MX2013008890A - Bakuchiol compositions for treatment of post inflammatory hyperpigmentation. - Google Patents

Abstract

Methods for treating excess pigmentation, including treatment of post inflammatory hyperpigmentation (PIH), are disclosed. The disclosed methods comprise administration of a composition comprising bakuchiol substantially free of furanocoumarins to a mammal. Compositions comprising bakuchiol and methods for their preparation are also disclosed.

Description

COMPOSITIONS OF BAKUCHIOL FOR THE TREATMENT OF HI POST-INFLAMMATORY ERPIGMENTATION Field of the Invention The present invention relates in general to bakuchiol compositions and their use for the treatment of post-infl ammatory hyperpigmentation.

Background of the Invention Post-inflammatory hyperpigmentation (PIH) is a unique skin pigmentation condition that involves increased melanin synthesis and deposition. PIH is also characterized by apoptosis of melanocyte cells due to oxidant stress and assaults of mediators and cytokines from inflammatory and immune responses. Melanin deposition (ie, hyperpigmentation) occurs beyond the epidermal level, releasing melanin significantly into the papillary dermis and trapped by large immune cells. : These unique histological features of the PIH present a number of difficulties for the treatment of PIH with traditional agents.

Common treatments for PIH focus on the prevention of additional pigment development by controlling inflammation with corychosteroids and using photoprotection agents. The desquamation compounds Rfef.242982 Chemicals, such as salicylic acid and glycolic acid, are also used to facilitate the function of skin renewal and to remove or diminish pigmentation. Topical retinoids have also been used to treat PIH, but such methods require up to 40 weeks before the significant benefits are seen.

Tyrosinase inhibitors, or skin whiteners, such as hydroquinone, azelaic acid, kojic acid and licorice extract, have also been used for the treatment of PIH. A significant disadvantage of using traditional skin whitening agents or thrykinase inhibitors is the non-specific discoloration of regular skin near the PIH site. This effect reduces the color of the background skin and makes the PIH site more prominent. In this way, these agents can be applied very carefully on the PIH site. In addition, thyrotinase inhibitors are only effective for epidermal hyperpigmentation since this is the site of the synthesis of melanin by thyrotoxin. Because the post-inflammatory pigmentation is a deep layer of the skin (eg, papillary dermis), it takes more than 6 months of continuous application of the hydroquinone drug before the visual changes of the dark marks are seen. Finally, hydroquinone-type skin whiteners or thrykinase inhibitors are associated with side effects including skin irritation, dryness, teratogenicity, in induction of vitiligo and skin cancers.

Post-inflammatory hyperpigmentation can be derived from endogenous inflammatory skin disorders such as acne, atopic dermatitis, allergic contact dermatitis, incontinent pigmentation, lichen planus, lupus erythematosus, morphea. Other causes of PIH include exogenous inflammatory stimuli such as mechanical trauma, ionization and radiation not by ionization, burns, laser therapies and skin infections. The current therapeutic agents for the above skin disorders are ineffective for the prevention, alleviation, reduction or treatment of PIH. For example, the above skin disorders are usually treated with anti-inflammatory agents, such as retinoids, COX inhibitors (e.g., salicylic acid), nonsteroidal anti-inflammatory drugs (NSAIDs), antimicrobial agents or hormonal drugs, but these treatments have shown that they are ineffective against PIH.

Although significant advances have been made in the field, there continues to be a need in the art for methods to prevent, alleviate, reduce or treat pigmentation in excess. For example, methods for the treatment of post-inflammatory hyperpigmentation are necessary. The present invention fulfills and provides other advantages related Brief Description of the Invention In general terms, the present invention is directed to methods for the prevention, alleviation, reduction or treatment of excess pigmentation. Excess pigmentation can be the result of a condition resulting from an inflammatory skin condition. For example, one embodiment of the present invention is a method for preventing, alleviating, reducing or treating post-inflammatory hyperpigmentation (PIH). Such PIH can be derived from any number of skin disorders, including acne. The method comprises administering an effective amount of a composition comprising bakuchiol and less than 500 ppm of total furanocoumarin impurities to a mammal.

In contrast to other skin bleaching agents, the bakuchiol compositions currently described are not inhibitors of tyrosinase. In this way, the specifically described compositions are decolorized at the site of the PIH and are useful for treating hyperpigmentation in deep layers of the skin (eg, papillary dermis). Accordingly, the currently described methods comprise certain advantages over previous methods for the treatment of hyperpigmentation and / or PIH.

Accordingly, one embodiment of the present disclosure is directed to a method for preventing, alleviating, reducing or treating excess pigmentation resulting from a condition derived from an inflammatory skin disorder, the method comprising administering to a mammal an effective amount of a composition comprising bakuchiol, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and less than 500 ppm of total furanocoumarin impurities.

In some modalities, the condition is post-inflammatory hyperpigmentation. In other embodiments, the composition comprises less than 100 ppm of total furanocoumarin impurities. In other embodiments, furanocoumarin impurities comprise psoralen, isopsoralen, or combinations thereof. In certain embodiments, the composition does not show an inhibitory activity of the kinokinase relative to a control of kojic acid.

In still other modalities, bakuchiol is synthesized or chemically isolated from a plant. For example, in some modalities bakuchiol is isolated from a plant. In some other modalities, the plant is of the Psoralea genus of plants, for example, Psoralea corylifolia L. (Luguminosa) or Psoralea glandulosa L. (Papilionácea).

In other modalities, the bakuchiol is made from seeds, stems, bark, branches, tubers, roots, root bark, young shoots, rhizomes, flowers or other reproductive organs, leaves or other aerial parts, or their combinations In some other modalities, post-inflammatory hyperpigmentation (PIH) is derived from acne, atopic dermatitis, allergic contact dermatitis, incontinent pigment, lichen planus, lupus erythematosus, morphea, mechanical trauma, radiation by ionization or non-ionization, burns, laser or drug therapies, skin infection or combinations thereof. For example, in some aspects post-inflammatory hyperpigmentation (PIH) is derived from acne.

In other embodiments, the composition comprises 0. 001% to 99.9% by total weight of bakuchiol and a pharmaceutical, dermatological or cosmetically acceptable carrier. For example, in some aspects the composition comprises from 0.1% to 2.0% by total weight of bakuchiol, 1.0% by total weight of bakuchiol or 0.5% by total weight of bakuchiol.

In other embodiments, the dermatologically acceptable carrier comprises a non-adherent gauze, a bandage, a swab, a cloth rag, a patch, a mask or a protector. In some other embodiments, the cosmetically acceptable carrier comprises a cleanser or an antiseptic.

In some aspects, the composition is formulated for topical administration. For example, in some aspects the composition further comprises a cream, a lotion, an ointment, a gel, an emulsion, a liquid, a paste, a soap, a powder or its combinations.

In other embodiments, the composition further comprises an adjuvant, skin penetration enhancer or liposomes. In still other embodiments, the adjuvant comprises a-hydroxy acids, salicylic acid, linoleic acid, retinoids, benzoyl peroxide, sodium sulfacetamide, clindamycin, erythromycin, dapsone, tetracycline, doxycycline, minocycline, zinc, estrogen or its derivatives, anti-androgens , sulfur, cortico steroids, cortisone, tazarotene, curcumin extract, acacia extract, skullcap extract, green tea extract, grape seed extract or combinations thereof.

In certain embodiments, the composition is formulated in a capsule, for example, controlled release capsule. In other embodiments, the composition is administered topically, by aerosol, by suppository, intradermally, intramuscularly or intravenously.

In some aspects, the method prevents excess pigmentation. In other aspects, the method relieves pigmentation in excess. In still other aspects, the method reduces pigmentation in excess. In still other aspects, the method treats pigmentation in excess. ' In other modalities, excess pigmentation occurs in a deep layer of the skin, for example, in a papillary layer in the dermis of the skin. In other modalities, The method further comprises reducing the anion of the super oxide. In some other embodiments, the method further comprises reducing melanogenesis. In still other embodiments, the method further comprises reducing the proliferation of melanocytes. In still other embodiments, the method further comprises preventing melanocyte apoptosis.

In certain other embodiments, the mammal is a human. In some other embodiments, the mammal is in need of preventing, alleviating, reducing or treating excess pigmentation resulting from a condition derived from a. Inflammatory disorder of the skin. For example, the mammal may have a need for treatment for PIH.

In another embodiment, the present disclosure is directed to a method for reducing melanogenesis, reducing melanocyte proliferation or preventing melanocyte apoptosis, the method comprising administering to a mammal an effective amount of a composition comprising bakuchiol, or one of its salts pharmaceutically acceptable, and a pharmaceutically acceptable carrier and less than 500 j.ppm of total furanocoumarin impurities. In some other modalities, the method further comprises reducing the anion of the super oxide.

In other embodiments, the composition comprises less than 100 ppm of total furanocoumarin impurities. In other modalities, furanocoumarin impurities they comprise psoralen, isopsoralen or combinations thereof. In certain embodiments, the composition does not show a thryo kinase inhibitory activity relative to a kojic acid control.

In still other modalities, bakuchiol is synthesized or chemically isolated from a plant. For example, in some modalities bakuchiol is isolated from a plant. In some other embodiments, the plant is of the Psoralea genus of plants, for example, Psoralea corylifolia L. (Luguminosa) or Psoralea glandulosa L. (Papilionacea).

In other modalities, Bakuchiol isolates seeds, stems, bark, branches, tubers, roots, root bark, young shoots, rhizomes, flowers or other reproductive organs, leaves or other aerial parts, or combinations thereof.

In some modalities, the melanogenesis, the proliferation of melanocytes or the melanocyte apoptosis is a result of post-inflammatory hyperpigmentation (PÍH). In some other modalities, post-inflammatory hyperpigmentation (PIH) is derived from acne, atopic dermatitis, allergic contact dermatitis, incontinent pigment, lichen planus, lupus erythematosus, morphea, mechanical trauma, radiation by ionization or non-ionization, burns, laser or drug therapies, skin infection: or combinations thereof. For example, in certain aspects the Post-inflammatory hyperpigmentation (PIH) is derived from acne.

