CN103458882B

CN103458882B - Be used for the treatment of the bakuchiol composition of postinflammatory hyperpigmentation

Info

Publication number: CN103458882B
Application number: CN201280015007.XA
Authority: CN
Inventors: 洪梅芬; 贾琦; 利迪亚·阿尔法洛·布朗奈尔
Original assignee: Unigen Corp
Current assignee: Unigen Corp
Priority date: 2011-02-02
Filing date: 2012-02-02
Publication date: 2015-08-05
Anticipated expiration: 2032-02-02
Also published as: CN105147533A; MX350719B; KR20200108120A; CA3128715A1; CN105147533B; KR20190025740A; BR112013019798A2; CA3128718A1; KR102156731B1; WO2012105990A1; AU2012212153B9; KR102333655B1; KR20210145864A; KR20230058727A; KR102642352B1; CA2826262C; CA2826262A1; CA3128711A1; CN103458882A; KR102525516B1

Abstract

Disclose the method being used for the treatment of hyperpigmentation, comprise the treatment of postinflammatory hyperpigmentation (PIH).Disclosed method comprises the compositions giving mammal and comprise the Bakuchiol that there is no furocoumarin.Also disclose the compositions and their preparation method that comprise Bakuchiol.

Description

Be used for the treatment of the bakuchiol composition of postinflammatory hyperpigmentation

Quoting of related application

The application requires the rights and interests of the US2011/026594 PCT application that on March 1st, 2011 submits to and the 61/438th, No. 890 U.S. Provisional Patent Application that on February 2nd, 2011 submits to according to 35U.S.C. § 119 (e).

Background

Technical field

Relate generally to bakuchiol composition of the present invention and be used for the treatment of the purposes of postinflammatory hyperpigmentation.

description of Related Art

Postinflammatory hyperpigmentation (PIH) is with the melanin genesis increased and deposits relevant rare skin pigmentation disorder state.The feature of PIH is also due to oxidative stress and the melanocytic apoptosis that produces from the invasion and attack of inflammation and immunoreactive amboceptor and cytokine.Melanocyte deposition (that is, hyperpigmentation) occurs outside epidermis aspect, to be released in papillary dermal layer and to be caught by large immunocyte with significant melanocyte.The histologic characteristics of these uniquenesses of PIH produces many difficulties to the traditional pharmaceutical treatment PIH of use.

The common treatment of PIH concentrates on prevents further pigment to develop by using corticosteroid and using bright protective agent to control inflammation.The Chemical peeling compound of such as salicylic acid and glycolic is also used to promote skin renewal function and for removing or reducing pigmentation.Local retinoic acid is also used for the treatment of PIH, but these class methods needed nearly 40 weeks before observing remarkable benefit.

Tyrosinase inhibitor or the skin whitener of such as hydroquinone, Azelaic Acid, kojic acid and Radix Glycyrrhizae extract are also used for the treatment of PIH.The remarkable shortcoming of conventional transdermal brightening agent or tyrosinase inhibitor is used to be that the extensive of normal skin being close to PIH position is faded.This effect makes the color of background skin die down and makes PIH position more outstanding.Therefore, these medicaments must be applied very carefully in PIH position.In addition, tyrosinase inhibitor only his-and-hers watches chromatosis is excessively effective, this is because epidermis is the position that melanocyte is synthesized by tryrosinase.Because pigmentation after inflammation is in the deep layer (such as, papillary dermal layer) of skin, the application of the hydroquinone medicine therefore needing continuous more than 6 months before observing the visible change of density bullet.Finally, the skin whitener of hydroquinone type or tyrosinase inhibitor relevant to side effect, comprise the induction of skin irritation, drying, teratogenecity and vitiligo and skin carcinoma.

Postinflammatory hyperpigmentation can be derived from the endogenous inflammatory cutaneous disease of such as acne, atopic dermatitis, allergic contact dermatitis, bloch-Siemens syndrome, lichen planus, lupus erythematosus, morphea.Other inducement of PIH comprises the exogenous inflammation sexual stimulus of such as mechanical injury, ionization and Non-ionizing radiation, burn, laser therapy and skin infection.The current therapeutic agent for above-mentioned skin disorder is invalid for prevention, alleviation, minimizing or treatment PIH.Such as, normal use such as retinoic acid, COX inhibitor are (such as, salicylic acid), the antiinflammatory of nonsteroidal anti-inflammatory drug (NSAIDs), antibacterial or hormone medicine treats above-mentioned skin disorder, but these treatments have been proved to be invalid to PIH.

Although obtain remarkable break-throughs in described field, described field is still needed badly for prevention, alleviates, is reduced or the Pigmented method of overmedication.Such as, the method being used for the treatment of postinflammatory hyperpigmentation is needed.The present invention realizes these to be needed and provides more associated advantages.

General introduction

Generally, the present invention relates to for prevention, alleviate, reduce or the Pigmented method of overmedication.Hyperpigmentation can be the result of the morbid state being derived from inflammatory skin disease state.Such as, one embodiment of the invention are for prevention, alleviation, minimizing or the method for the treatment of postinflammatory hyperpigmentation (PIH).This PIH can be derived from many skin disorders, comprises acne.Described method comprises and gives comprising Bakuchiol and being less than the compositions of total furanocoumarins impurity of 500ppm of mammal effective dose.

Contrary with other skin whitener, bakuchiol composition disclosed herein is not tyrosinase inhibitor.Therefore, disclosed compositions is decoloured and the hyperpigmentation be used for the treatment of in deep skin (such as, papillary dermal layer) at PIH position especially.Therefore, compared with being used for the treatment of the method for hyperpigmentation and/or PIH, disclosed method comprised some advantages at present in the past.

Therefore, an embodiment of the present disclosure relates to the method for preventing, alleviating, reduce or treat the hyperpigmentation caused by the morbid state being derived from inflammatory cutaneous disease, described method comprise give mammal effective dose comprise Bakuchiol or the acceptable salt of its medicine, and medicine acceptable carrier and be less than the compositions of total furanocoumarins impurity of 500ppm.

In some embodiments, described morbid state is postinflammatory hyperpigmentation.In other embodiments, described compositions comprises the total furanocoumarins impurity being less than 100ppm.In other embodiments, described furanocoumarin impurities comprises psoralen, isopsoralen or its combination.In some embodiments, relative to kojic acid contrast, described compositions does not show tyrosinase inhibitory activity.

In other embodiments, Bakuchiol is chemosynthesis or is separated from plant.Such as, in some embodiments, Bakuchiol is separated from plant.In some other embodiment, described plant from plant Psoralea (Psoralea genus), such as Fructus Psoraleae (Psoraleacorylifolia L.) (pulse family) or Psoralea glandulosa L. (Papilionaceae).

In other embodiments, Bakuchiol is separated from seed, stem, bark, branch, tuber, root, root bark, plumelet, rhizome, flower or other genitals, leaves or other aerial parts or its combination.

In some of the other embodiments, postinflammatory hyperpigmentation (PIH) is derived from acne, atopic dermatitis, allergic contact dermatitis, bloch-Siemens syndrome, lichen planus, lupus erythematosus, morphea, mechanical injury, ionization or Non-ionizing radiation, burn, laser or Drug therapy, skin infection or its combination.Such as, in certain aspects, postinflammatory hyperpigmentation (PIH) is derived from acne.

In other embodiments, described compositions comprises Bakuchiol and pharmacy, dermatological or the beauty treatment acceptable carrier of 0.001% to 99.9% gross weight.Such as, in certain aspects, described compositions comprises the Bakuchiol of the Bakuchiol of 0.1% to 2.0% gross weight, the Bakuchiol of 1.0% gross weight or 0.5% gross weight.

In other embodiments, dermatological acceptable carrier comprises nonsticking gauze, binder, cotton swab, cleaning wiping cloth, plaster, mask or protective agent.At some in other embodiment, beauty treatment acceptable carrier comprises cleaning agent or antibacterial.

In certain aspects, described compositions is prepared for topical.Such as, in certain aspects, described compositions also comprises ointment, lotion, ointment, gel, Emulsion, liquid, paste, soap, powder agent or its combination.

In other embodiments, described compositions also comprises adjuvant, skin penetration enhancer or liposome.In other embodiments, described adjuvant comprises 'alpha '-hydroxy acids, salicylic acid, linoleic acid, retinoic acid, benzoyl peroxide, sodium sulfacetamide, clindamycin, erythromycin, dapsone, tetracycline, doxycycline, minocycline, zinc, estrogen or derivatives thereof, androgen antagonist, sulfur, steroid, cortisone, tazarotene, curcumin extract, arabic gum extract, Radix Scutellariae extract, Green tea extract, OPC or its combination.

In some embodiments, prepare described compositions with capsule form, such as, controlled release capsule.In other embodiments, by aerosol, by suppository, skin, intramuscular injection or intravenous injection local give described compositions.

In certain aspects, described method prevention hyperpigmentation.In other side, described method alleviates hyperpigmentation.In other side, described method reduces hyperpigmentation.In other side, described method overmedication pigmentation.

In other embodiments, hyperpigmentation occurs in the deep layer of skin, such as, in the papillary dermal layer of skin.In other embodiments, described method also comprises minimizing superoxide anion.At some in other embodiment, described method also comprises and reduces melanogen and generate.In other embodiments, described method also comprises minimizing melanocyte proliferation.In other embodiments, described method also comprises prevention melanocyte apoptosis.

In some of the other embodiments, mammal is behaved.At some in other embodiment, mammal needs to prevent, alleviates, reduces or treat the hyperpigmentation caused by the morbid state being derived from inflammatory cutaneous disease.Such as, mammal may need to treat PIH.

