2015-03-05 2017-11-28 雅芳产品公司 用于处理皮肤的方法
US10076479B1 (en) 2018-05-08 2018-09-18 Avon Products, Inc. Methods for treating skin
WO2023099793A1 (fr) * 2021-12-03 2023-06-08 Dsm Ip Assets B.V. Nouvelles compositions comprenant des rétinoïdes

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JPH04364119A (ja) * 1991-06-11 1992-12-16 Tsumura & Co 浴剤組成物
DE4305460C2 (de) * 1993-02-23 1997-09-04 Albert Dr Scheller Pharmazeutische oder kosmetische, Enzyme enthaltende Zubereitung, Verfahren zu deren Herstellung und deren Verwendung
AU7656894A (en) * 1993-09-15 1995-04-03 Unilever Plc Skin care method and composition
FR2737115B1 (fr) * 1995-07-25 1997-08-22 Oreal Composition stable contenant une enzyme
DE19600480A1 (de) * 1996-01-09 1997-07-10 Beiersdorf Ag Verwendung von Serin-Proteinasen gegen Akne und entzündete Comedonen
US5976556A (en) * 1996-06-13 1999-11-02 Active Organics, Inc. Combination of acid protease enzymes and acidic buffers and uses thereof

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