In other embodiments, the composition comprises from 0.001% to 99.9% by total weight of bakuchiol and a pharmaceutically, dermatologically or cosmetically acceptable carrier. For example, in some aspects the composition comprises from 0.1% to 2.0% by total weight of bakuchiol, 1.0% by total weight of bakuchiol or 0.5% by total weight of bakuchiol.

In other embodiments, the dermatologically acceptable carrier comprises a non-adherent gauze, a bandage, a swab, a cloth rag, a patch, a mask or a protector. In some other embodiments, the cosmetically acceptable carrier comprises a cleanser or an antiseptic.

In some aspects, the composition is formulated for topical administration. For example, in some aspects the composition further comprises a cream, a lotion, an ointment, a gel, an emulsion, a liquid, a paste, a soap, a powder or combinations thereof.

In other modalities the composition. it also comprises an adjuvant, penetration enhancer in the skin or liposomes. In still other embodiments, the adjuvant comprises a-hydroxy acids, salicylic acid, linoleic acid, retinoids, benzoyl peroxide, sodium sulfacetamide, clindamycin, erythromycin, dapsone, tetracycline, doxycycline, minocycline, zinc, estrogen or its derivatives, anti-androgens, sulfur, steroid cortisone, cortisone, tazarotene, curcumin extract, acacia extract, skullcap extract, green tea extract, grape seed extract or combinations thereof.

In certain embodiments, the composition is formulated in a capsule, for example, controlled release capsule. In other embodiments, the composition is administered topically, by aerosol, by suppository, intradermally, intramuscularly or intravenously.

In some aspects, the method prevents excess pigmentation. In other aspects, the method alleviates pigmentation in excess. In still other aspects, the method reduces pigmentation in excess. In still other aspects, the method treats pigmentation in excess. In some modalities, excess pigmentation occurs in a deep layer of the skin, for example, in a papillary layer in the dermis of the skin.

In some other modalities, the method reduces melanogenesis. In still other modalities, the method reduces the proliferation of melanocytes. In still other modalities, the method prevents melanocyte apoptosis.

In certain other embodiments, the mammal is a human. In some other modalities, the mammal is in need of treatment to reduce melanogenesis, reduce proliferation of melanocytes or prevent apoptosis of melanocytes.

In still other embodiments, the composition further comprises salicylic acid or a pharmaceutically acceptable salt thereof.

Other embodiments of the present disclosure are directed to a method for treating inflammatory or non-inflammatory lesions, the method comprising administering an effective amount of a composition comprising bakuchiol or a pharmaceutically acceptable salt thereof and salicylic acid or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier to a mammal. For example, in some modalities injuries include inflammatory acne lesions. In other embodiments, the method treats inflammatory or noninflammatory lesions.

In certain other embodiments of the foregoing, the mammal is a human. In some other embodiments, the mammal is in need of treatment of inflammatory or non-inflammatory lesions.

In other embodiments, the present invention includes a composition comprising bakuchiol or a pharmaceutically acceptable salt thereof and salicylic acid or a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier. In certain embodiments, the composition is formulated for topical administration. ! ' These and other aspects of the invention will be evident on the reference to the following detailed description.

Brief Description of the Figures In the figures, the identical reference numbers identify similar elements. The sizes and relative positions of the elements in the figures are not necessarily drawn to scale and some of these elements were lengthened and placed arbitrarily to improve the legibility of the figure. In addition, the particular forms of the elements as drawn did not pretend to disclose any information regarding the current form of the particular elements, and have only been selected to facilitate recognition in the figures.

Figure 1 describes a standard chromatogram of bakuchiol, psoralen and isopsoralen.

Figure 2 shows chromatograms of bakuchiol compositions before and after hydrolysis.

Figure 3 presents data showing the strong antioxidant properties of bakuchiol compositions. Protection of ROS. The cells were plated and treated with test compounds alone and with 4-TBP at two concentrations to evaluate the protective properties of the test compounds against ROS induced by 4-TBP. As a positive control, TBHP, an activated form of H2O2 was used as well as treatment with 4-TBP in a form dependent on the. dose.

The treatment induced fluorescence indicating the presence of ROS. UP256 mitigated the effects of '4-TBP treatment while sustaining viability.

Figure 4 is a graph of the inhibitory activity of the kinokinase of bakuchiol and kojic acid compositions.

Figure 5 shows the changes in the PIH severity of individual test subjects.

Figure 6 presents a graph of the percentage change in facial area affected by PIH of individual test subjects.

Figure 7 shows the change in mean percentage in PIH and the severity of PIH in five test subjects.

Figure 8 describes the reduction of the average PIH grade level and the PIH severity at each visit compared to the baseline. ! "Figure 9 shows photographs of two participants in the study at various time intervals.

Detailed description of the invention In the following description, certain specific details are determined in order to provide a thorough understanding of various modalities. However, one skilled in the art will understand that the invention can be practiced without these details. In other cases, well-known structures have not been shown or described in detail to avoid unnecessarily obscure descriptions of the modalities. Unless the context requires otherwise, throughout the following description and claims, the word "comprises" and its variations, such as "comprising" or "comprising" shall be constructed in an open, inclusive sense, that is, as " including, but not limited to this. " In addition, the headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

The reference throughout this description to "one modality" or "one modality" means that a particular feature, structure or aspect is included in at least one modality. In this way, the occurrences of the phrases "in one modality" or "within one modality" in several places in all this description do not necessarily all refer to the same modality. In addition, the characteristics, structures or particular aspects can be combined in any suitable form in one or more modalities. Also, as used in this description and the appended claims, the singular forms "a", "an", "the", include plural referents unless the content clearly indicates otherwise. "or" is generally used in its sense including "and / or" unless the content clearly indicates otherwise.

Definitions As used herein, and unless the context dictates otherwise, the following terms have the meanings specified below.

"Bakuchiol" as used herein refers to the compound having the following formula: Bakuchiol wherein the benzylic double bond can be either cis or trans. As used herein, bakuchiol includes pharmaceutically acceptable salts and tautomers of bakuchiol. Phenolic compounds structurally related to bakuchiol are also included within this definition.

"Bakutrol ™" is a composition comprising bakuchiol and may also additionally comprise fatty acids extracted from Psoralea plants.

"UP256" refers to 0.5% (w / w) of the bakuchiol formulation.

"What prevents", "prevention" and "prevent" i in the context of the methods described all refer to prophylactic methods that prevent or stop the appearance of a particular condition, for example PIH.

"What alleviates", "relieves" and "relieves" in the context of the described methods all refer to the reduction or mitigation of the effects or symptoms of a particular condition, for example PIH.

"Reduce", "Reduce" and "Reduce" in the context of the methods described all refer to the diminution of the effects or symptoms of a particular condition, for example PIH.

"Treating", "treating" and "treating" in the context of the methods described all relate to techniques or methods intended to ameliorate the symptoms of or diminish or stop the onset of a particular condition, e.g. PIH.

"Impurity" includes any substance that is not desired in the bakuchiol composition, typically resulting from the isolation of bakuchiol from natural sources. The term "impurity" includes, but is not limited to, furanocoumarin compounds including, but not limited to, psoralen, isopsoralen and other impurities of the coumarin type. The impurities also refer to impurities that result from synthetic processes to obtain these compositions.

"Therapeutic" includes treatment and / or prophylaxis. When used, therapeutic refers to humans a.sy as to other animals.

"Dosage or pharmaceutical, cosmetic or therapeutic amount" refers to a dose level sufficient to induce a desired biological or functional result. This result can be the relief of the signs, symptoms or causes of a disease, a skin condition or any other alteration of a biological system that is desired.

"Placebo" refers to the substitution of the dose or amount pharmaceutically or therapeutically effective sufficient to induce a desired biological function that can alleviate the signs, symptoms or causes of a disease with a non-active substance.

A "host" or "subject" or "patient" is a subject, human or living animal, in which the compositions described herein are administered. In this way, the compositions described herein can be used for veterinary applications as well as human applications and the terms "patient" or "subject" or "host" should not be constructed in a limiting manner. In the case of veterinary applications, the dose ranges can be determined as described below, taking into account the animal's body weight.

As noted above, one embodiment of the present disclosure relates to the use of a composition comprising bakuchiol essentially free of furanocoumarin impurities for the prevention, alleviation, reduction or treatment of excess pigmentation resulting from a condition derived from an inflammatory skin disorder. For example, the described methods are useful for the treatment of post-inflammatory hyperpigmentation (PIH). In certain modalities, PIH can be caused by acne. The described method has demonstrated clinical efficacy in humans in the prevention, alleviation, reduction and treatment of post-inflammatory hyperpigmentation derived from skin disorders such as acne, atopic dermatitis, allergic contact dermatitis, incontinent pigment, lichen planus, lupus erythematosus, morphea; and post-inflammatory hyperpigmentation caused by mechanical trauma, radiation by ionization and non-ionization, burns, laser and drug therapies, and skin infections by the use of synthetic bakuchiol or bakuchiol composition with psoralea extract without furanocoumarin. These and other aspects and various modalities of the present description will become apparent after reference to the following description.

? Compositions of Bakuchiol In one embodiment, the present disclosure provides a composition that. comprises bakuchiol, which is substantially free of impurities, particularly impurities of furanocoumarin. This composition is also referred to herein as Bakutrol ™. In some embodiments, the composition is obtained by the organic synthesis of simple compounds as demonstrated in the literature (Hongli Chen and Yuanchao Li, Letters in Organic Chemistry, 2008, 5, 467-469) or of a plant. In certain embodiments, the composition of bakuchiol is isolated from a plant. Plant sources of bakuchiol include the family of plants that include, but are not limited to Luguminosae, Papilionaceae, Lauraceae and Magnoliaceae and the genus of plants that include, but are not limited to Psorlea, Sassafras, Magnolia and Astractylodes. For example, bakuchiol compositions can be isolated from Psoralea corylifolia L. (Luguminosa) or Psoralea glandulosa L. (Papilionacea). The compositions may be obtained from the whole plant or from one or more individual parts of the plant including, but not limited to seeds, stems, bark, branches, tubers, roots, root bark, young shoots, rhizomes, flowers and other reproductive organs, leaves, and other parts or their combinations. Methods for asynchronizing bakuchiol from plants can include solvent extraction, supercritical fluid extraction, distillation, physical compression, or combinations thereof. | The Bakuchiol, the structure of which is illustrated Next, it is a phenolic compound having a single hydroxyl group in the aromatic ring and an individual hydrocarbon chain in the aromatic ring and an unsaturated hydrocarbon chain. Although it is represented as trans in the following structure, the benzyl double bond of bakuchiol can also be cis.