In another embodiment, the disclosure relates to the method generating, reducing melanocyte proliferation or prevention melanocyte apoptosis for reducing melanogen, and described method comprises and gives comprising Bakuchiol or the acceptable salt of its medicine and medicine acceptable carrier and being less than the compositions of total furanocoumarins impurity of 500ppm of mammal effective dose.At some in other embodiment, described method also comprises minimizing superoxide anion.

In other embodiments, described compositions comprises the total furanocoumarins impurity being less than 100ppm.In other embodiments, furanocoumarin impurities comprises psoralen, isopsoralen or its combination.In some embodiments, contrast described compositions relative to kojic acid and do not show tyrosinase inhibitory activity.

In other embodiments, Bakuchiol chemosynthesis or separation from plant.Such as, in some embodiments, Bakuchiol is separated from plant.In some of the other embodiments, plant such as, from the Psoralea (Psoralea genus) of plant, Fructus Psoraleae (Psoraleacorylifolia L.) (pulse family) or Psoralea glandulosa L. (Papilionaceae).

In some embodiments, melanogen generation, melanocyte proliferation or melanocyte apoptosis are the results of postinflammatory hyperpigmentation (PIH).At some in other embodiment, postinflammatory hyperpigmentation (PIH) is derived from acne, atopic dermatitis, allergic contact dermatitis, bloch-Siemens syndrome, lichen planus, lupus erythematosus, morphea, mechanical injury, ionization or Non-ionizing radiation, burn, laser or Drug therapy, skin infection or its combination.Such as, in certain aspects, postinflammatory hyperpigmentation (PIH) is derived from acne.

In certain aspects, described method prevention hyperpigmentation.In other side, described method alleviates hyperpigmentation.In other side, described method reduces hyperpigmentation.In other side, described method overmedication pigmentation.In some embodiments, hyperpigmentation occurs in the deep layer of skin, such as, in the papillary dermal layer of skin.

At some in other embodiment, described method reduces melanogen and generates.In other embodiments, described method reduces melanocyte proliferation.In other embodiments, described method prevention melanocyte apoptosis.

In some of the other embodiments, mammal is behaved.At some in other embodiment, mammal needs treatment to generate to reduce melanogen, reduce melanocyte proliferation or prevent melanocyte apoptosis.

In other embodiments, described compositions also comprises salicylic acid or the acceptable salt of its medicine.

Other embodiment of the present disclosure relates to the method for the treatment of inflammatory or non-inflammatory lesions, and described method comprises the compositions comprising Bakuchiol or the acceptable salt of its medicine and salicylic acid or the acceptable salt of its medicine and medicine acceptable carrier giving mammal effective dose.Such as, in some embodiments, pathological changes comprises inflammatory acne lesions.In other embodiments, described method treatment inflammatory and non-inflammatory lesions.

In some of the other embodiments above, mammal is behaved.At some in other embodiment, mammal needs treatment inflammatory or non-inflammatory lesions.

In other embodiments, the present invention includes the compositions comprising Bakuchiol or the acceptable salt of its medicine and salicylic acid or the acceptable salt of medicine and medicine acceptable carrier.In some embodiments, described compositions is prepared for topical.

Based on inciting somebody to action apparent with reference to following detailed description these and other aspect of the present invention.

Accompanying drawing is sketched

In the accompanying drawings, element like identical reference number representation class.In accompanying drawing, the size of element and relative position need not be drawn and some in these elements are arbitrarily enlarged and place to improve accompanying drawing readability in proportion.In addition, the special shape of element as drawn is not intended to transmit any information about special elements true form, and is only selected for and is easy in the accompanying drawings identify.

Fig. 1 describes the chromatogram of Bakuchiol, psoralen and isopsorapen standard substance.

Fig. 2 shows the chromatogram of bakuchiol composition before and after hydrolysis.

Fig. 3 provides the data of the strong anti-oxidation character of display bakuchiol composition.

Fig. 4 is the chart of the tyrosinase inhibitory activity of bakuchiol composition and kojic acid.

Fig. 5 shows the change of the individual PIH order of severity of indivedual test.

Fig. 6 represents the chart of the percentage ratio change of the facial zone of the PIH infection that indivedual test is individual.

Fig. 7 demonstrates the average percent change of PIH and the PIH order of severity of five test individualities.

The average rank level that Fig. 8 describes PIH and the PIH order of severity when making a house call at every turn compared with benchmark reduces.

Fig. 9 shows the photo of two research participants under different time interval.

Describe in detail

In the following description, some details are set forth to provide the thorough understanding of each embodiment.But those skilled in the art understand not to be had can implement the present invention under these details.In other cases, do not illustrate or describe well known structures in detail with the vague description avoiding embodiment unnecessary.Unless the context requires otherwise, in description below and claim, word " comprises (comprise) " and variant, such as " to comprise (comprises) " and " comprising (comprising) " is interpreted as opening, comprising property implication, that is, such as " include but not limited to ".In addition, title provided herein only for convenience's sake and do not represent scope or the implication of claimed invention.

In this manual, quoting of " embodiment (one embodiment) " or " embodiment (anembodiment) " is referred to that special characteristic, structure or the characteristic described about embodiment comprises at least one embodiment.Therefore, in each position of this description, the appearance of phrase " in one embodiment (in one embodiment) " or " in embodiments (in an embodiment) " need not all about identical embodiment.In addition, described special characteristic, structure or characteristic can be combined in any suitable manner in one or more embodiment.In addition, as used in this description and accessory claim, singulative " a ", " an " and " the " comprise plural object of reference, except non-content clear regulation in addition.Be also to be noted that except non-content clear regulation in addition, usual term " or " use comprise the implication of "and/or".

definition

Unless as used herein and context specifies in addition, following term has the implication as hereafter specified.

As used herein, " Bakuchiol " refers to the compound with following formula:

Wherein benzyl double bond can be cis or trans.As used herein, Bakuchiol comprises the tautomer of the acceptable salt of medicine and Bakuchiol.The oxybenzene compound relevant to Bakuchiol structure is also included within this definition.

" Bakutrol ^tM" be comprise Bakuchiol compositions and the fatty acid extracted from Psoralea (Psoralea) plant can be comprised in addition.

" UP256 " refers to 0.5% (wt/wt) preparation of Bakuchiol.

" prevention (Preventing) ", " prevention (prevention) " and " prevention (prevent) " in the context of open method all refers to the prevention method of the generation of the special disease state stoping or stop such as PIH.

" alleviating (Alleviating) ", " alleviating (alleviation) " and " alleviating (alleviate) " in the context of open method all refers to impact or the symptom of the special disease state alleviating or relax such as PIH.

" reducing (Reducing) ", " reducing (reduction) " and " reducing (reduce) " in the context of open method all refers to impact or the symptom of the special disease state reducing such as PIH.

" treatment (Treating) ", " treatment (treatment) " and " treatment (treat) " in the context of open method all refers to the symptom or minimizing or the technology stopping it occurring or method that are intended to improve the special disease state of such as PIH.

" impurity " comprises any material undesirably in bakuchiol composition, and it derives from the Bakuchiol be separated from natural origin usually.Term impurity includes but not limited to furocoumarin compound, and described furocoumarin compound includes but not limited to psoralen, isopsoralen and other coumarin type dopant.Impurity also refers to the impurity deriving from the synthetic method obtaining these compositionss.

" treatment " comprises and treating and/or preventing.When deployed, treatment refers to people and other animal.

" pharmacy, beauty treatment or treatment effective dose or amount " refers to the dosage level being enough to induce biology or the function result expected.Described result can be alleviate disease, the sign of dermatosis state, symptom or inducement or expectation any other of biosystem change.

" placebo " refers to the biological medicine of the expectation being enough to induce sign, symptom or the inducement that can use inert matter alleviation disease or the substitute for the treatment of effective dose or amount administration.

" receptor (host) " or " individuality " or " patient " are the living individuals, the human or animal that are given compositions described herein.Therefore, compositions described herein can be used for veterinary and people application and term " patient " or " individuality " or " receptor " should do not explained with ways to restrain.When veterinary applies, described dosage range can be given according to the body weight of animal as described below.

As mentioned above, an embodiment of the present disclosure relates to use and comprises the compositions of the Bakuchiol that there is no furanocoumarin impurities for preventing, alleviating, reduce or treat the hyperpigmentation caused by the morbid state being derived from inflammatory cutaneous disease.Such as, disclosed method is applicable to treatment postinflammatory hyperpigmentation (PIH).In some embodiments, PIH can be derived from acne.Disclosed method has shown in prevention, alleviated, has reduced and treat the postinflammatory hyperpigmentation being derived from the skin disorder of such as acne, atopic dermatitis, allergic contact dermatitis, bloch-Siemens syndrome, lichen planus, lupus erythematosus, morphea; With the postinflammatory hyperpigmentation caused by mechanical injury, ionization and Non-ionizing radiation, burn, laser and Drug therapy, and by using the people's clinical efficacy in the skin infection of Psoralea (psoralea) the extract bakuchiol composition synthesizing Bakuchiol or do not have furocoumarin.Based on reference description below, these and other aspect of the present disclosure and each embodiment will become obvious.

a. bakuchiol composition

In one embodiment, present disclose provides the compositions comprising Bakuchiol, described Bakuchiol there is no impurity, particularly furanocoumarin impurities.Said composition is also called Bakutrol herein ^tM.In some embodiments, as at document (Hongli Chen and Yuanchao Li, Letters in Organic Chemistry (organic chemistry communication), 2008,5,467-469) in show by the organic synthesis from simple compounds or obtain described compositions from plant.In some embodiments, bakuchiol composition is separated from plant.The plant source of Bakuchiol comprises the section of plant, the section of described plant includes but not limited to pulse family (Luguminosae), Papilionaceae (Papilionaceae), Lauraceae (Lauraceae) and Magnoliaceae (Magnoliaceae), belong to plant, described plant genus includes but not limited to Psoralea (Psorlea), Sassafras (Sassafras), Magnolia (Magnolia) and [WTBX (Astractylodes).Such as, bakuchiol composition can be from Fructus Psoraleae (Psoralea corylifolia L.) (pulse family) or Psoralea glandulosa L. (Papilionaceae) be separated.Can include but not limited to obtain described compositions seed, stem, bark, branch, tuber, root, root bark, plumelet, rhizome, flower or other genitals, leaves or other aerial parts or its combination from whole plant or from one or more unitary part of plant.Method for being separated Bakuchiol from plant can comprise solvent extraction, supercritical fluid extraction, distillation, physical squeezing or its combination.

