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US20160030321A1 - Calcium sequestration compositions and methods of treating skin pigmentation disorders and conditions - Google Patents

Calcium sequestration compositions and methods of treating skin pigmentation disorders and conditions Download PDF

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Publication number
US20160030321A1
US20160030321A1 US14/794,462 US201514794462A US2016030321A1 US 20160030321 A1 US20160030321 A1 US 20160030321A1 US 201514794462 A US201514794462 A US 201514794462A US 2016030321 A1 US2016030321 A1 US 2016030321A1
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skin
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acid
calcium
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US14/794,462
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Frank Dreher
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Neocuitis SA
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Neocuitis SA
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/55—Phosphorus compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
    • A61K31/6615—Compounds having two or more esterified phosphorus acid groups, e.g. inositol triphosphate, phytic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/04—Dispersions; Emulsions
    • A61K8/06—Emulsions
    • A61K8/066—Multiple emulsions, e.g. water-in-oil-in-water
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2121/00—Preparations for use in therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/80—Process related aspects concerning the preparation of the cosmetic composition or the storage or application thereof
    • A61K2800/88—Two- or multipart kits

Definitions

  • the invention relates generally to compositions containing one or more calcium sequestration agents and methods for topical application to the skin to treat skin pigmentation disorders, such as melasma, post-inflammatory hyperpigmentation, pigmentation changes due to skin aging, or any other skin conditions related with normal such as skin of color or abnormal pigmentation such as hypo- or hyper-pigmentation in humans.
  • skin pigmentation disorders such as melasma, post-inflammatory hyperpigmentation, pigmentation changes due to skin aging, or any other skin conditions related with normal such as skin of color or abnormal pigmentation such as hypo- or hyper-pigmentation in humans.
  • melanocytes In humans, skin color arises from a complex series of cellular processes that are carried out within a group of cells known as melanocytes. Melanocytes are located in the lower part of the epidermis and their function is to synthesize a pigment, melanin, which protects the body from the damaging effects of ultraviolet radiation. Melanin is a biopolymer originating from conversions of the amino acids phenylalanine or tyrosine.
  • melanin typically, the darker (or more tanned) the skin.
  • melanogenesis and skin pigmentation can be disturbed or disorder, which may lead to undesirable pigmentation patterns.
  • pigmentation disorders i.e., disorders where pigmentation is disturbed or disordered
  • tyrosinase the enzyme which catalyses the initial steps in the generation of melanin.
  • Skin pigmentation has been of concern to human beings for many years.
  • hyperpigmentation i.e., areas of darker skin color than the surrounding or adjacent, normal pigmented skin
  • skin complexion i.e., areas of skin color than the surrounding or adjacent, normal pigmented skin
  • skin tone i.e., areas of skin color than the surrounding or adjacent, normal pigmented skin
  • general body whitening is desirable.
  • hypopigmentation i.e., areas of less dark skin color than the surrounding or adjacent, normal pigmented skin
  • hyperpigmentation disorders that are desirable to treat.
  • the ability to generate a tanned appearance without incurring photodamage due to solar radiation is important to many individuals.
  • depigmentationation i.e., reduction or limitation of skin pigmentation or skin color.
  • arbutin, kojic acid, hydroquinone, retinoids, and other chemical compounds have been used for depigmentation.
  • Chemicals that allow depigmentation of skin are also called skin lighteners, skin brighteners, skin whiteners, skin bleachers or actives with skin lightening, skin brightening, skin whitening or skin bleaching properties.
  • compositions which inhibit melanogenesis and reduce skin pigmentation by modulating one or more of the multiple steps involved in melanogenesis and skin pigmentation.
  • compositions that allow skin depigmentation without irritation.
  • the compositions and methods of the present invention address these long felt needs in the art.
  • the present invention provides compositions containing at least one calcium sequestering or calcium binding agent for treating or ameliorating at least one symptom of a skin pigmentation disorder or condition, in a subject in need thereof.
  • the calcium sequestering or binding agent is a phosphate. More preferably, the phosphate is glycerophosphoric acid or a, non-calcium, salt thereof. Most preferably, the phosphate is sodium glycerophosphate.
  • the calcium sequestering or binding agent is present in the composition in the amount of about 0.1% to about 25%. When the calcium sequestering or binding agent is phosphate it is preferably present in the composition in the amount of about 1% to about 5% by weight.
  • compositions for treating or ameliorating at least one symptom of a skin pigmentation disorder or condition in a subject in need thereof can contain a calcium sequestering or binding agent and can further contain one or more of the following agents, which modulate or regulate at least one step of melanogenesis: L-alanine, glycine, L-isoleucine, L-leucine, hydroquinone, 4-(1-phenylethyl)1,3-benzenediol, arbutin, bearberry leaf extract, kojic acid, oxyresveratrol, gnetol, retinoic acid or retinol, melanosome transfer inhibitor, or ⁇ -MSH antagonist.