Bakuchiol The amount of Bakuchiol (ie, the percentage by weight (% w / w)) in the purified plant extract depends on the extraction method and the degree of purification of the crude extract. In one embodiment the amount of ba'kucftiol in the extract is in the range of 13.7% to 29.1% as shown in Table 2. In other embodiments the amount of bakuchiol in the extract 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 certain modalities, the amount of Bakuchiol in the extract is 100%. In certain other embodiments, the amount of bakuchiol in the composition is not less than 60%. Examples 6-8 provide examples of extracts that comprise various amounts of bakuchiol Although bakuchiol is a biologically active natural product that has much potential to be used in the prevention and treatment of various diseases and conditions, there are a number of limitations associated with the use of this compound. Some limitations include its low concentration in natural sources and the presence of toxic components coexisting in the bakuchiol source. The impurities present in the bakuchiol compositions will vary with the bakuchiol source. For example, psoralens, also known as furanocoumarins, are secondary metabolites of natural existence in plants of the genus Psoralea (a source of bakuchiol) and also exist in many fruits and vegetables. Examples of furanocoumarins that usually coexist with bakuchiol include psoralen and isopsoralen.

Psoralen Isopsoralen A number of human risks have been associated: with the management, topical application and ingestion of plants containing psoralen and synthetic psoralens. It is well known that psoralens are phototoxic agents, which add to the sensitivity of the skin to ultraviolet radiation and promote skin cancer (Epstein (1999) Med. Surg. 18 (): 274-284). Psoralen has been shown to induce growth inhibition in rats (Diawara et al. (1997) Cancer Lett. 114 (1-2): 159-160). The gonadal toxicity of crude extracts of Psoralea plants has been directly linked to the alteration of the hypothalamo-pituitary-gonads axis (Takizawa et al. (2002) J. Toxicological Sciences 27 (2): 97-105). The oral administration of psoralens, bergapten (5-methoxypsoralen) and xantotoxin (8-methoxypsoralen), in the diet of female rats reduced the birth rate, the number of implant sites, puppies, corpora lutea, full and empty uterus weight and estrogen levels circulating in a dose-dependent manner (Diawara et al. (1999) J. Biochem. Molecular Toxicology 13 (3/4): 195-203). Psoralens have also been shown to induce mRNAs of the liver enzymes CYP1A1 and UGT1A6, suggesting that the estrogen metabolism potentiated by psoralens may explain the reproductive toxicity and the observed reduction in ovarian follicular function and ovulation (Diawara et al. (May-June, 2003) Pediatr Pathol Mol Med. 22 (3): 247-58). Because the toxicity of furanocoumarins, it is important to remove psoralen and isopsoralen from the bakuchiol compositions intended to treat post-inflammatory hyperpigmentation or other terms .

Psoralen and isopsoralen represent about 0.1-2% of the dry weight of Psoralea seeds and about 1-20% of the weight- in solvent in supercritical fluid extracts. The crude extracts of a plant of the genus Psoralea can be obtained by the extraction of solvents, or supercritical fluid extraction, distillation, physical compression or a combination of the above extraction methods. An enriched Bakuchiol composition can be obtained by chromatographic separations, solvent partitions (Patent Publication of India # 00570 / KOL / 2005), distillations, recrystallizations and other wet chemical and physical processes. The Patent Application of E.U.A. published No. 2006/0251749, which is incorporated herein by reference in its entirety, discloses solvent extraction followed by hydroxylation to remove furanocoumarin rings and obtain an enriched composition of bakuchiol essentially free of furanocoumarin impurities (e.g. less than 500 ppm, or less than 100 ppm impurities of furanocoumarin). The published method comprises the steps of extracting the compound from a plant source, hydrolysis of the crude extract with a basic solution under heat, and purification through a method that includes but is not limited to chromatography. column, extraction followed by crystallization, solvent partition, recrystallization and combinations thereof. Applicants have found that such a composition of a psoralea extract enriched with bakuchiol essentially free of furanocoumarin impurities can be used for the prevention, alleviation, reduction or treatment of excess pigmentation. For example, the bakuchiol compositions described are effective for the prevention, alleviation, reduction, or treatment of post-inflammatory hyperpigmentation (PIH).

The present disclosure is also directed to methods for isolating and purifying crude compositions of bakuchiol and related compounds obtained from natural sources. The method for isolating and purifying these compositions comprises the steps of extracting the compounds from a plant source, hydrolysis of the crude extract with a basic solution, and purification through a method that includes but is not limited to column chromatography, followed by extraction. by crystallization, solvent partition, recrystallization and combinations thereof. · Crude extracts purified in this form are essentially free of impurities of furanocoumarin, such as psoralen and isopsoralen. In this way, "the potential phototoxicity, topical irritation, carcenogenicity, and reproductive toxicity associated with these compounds are essentially eliminated.

In certain embodiments, the described compositions comprise less than 500 ppm, less than 250 ppm, less than 100 ppm, or less than 50 ppm of total furanocoumarin impurities. The concentration of the furanocoumarin impurities can be determined by any means known to the person skilled in the art. For example, in one embodiment the content of furanocoumarin can be determined by HPLC.

The efficiency of bakuchiol extraction from plant sources was evaluated using six different organic solvent systems under two sets of extraction conditions as described in Example 2. The results are set forth in Table 2. With reference to Table 2 , it can be seen that bakuchiol can be extracted from: Psoralea plants with any number of organic solvents and / or their combinations. The amount of bakuchiol | in r 'the various extracts in the range of 13.7% to 29.1% by weight. Other methods of extraction include, but are not limited to, extraction with C02 of supercritical fluid and water distillation. Exudates squeezed from fresh parts of the plant such as seeds can also be used to obtain Bakuchiol compositions from natural sources.

The effectiveness of extract purification? of crude bakuchiol by column chromatography was demonstrated in Example 3 and Table 3. Eight different types of resins were evaluated specifically for their ability to separate bakuchiol from furanocoumarin impurities. Both silica gel resins and CG-161 demonstrated a satisfactory separation. The chromatographic separation by column of crude plant extracts on an industrial scale, however, is typically not economically feasible because it requires expensive equipment and reagents and experienced personnel. The extremely low loading capacity of these samples due to the complexity of crude plant extracts also makes column chromatography on an industrial scale difficult.

Example 4 describes a method for separating bakuchiol from furanocoumarin impurities. The method comprises the treatment of compositions containing furanocoumarin impurities with a base. As illustrated by the following Reaction Scheme 1, using NaOH: for purposes of illustration, heating with a; base opens the lactone ring of the furanocoumarins, thus converting them into the salts of corresponding carboxylic acids. These salts can then be easily separated from the rest of the mixture through a variety of methods. The method described allows the preparation of the bakuchiol compositions essentially free of furanocoumarin impurities (eg, less than 500 ppm). Such Highly pure bakuchiol compositions can not be obtained using standard chromatographic techniques without the hydrolysis described.

Diagram of Reaction 1. Hydrolysis of Furanocoumarins The basic solution may comprise any base capable of opening the lactone rings, which include, but are limited to, sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide or combinations thereof.

The solution can have different values, in concentration and pH to maximize the conversion in acid salt. The reaction mixture can also be heated under different temperatures and pressures to maximize the degree of reaction, efficiency and yield.

The course of the reaction can be followed by 'HPLC to ensure the complete conversion of the furanocoumarins in their respective carboxylic acid salts. The HPLC chromatograms of the crude composition before and after the hydrolysis are illustrated in Figure 2. After the completion of the reaction (as determined by HPLC), the reaction solution can be processed using various methods, including but not limited to column chromatography, crystallization, solvent partitioning, precipitation, solvent washing or combinations thereof ... Organic solvents that can be used for solvent partitioning include, but are not limited to, petroleum ether, ethyl acetate, ethyl ether, hexane , chloroform, propanol, butanol, and methylene chloride, as well as other organic solvents immiscible in water.

The crude extracts purified in this form are essentially free of furanocoumarin impurities such as psoralen and isopsoralen. For example, the purified excipient may comprise less than 500 ppm, less than 250 ppm, less than 100 ppm or even less than 50 ppm of furanocoumarin impurities. Additionally, the color of these highly pure bakuchiol furanocoumarin free compositions is light brown or red and are very stable with respect to both color and composition of the active agent, making them particularly suitable for formulation, storage and cosmetic applications.

Also included in the present description is a method to analyze compositions of bakuchiol, which allows the detection and quantification of impurities. In this embodiment, the method for analyzing bakuchiol compositions comprises the step of analyzing the compositions by high pressure liquid chromatography (HPLC). The HPLC analysis allows the quantification of the various components in the mixture and also provides means to screen bakuchiol, psoralen, isopsoraleho and other natural components in Psoralea plants to guide the extraction, hydrolysis and purification processes. A method for analyzing bakuchiol compositions using high pressure liquid chromatography (HPLC) is described in Example 1 (Table 1).