Bakuchiol, its structure illustrates below, is the oxybenzene compound with a hydroxyl at aromatic ring and aliphatic unsaturated hydrocarbon.Although represent with trans forms in having structure, the benzyl double bond of Bakuchiol also may be cis.

In pure plant extract, the amount (that is, percentage by weight (w/w%)) of Bakuchiol depends on the degree of purification of extracting process and thick extract.In one embodiment, as shown in table 2, in extract, the amount of Bakuchiol is 13.7% to 29.1%.In other embodiments, in extract, the amount of Bakuchiol is at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 70%, at least 80% or at least 90%.In some embodiments, in extract, the amount of Bakuchiol is 100%.In some other embodiment, in described compositions, the amount of Bakuchiol is not less than 60%.Embodiment 6-8 provides the example of the extract of the Bakuchiol comprising each amount.

Although Bakuchiol is the bioactive natural products with very large potentiality for the various disease of prevention and therapy and morbid state, there is the many restriction relevant with the use of this compound.Some restrictions comprise the existence of the common toxic component existed in its low concentration in natural source and Bakuchiol source.The impurity existed in bakuchiol composition changes with Bakuchiol source.Such as, psoralen, is also called furocoumarin, is naturally occurring secondary metabolites and existing in many fruits and vegetables in Psoralea (Psoralea genus) plant (a kind of Bakuchiol source).The example of the furocoumarin that normal discovery and Bakuchiol exist jointly comprises psoralen and isopsorapen.

Many health risks and process, topical application and picked-up containing psoralen plant and to synthesize psoralen relevant.Known psoralen is phototoxicity agent, and it increases skin and promotes skin carcinoma (Epstein (1999) Med.Surg.18 (4): 274-284) to the sensitivity of ultraviolet radiation.Psoralen is proved the growth inhibited (Diawara etc. people (1997) CancerLett.114 (1-2): 159-160) in induced rat.The Sex problem of thick extract and the destruction of hypothalamic pituitary gonadal axis that are derived from Psoralea (Psoralea) plant are contacted directly (people (2002) the J.Toxicological Sciences (toxicology Scientific Periodicals) 27 (2): 97-105 such as Takizawa).Orally in the diet of female rats give that psoralen, bergapten (5-MOP) and xanthotoxin (8-methoxypsoralen) lower the birth rate with dose dependent fashion, the quantity of transplantation site, doggie, corpus luteum, full and empty uterus weight and circulation estrogen level people (1999) J.Biochem.Molecular Toxicology (biochemical molecule toxicology periodical) 13 (3/4): 195-203 such as () Diawara.Psoralen has also been proved the mRNAs of induction liver enzyme CYP1A1 and UGT1A6, shows the minimizing (people such as Diawara (in May, 2003-June) Pediatr Pathol Mol Med.22 (3): 247-58.) being improved the soluble genotoxicity of estrogenic metabolism and folliculus ovarii function and ovulation observation by psoralen.Due to furocoumarin toxicity, therefore importantly from the bakuchiol composition being intended for treatment postinflammatory hyperpigmentation or Other diseases state, remove psoralen and isopsorapen.

Psoralen and isopsorapen accounts for the dry weight of the Psoralea seed of about 0.1%-2% and in solvent or supercritical fluid extract, accounts for the weight of about 1%-20%.Combination by solvent extraction or supercritical fluid extraction, distillation, physical squeezing or above-mentioned extracting process obtains the thick extract from Psoralea (Psoralea genus) plant.The bakuchiol composition of enrichment is obtained by chromatographic isolation, demixing of solvents (the open #00570/KOL/2005 of indian patent), distillation, recrystallization and other Wet chemical and physical method.Disclosed No. 2006/0251749 U.S. Patent application, be incorporated to herein by reference with its overall content, disclose solvent extraction subsequently hydroxylating to decompose furocoumarin ring and to obtain the bakuchiol composition (such as, be less than 500ppm or be less than the furanocoumarin impurities of 100ppm) that there is no the enrichment of furanocoumarin impurities.Disclosed method comprising from plant source extract compounds, using aqueous slkali to be hydrolyzed thick extract and the step of method purification by including but not limited to column chromatography, extraction subsequent crystallisation, demixing of solvents, recrystallization and combination thereof under heating.The applicant find this there is no the compositions of Psoralea (psoralea) extract of the Bakuchiol enrichment of furanocoumarin impurities can be used for prevention, alleviate, reduce or overmedication pigmentation.Such as, disclosed bakuchiol composition is effective to prevention, alleviation, minimizing or treatment postinflammatory hyperpigmentation (PIH).

The disclosure also relate to for separating of with the thick compositions of purification Bakuchiol and the method for related compound that obtains from natural source.Comprising from plant source extract compounds for separating of the method with these compositionss of purification, using aqueous slkali to be hydrolyzed thick extract and the step of method purification by including but not limited to column chromatography, extraction subsequent crystallisation, demixing of solvents, recrystallization and combination thereof.The thick extract of purification there is no the furanocoumarin impurities of such as psoralen and isopsorapen in like fashion.Therefore, relevant with these compounds potential phototoxicity, local irritation, carcinogenecity and genotoxicity are eliminated substantially.

In some embodiments, disclosed compositions comprises and is less than 500ppm, is less than 250ppm, is less than 100ppm or is less than the total furanocoumarins impurity of 50ppm.The concentration of furanocoumarin impurities is measured by any method well known by persons skilled in the art.Such as, in one embodiment, furocoumarin content is measured by HPLC.

As described in example 2, the effect of the Bakuchiol extraction that the organic solvent system evaluation that use six kinds is different under two groups of extraction conditionss extracts from plant source.Result is set forth in table 2.Reference table 2, can find out and many organic solvents and/or its combination can be used from Psoralea (Psoralea) plant to extract Bakuchiol.In each extract, the amount of Bakuchiol is 13.7% to 29.1% weight ratio.Other extracting process includes but not limited to CO ₂supercritical fluid extraction and water distillation.Squeezing transudate from the fresh plant part of such as seed also can be used for obtaining bakuchiol composition from natural source.

Shown in embodiment 3 and table 3 by the effect of the thick Bakuchiol extract of column chromatography purification.Have rated the ability that eight kinds of dissimilar resins are separated Bakuchiol from furanocoumarin impurities especially.Silica column shows gratifying separation with CG-161 resins.But the thick plant extract of column chromatography for separation is not economically viable usually at industrial scale, because its needs expensive equipment and reagent and experienced personnel.The low-down load capacity of these samples that complexity due to thick plant extract causes also makes commercial scale column chromatography difficulty.

Embodiment 4 describes the economic means for being separated Bakuchiol from furanocoumarin impurities.Described method comprises the compositions using alkali treatment to comprise furanocoumarin impurities.As illustrative by following scheme 1, using NaOH to illustrate, using alkali heating to open the lactonic ring of furocoumarin, thus they being converted into corresponding carboxylate.Then, these salt are easily separated by multiple method from the remainder of mixture.Disclosed method allows preparation to there is no the bakuchiol composition of furanocoumarin impurities (such as, being less than 500ppm).Do not having under disclosed hydrolysis, to use Standard chromatographic techniques can not obtain so highly pure bakuchiol composition.

Aqueous slkali can comprise any alkali can opening lactonic ring, includes but not limited to sodium hydroxide, potassium hydroxide, calcium hydroxide, Lithium hydrate or its combination.Solution can have variable concentrations and pH value to be converted into hydrochlorate to greatest extent.Can also at different temperatures and pressures reacting by heating mixture to make reaction rate, efficiency and maximize yield.

Course of reaction subsequently HPLC to guarantee that furocoumarin is converted into their corresponding carboxylates completely.The HPLC chromatogram of the thick compositions before and after hydrolysis illustrates in fig. 2.Reaction complete after (as measured by HPLC), can use multiple method processing reaction solution, include but not limited to column chromatography, crystallization, demixing of solvents, precipitation, solvent wash or its combine.The organic solvent that can be used for demixing of solvents includes but not limited to petroleum ether, ethyl acetate, ether, hexane, chloroform, propanol, butanols and dichloromethane and the immiscible organic solvent of other water.

The thick extract of purification there is no the furanocoumarin impurities of such as psoralen and isopsorapen in like fashion.Such as, the extract of purification can comprise and be less than 500ppm, be less than 250ppm, is less than 100ppm or is even less than the furanocoumarin impurities of 50ppm.In addition, the color of furocoumarin, bakuchiol composition that what these were highly pure do not have be light brown or red and they about the color of activating agent and composition highly stable, make them be specially adapted to preparation, store and cosmetic applications.