  • agents which modulate or regulate at least one step of melanogenesis: L-alanine, glycine, L-isoleucine, L-leucine, hydroquinone, 4-(1-phenylethyl)1,3-benzenediol, arbutin, bearberry leaf extract, kojic acid,
  • compositions that include at least one additional agent selected from the group consisting of skin moisturization or skin rejuvenation agents.
  • the skin moisturization or skin rejuvenation agents may be ascorbic acid, vitamin E, jojoba oil, shea butter, human fibroblast lysate, retinoic acid, retinol, and/or any derivatives thereof.
  • compositions for treating, or ameliorating at least one symptom of, a skin pigmentation disorder or condition, in a subject in need thereof are formulated for topical administration.
  • the compositions of the invention can be in the form of a solution, an oil-in-water emulsion, a water-in-oil emulsion, a gel, an ointment, a patch, a paste, a liquid, a foam, a mousse, a spray, an aerosol, a triple emulsion, a nanoemulsion, a microemulsion, a hydrogel, a jelly, a dispersion, a suspension, and/or a tape.
  • the compositions are stable, substantially free of calcium, do not cause an acnegenic/comedogenic response, and/or produce only minor skin irritation upon administration.
  • the skin pigmentation disorder can include, but is not limited to, melasma, post-inflammatory hyperpigmentation, pigmentation changes due to skin aging, age or liver spots, freckles, or any other skin conditions related with normal such as skin of color or abnormal pigmentation such as hypo- or hyper-pigmentation.
  • administration of the compound reduces skin pigmentation.
  • the subject can be any mammal, preferably a human.
  • the invention also provides pharmaceutical formulations containing any of the compositions described herein and at least one pharmaceutically acceptable carrier.
  • the invention also provides cosmetic formulations containing any of the compositions described herein an at least one cosmetically acceptable carrier.
  • the invention provides kits including, in one or more containers, these pharmaceutical or cosmetic formulations. Those skilled in the art will recognize that such kits may optionally contain instructions for use of the pharmaceutical or cosmetic formulations in the treatment or amelioration of said skin pigmentation disorder or condition.
  • the invention also includes unit dosage forms containing therapeutically effective amounts of any of the compositions and/or pharmaceutical formulations described herein.
  • compositions or formulations described herein can be used in methods of reducing skin pigmentation in a patient by administering an effective amount of the composition and/or formulation to the patient.
  • the effective amount of the composition is administered topically to the patient.
  • compositions for treating or ameliorating at least one symptom of a skin pigmentation disorder or condition that include 59.68% (by weight) water, 0.1% (by weight) disodium EDTA, 0.3% (by weight) xanthan gum, 0.3% (by weight) chlorphenesisn, 0.6% (by weight) phenoxyethanol, 0.5% (by weight) undecylenoyl phenylalanine, 3.00% (by weight) sodium glycerophosphate, 1.00% (by weight) leucine, 6.00% (by weight) cetearyl alcohol/ceteareth-20, 6.00% (by weight) glyceryl stearate, 3.00% (by weight) diisopropyl adipate, 3.00% (by weight) caprylyl methicone, 1.00% (by weight) dimethicone, 1.00% (by weight) simmondsia chinensis (jojoba) seed oil, 1.00% (by weight) butryosperm
  • the invention further provides a composition for treating or ameliorating at least one symptom of a skin pigmentation disorder or condition containing 63.41% (by weight) water, 0.1% (by weight) disodium EDTA, 0.3% (by weight) xanthan gum, 0.3% (by weight) chlorphenesisn, 0.6% (by weight) phenoxyethanol, 0.5% (by weight) undecylenoyl phenylalanine, 3.00% (by weight) sodium glycerophosphate, 1.00% (by weight) leucine, 1.92% (by weight) citric acid 50% solution, 8.25% (by weight) cetearyl alcohol/ceteareth-20, 6.00% (by weight) glyceryl stearate, 5.00% (by weight) diisopropyl adipate, 3.00% (by weight) caprylyl methicone, 1.00% (by weight) dimethicone, 1.00% (by weight) simmondsia chinensis (jojoba)
  • FIG. 1 is a graph showing skin irritation of a composition of the present invention (see Example 3, infra) as compared to other known compositions (e.g.: Compositions A to D), which are not part of this invention.
  • This graph which represents a “survival” type curve, shows the percentage of subjects who did not show any irritancy reaction reaching an evaluation score of “3” or higher as a function of time (i.e., observation) during the repetitive human irritancy patch test of three weeks (21 days) duration.
  • composition of the present invention was better tolerated (i.e., fewer subjects reached an evaluation score of “3” or higher with continued, prolonged application of patch with test material) as compared to Compositions A to D).