B. Treatment of Pigmentation in Excess with Compositions of Bakuchiol One embodiment of the present disclosure relates to the use of a composition comprising bakuGhiol essentially free of furanocoumarin impurities for the prevention, alleviation, reduction or treatment of excess pigmentation resulting from a condition derived from an inflammatory skin disorder. For example, the described methods include the prevention, alleviation, reduction or treatment of post-inflammatory hyperpigmentation (PIH). In certain modalities, PIH can be caused by acne. The description includes the formulation of a composition of bakuchiol in a typical cosmetic vehicle and also in a skin care cream, gel lotion and other formulations as explained in more detail below. As shown in the Examples, Applicants herein demonstrated the unexpected clinical efficacy in humans of bakuchiol compositions in the prevention, alleviation, reduction or treatment of post-inflammatory hyperpigmentation (PIH) derived from skin disorders such as acne. , atopic dermatitis, allergic contact dermatitis, incontinent pigment, lichen planus, lupus erythematosus, morphea; and post-inflammatory hyperpigmentation caused by mechanical trauma, radiation by ionization and non-ionization, burns, laser and drug therapies, and skin infections.

The disclosed methods comprise administering to a mammal (e.g., a human patient) an effective amount of a composition comprising bakuchiol, which. it is substantially free of furanocoumarin impurities. For example, the compositions may comprise less than 500 ppm furanocoumarin impurities. The composition may comprise from about 0.0001% to about 100% bakuchiol. For example, in certain embodiments the composition comprises from about 0.1% to about 2% bakuchiol or from about 0.5% to about 1% bakuchiol. In other examples the composition comprises of 3 approximately 0.5% or approximately 1.0% bakuchiol. In certain embodiments, the mammal is a human, and in other embodiments the mammal is in need of prevention, alleviation, reduction or treatment of excess pigmentation resulting from a condition derived from an inflammatory skin disorder, for example mammal may have a need for treatment for PIH.

The present disclosure demonstrates the unexpectedly unique biological properties of synthetic or natural bakuchiol compositions. As shown in Example 5 and Table 4, a Bakutrol composition comprising approximately 57.35% bakuchiol has an unexpectedly high anti-oxidant capacity especially against the super oxide anion (> 69,000 pmol TE / g) with a value Total ORAC versus five predominant reactive species a > 92,000 μ ???? TE / g.; The super oxide is an anion with the chemical formula 02 ~. A chronic inflammatory condition, such as acne vulgaris, can have a dramatically increased super oxide anion production of keratinocytes, which are stimulated by such a gram-positive anaerobic bacterium; as P. acnes (Grange PA., and other Píos Pathogens 2009, 5 (7) 1-14.). The super oxide is biologically quite toxic and is used by the immune system to kill invading microorganisms. In phagocytes, the super 'Oxide it is produced in large quantities by the enzyme NADPH oxidase for use in the oxygen-dependent annihilation mechanisms of invading pathogens. The anion of the super oxide and other reactive oxygen species in inflamed skin can also induce melanogenesis, melanocyte proliferation, and melanocyte apoptosis, which is a major causative factor of post-inflammatory hyperpigmentation. Accordingly, one embodiment of the present disclosure is a method for alleviating, reducing or treating excess pigmentation resulting from a condition derived from an inflammatory skin disorder by reducing the super oxide with a composition comprising bakuchiol essentially free of impurities. of furanocoumarin. In a modality, - the condition is PIH. In another embodiment, the present disclosure provides a method for reducing melanogenesis or proliferation of melanocytes or the inhibition of melanocyte apoptosis, for example, by reducing the super oxide anion. The method comprises administering an effective amount of a composition comprising bakuchiol essentially free of furanocoumarin impurities to a mammal. In certain embodiments, the mammal is a human, and in other embodiments the mammal is in need of reducing melanogenesis or proliferation of melanocytes or inhibiting melanocyte apoptosis. ! As demonstrated in Example 6 and Figure 3 > a composition comprising 77.02% bakuchiol, which is substantially free of impurities, particularly impurities of furanocoumarin showed a protective effect on the oxidative stress induced by 4-teriabutylphenol (4-TBP). The cytotoxicity for the melanocytes of the oxygen reactive species generated by 4-TBP was protected by the bakuchiol compositions in the two concentrations tested. Although it wishes to be bound by no theory, the Applicants hereby believe that the unexpected clinical benefits of a synthetic or natural bakuchiol composition of reducing, alleviating, preventing or treating post-inflammatory hyperpigmentation (PIH) derive from its unique and unexpected ability to neutralize reactive oxygen species, especially the super oxide anion, and protect melanocytes from oxidative stress under conditions of inflammation that lead to reduced epidermal melanosis and / or dermal melanosis.

In addition to their unexpectedly high antioxidant capacity, the Applicants have discovered that the bakuchiol compositions described are not inhibitors of thirokinase. This is in contrast to the other reports that describe bakuchiol as a skin whitening agent by the inhibition of thirokinase (Japanese Patent No. P1107123). This unexpected discovery leads the Requesters of the present to "the Currently described methods to treat PIH where pigmentation occurs in the deep layer of the skin and the inhibitors of thyrotoxin are ineffective. The lack of inhibition of tyrosinase from the bakuchiol compositions described is shown in Example 7 and Figure 4. Both pure Bakuchiol (100%) and enriched Bakuchiol (77.02%) with no more than 100 ppm of furanocoumarins from natural sources do not have the inhibition function of thrykinase at eight different doses.

The compositions comprising bakuchiol at concentrations of 86.54% and 77.02% bakuchiol were evaluated for their safety profiles. As shown in Example 9 and Table 6, based on in vitro clinical tests? in humans, the compositions of Bakutrol (UP256) showed no irritation in the eyes, skin irritation in normal and scarred skin, sensitization in contact with the skin, phototoxicity and mutagenic toxicity. The topical creams of the Bakuchiol composition were well tolerated in all tests in humans and in vitro.

As demonstrated in Example 10, a natural bakuchiol (Bakutrol ™) composition comprising 77.02 ·% bakuchiol and less than 100 ppm furanocoumarin extracted and enriched from seeds of Psoralea corylifolia were tested in a human clinical experiment on subjects: with post-inflammatory hyperpigmentation (PIH) derived from acne vulgar light or moderate. The bakuchiol composition was formulated at 0.5% bakuchiol for topical application. After daily topical application of the 0.5% Bakutrol cream, a dramatic reduction in post-inflammatory hyperpigmentation (PIH) was observed in all five subjects. As shown in Figure 5, the five subjects had at least one degree in the PIH severity reduction level. We obtained more than 50% improvement in the facial area affected by PIH after 8 weeks, of continuous topical application of the cream with 0.5% Bakutrol (Figure 6). The improvements in the mean percentage and the absolute grade level of both PIH and their severity are summarized in Figures 7 and 8. The improvements of more than 40%, or more than one degree in the level of reduction of both PIH and severity , were obtained as early as 4 weeks after using the bakuchiol composition. The substantial reduction of PIH in the affected skin sites is clearly evident in the photographs of two subjects as shown in Figure 9. Both subjects showed a progressive improvement of Post-inflammatory skin hyperpigmentation (PIH) associated with light acnes. and moderate after the topical application of a Bakutrol cream.; Table 7 (Example 10) summarizes the clinical results of using a furanocoumarin-free Bakuchiol composition (ie, Bakutrol) in comparison with Popular acne treatment products that contains either an antimicrobial or an anti-inflammatory or its combinations. The data in Table 7 clearly demonstrate that the furanocoumarin-free Bakuchiol composition not only improved the counts of inflammatory and non-inflammatory lesions, but also significantly improved the skin in Post-Inflammatory Hyperpigmentation. The PIH that benefits from the Bakuchiol composition was not expected based on its lack of inhibitory activity of the thryokinase.

Table 8 (Example 11) presents data showing the reduction in the PIH grade (ie, the degree of pigmentation). The data clearly show that bakuchiol is more effective than both placebo and salicylic acid for the treatment of PIH. In addition, the applicants of the present have also discovered that bakuchiol (or compositions comprising it) are effective even. the treatment of inflammatory lesions, such as acne lesions. Table 9 (Example 11) demonstrates the effectiveness of bakuchiol in the treatment of inflammatory lesions compared to placebo or salicylic acid treatment.

In addition to the methods comprising treatment with compositions comprising bakuchiol, the present invention includes modalities in which a mammal is treated with a composition comprising bakuchiol and salicylic acid. For example, applicants for the present have discovered that salicylic acid is effective for the treatment of non-inflammatory lesions, while bakuchiol is effective for the treatment of inflammatory lesions. Accordingly, one embodiment of the present invention is directed to a method of treating inflammatory lesions (e.g., acne lesions), the method comprising administering an effective amount of a composition comprising bakuchiol or a pharmaceutically acceptable salt thereof to a mammal. Another modality 10 is directed to a method for treating inflammatory and / or non-inflammatory lesions (e.g., acne lesions), the method comprising administering an effective amount of a composition comprising bakuchiol and salicylic acid (or its pharmaceutically acceptable salts) to a mammal . Other 15 modalities include the treatment of non-inflammatory lesions by administering an effective amount of a composition comprising salicylic acid or a pharmaceutically acceptable salt thereof to a mammal. In certain embodiments of the foregoing, the mammal is a 20 human. In other embodiments, the mammal is in need of treatment for inflammatory and / or non-inflammatory lesions, such as acne.; In addition to the treatment of injuries, the combination of bakuchiol and salicylic acid is effective for: treating ? any of the above conditions (for example, PIH, reduce melanogenesis, reduce the proliferation of melanocytes or prevent the apoptosis of melanocytes, etc.). Accordingly, some embodiments are directed to treatment with a composition comprising bakuchiol and salicylic acid. Other embodiments include a composition comprising bakuchiol or a pharmaceutically acceptable salt thereof, salicylic acid or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

The above methods are effective to substantially eliminate inflammatory and / or non-inflammatory lesions. For example, in some embodiments, the methods reduce injury from about 1% to about 99% or from about 10% to about 90%. In other modalities, the methods reduce injuries by more than 50%.

The ratio of bakuchiol to salicylic acid is not particularly limited and can be determined by one skilled in the art based on the desired result. For example, in some embodiments the weight ratio of bakuchiol to salicylic acid is in the range of about 1: 100 to about 100: 1. In other embodiments, the weight ratio is in the range of about 10:90, about 20:80, about 30:70, about 40:60, about 50:50, about 60:40, about 70:30, about 80:20 to approximately 10:90. The compositions may be formulated according to any of the formulations described herein.