The method of the compositions that what the disclosure also comprised is for analyzing Bakuchiol, it can detect and quantitative impurity.In this embodiment, the method for analyzing bakuchiol composition comprises the step being analyzed described compositions by high pressure liquid chromatography (HPLC).By HPLC analyze can realize each component in mixture quantitatively and the method providing Bakuchiol, psoralen, isopsoralen and other natural constituents of following the tracks of in Psoralea (Psoralea) plant to instruct extraction, to be hydrolyzed and purification process.The method using high pressure liquid chromatography (HPLC) to analyze the compositions of Bakuchiol describes in embodiment 1 (table 1).

b. bakuchiol composition overmedication pigmentation is used

An embodiment of the present disclosure relates to use and comprises the compositions of the Bakuchiol that there is no furanocoumarin impurities for preventing, alleviating, reduce or treat the hyperpigmentation caused by the morbid state being derived from inflammatory cutaneous disease.Such as, disclosed method comprises prevention, alleviation, reduces or treatment postinflammatory hyperpigmentation (PIH).In some embodiments, PIH may be derived from acne.Describedly openly to be included in typical beauty treatment vehicle and at protective skin cream, skin cream (gel lotion) with hereafter prepare bakuchiol composition in other preparation in greater detail.As shown in an embodiment, the applicant has confirmed bakuchiol composition unexpected people's clinical efficacy in prevention, alleviation, minimizing or treatment postinflammatory hyperpigmentation (PIH), and wherein PIH is derived from skin disorder such as acne, atopic dermatitis, allergic contact dermatitis, bloch-Siemens syndrome, lichen planus, lupus erythematosus, morphea; With the postinflammatory hyperpigmentation caused by mechanical injury, ionization and Non-ionizing radiation, burn, laser and Drug therapy and skin infection.

Disclosed method comprises the compositions comprising the Bakuchiol that there is no furanocoumarin impurities giving mammal (such as, people patient) effective dose.Such as, described compositions can comprise the furanocoumarin impurities being less than 500ppm.Described compositions can comprise the Bakuchiol of about 0.0001% to about 100%.Such as, in some embodiments, described compositions comprises the Bakuchiol of about 0.1% to about 2% or the Bakuchiol of about 0.5% to about 1%.In other example, described compositions comprises the Bakuchiol of about 0.5% or about 1.0%.In some embodiments, mammal is people, such as, and in other embodiments, mammal needs prevention, alleviates, reduces or treats the hyperpigmentation caused by the morbid state being derived from inflammatory cutaneous disease, and described mammal may need to treat PIH.

The disclosure represents the biological property of the unexpected uniqueness of synthesis or natural bakuchiol composition.As shown in embodiment 5 and table 4, the Bakutrol compositions comprising the Bakuchiol of about 57.35% has unexpectedly high oxidation resistance, particularly resist superoxide anion (>69,000 μm of ole TE/g), resist five kinds of chief active kinds to have and be in >92, total ORAC value of 000 μm of oleTE/g.

Superoxides has chemical molecular formula O ₂ ^-anion.The chronic inflammatory disease state of such as acne vulgaris can have the superoxide anion produced from keratinocyte significantly increased, its gram-positive anaerobic bacterium by such as propionibacterium acnes (P.acnes) stimulates (people such as Grange PA., Plos Pathogens (Public science library pathogen) 2009,5 (7) 1-14.).Superoxides is that bio-toxicity is very high and scatter to kill the microorganism of invasion and attack by immune system.In phagocyte, the oxygen dependence that superoxides is produced for attacking pathogen in a large number by enzyme nadph oxidase kills mechanism.Superoxide anion in inflammation skin and other reactive oxygen species can also induce melanogen generation, melanocyte proliferation and melanocyte apoptosis, and it is the main pathogenic of postinflammatory hyperpigmentation.Therefore, an embodiment of the present disclosure is by using the compositions comprising the Bakuchiol that there is no furanocoumarin impurities to reduce the method that the hyperpigmentation caused by the morbid state being derived from inflammatory cutaneous disease is alleviated, reduces or treated to superoxides.In one embodiment, morbid state is PIH.In another embodiment, present disclose provides the method reducing melanogen generation or melanocyte proliferation or suppression melanocyte apoptosis, such as, by reducing superoxide anion.Described method comprises the compositions comprising the Bakuchiol that there is no furanocoumarin impurities giving mammal effective dose.In some embodiments, mammal is people, and in other embodiments, mammal needs reduce melanogen generation or melanocyte proliferation or suppress melanocyte apoptosis.

As embodiment 6 and Fig. 3 confirm, comprise 77.02% there is no impurity, the particularly protective effect of compositions display to the oxidative stress of being induced by 4-tetrabutyl phenol (4-TBP) of the Bakuchiol of furanocoumarin impurities.Test under two concentration, the melanocytic cytotoxicity carrying out the reactive oxygen species that free 4-TBP produces is protected by bakuchiol composition.Although undesirably by described theory constraint; but the applicant think derive from synthesis or the minimizing of natural bakuchiol composition, alleviation, prevention or treatment postinflammatory hyperpigmentation (PIH) unexpected clinical benefit derive from its unique and unexpected Neutralization effect oxygen kind; the particularly ability of superoxide anion, and protect melanocyte from oxidative stress under the epidermis casting skin speckle causing reducing and/or the melanistic Inflammatory disease states of corium.

Except the oxidation resistance that it is unexpectedly high, the applicant finds that disclosed bakuchiol composition is not tyrosinase inhibitor.This reports contrary as other of the skin whitener suppressed by tryrosinase (P1107123 Japan Patent) with open Bakuchiol.This is unexpected finds to guide the applicant to arrive and is used for the treatment of the at present disclosed method of PIH, and wherein pigmentation occurs and tyrosinase inhibitor is invalid in dark skin layer.The disclosed bakuchiol composition not having tryrosinase to suppress is shown in embodiment 7 and Fig. 4.Pure Bakuchiol (100%) and have the furocoumarin from natural source being not more than 100ppm enrichment Bakuchiol (77.02%) the two under eight kinds of various dose, there is no tryrosinase inhibit feature.

Evaluate the safety comprising the compositions of Bakuchiol under concentration is the Bakuchiol of 86.54% and 77.02%.As shown in embodiment 9 and table 6; based on external and people's clinical trial, Bakutrol (UP256) compositions does not show eye irritation, skin that is normal or galling is not had to skin irritation, do not have contact skin sensitization, do not have phototoxicity and do not have mutagenic toxicity.The topical cream of bakuchiol composition all well-tolerated in everyone and in vitro tests.

As embodiment 10 is shown, on the individuality with the postinflammatory hyperpigmentation (PIH) being derived from slight or moderate acne vulgaris, in people's clinical trial, test pack contains the Bakuchiol of 77.02% and is less than the extraction of the seed from Fructus Psoraleae (Psoralea corylifolia) of furocoumarin and the natural bakuchiol composition (Bakutrol of enrichment of 100ppm ^tM).Bakuchiol composition is prepared for topical application under the Bakuchiol of 0.5%.After the Bakutrol emulsifiable paste of topical application 0.5% every day, in all five individualities, observe the remarkable minimizing of postinflammatory hyperpigmentation (PIH).As shown in Figure 5, all five individualities have the reduction of the PIH order of severity of at least one hierarchy level.The improvement (Fig. 6) of the facial zone of the PIH impact being greater than 50% is realized after 8 weeks continue the Bakutrol emulsifiable paste of topical application 0.5%.PIH and the average percent both the order of severity thereof and absolute scale level are improved and are summarized in figures 7 and 8.As far back as use bakuchiol composition just achieve after 4 weeks both PIH and the order of severity be greater than 40% improvement, or be greater than the reduction of a hierarchy level.As shown in Figure 9, in two individual photos, on the skin of face position of impact, the significantly minimizing of PIH is apparent.After topical application Bakutrol emulsifiable paste, two individualities show the progressively improvement with hyperpigmentation (PIH) after the slight scytitis relevant with moderate acne.

Table 7 (embodiment 10) outlines and comprises compared with popular acne treatment product that antibacterial or antiinflammatory or its combine, uses the clinical success not having the bakuchiol composition (that is, Bakutrol) of furocoumarin.Data in table 7 are known and are shown do not have the bakuchiol composition of furocoumarin not only to improve inflammatory and non-inflammatory lesions counting, and significantly improve hyperpigmentation after scytitis.Lack tryrosinase suppression activity based on it, it is unexpected that PIH has benefited from bakuchiol composition.

Table 8 (embodiment 11) provides the data of the reduction of display PIH grade (that is, pigmentation level).Data know that display Bakuchiol is more effective than the placebo and salicylic acid being used for the treatment of PIH.In addition, the applicant also finds that Bakuchiol (or comprising the compositions of described Bakuchiol) is effective for the inflammatory lesion for the treatment of such as acne lesion.Table 9 (embodiment 11) shows that, compared with use placebo or salicylic treatment, Bakuchiol is for the effectiveness for the treatment of inflammatory lesion.

Except comprise use the compositions treatment comprising Bakuchiol method except, the present invention includes wherein to use and comprise Bakuchiol and salicylic compositions treats mammiferous embodiment.Such as, the applicant finds that salicylic acid is effective to treatment non-inflammatory lesions, and Bakuchiol is effective to treatment inflammatory lesion simultaneously.Therefore, one embodiment of the invention relate to the method for the treatment of inflammatory lesion (such as, acne lesion), and described method comprises the compositions comprising Bakuchiol or the acceptable salt of its medicine giving mammal effective dose.Another embodiment relate to treatment inflammatory and/or non-inflammatory lesions (such as, acne lesion) method, described method comprises the compositions comprising Bakuchiol and salicylic acid (or the acceptable salt of its medicine) giving mammal effective dose.Other embodiment comprises the compositions treatment non-inflammatory lesions comprising salicylic acid or the acceptable salt of its medicine by giving mammal effective dose.In some embodiments above, mammal is behaved.In other embodiments, mammal needs inflammatory and/or the non-inflammatory lesions for the treatment of such as acne.