C. Formulation of Bakuchiol Compositions The bakuchiol compositions of the present disclosure can be formulated by any means known to the person skilled in the art. As shown in Example 8 and Table 5, the compositions of the present disclosure can be formulated as pharmaceutical compositions, cosmetic or dermatological, and may include other components such as active, excipients, adjuvants, carriers or their pharmaceutical combinations: and / or cosmetically acceptable. An excipient is an inert substance used as a diluent or vehicle for dermatological and cosmetically accepted products and drugs. Examples of such excipients include, but are not limited to water, wafers, saline, glycerin, hydrated silica, propylene glycol, aluminum oxide, carrageenan, cellulose gum, titanium dioxide, Ringer's solution, dextrose solution, mannitol, solution of Hank, preservatives and other physiologically balanced saline solutions. Non-aqueous vehicles, such as fixed oils, sesame oil, ethyl oleate, or triglycerides may also be used. Other useful formulations include suspensions containing viscosity enhancing agents, such; 'as Sodium carboxymethylcellulose, sorbitol and dextran.

In Example 8, the compositions of the present disclosure were formulated in transcutol, or caprylic triglyceride, or polysorbate-20, or purified water, or combinations of two or more of the above vehicles. The excipients may also contain minor amounts of additives, such as EDTA, disodium DDTA, BHA, BHT, diammonium citrate, nordihydroguaracetic acid, propyl gallate, sodium gluconate, sodium metabisulfite, t-butyl hydroquinone, SnCl2, H202, and 2. ,, 5-trihydroxybutyrophenone, vitamin C vitamin E, vitamin E acetate, fenonip, and other substances that improve isotonicity and chemical stability.

Examples of substances for adjusting the pH of the formulation include sodium hydroxide, sodium carbonate, sodium bicarbonate, pentasodium triphosphate, tetrasodium pyrophosphate, sodium lauryl sulfate, calcium peroxide, phosphate pH regulator, bicarb pH regulator ato, pH regulator tris, histidine, citrate, and glycine, or their mixtures. Examples of flavors include, but are not limited to thimerosal, m- or o-cresol, formalin, fruit extracts, and benzyl alcohol. Standard formulations can be either liquid or solid, which can be absorbed in a suitable liquid as a suspension or solution for administration. In this way, in a non-liquid formulation, the excipient may comprise dextrose, human serum albumin, preservatives, etc., to which sterile or saline water may be added before administration.

In one embodiment, the composition of bakuchiol is formulated with other active compounds that activate different mechanisms of action for the reduction of skin pigmentation. Such active ingredients include, but are not limited to, hydroquinone, monobenzylether, arbutin, deoxyarbutine, mequinol, N-acetyl-4-S-cysteaminylgenol, kojic acid, azelaic acid, glycolic acid, gentisic acid, flavonoids, aloesin, stilbene and stilbene derivatives. , licorice extracts, bearberry extract, blackberry extract, aloe vera gel, glabridin, vitamin C derivatives, magnesium ascorbyl phosphate, tetrahexyldecyl ascorbate, vitamin E derivatives, tranexamic acid and its derivatives, biometrics of TGF-B proteins , centaureidin, niacinamide, inhibitors' PAR-2, lectins, neoglycoproteins, resorcinol and its derivatives, and Nivitol ™. '·' -| ·· In another embodiment, the composition comprises anti-inflammatory and antimicrobial agents that can work synergistically with the bakuchiol composition to reduce infection, inflammation related to the infection, and acceleration of skin recovery. Such active ingredients include, but are not limited to, α-hydroxy acids, salicylic acid, linoleic acid, retinoids, peroxides. benzoyl, sodium sulfacetamide, clindamycin, erythromycin, dapsone, tetracycline, doxycycline, minocycline, zinc, estrogen and its derivatives, anti-androgens, sulfur, steroid cortisone, cortisone, tazarotene, curcumin extract, acacia extract, skullcap extract, green tea extract, and grape seed extract.

In certain embodiments, the composition comprises an adjuvant or a carrier. Adjuvants are typically substances that generally improve the biological response of a mammal to a specific bioactive agent. Suitable adjuvants include but are not limited to, Freund's adjuvant; other components of the bacterial cell wall; aluminum, calcium, copper, iron, zinc, magnesium, tin-based salts; silica; microdermabrasion agent, polynucleotides; toxoids; serum proteins; proteins with viral cover; other preparations derived from bacteria; interferon gamma; adjuvants: block copolymer, such as Hunter's Titermax adjuvant (Vaxcel.TM., Inc. Norcross, Ga.); adjuvants Ribi (available from Ribi ImmunoChem Research, Inc., Hamilton, Mont.); and saponins and their derivatives, such as Quil A (available from Superfos Biosector A / S, Denmark). '. Carriers are typically compounds that increase the half-life of a therapeutic composition in the treated host. Suitable carriers include, but river limit to, controlled release polymer formulations, biodegradable implants, nanocapsulation, nanoparticles, bacteria, viruses, oils, esters, and glycols.

In other examples, the composition is prepared as a controlled release formulation, which slowly releases the composition into the host. As used herein, a controlled release formulation comprises a bakuchiol composition in a controlled release vehicle. Suitable controlled release vehicles will be known to those skilled in the art. Examples of controlled release formulations are biodegradable (ie, bioerodible) and include capsules.

In one modality, an appropriate ointment; is comprised of the desired UP256 (bakuchiol) concentration which is an effective, non-toxic amount generally selected from the range of 0.001% to 100% based on the total weight of the topical formulation, from 65% to 100% · (e.g. , 75% to 96%) of white soft paraffin, from 0% to 15% liquid paraffin, and from 0% to 7% (for example 3 to 7%) of lanolin or a derivative or synthetic equivalent thereof. In another embodiment the ointment may comprise polyethylene-liquid paraffin matrix.

In one modality, a suitable cream: it is comprised of an emulsifier system together with the desired UP256 (bakuchiol) concentration synthesized and / or isolated from a single plant or multiple plants as provided above. The emulsifier system is preferably comprised of 2 to 10% polyoxyethylene alcohols (for example, the mixture available for the trade name Cetomacrogol ™ 1000), 10 to 25% stearyl alcohol, 20 to 60% liquid paraffin, and 10 to 65% water; together with one or more preservatives, for example from 0.1 to 1% N, N "-methylenebis [? ' - [3- (hydroxymethyl) -2,5-dioxo-4-imidazolidinyl] urea] (available for the name of Imidurea USNF), from 0.1 to 1% alkyl 4-hydroxybenzoates * '(for example the available mixture of Ñipa Laboratories under the trade name of Nipastat), from 0.01 to 0.1% sodium butyl 4-hydroxybenzoate (available from ipa Laboratories under the trade name Nipabutyl Sodium.), And from 0.1 to 2% phenoxyethanol.

In one embodiment, a suitable gel is comprised of a semi-solid system wherein the liquid phase is limited within a three-dimensional polymer matrix with a [high degree of entanglement. The liquid phase may be comprised of water, together with the desired amount of UP256 (bakuchiol), from 0.01 to 20% of miscible additives in water, i for example glycerol, polyethylene glycol, or propylene glycol, and from 0.01 to 10%, preferably from 0.5 to 2%, of an agent thickener, which may be a natural product, for example tragacanth, pectin, carrageenan, agar and alginic acid, or a synthetic or semi-synthetic compound, for example methylcellulose and carboxypolymethylene (carbopol); together with one or more preservatives, for example from 0.1 to 2% of methyl 4-hydroxybenzoate (methylparaben) or phenoxyethanol-differential. Another suitable formulation is comprised of the desired amount of UP256 (bakuchiol), together with 70 to 90% polyethylene glycol (for example, polyethylene glycol ointment with 40% polyethylene glycol 3350 and 60% polyethylene glycol 400, prepared in accordance with the US National Form (USNF, for its acronym in English)), of > 5 to 20% water, 0.02 to 0.25% of an antioxidant (for example, butylated hydroxytoluene), and 0.005 to 0.1% of a chelating agent (for example ethylenediamine tetraacetic acid) (EDTA)).; The term soft paraffin is previously used to encompass the bases of cream or ointment of soft white paraffin and soft yellow paraffin. The term lanolin covers native wool fat and purified wool fat.; Lanolin derivatives in particular include lanolins which have been chemically modified in order to alter their physical and chemical properties and the synthetic equivalents of lanolin include in particular synthetic and semi-synthetic compounds and mixtures that are known and used in the pharmaceutical and cosmetic arts as alternatives to lanolin and can, for example, be referred to as lanolin substitutes.

A suitable synthetic equivalent of lanolin that can be used is the material available under the trade name Softisan ™ known as Softisan 649. Softisan 649, available from Dynamit Nobel Aktiengesellschaft, is an ester of natural vegetable fatty acids, isostearic acid or adipic acid; their properties are explained in H. Hermsdorf in Fette, Seifen, Anstrichmittel, Issue No. 84, No.3 (1982), pp. 3-6.

The other substances mentioned hereinabove as constituents of suitable ointment bases and creams are explained in standard reference works, for example the US Pharmacopoeia. Cetomacrogol 1000 has the formula CH3 (CH2) m (OCH2CH2) nOH, wherein m can be 15 or 17 and n can be from 20 to 24. Butylated hydroxytoluene is 2,6-di-tert-butyl-p-cresol. Nipastat is a mixture of methyl, ethyl, propyl and butyl 4-hydroxybenzoate.

The compositions described can be produced by conventional pharmaceutical techniques. In this way the aforementioned compositions, for example, can conveniently be prepared by mixing together at an elevated temperature, for example 60-70 ° C, soft paraffin, liquid paraffin if present, and lanolin or one of its derivatives or synthetic equivalent. The mixture can then be cooled to room temperature, and after the addition of the hydrated crystalline calcium salt of mupirocin, together with the cortico steroid and other ingredients, stir to ensure adequate dispersion.