Except treatment pathological changes, Bakuchiol and salicylic combination are effective to any one in treatment aforementioned diseases state (such as, PIH, reduce melanogen generate, reduce melanocyte proliferation or prevention melanocyte apoptosis etc.).Therefore, some embodiments relate to use and comprise Bakuchiol and the treatment of salicylic compositions.Other embodiment comprises the compositions comprising Bakuchiol or the acceptable salt of its medicine, salicylic acid or the acceptable salt of its medicine and medicine acceptable carrier.

Preceding method is to substantially eliminating inflammatory and/or non-inflammatory lesions is effective.Such as, in some embodiments, described method reduces pathological changes about 1% to about 99% or about 10% to about 90%.In other embodiments, described method minimizing pathological changes is greater than 50%.

Bakuchiol and salicylic ratio are not particularly limited and can be determined based on expected result by persons skilled in the art.Such as, in some embodiments, Bakuchiol and salicylic weight ratio are about 1:100 to about 100:1.In other embodiments, weight ratio is that about 10:90, about 20:80, about 30:70, about 40:60, about 50:50, about 60:40, about 70:30, about 80:20 are to about 10:90.Can according to any formulated described herein compositions.

c. the preparation of bakuchiol composition

Bakuchiol composition of the present disclosure is prepared by any method well known by persons skilled in the art.As shown in embodiment 8 and table 5, compositions of the present disclosure can be prepared with pharmacy, beauty treatment or dermatological compositions form, and other component can be comprised, such as pharmacy and/or acceptable active matter of improving looks, excipient, adjuvant, carrier or its combination.Excipient is used as the diluent of dermatological and the acceptable prodrug of beauty treatment and medicine or vectorial inert substance.The example of this kind of excipient includes but not limited to water, buffer agent, saline, glycerol, hydrated SiO 2, propylene glycol, aluminium oxide, carrageenin, cellulose gum, titanium dioxide, Ringer's mixture, glucose solution, mannitol, Han Keshi solution, antiseptic and other aqueous physiological equilibrium saline solution.Also can use the non-aqueous vehicles of such as fixing oil, Oleum sesami, ethyl oleate or triglyceride.Other useful preparation comprises the suspending agent of the viscosifier comprising such as sodium carboxymethyl cellulose, sorbitol or glucosan.

In embodiment 8, in carbitol or Trivent OCG or polysorbate-20 or pure water or two or more above-mentioned vectorial combinations, prepare compositions of the present disclosure.Excipient can also comprise the additive of trace, and such as EDTA, disodium DDTA, BHA, BHT, dibasic ammonium citrate, nordihydroguaiaretic acid, propyl gallate, gluconic acid sodium salt, partially bisulfite are received, tertiary butylated hydroquinone, SnCl ₂, H ₂o ₂with 2,4,5-THBP 2,4,5 trihydroxybutyrophenone, vitamin C, vitamin E, alpha-tocopherol acetate, phenonip and other improve the material of isotonicity and chemical stability.

Example for the material regulating the pH of preparation comprises sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium triphosphate, tetrasodium pyrophosphate, sodium lauryl sulphate, calper calcium peroxide, phosphate buffer, bicarbonate buffer, tris buffer, histidine, citrate and glycine or its mixture.The example of flavoring agent includes but not limited to thimerosal, metacresol or orthoresol, formalin, fruit extract and benzylalcohol.Standard preparation can be liquid or solid, can be dissolved and be used for administration in suitable liquid is as suspension or solution.Therefore, in non-liquid formulation, excipient can comprise glucose, human serum albumin, antiseptic etc., can add sterilized water or saline before administration to it.

In one embodiment, bakuchiol composition can be prepared together from the reactive compound that other targeting reduces the different mechanism of action of cutaneous pigmentation.This kind of active matter includes but not limited to hydroquinone, single-benzyl ether, arbutin (arbuting), deoxyarbutin, p methoxy phenol, N-acetyl group-4-S-cysteamine base phenol, kojic acid, Azelaic Acid, glycolic, gentisic acid, flavonoid, Aloe resin B, stilbene and diphenyl ethylene derivatives, Radix Glycyrrhizae extract, Folium Vaccinii vitis-idaeae extract, mulberry extract, Aloe glue, glabridin, vitamin C derivatives, magnesium ascorbyl phosphate, four base ascorbic acid in the last of the ten Heavenly stems, vitamin derivative, tranexamic acid and derivant thereof, TGF-B protein bionical, centaurcidin, nicotiamide, PAR-2 inhibitor, agglutinin, Neoglycoproteins, resorcinol and derivant thereof and Nivitol ^tM.

In another embodiment, described compositions comprises and can infect to reduce, infect relevant inflammation and accelerate epidermal renewal to the synergistic antiinflammatory of bakuchiol composition and antibacterial.This kind of active matter includes but not limited to 'alpha '-hydroxy acids, salicylic acid, linoleic acid, retinoic acid, benzoyl peroxide, sodium sulfacetamide, clindamycin, erythromycin, dapsone, tetracycline, doxycycline, minocycline, zinc, estrogen and derivant thereof, androgen antagonist, sulfur, steroid, cortisone, tazarotene, curcumin extract, arabic gum extract, Radix Scutellariae extract, Green tea extract and OPC.

In some embodiments, described compositions comprises adjuvant or carrier.Usually, adjuvant is usually strengthen the material of mammal to the biological respinse of particular bioactive agent.Suitable adjuvant includes but not limited to Fo Shi reagent; Other bacterial cell wall components; Aluminum, calcium, copper, ferrum, zinc, magnesium, stannum class salt; Silicon dioxide; The agent of crystallite mill skin, polynucleotide; Toxoid; Serum proteins; Viral capsid proteins; Other bacterial derivation preparation; IFN-γ; The block copolymer adjuvants (Vaxcel.TM., Inc.Norcross, Ga.) of such as Heng Teshi Titermax adjuvant; Ribi adjuvant (purchased from RibiImmunoChem Research, Inc., Hamilton, Mont.); With saponin and derivant thereof, such as Quil A (purchased from Superfos Biosector A/S, Denmark).Carrier is generally the compound of the half-life increasing therapeutic combination in subject receptor.Suitable carrier includes but not limited to polymer release-control preparation, biodegradable implant, liposome, Nano capsule, nano-particle, antibacterial, virus, oil, esters and glycols.

In other example, prepare described compositions with compositions described in slow releasing to the controlled release formulation of receptor.As used herein, controlled release preparation is included in the bakuchiol composition in controlled release vehicles thing.Suitable controlled release vehicles thing is well known by persons skilled in the art.The example of controlled release preparation is biodegradable (that is, biological digestible) and comprises capsule.

In one embodiment, suitable ointment is by expecting that the gross weight based on topical formulations of concentration is generally selected from the UP256 (Bakuchiol), 65% to 100% of effective, the non-toxic, amount of 0.001% to 100% (such as, 75% to 96%) White soft paraffin, 0% to 15% liquid paraffin and 0% to 7% (such as, 3% to 7%) lanoline or derivatives thereof or synthesis equivalent composition.In another embodiment, ointment can comprise polyethylene-liquid paraffin substrate.

In one embodiment, suitable ointment by emulsification system together with expect concentration synthesis and/or the UP256 (Bakuchiol) that is separated from the above-mentioned single plant that provides or various plants form.Emulsification system preferably comprise 2% to 10% polyoxyethylene alcohol (such as, with trade mark be CetomacrogolTM1000 obtain mixture), the stearyl alcohol of 10% to 25%, the liquid paraffin of 20% to 60% and 10% to 65% water; Together with one or more antiseptic, the N of such as 0.1% to 1%; N "-di-2-ethylhexylphosphine oxide [N '-[3-(methylol)-2,5-dioxo-4-imidazolidinyl] urea] (being called that miaow urea USNF obtains with name), the 4-HBA Arrcostab (being such as called the mixture of Nipastat purchased from Nipa Laboratories with trade mark) of 0.1% to 1%, the 4-HBA sodium butyrate (being called Nipabutyl sodium purchased from Nipa Laboratories with trade mark) of 0.01% to 0.1% and 0.1% to 2% phenoxyethanol.

In one embodiment, the semisolid systems that suitable gel is limited in having in the three-dimensional polymer matrix that high level is cross-linked by wherein liquid phase forms.Liquid phase can comprise the additive and 0.01% to 10% of water together with the UP256 (Bakuchiol) of desired amount, the such as glycerol of 0.01% to 20%, the water soluble of Polyethylene Glycol or propylene glycol, the preferably thickening agent of 0.5% to 2%, described thickening agent can be natural product, such as tragacanth, pectin, carrageenin, agar and alginic acid, or synthesis or semi-synthetic compound, such as methylcellulose and carbopol (carbopol); Together with one or more antiseptic, the 4-HBA methyl ester (methyl parahydroxybenzoate) of such as 0.1% to 2% or phenoxyethanol-difference (differential).Preparation suitable is in addition by the UP256 (Bakuchiol) of desired amount, Polyethylene Glycol together with 70% to 90% (such as, comprise the polyethylene glycol ointment agent of the PEG3350 of 40% and the PEG400 of 60%, prepare according to dispensatory of the United States of America (USNF)), the water of 5% to 20%, the antioxidant (such as Yoshinox BHT) of 0.02% to 0.25% and 0.005% to 0.1% chelating agen (such as ethylenediaminetetraacetic acid (EDTA)) composition.

The term soft paraffin used above comprises ointment or ointment off-white color soft paraffin and yellow soft paraffin.Term lanoline comprises natural wool fat and refined wool fat fat.The derivant of lanoline particularly including be chemically modified to change their physics or the lanoline of chemical property and the synthesis equivalent of lanoline particularly including known and may such as be called lanoline succedaneum for medicine and beauty treatment fields as the synthesis of the substitute of lanoline or semi-synthetic compound and mixture.

A kind of suitable synthesis equivalent of spendable lanoline is the material that trade mark is called SoftisanTM acquisition, and it is called as Softisan 649.Softisan 649 is the glycerine ester of natural vegetable fatty acids, isostearic acid and fatty acid purchased from Dynamit NobelAktiengesellschaft; Its character, is discussed in issue number 84, No.3 (1982), pp.3-6 at Fette, Seifen, Anstrichmittel by H.Hermsdorf.

Discuss in canonical reference book as other material mentioned above of the composition of suitable ointment or cream base and their character, such as American Pharmacopeia.Cetomacrogol 1000 has general formula CH ₃(CH ₂) _m(OCH ₂cH ₂) _noH, wherein m can be 15 or 17 and n can be 20 to 24.Yoshinox BHT is 2,6-di-t-butyl-paracresol.Nipastat is the mixture of 4-HBA methyl ester, ethyl ester, propyl ester and butyl ester.

Compositions disclosed herein is prepared by conventional phamaceutical techniques.Therefore, such as, above-mentioned composition is prepared easily if mixed by the liquid paraffin that at high temperature existed by soft paraffin at such as 60 DEG C-70 DEG C and lanoline or derivatives thereof or synthesis equivalent.Then, described mixture can be cooled to room temperature and after the crystalline hydrate calcium salt adding mupirocin, together with corticosteroid and other composition any, stir to guarantee abundant dispersion.

Finally, Bakuchiol has the partition coefficient of log P=6.13.The partition coefficient of chemical compound provides the thermodynamics detection of its hydrophilic/Lipophilic Balance, because herein is provided its potential source biomolecule availability.The partition coefficient with 6.13 refers to that this compound has high membrane permeability and bioavailability when preparing in delivery system.The quantitative Cutaneous permeation of reactive compound-Bakuchiol in protective skin cream in vitro tests in the application on human skin be separated.Result shows good Cutaneous permeation and bioavailability.In some embodiments, disclosed compositions comprises skin penetration enhancer.

d. bakuchiol composition is given

Any method known by persons skilled in the art gives compositions of the present disclosure.Such as, oral or locally disclosed compositions can be given.Medication includes but not limited to enteral (oral) administration, parenteral (intravenous injection, subcutaneous injection and intramuscular injection) administration and topical application.In some embodiments, local gives described compositions.

The content of bakuchiol composition can be 0.001% to 99.9% weight ratio in for the final skin-protection product of PIH.In some embodiments, described compositions comprises the Bakuchiol of 0.1% to 2%.In other embodiments, described compositions comprises the Bakuchiol of 0.5% or 1.0%.In some embodiments, in PIH protective skin cream, the amount of bakuchiol composition is 0.5%-1%.Method of the present disclosure comprises oral or local and gives the compositions comprising Bakuchiol of mammalian therapeutic effective dose, it is for synthesis completely or (or its combination) that be separated from natural source and there is no impurity, particularly furanocoumarin impurities (such as, being less than 500ppm).

Give therapeutic agent of the present disclosure by any suitable method local well known by persons skilled in the art and give therapeutic combination for local.This medication includes but not limited to ointment, gel, lotion or cream base form or with Emulsion form, with patches, the drug of topical application or facial film, nonsticking gauze, binder, cotton swab or cleaning wiping cloth.Any standard method becoming known for topical can be used to give any infected zone by this topical application local.Therapeutic combination can be given with multiple unit dosage forms according to medication.Mode is sent for special, can with above-mentioned excipient form preparation therapeutic combination.Any receptor can be given by therapeutic combination of the present disclosure, preferably give mammal, and more preferably give people.Special administering mode depends on subject morbid state.

No matter which kind of administering mode, according to the concrete dosage of approximation re-computation of receptor.Determine that the further optimization of the necessary calculating of suitable dose of the treatment relevant with each preparation above-mentioned is undertaken by persons skilled in the art routine and do not needed undo experimentation, particularly according to dosage information disclosed herein and inspection in the working range that their routine is carried out.Determine that by using the inspection of setting up these dosage are for determining the dosage used in conjunction with suitable dose response data.In some embodiments, the dosage comprising the compositions of Bakuchiol is the every kg body weight of 0.001mg to 200mg.

In order to illustrate, unrestricted object provides the following example.

Embodiment

embodiment 1

By the quantitative Bakuchiol of HPLC, psoralen and isopsorapen

By using the amount of Bakuchiol, psoralen and isopsorapen in high pressure liquid chromatography (HPLC) the quantified extract thing of photodiode array detector (HPLC/PDA), fraction, raw materials technology, composition and final formulated product.Using acetonitrile (ACN) or first alcohol and water gradient to be 36% to the 100%CAN time is 12 minutes, and the 100%CAN time is 3 minutes eluting target compounds from Luna Phenyl-hexyl column (250mm × 4.6mm) subsequently.The detailed HPLC condition used is set forth in Table 1.The chromatogram that HPLC is separated is shown in Figure 1.Use and be purchased pure Bakuchiol, psoralen and isopsorapen as plasmid standards for quantitation, based on retention time and the identification of UV peak area and quantitative objective compound.The retention time of Bakuchiol, psoralen and isopsorapen is respectively 18.19 minutes, 7.33 minutes and 7.95 minutes.

Table 1. is for the HPLC condition of quantitative Bakuchiol, psoralen and isopsorapen

embodiment 2

For extracting the conventional method of Bakuchiol from Psoralea (PSORALEA) plant

method A-add solvent (100mL) and Fructus Psoraleae seed powder (10g) to flask, and at room temperature on manual shaking table, mixture is shaken 1 hour.Then, mixture is collected filtrate by filter.Use fresh solvent to repeat once by extraction process, merging filtrate, remove solvent on a rotary evaporator and dry residue under a high vacuum.

method B-add solvent (50mL) and Fructus Psoraleae seed powder (10g) to flask, and 40min that mixture is refluxed.Then, solution filtered and use fresh solvent to be repeated twice by extraction process.Solvent is also evaporated to obtain dry extract by merging filtrate.

According to above-mentioned extracting process, use following solvent extraction samples Plant material: dichloromethane (DCM), ethyl acetate (EtOAc), acetone, methanol (MeOH), petroleum ether (BP 35-60 DEG C) and petroleum ether (BP 60-90 DEG C).Then, as described in Example 1, analyze analytical extraction thing and plant material by HPLC.Result is set forth in table 2.

Table 2. various Fructus Psoraleae extract quantitative

embodiment 3

For the chromatography method of purification Bakuchiol extract

Multiple chromatography method is used for purification Bakuchiol from thick solvent extract, and described thick solvent extract uses the method described in embodiment 2 to be separated from the seed of Fructus Psoraleae.Show that the efficiency of particular column enrichment method is as the method for high-purity Bakuchiol obtaining the pollutant, particularly psoralen that do not have furocoumarin/isopsoralen pollutant.Briefly, each empty column shell (1.3cm internal diameter (ID) and 20mL volume, derive from Bio-Rad) filled up different media and use different solvents eluting to attempt to be separated furanocoumarin impurities from Bakuchiol.Fraction (each fraction of 10mL) is collected and the silica gel tlc plate analysis using 20%EtOAc/ petroleum ether to launch in test tube.Based on their retention time identification target compound, Bakuchiol, the psoralen and isopsorapen that use the solution of n-compound to determine.Result is set forth in table 3.The method described in many tables 3 is used for being separated furocoumarin and Bakuchiol from synthesis and natural source, but may not be economically viable for the cost of large-scale production the method.

Table 3. in the thick extract of Fructus Psoraleae from the general introduction of furocoumarin column chromatography for separation Bakuchiol

embodiment 4

The hydrolysis of the extract be separated from the seed of Fructus Psoraleae

The hexane extraction thing of Fructus Psoraleae seed of Bakuchiol or the CO of about 25% will be comprised ₂supercritical fluid extract mixes with 1M NaOH solution.Solution is heated to 80 DEG C or be at least 1 hour higher than the temperature-time of 80 DEG C in reaction vessel.Periodically from flask, take out sub-fraction solution and to be analyzed by HPLC as described in Example 1.Stopped reaction, after HPLC analyzes, the peak of display psoralen and isopsorapen disappears completely.Then, reactant mixture be cooled to room temperature and remove aqueous phase.The saturated NaCl solution of use by solution washing repeatedly after, use ethyl acetate or other organic solvent extraction organic layer.Organic solution filtration, washing, dry also evaporation are had Bakuchiol content with generation and be not less than 50% and total total brownish red syrup being not more than the psoralen and isopsorapen (isopsoralen) of 100ppm.

embodiment 5

There is no the antioxidant properties of the bakuchiol composition of furocoumarin

At Brunswick laboratory, Norton, MA USA evaluates the Bakuchiol comprising 57.35% and natural bakuchiol composition (batch number UP256-0906MP) oxidation resistance to peroxy radical, hydroxyl free radical, Peroxynitrite, superoxide anion and singlet oxygen of psoralen and isopsorapen (isopsoralen) being altogether less than 100ppm.According to disclosed technology (people such as Ou, B., J Agric and Food Chem (agriculture and food chemical periodical), 2001,49 (10): 4619-4626; The people such as Prior, RL., J Agric and Food Chem (agriculture and food chemical periodical), 2005,53:4290-4302) detect the total oxygen radical absorbability of bakuchiol composition.Result list display in table 4.