Finally, bakuchiol has a partition coefficient of log P = 6.13. The partition coefficient of a chemical compound provides a thermodynamic measure of its hydrophilicity / lipophilicity balance and thus its potential bioavailability. Having a partition coefficient of 6.13 means that the compound has a high penetration in the cell membrane and bioavailability when formulated in a distribution system. The penetration into the skin of the active compound - bakuchiol in a skin care cream is an ex-vivo test was quantified in an ex vivo test on isolated human skin. The results showed good penetration in the skin and bioavailability. In certain embodiments, the disclosed compositions comprise a skin penetration enhancer.

D- Administration of Compositions of Bakuchiol The compositions of the present disclosure can be administered by any method known to the person skilled in the art. For example, the compositions described can be administered internally or topically. The modes of administration include, but are not limited to, enteral administration (oral), parenteral administration (intravenous, subcutaneous, and intramuscular) and topical application. In certain embodiments, the compositions are administered topically.

The content of a bakuchiol composition in finished skin care products for PIH may be in the range of 0.001% to 99.9% by weight. In some embodiments, the composition comprises from 0.1% to 2% bakuchiol. In other examples the composition comprises 0.5% or 1.0% bakuchiol. In certain embodiments the amount of the bakuchiol composition in a skin care cream is in the range of 0.5-1%. Methods according to this disclosure comprise administering internally or topically to a mammal a therapeutically effective amount of a composition comprising bakuchiol, which is fully synthesized or isolated from natural sources (p one of their combinations) and is substantially free of impurities, particularly furanocoumarin impurities · (eg, less than 500 ppm).

The therapeutic agent of the present disclosure can be administered topically by any suitable means known to the person skilled in the art for the topical administration of pharmaceutical compositions. Such modes of administration include, but are not limited to, 'as an ointment, gel, lotion, or base. cream or as a emulsion, such as a patch, bandage or mask, a non-stick gauze, a bandage, a swab or a cloth rag. Such topical applications can be administered locally in any affected area, using any standard means known for topical administration. A therapeutic composition can be administered in a variety of unit dosage forms depending on the method of administration. For particular modes of distribution, the therapeutic compositions can be formulated in an excipient as explained above. A therapeutic composition of the present disclosure can be administered to any host, preferably to mammals, and more preferably to humans. The particular mode of administration will depend on the condition to be treated.

Regardless of the form of administration, the specific dose is calculated according to the approximate body weight of the host. Further refinement of the calculations necessary to determine the appropriate dose of treatment involving each of the aforementioned formulations is made by the person skilled in the art and is within the scope of the routine tasks in view of the dosage information and the assays. described in the presiente. These doses can be assessed through the use of established trials to determine the doses used in conjunction with the appropriate dose-response data. In certain embodiments, the dose of the composition comprising bakuchiol is in the range of 0.001 to 200 mg per kilogram of body weight.

The following examples are provided for purposes of illustration, not limitation.

EXAMPLES EXAMPLE 1 QUANTIFICATION OF BAKUCHIOL, PSORALENE AND ISOPSORALENE BY HPLC The amount of bakuchiol, psoralen and isopsoralen in the extracts, fractions, process materials, ingredients and final formulated products were quantified by high pressure liquid chromatography (HPLC) using a Photo-diode Array detector (HPLC / PDA, for its acronym in English). The objective compounds were eluted from a Luna Phenyl-hexyl column (250 mm × 4.6 mm) using a gradient of acetonitrile (ACN) or methanol and water of 36% to 100% ACN for a period of 12 minutes, followed by 100% ACN for three minutes. The detailed HPLC conditions used are determined in Table 1. A chromatogram of the HPLC separation is shown in Figure 1. The target compounds were identified and quantified with base on retention time and peak UV area using pure bakuchiol. commercially available, psoralenó and isopsoralen as quantification standards.

The reaction for bakuchiol, psoralen and isopsoralen were 18.19 minutes, 7.33 minutes and 7.95 minutes, respectively.

Table 1. HPLC conditions for the quantification of Bakuchiol, Psoralen and Isopsoralen Example 2 GENERAL METHODS FOR THE EXTRACTION OF BAKUCHIOL FROM PLANTS PSORALEA Method A - To a bottle was added solvent (100 ml) and Psoralea corylifolia seed powder (10 g), and the mixture was stirred in a wrist mixer at room temperature for one hour. The mixture was then passed through a filter and the filtrate was collected. The extraction process was repeated once more with fresh solvent, the filtrates were combined, the solvent was removed, in a broken evaporator, and the residue was dried under high vacuum.

Method B '- Solvent (50 ml) and Psoralea corylifolia seed powder (10 g) were added to one flask, and the mixture was refluxed for 40 min. The solution was then filtered and the extraction process repeated twice more with fresh solvent. The filtrates were combined, and the solvent was evaporated to obtain a dry extract.

Following the above extraction methods, the sample plant material was extracted with the following solvents: dichloromethane (DCM), ethyl acetate (EtOAc), acetone, methanol (MeOH), petroleum ether (BP 35-60 ° C) and : petroleum ether (BP 60-90 ° C). The extracts and plant materials were then analyzed by HPLC analysis as described in Example 1. The results are defined in Table 2.: Table 2. Quantification of Various Extracts of Psoralea Corylifolia EXAMPLE 3 CHROMATOGRAPHY METHODS FOR PURIFYING BAKUCHIOL EXTRACTS Various chromatographic methods were used to purify bakuchiol from crude solvent extracts isolated from the seeds of Psoralea corylifolia using the method described in Example 2. The efficiency of a specific column enrichment method was demonstrated as a means of obtaining bakuchiol a high purity free of contamination by furanocoumarins, particularly contamination of psoralen / isopsoralen. In summary, each cartridge empty column (internal diameter (ID) of 1.3 cm) and 20 ml capacity, from Bio-Rad) was packed with a different medium and eluted with different solvents in an attempt to separate the impurities of furanocoumarin from bakuchiol. The fractions (10 ml per fraction) were collected in test tubes and analyzed with TLC plates on silica gel developed with 20% EtOAc / petroleum ether. The objective compounds, bakuchiol, psoralen and isopsoralen, were identified based on their retention times, which were determined using standard compound solutions. The results are shown in Table 3. Many of the methods described in Table 3 were useful for the separation of furanocoumarins and bakuchiol from both synthetic and natural sources, however the cost of > this methodology may not be economically feasible for large-scale production.

Table 3. Summary of Chromatographic Separation in Bakuchiol Column of Furanocoumarins in Raw Extracts of Psoralea Corylifolia · Size of Half column / Loading Elution Solvent Extract results Ether of Oil / EtOAc gradient in Some increase of 20% separation XAD-7 (100% ether ether resin) of oil at 100% 8 ml / 16 mg polyacrylate MeOH amerlite) eOH / gradient water in increments Little of 20% of 100% of Oil ether separation to 100% MeOH 1. Petroleum ether 2. 5% acetone / ether Sin; Polyamide 5 ml / 50 mg oil separation 3. Acetone Without LH-20 8 ml / 50 mg Petroleum Ether separation 1. Ether of Good Oil Silica gel 5 ml / 50 mg 2. 15% EtOAc / pet ether separation. 1. Ether of Without CG-71md 5 ml / 50 mg Petroleum separation: 2. Acetone Without 5 ml / 50 mg Petroleum Ether separation Good CG-161cd MeOH / separation gradient: 6 ml / 50 mg Low water step performance EXAMPLE 4 HYDROLYSIS OF AN ISOLATED ABSTRACT OF THE SEEDS OF! PSORALEA CORYLI FOLIA An extract of hexane or a super-critical CO2 fluid extract of Psoralea corylifolia seeds, 1 containing about 25% bakuchiol, was mixed with a 1M NaOH solution. The solution was heated in a reaction vessel at a temperature at or above 80 ° C for at least one hour. A portion of the solution was taken from the flask periodically and analyzed by HPLC as described in Example 1. The reaction was stopped after the HPLC analysis showed that the peaks for psoralen and isopsoralen had completely disappeared. The reaction mixture was then cooled to room temperature and the aqueous phase was stirred. After the solution was washed multiple times with saturated NaCl solution, the organic layers were extracted with ethyl acetate or other organic solvents. The organic solution was filtered, washed, dried and evaporated to produce a brown red syrup with a bakuchiol content of not less than 50% and a combined total of not more than 100 ppm of psoralen and angelicin (isopsoralen).

EXAMPLE 5; : ANTIOXIDANT PROPERTIES OF BAKUCHIOL CMOPOSITION. FREE OF FURANOCOUMARINA "A composition of natural bakuchiol (Lot # UE256- ll 0906MP) comprising 57.35% of bakuchiol and a combined total of less than 100 ppm of psoralen and angelicin (isopsoralen) was evaluated for its antioxidant capacity against peroxy radicals, hydroxyl radicals, peroxynitrite, super oxide anion and an oxygen singlet in the Laboratories Brunswick, Norton, A USA. The total oxygen radical absorbency of the bakuchiol composition was measured according to the published methodology (Ou, B. et al., J Agrie and Food Chem, 2001, 49 (10): 4619-4626; Prior, RL. and others, J Agrie and Food Chem, 2005, '53: 4290-4302). The results are tabulated in Table 4.

Table 4: Antioxidant profile of Bakutrol ™ (UP256) Acceptable accuracy of the ORAC trial is < 15% relative to the standard deviation ^ Liquid samples weighted and extracted due to viscosity.