Table 4:Bakutrol ^tM(UP256) oxidation resistance properties

embodiment 6

Bakuchiol composition is to the evaluation of the Cytotoxic anti-oxidation protection effect of 4-TBP

Comprise the Bakuchiol of 77.02% by the aptitude tests of oxidative stress evaluated its prevention 4-TBP (4-TBP) and induce at 5-days treatments period of the compound of working concentration under 95% feasibility dosage and be altogether less than the antioxidant properties of natural bakuchiol composition of psoralen and isopsorapen (isopsoralen) of 100ppm.The generation of reactive oxygen species (ROS) is checked to measure oxidative stress by using Image-iT green reactive oxygen species detection kit (In Vitrogen) alive.In this inspection, by carboxyl-2 ', it is 30 minutes that 7 '-dichlorofluorescin diacetate esters is added to the cultured cells time, it diffuses to melanocyte and is hydrolyzed to 2 ' by cell lactone there, 7 '-dichlorofluorescein (DCF), itself and ROS react to produce fluorescence DCF.After the 4-TBP of use 200 μMs or 400 μMs treats 5 days, in melanocyte, the generation of ROS confirms dose response (that is, being respectively gentle to strong), but melanocyte that is untreated and DMSO treatment does not show ROS produces.When therapeutic scheme comprises test compounds, UP256 (Bakuchiol) shows strong antioxidant properties as shown in Figure 3.

embodiment 7

The tyrosinase inhibitory activity of bakuchiol composition

Test the tyrosinase inhibitory activity that two kinds comprise the natural bakuchiol composition of the Bakuchiol (100% purity) of 77.02%.Two kinds of materials comprise the total psoralen and isopsorapen (isopsoralen) being altogether less than 100ppm.

Use the people such as Jones, (2002) Pigment.Cell Res. 15: the method for 335 reports is carried out tryrosinase and is suppressed inspection.Use the method, follow the tracks of L-3,4 dihydroxyphenylalanine by monitoring absorption at 450 nm, the substrate conversion of tryrosinase is dopachrome.At pH 6.8 (inspection buffer), in 50mM kaliumphosphate buffer, prepare tryrosinase under 2000U/ml and store at-20 DEG C with 1ml decile before the use.In order to for inspection, the enzymatic solution of storage is thawed and service test buffer be diluted to 200U/ml.In inspection buffer, prepare the Treatment Solution of 2mM substrate, L-DOPA is used for each inspection.Sample is dissolved in 10%DMSO (0.5ml) and service test buffer is diluted to 5ml.Reactant mixture comprises 0.050ml 2mML-DOPA, 0.050ml 200U/ml Mushroom Tyrosinase and 0.050ml inhibitor.Reaction volume is adjusted to 200 μ l by service test buffer.Test in 96 hole Falcon 3097 flat-bottom microtiter plates (Beckton Dickinson, NJ).WALLAC 1420 multiple labeling enumerator (Turku, Finland) is used to detect the outward appearance of dopachrome.As passed through 450nm lower absorbance (Δ A per minute ₄₅₀) change-detection, from linear enzyme rate determination Mean Speed.Formula (1) is used to be suppressed with the percentage ratio of the absorbance measurement contrasted by the tryrosinase testing sample by comparative sample:

(negative control absorption-absorption of sample)/negative control absorbs × 100 (1)

As shown in Figure 4, two kinds of bakuchiol composition do not show tyrosinase inhibitory activity, and positive control (kojic acid) show dose reaction tryrosinase suppresses the IC with 63.9 μMs ₅₀value.

embodiment 8

The preparation of the bakuchiol composition of cosmetic cream, gel and lotion form

As shown below, prepare with improve looks vehicle or complicated protective skin cream, gel or lotion form the natural bakuchiol composition that two kinds comprise the Bakuchiol of 86.54% and the Bakuchiol of 77.02%.

Preparation A

Bakuchiol 1.0%

Vitamin e acetate 0.1%

Phenonip 0.5%

Carbitol 98.4%

Preparation B

Bakuchiol 1.0%

Vitamin e acetate 0.1%

Trivent OCG 98.4%

Phenonip 0.5%

Formulation C

Table 5. preparation D

embodiment 9

The evaluation of bakuchiol composition security attribute

With improve looks vehicle or complicated protective skin cream form prepare two kinds comprise the Bakuchiol of 86.54% and the Bakuchiol of 77.02% and be altogether less than 100ppm psoralen and isopsorapen (isopsoralen) natural bakuchiol composition and in vitro in model or test their security attribute in people's clinical trial.As table 6 is shown, bakuchiol composition does not show eye irritation, does not have skin irritation, does not have skin allergy contact sensitization and do not have phototoxicity.Described compositions has solid security attribute (Bakuchiol of 20% to 100% weight ratio) and good Cutaneous permeation character under the concentration level of wide region.

Table 6:Bakutrol ^tMthe result of safety test

embodiment 10

There is no the clinical evaluation of the bakuchiol composition of furocoumarin

With beautifying and skin-protecting cream form (preparation D, embodiment 8) preparation from the seed of Fructus Psoraleae extraction and enrichment and the Bakuchiol comprising 77.02% and the natural bakuchiol composition (Bakutrol of furocoumarin being less than 100ppm ^tM) and test in people's clinical trial.Research is for tentative, open people's research is to evaluate Bakutrol ^tMclinical benefit after topical application under the concentration of 0.5%.Research comprises 5 individualities meeting eliminating/inclusion criteria for evaluating natural bakuchiol composition for the benefit improving postinflammatory hyperpigmentation (PIH).The research persistent period is 12 weeks.Individuality is instructed to early apply twice Bakutrol with evening every day ^tM0.5% emulsifiable paste, and be back to position and amount to 9 times and make a house call, comprise screening and make a house call.Evaluation comprises the researcher net assessment of skin condition (IGA), with whole grade of hyperpigmentation after scytitis (PIH) and the order of severity and other relevant dermatosis state, comprise the evaluation of erythema, drying, decortication, oiliness, safety and toleration.Individual questionnaire survey comprises the safety relevant with the use of zest, skin-friendliness, other products and sunscreen cream and compliance problem.At benchmark, within the 4th week, the 8th week and the 12nd week, take pictures.Record and analyze the PIH order of severity from the change of benchmark, the change of PIH grade from benchmark and the successful ratio according to IGA scale.The gross area of the buccal surface that the PIH grade of the order of severity of following 6 levels (0=does not have, and 1=is slight, and 2=is slight, 3=moderate, and 4=is seriously medium, and 5=is serious) and PIH infect is used for clinical output analysis.

As shown in Figure 5, Bakutrol is comprised 0.5% time use ^tMall five individualities of local cream treatment there is the reduction of at least one grade of the PIH order of severity.After the lasting application of 8 weeks, the percentage ratio improvement of the facial zone that PIH infects is greater than 50% (see Fig. 6).PIH and the average percent both the order of severity thereof and absolute scale level are improved and are summarized in figures 7 and 8.As far back as use from the seed of Fructus Psoraleae extraction and enrichment and the Bakuchiol comprising 77.02% and the natural bakuchiol composition of the furocoumarin being less than 100ppm just realize both PIH and the order of severity after 4 weeks be greater than 40% or be greater than the improvement of a hierarchy level.On the skin of face position of infecting, the remarkable minimizing of PIH clearly illustrates that in the individual photo of two shown in Fig. 9.At topical application Bakutrol ^tMafter emulsifiable paste, two individualities show the progressively improvement with hyperpigmentation (PIH) after the slight scytitis relevant with moderate acne.

Table 7 outlines and comprises antibacterial or antiinflammatory or its epidemic acne combined and treat compared with product, uses the clinical output not having the bakuchiol composition of furocoumarin.Data clearly show does not have the bakuchiol composition of furocoumarin not only improve inflammatory and non-inflammatory lesions counting but also significantly improve hyperpigmentation after scytitis.As embodiment 7 confirms, lack tryrosinase based on it and suppress, the PIH benefit deriving from bakuchiol composition is unexpected.

The clinical report of table 7.Bakutrol and OTC medicine is summarized

embodiment 11

There is no the bakuchiol composition of furocoumarin to the impact assessment reducing postinflammatory hyperpigmentation

The PIH relevant with acne is used for the treatment of with the positive safety controlling Bakuchiol (UP256) emulsifiable paste evaluating 0.5% (wt/wt) in research with effect at double-blind placebo-controlled.Bakuchiol emulsifiable paste under 0.5% concentration in research evaluation Asia population, the salicylic acid emulsifiable paste of 2% and placebo emulsifiable paste (vehicle).Participant is instructed to apply twice (AM/PM) to facial every day and studies emulsifiable paste.Research participant is given application note and provides sunscreen cream.

Object of study is by being greater than 18 years old and being less than 40 years old and as consisting of the masculinity and femininity individuality being in overall physical health that case history is determined.18 individualities are collected by Bakuchiol seminar, and 20 individualities are collected by salicylic acid (SAL) seminar, and 19 individualities are collected by placebo seminar.

Investigator and research worker discussion and the clearly definition (it does not comprise freckle (Ephilides), solar lentigines freckle (freckle (lentigines)) or chloasma (melisma)) decided through consultation as the PIH relevant with acne or other tissue injury.PIH grade is the measuring of the Hyperpigmented order of severity (higher number=more serious pigmentation).PATIENT POPULATION has PIH grade >3 and acne is slight to moderate grade 2-3, the PIH that principal element is current with inflammation or after inflammation, acne is relevant.

Main goal in research:

1.PIH IGA time frame: benchmark and the 2nd week, the 4th week and the 8th week

2.PIH% distribution time framework: benchmark and the 2nd week, the 4th week and the 8th week

Use t-test method(s) or/and variance analysis based on from the change (p<0.05) of benchmark and in other treatment group (p<0.05) evaluate PIH effect.

By-end: security evaluation

Individual evaluation questionnaire investigation and tolerability evaluations is collected benchmark and the 2nd week, the 4th week and the 8th week.The urine pregnancy test having the women of reproductive potential is collected benchmark and the 8th week.