There are five predominant reactive species found in the body; peroxyl radicals, hydroxyl radicals, peroxynitrite, super oxide anion, and oxygen singlet. Total ORACFN provides a measure of the total antioxidant power of a food / nutrient product versus five predominant reactive species. , ' EXAMPLE 6 EVALUATION OF A BAKUCHIOL COMPOSITION FOR EFFECT PROTECTOR ANTIOXI DANTGE IN CITOTOXICI DAD 4-TBP CYTOTOXICITY A natural bakuchiol composition comprising 77.02% bakuchiol and a combined total of less than 100 ppm psoralen and angelicin (isopsoralen) was tested for its antioxidant property by evaluating its ability to prevent the induction of tertiary 4-butylphenol (4"TBP) Oxidizing tension during a treatment period of 5 days using compound concentrations at a dose of 95% viability Oxidizing tension was determined by testing the generation of Reactive Oxygen Species (ROS) using the Live Green Reactive Oxygen Species Detection Kit Image-iT (InVitrogen) In this assay, carboxy-2 ', 7'-dichlorodihydrofluorescein diacetate was added to the cultured cells for 30 minutes when diffused into melanocytes and are hydrolyzed by intracellular esters for 2 ', 7'-dichlorofluorescein (DCF) which reacts with ROS to generate fluorescent DCF. After 5 days of treatment with 200 μ? or 400 μ? of 4-TBP, ROS generation in melanocytes demonstrated a dose response (ie, moderate to robust, respectively), while untreated melanocytes treated with DMSO did not exhibit ROS generation. When the treatment protocol included the test compounds, UP256. (Bakuchiol) showed a strong antioxidant property as shown in Figure 3.

EXAMPLE 7 INHIBITOR ACTIVITY OF THYROCINASE OF A COMPOSITION OF BAKUCHIOL ' Two compositions of natural bakuchiol comprising 77.02% bakuchiol (100% purity) for inhibition of thryo kinase activity were tested. Both materials contained a combined total of less than 100 ppm of psoralen and total angelicin (isopsoralen).

A thyrotoxin inhibition assay was carried out using the method reported by Jones et al. (2002) Pigment. Cell Res. 15: 335. Using this method, the conversion of L-Dopa, to the substrate ^ of thirokinase, in dopachrome was followed by monitoring the absorption at 450 nm. Thyrokinase was prepared in 50 mM potassium phosphate pH regulator. 6.8 (assay pH regulator) at 2000 U / ml and stored at -20 ° C in 1 ml aliquots before use. For use in assays, stock enzyme solutions were thawed and diluted to 200 U / ml with assay pH buffer. 2 mM of an operating solution of the substrate;, L-DOPA, was prepared in assay pH regulator for each assay .. The samples were dissolved in 10% DMSO (0.5 ml) and diluted to 5 ml with pH regulator from test. The reaction mixture comprised 0.050 ml 2 mM L-DOPA, 0.050 ml 200 U / ml mushroom mydrokinase and 0.050 ml inhibitor. The reaction volume was adjusted to 200 μ? with test pH regulator. Assays were performed in Falcon '3097 96-well flat bottom microtiter plates (Beckton Dickinson, NJ). The appearance of the dopachrome was measured with an ALLAC 1420 Multilatable Counter (Turku, Finland). The average velocity was determined from the linear enzyme degree as measured by the change 'eq- | the absorbance (?? 45?) At 450 nm per minute. The percentage of thyrkinase inhibition by means of test samples was determined by comparing; the absorbance of the samples against the control using formula (1): I (Absorption of the negative control - Absorption of the sample) / Absorption of the negative control x 100 (1) As shown in Figure 4, both compositions of bakuchiol did not show inhibitory activity of the tirokinase, while the positive control (kojic acid) showed inhibition in response to the dose with an IC50 value of 63.9 μ ?.

EXAMPLE 8 FORMULATION OF A COMPOSITION OF BAKUCHIOL IN A CREAM, GEL AND COSMETIC LOTION Two natural bakuqhiol compositions comprising 86.54% bakuchiol and 77.02% bakuchiol were formulated in a cosmetic vehicle or cream, gel or complex skin care lotions as demonstrated below.

Formulation A 'Bakuchiol 1.0% Vitamin E acetate 0.1% Fenonip 0.5% ·: Transcutol 98.4% i Formulation B; Bakuchiol 1.0% Vitamin E acetate 0.1%: Capitlic triglyceride 98.4% j Fenonip 0.5% ¡; : Formulation C: Bakuchiol 1.0% Polysorbate-20 15.0%: ll Transcutol 5.0% Vitamin E acetate 0.1% Purified water 78.2% Fenonip 0.5% Table 5. Formulation D EXAMPLE 9 EVALUATION OF THE SAFETY PROFILE OF A COMPOSITION OF BAKUCHIOL COMPOSITION Two natural bakuchiol compositions comprising 86.54% bakuchiol and 77.02% bakuchiol and a combined total of less than 100ppm psoralen and angelicin (isopsoralen) were formulated in a cosmetic vehicle or complex skin care cream, and they were tested in in vitro models or in human clinical trials for their safety profile. As shown in Table 6, the bakuchiol compositions did not show eye irritation, skin irritation, sensitization by allergic contact on the skin, and phototoxicity. The compositions had a solid safety profile at a wide range of levels of concentration (20% to 100% by weight of bakuchiol) with good skin penetration properties.

Table 6: Results of the Safety Test of Bakutrol ™ EXAMPLE 10: CLINICAL EVALUATION OF A BAKUCHIOL COMPOSITION WITHOUT FURANOCOUMARINE A natural bakuchiol composition was formulated (Bakutrol ™) extracted and enriched from the seeds of Psozalea corylifolia and comprising 77.02% bakuchiol and less than 100 ppm furanocoumarin in a cosmetic skin care cream (formulation D, Example 8) and tested in a clinical trial in humans. This study was an open-label human, pilot study to evaluate the clinical benefits of Bakutrol ™ at 0.5% concentration after topical application. The study included 5 subjects who met the exclusion / inclusion criteria for the evaluation of the benefits of the natural composition of bakuchiol to improve Post-Inflammatory Hyperpigmentation (PIH). The duration of the study was 12 weeks. The subjects were instructed to apply Bakutrol ™, 0.5% cream twice a day, in the morning, and at night, and return to the site for a total of 9 visits, including the classification visit. The evaluation included the Global Researcher's Assessment of Skin Conditions (IGA), and the Evaluation of the overall grade and severity of the skin in Post-Inflammatory Hyperpigmentation (PIH) and other conditions of the skin. associated skin, including erythema, dryness, peeling, oiliness, safety and tolerability. The questionnaires of the subject included questions of safety and acceptance related to irritation, skin comfort, use of other products and sunscreens. The photographs were taken at the baseline, Week 4, Week 8 and Week 12. The change; baseline on the severity of PIH, change of the baseline in the PIH Degree, and the proportion of success according to the IGA scale were recorded and analyzed. The next 6 levels of the PIH degree of severity (0 = absent, 1 = light, 2 = mild, 3 = moderate, 4 = moderately severe, 5 = severe) and the total surface area affected by PIH were used for the analysis of clinical results.

As shown in Figure 5, the five subjects treated with a topical cream comprising Bakutrol ™ at 0.5% had at least a degree of reduction in the severity of PIH. The percentage of facial area improvement affected by PIH was more than 50% after 8 weeks of continuous application1 (see Figure 6). The average percentage and absolute grade level improvements of both PIH and their severity are summarized in Figures 7 and 8. Improvements of more than 40%, or a reduction of more than one grade level of both PIH and severity, were obtained as early as 4 weeks after using a natural bakuchiol composition enriched with seeds of. PsQralea corylifolia and comprising 77.02% of bakuchiol and less than 100 PPM of furanocoumarin. The substantial reduction of PIH in the affected facial skin sites is clearly evident in the photographs of two subjects as shown in Figure 9. Both subjects showed progressive improvements in Post-Inflammatory Hyperpigmentation (PIH) in the skin. associated with mild and moderate acnes after the topical application of a Bakutrol ™ cream.

Table 7 summarizes the clinical results by the use of a furanocoumarin-free Bakuchiol composition compared to popular acne treatment products that already contain an antimicrobial or an anti-inflammatory or a combination of these. The data clearly demonstrate that the furanocoumarin-free Bakuchiol composition not only improved the counts of inflammatory and non-inflammatory lesions but also significantly improved Post-Inflammatory Hyperpigmentation. The PIH that benefits from the composition of Bakuchiol is unexpected based on its lack of inhibition of the kinokinase as demonstrated in Example 7.

Table 7. Summary of the Bakutrol Clinical Report and OTC Drugs EXAMPLE 11 EVALUATION OF A COMPOSITION OF BACUCHIOL WITHOUT FURANOCOUMARIN IN THE MITIGATION OF THE EFFECTS OF POST-INFLAMMATORY HYPERPIGMENTATION The safety and efficacy of a cream of 0.5% (w / w) of bakuchiol (UP256) was evaluated in a double-positive, placebo-controlled study blind for the treatment of PIH related to acne. The study evaluated a bakuchiol cream at a concentration of 0.5%, 2% salicylic acid cream and a placebo cream. (Vehicle) in an Asian population. Participants were instructed to apply face creams twice a day (AM / PM). The study participants were given instructions for the application, and a sunscreen was provided.

The study population consisted of male and female subjects older than 18 years and under 40 years of age, and generally in good health as determined by a medical history. The arm of the study with bakuchiol enrolled 18 subjects, the arm of the study with salicylic acid (SAL) enrolled 20 subjects, and the arm of the study with placebo enrolled 19 subjects.

Researchers and study staff discussed and agreed after the clear definition of PIH as related to acne and other tissue damage (which does not include freckles (Ephilides), sun dots, or melisma.) The degree of PIH is a measure of the severity of the hyperpigmentation (higher number = more severe pigmentation) The patient population had a PIH grade> 3 and the acne was mild to moderate, Grade 2-3, the key factor was the PIH as related with current or past inflammatory acne.

Primary Objectives of the Study: 1. IGA PIH Time Frame: Baseline and weeks 2, 4 and 8 2. PIH% Distribution Time Frame: Baseline and weeks 2, 4 and 8 ' The effectiveness of the PIH was evaluated based on changes in the baseline (p <0.05) and on other treatment groups (p <0.05) using the t o / and ANOVA test. · Secondary Objectives: Security Assessments The evaluation questionnaires and the Tolerability Assessments of the Subjects were collected in the baseline and weeks 2, 4, and 8. The urine tests for pregnancy in women with maternity potential were collected in the baseline and week 8.