Data analysis

Collect following data:

The 1.PIH order of severity is from the change of benchmark;

2.PIH grade is from the change of benchmark; With

3. pathological changes counting is from the change of benchmark

Result:

Make a house call at every turn Shi Bingcong the stipulated time point shooting photo in from investigator assessment analytical data.Before research is not mixed by second investigator's group and two independent dermatologist's evaluations from the photo of benchmark, the 4th week and the 8th week to confirm that crowd meets standard further.The data analyzed, based on the assessment confirmed, do not have the photo of second week, in analysis, therefore do not comprise the data of second week.Table 8 outlines data.

The PIH change of rank of table 8. seminar

Bakutrol (UP256) group be presented at the 8th week PIH grade (that is, lower PIH grade) from the significant change (p<0.05) of benchmark.In addition, Bakutrol group is presented at the significant change (p<0.05) on the 8th week placebo.It is the group (p=0.0083) uniquely with time and the remarkable p value for the treatment of that data also show bakutrol treatment group.

The inflammatory acne lesions that table 9. is all groups

Bakutrol (UP256) group is presented at the 4th week and the 8th week significant change (p<0.001) from benchmark.Bakutrol group is also presented at the significant change (p<0.05) on the 8th week placebo.In addition, UP256 is that unique inflammatory lesion that reached at the 8th week reduces the group (57%) being greater than 50%.

Significant change (data do not show) is not had in non-inflammatory lesions kind apoplexy due to endogenous wind Bakutrol (UP256) group; But, reach p value <0.05 in non-inflammatory lesions kind apoplexy due to endogenous wind salicylate treatment group when the treatment of the 4th week.

Table 10: the general introduction of questionnaire survey and investigator's security evaluation

Conclusion:

Result be presented at the topical application of only 4 weeks after Bakutrol (UP256) emulsifiable paste significantly reduce the postinflammatory hyperpigmentation (PIH) relevant with acne.After the 8th week, UP256 also significantly reduces inflammatory acne lesions (<0.05) 57%.

Bakutrol (UP256) emulsifiable paste has good security attribute and to study the toleration of participant good.The beauty treatment that the beauty treatment acceptability of emulsifiable paste is considered to be better than or equal their former local OTC (over-the-counter) (OTC) acne treatments is acceptable.

embodiment 12

The treatment of inflammatory and non-inflammatory acne lesions

Preparation comprises the compositions of both Bakuchiol and salicylic acid.Described compositions is used to treat the patients with acne with the pathological changes of inflammatory, both non-inflammatories or two types.Described compositions to treatment inflammatory and non-inflammatory lesions effective, when the treatment of the 4th week, there is p value <0.05.Pathological changes be reduced to about 10% to about 90%.

Can by above-mentioned each embodiment combination to provide other embodiments.The all United States Patent (USP)s mentioned in description and/or enumerate in request for data table, U.S. Patent Application Publication, U.S. Patent application, foreign patent, foreign patent application and non-patent application are incorporated to herein by reference with their overall content.If needed, the many aspects of energy revision for execution scheme are to use each patent, application and disclosed concept thus to provide other embodiments.Can be carried out these and other according to foregoing detailed description to embodiment to change.Usually, in following patent requires, the term used should not be construed as the right of specific embodiments disclosed in restriction description and claim, and should be interpreted as the four corner comprising the equivalent that all possible embodiment gives together with such claim.Therefore, claim does not limit by disclosure.

Claims

1. comprise Bakuchiol or the acceptable salt of its medicine and medicine acceptable carrier and be less than 500ppm total furanocoumarins impurity compositions for the preparation of prevention, alleviate, reduce or treat the purposes in the medicine of the hyperpigmentation caused by the morbid state being derived from inflammatory cutaneous disease.

2. purposes as claimed in claim 1, wherein said morbid state is postinflammatory hyperpigmentation.

3. purposes as claimed in claim 1 or 2, wherein said compositions comprises the total furanocoumarins impurity being less than 100ppm.

4. purposes as claimed in claim 1, wherein contrasts described compositions relative to kojic acid and does not show tyrosinase inhibitory activity.

5. purposes as claimed in claim 1, wherein said furanocoumarin impurities comprises psoralen, isopsoralen or its combination.

6. purposes as claimed in claim 2, wherein said postinflammatory hyperpigmentation is derived from acne, atopic dermatitis, allergic contact dermatitis, bloch-Siemens syndrome, lichen planus, lupus erythematosus, morphea, mechanical injury, ionization or Non-ionizing radiation, burn, laser or Drug therapy, skin infection or its combination.

7. purposes as claimed in claim 6, wherein said postinflammatory hyperpigmentation is derived from acne.

8. purposes as claimed in claim 1, wherein said compositions comprises Bakuchiol and pharmacy, dermatological or the beauty treatment acceptable carrier of 0.001% to 99.9% gross weight.

9. purposes as claimed in claim 1, wherein said compositions is local, by aerosol, is given by suppository, intradermal injection, intramuscular injection or intravenous injection.

10. purposes as claimed in claim 1, wherein prepares described compositions for topical.

11. purposes as claimed in claim 1, wherein said compositions comprises the Bakuchiol of about 0.1% to about 2.0% gross weight.

12. purposes as claimed in claim 1, wherein said compositions comprises the Bakuchiol of about 0.5% gross weight.

13. purposes as claimed in claim 1, wherein said compositions prevention hyperpigmentation.

14. purposes as claimed in claim 1, wherein said compositions alleviates hyperpigmentation.

15. purposes as claimed in claim 1, wherein said compositions reduces hyperpigmentation.

16. purposes as claimed in claim 1, wherein said compositions overmedication pigmentation.

17. purposes as claimed in claim 1, wherein said hyperpigmentation occurs in the deep layer of skin.

18. purposes as claimed in claim 17, wherein said hyperpigmentation occurs in the papillary dermal layer of skin.

19. purposes as claimed in claim 1, it also comprises minimizing superoxide anion.

20. purposes as claimed in claim 1, it also comprises minimizing melanogen and generates.

21. purposes as claimed in claim 1, it also comprises minimizing melanocyte proliferation.

22. purposes as claimed in claim 1, it also comprises prevention melanocyte apoptosis.

23. purposes as claimed in claim 1, wherein said compositions also comprises salicylic acid or the acceptable salt of its medicine.

24. comprise Bakuchiol or the acceptable salt of its medicine and medicine acceptable carrier is generating with the compositions of the total furanocoumarins impurity being less than 500ppm for the preparation of reducing melanogen, is reducing melanocyte proliferation or prevent the purposes in the medicine of melanocyte apoptosis.

25. purposes as claimed in claim 24, it also comprises minimizing superoxide anion.

26. purposes as described in claim 24 or 25, wherein said compositions comprises the total furanocoumarins impurity being less than 100ppm.

27. purposes as claimed in claim 24, wherein contrast described compositions relative to kojic acid and do not show tyrosinase inhibitory activity.

28. purposes as claimed in claim 24, wherein said Bakuchiol is chemosynthesis or separation.

29. purposes as claimed in claim 24, wherein said furanocoumarin impurities comprises psoralen, isopsoralen or its combination.

30. purposes as claimed in claim 24, wherein said melanogen generation, melanocyte proliferation or melanocyte apoptosis are the results of postinflammatory hyperpigmentation.

31. purposes as claimed in claim 30, wherein said postinflammatory hyperpigmentation is derived from acne, atopic dermatitis, allergic contact dermatitis, bloch-Siemens syndrome, lichen planus, lupus erythematosus, morphea, mechanical injury, ionization or Non-ionizing radiation, burn, laser or Drug therapy, skin infection or its combination.

32. purposes as claimed in claim 31, wherein said postinflammatory hyperpigmentation is derived from acne.

33. purposes as claimed in claim 24, wherein said compositions comprises Bakuchiol and pharmacy, dermatological or the beauty treatment acceptable carrier of 0.001% to 99.9% gross weight.

34. purposes as claimed in claim 24, wherein prepare described compositions for topical.

35. purposes as claimed in claim 24, wherein said compositions comprises the Bakuchiol of 0.1% to 2.0% gross weight.

36. purposes as claimed in claim 24, wherein said compositions comprises the Bakuchiol of about 0.5% gross weight.

37. purposes as claimed in claim 24, wherein said compositions prevention hyperpigmentation.

38. purposes as claimed in claim 24, wherein said compositions alleviates hyperpigmentation.

39. purposes as claimed in claim 24, wherein said compositions reduces hyperpigmentation.

40. purposes as claimed in claim 24, wherein said compositions overmedication pigmentation.

41. purposes as described in claim arbitrary in claim 37-40, wherein said hyperpigmentation occurs in the deep layer of skin.

42. purposes as claimed in claim 24, wherein said hyperpigmentation occurs in the papillary dermal layer of skin.

43. purposes as claimed in claim 24, wherein said compositions reduces melanogen and generates.

44. purposes as claimed in claim 24, wherein said compositions reduces melanocyte proliferation.

45. purposes as claimed in claim 24, wherein said compositions prevention melanocyte apoptosis.

46. purposes as claimed in claim 24, wherein said compositions also comprises salicylic acid or the acceptable salt of its medicine.

The purposes of 47. compositionss comprising Bakuchiol or the acceptable salt of its medicine and salicylic acid or the acceptable salt of its medicine and medicine acceptable carrier in the medicine for the preparation for the treatment of inflammatory or non-inflammatory lesions.

48. purposes as claimed in claim 47, wherein said pathological changes comprises inflammatory acne lesions.

49. purposes as described in claim 47 or 48, wherein said compositions treatment inflammatory and non-inflammatory lesions.