Data analysis The following data was collected: 1. Change of baseline in severity of the PIH; 2. Change of baseline in the PIH Degree; and 3. Change of baseline in Injuries counts Results: The data was analyzed from the researcher's evaluations at each visit and from the photographs taken at the specified time points. The photographs of the baseline, week 4, and week 8 were evaluated by a second group of researchers and two independent dermatologists before the study was disharmonized to confirm that the population met the criteria. The data analyzed were based on the confirmed evaluations, there were no photographs for week two therefore the data for week two were not included in the analysis. Table 8 summarizes the data.

Table 8. Changes in the change of PIH for the Study Groups 7 The Bakutrol group (UP256) showed a significant change in the PIH grade (ie, lower PIH grade) from the baseline to week 8 (p <0.05). Additionally, the Bakutrol group showed a significant change over placebo at week 8 (p <0.05). The data also show that the group treated with bakutrol is the only group that had a time and p value and of significant p-value treatment (p = 0.0083).

Table 9. Inflammatory Acne Lesions for All Groups The Bakutrol group (UP256) showed a significant change of the baseline at weeks 4 and 8 (p <0.001). The Bakutrol group also showed a significant change over the placebo at week 8 (p <0.05). In addition, UP256 is the only group that achieved a greater than 50% reduction in inflammatory lesions at 8 weeks (57%).

There were no significant changes for the Bakutrol group (UP256) in the non-inflammatory lesion category (data not shown); however, the groups treated with salicylic acid in the category of noninflammatory lesion obtained a p-value of < 0.05 after 4 weeks of treatment.

Table 10: Summary of the Investigator's Questionnaire and Safety Assessment Conclusion: The results show that Bakütrol cream (UP256) significantly reduced post-hyperpigmentation.

Inflammatory (PIH) related to acne after only 4 weeks of topical application. UP256 also significantly reduced inflammatory acne lesions (<0.05) by 57% after 8 weeks.

The Bakutrol cream (UP256) had a good safety profile and was well tolerated by the study participants. The cosmetic acceptability of the cream was classified as better than, as good as, those of its previous over the counter (OTC) therapies.

EXAMPLE 12 TREATMENT OF INFLAMMATORY ACNE INJURIES AND NO INFLAMMATORY A composition comprising both bakuchiol and salicylic acid was prepared. Patients who have both types of acne, inflammatory and noninflammatory, were treated with the composition. The composition is effective to treat both inflammatory and non-inflammatory lesions with a valpr p < 0.05 after 4 weeks of treatment. The reduction is in the range of lesions from about 10% to about 90%.

The various embodiments described above can be combined to provide additional modalities. All patents of E.U.A. , publications of patent applications of E.U.A, patent applications of E.U.A. , foreign patents, foreign patent applications, and non-patent publications referred to in this description and / or listed in the Application Data Sheet, are incorporated by reference in their entirety. Aspects of the modalities may be modified, if necessary, to employ concepts of the various patents, applications and publications to provide additional modalities. These and other changes can be made to the modalities in view of the above detailed description. In general, in the following claims, the terms used should not be constructed to limit the claims to the specific embodiments described in the description and the claims, but should be constructed to include all possible modalities together with the full scope of equivalents to which they are assigned. entitle the claims. Accordingly, the claims are not limited by the description.

It is noted that in relation to this date, the best method known by the applicant to bring the said invention into practice is that which is clear from the present description of the invention.

Claims (51)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. A method for preventing, alleviating, reducing or treating excess pigmentation resulting from a condition derived from an inflammatory skin disorder, characterized in that it comprises administering to a mammal an effective amount of a composition comprising bakuchiol, or a pharmaceutically acceptable salt thereof acceptable, and a pharmaceutically acceptable carrier and less than 500 ppm of total furanocoumarin impurities.

2. The method according to claim 1, characterized in that the condition is post-inflammatory hyperpigmentation. :

3. The method according to any of the preceding claims, characterized in that · the composition comprises less than 100 ppm of total furanocoumarin impurities.;

4. The method according to any of the preceding claims, characterized in that the composition does not show a thyrotinase inhibitory activity in relation to a kojic acid control.

5. The method of compliance with any of the previous claims, characterized in that the furanocoumarin impurities comprise psoralen, isopsoralen or combinations thereof.

6. The method according to claim 2, characterized in that the post-inflammatory hyperpigmentation (PIH) is derived from acne, atopic dermatitis, allergic contact dermatitis, incontinent pigment, lichen planus, lupus erythematosus, morphea, mechanical trauma, ionization radiation or no ionization, burns, laser or drug therapies, skin infection or combinations thereof.

7. The method according to claim 6, characterized in that the post-inflammatory hyperpigmentation (PIH) is derived from acne.

8. The method according to any of the preceding claims, characterized in that the composition comprises from 0.001% to 99.9% by weight tota ^ l of bakuchiol and a pharmaceutical, dermatological, or cosmetically acceptable carrier.

9. The method according to any of the preceding claims, characterized in that the composition is administered topically, by aerosol, ..... by suppository, intradermally, intramuscularly or intravenously.

10. The method according to any of the preceding claims, characterized in that the composition is formulated for topical administration.

11. The method according to any of the preceding claims, characterized in that the composition comprises from about 0.1% to about 2.0% by total weight of bakuchiol.

12. The method according to any of the preceding claims, characterized in that the composition comprises approximately 0.5% by total weight of bakuchiol.

13. The method according to any of the preceding claims, characterized in that it prevents excess pigmentation.

14. The method according to any of the preceding claims, characterized in that it alleviates pigmentation in excess.

15. The method according to any of the preceding claims, characterized in that it reduces excess pigmentation.

16. The method according to any of the preceding claims, characterized in that it treats pigmentation in excess.

17. The method according to any of the preceding claims, characterized in that the excess pigmentation occurs in a deep layer of the skin.

18. The method in accordance with the claim 17, characterized in that the excess pigmentation occurs in a papillary layer in the dermis of the skin.

19. The method according to any of the claims. above, characterized in that it also comprises reducing the anion of the super oxide.

20. The method according to any of the preceding claims, characterized in that it also comprises reducing melanogenesis.

21. The method according to any of the preceding claims, characterized in that it further comprises reducing the proliferation of melanocytes.

22. The method according to any of the preceding claims, characterized in that it further comprises preventing the apoptosis of melanocyte.

23. The method according to any of the preceding claims, characterized in that the composition further comprises salicylic acid or a pharmaceutically acceptable salt thereof.

24. A method for reducing melanogenesis, reducing the proliferation of melanocytes or preventing melanocyte apoptosis, characterized in that it comprises administering to a mammal an effective amount of a composition comprising bakuchiol or one of its pharmaceutically acceptable salts and a pharmaceutically acceptable carrier and less than 500 ppm of total furanocoumarin impurities.

25. The method according to claim 24, characterized in that it also comprises reducing the anion of the super oxide.

26. The method according to any of claims 24-25, characterized in that the composition comprises less than 100 ppm of total furanocoumarin impurities.

27. The method according to any one of claims 24-26, characterized in that the composition does not show a thryo kinase inhibitory activity in relation to a kojic acid control.

28. The method according to any of claims 24-27, characterized in that the bakuchiol is synthesized or chemically isolated

29. The method according to any of claims 24-28, characterized in that the impurities of furanocoumarin comprise psoralen, isopsoralen or: combinations thereof. '

30. The method of compliance with any djs. claims 24-29, characterized in that melanogenesis, melanocyte proliferation or melanocyte apoptosis is a result of post-inflammatory hyperpigmentation (PIH).

31. The method according to claim 30, characterized in that the ipost-inflammatory hyperpigmentation (PIH) is derived from acne, atopic dermatitis, allergic contact dermatitis, incontinent pigment, lichen planus, lupus erythematosus, morphea, mechanical trauma, radiation by ionization or non-ionization, burns, laser or drug therapies, skin infection or combinations thereof.

32. The method according to claim 31, characterized in that the post-inflammatory hyperpigmentation (PIH) is derived from acne.

33. The method according to any of claims 24-32, characterized in that the composition comprises from 0.001% to 99.9% by total weight of bakuchiol and a pharmaceutical, dermatological or cosmetically acceptable carrier.

3 . The method according to any of claims 24-33, characterized in that the composition is formulated for topical administration.

35. The method according to any of claims 24-34, characterized in that the composition comprises from 0.1% to 2.0% by total weight of bakuchiol.

36. The method according to any of claims 24-35, characterized in that the composition comprises approximately 0.5% by total weight of bakuchiol.

37. The method according to any of claims 24-36, characterized in that it prevents excess pigmentation.

38. The method of compliance with any of the claims 24-37, characterized in that it alleviates pigmentation in excess.

39. The method according to any of claims 24-38, characterized in that it reduces excess pigmentation.

40. The method according to any of claims 24-39, characterized in that it treats pigmentation in excess.

41. The method according to any of claims 37-40, characterized in that the excess pigmentation occurs in a deep layer of the skin.

42. The method according to any of claims 24-41, characterized in that the excess pigmentation occurs in a papillary layer in the dermis of the skin.

43. The method according to any of claims 24-42, characterized in that I reduced the melanogenesis.

44. The method according to any of claims 24-43, characterized in that it reduces the proliferation of melanocytes.

45. The method according to any of claims 24-44, characterized in that it prevents melanocyte apoptosis.

46. The method according to any of claims 24-45, characterized in that the composition it further comprises salicylic acid or a pharmaceutically acceptable salt thereof.

47. A method for treating inflammatory or noninflammatory lesions, characterized in that it comprises administering an effective amount of a composition comprising bakuchiol or a pharmaceutically acceptable salt thereof and salicylic acid or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier to a mammal.

48. The method according to claim 47, characterized in that the lesions comprise inflammatory acne lesions.

49. The method according to any of claims 47-48, characterized in that the method treats inflammatory or non-inflammatory lesions.

50. A composition characterized in that it comprises bakuchiol or one of its pharmaceutically acceptable salts and salicylic acid or a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

51. The composition in accordance with; Claim 50, characterized in that it is formulated: for topical administration. :