  • FIG. 2 shows the color stability of a composition of the present invention (Composition A) as compared to other, control compositions (e.g.: Compositions B, C and D), which are not part of this invention.
  • FIG. 3 is a photograph showing the reduction of pigmentation in the skin of a patient using the compounds of the present invention (i.e., the composition described in Example 3, infra).
  • Panel A shows the hyperpigmentation of the patient's skin prior to administration of a compound of the present invention.
  • Panel B shows the reduction in skin pigmentation following 12 weeks of treatment with a composition of the present invention.
  • the present invention is directed to modulating (increasing or decreasing) various steps of melanogenesis (melanin formation) and to reduce skin pigmentation (skin color). More specifically, the present invention provides compositions for treating or ameliorating a symptom of a pigmentation disorder or condition involving a single active agent which modulates more than one step in the multi-step process of melanin formation and skin pigmentation.
  • the present invention also provides compositions which contain at least two active agents (e.g., 2, 3, 4, 5, or more), where each active agent can target at least one step in the multi-step process of melanin formation. These multiple agents decrease melanin formation and skin pigmentation. By targeting multiple steps of melanogenesis and skin pigmentation, the compositions of present invention provide superior properties as compared to hypopigmentation products currently known in the art.
  • Calcium (Ca 2+ ) may be an important regulator of some steps in melanogenesis and skin pigmentation. For instance, increase in calcium is believed to promote active transport of L-phenylalanine and its turnover via phenylalanine hydroxylase to L-tyrosine to significantly increase the pool of this substrate for melanogenesis. (See Dermatol Clin 25, 2007, pp. 283-291). Further, there is some evidence from in vitro studies that calcium impacts the melanosome transfer. (See Pigment Cell Res 20, 2007, pp. 380-384).
  • the present invention provides compositions and methods for skin depigmentation which interferes one or more steps in the melanogenesis and skin pigmentation process where calcium is involved by administering a composition suitable for topical application containing at least one calcium sequestration or binding agent.
  • Examples of calcium sequestering or binding agents include either inorganic, organic (or a combination thereof, or organo-metallics) derived molecules.
  • the agents are calcium-free oxoanions of any or all possible oxidation states, achiral or chiral, selected from phosphates, phosphate esters, phosphonates, phosphonate esters, phosphoramidites, sulfates, sulfate esters, sulfonates, sulfonate esters, sulfites, siloxanes, carbonates, boronates, borinates, borinate esters, siloxanes, siloxane esters, polysiloxanes, sulfoxides, sulfonamides, sulfinic acids, sulfinimides, thiol esters, thioureas, and tosylates.
  • the organic agents would possess calcium free anionic or neutral Lewis Base donors, achiral or chiral selected from carboxylic acids, polycarboxylates, carboxylic esters, nitriles, isocyanates, hydrazines, hydrazones, ureas, carboxylic esters, oximes, amides, amidines, thioethers, ethers, amines, alcohols, alkoxides, thiols, thiolates.
  • Lewis Base donors achiral or chiral selected from carboxylic acids, polycarboxylates, carboxylic esters, nitriles, isocyanates, hydrazines, hydrazones, ureas, carboxylic esters, oximes, amides, amidines, thioethers, ethers, amines, alcohols, alkoxides, thiols, thiolates.
  • Table 1 recites non-limiting, representative, examples of carboxylic acids, boronic acids, amines, sulfates suitable to be utilized as calcium sequestration or binding agents
  • Table 13 recites non-limiting, representative, examples of carboxylic acids suitable to be utilized as calcium sequestration or binding agents.
  • Table 14 recites non-limiting, representative, examples of aryl carboxylic acids suitable to be utilized as calcium sequestration or binding agents.
  • Table 15 recites non-limiting, representative, examples of cycloalkyl carboxylic acids suitable to be utilized as calcium sequestration or binding agents.
  • Table 16 recites non-limiting, representative, examples of heteroaryl and biaryl acids suitable to be utilized as calcium sequestration or binding agents.
  • Table 17 recites non-limiting, representative, examples of ureas suitable to be utilized as calcium sequestration or binding agents.
  • Table 18 recites non-limiting, representative, examples of hydrazones suitable to be utilized as calcium sequestration or binding agents.
  • the “calcium sequestration agent” or “calcium binding agent” of the present invention is any agent capable of binding or sequestering calcium ion (Ca II ) such that the bound or sequestered calcium ion is prevented or inhibited (i.e., reduced) from interacting with other binding agents.
  • the calcium sequestration or binding agent when administered to the skin of a patient in need of such treatment, binds or sequesters calcium ion in the local area of topical administration and regulates or modulates (i.e., prevents, limits, or inhibits) calcium from acting as a regulator in several (i.e., at least two) steps of melanogenesis and skin pigmentation.
  • the present composition contain a calcium sequestration or binding agent in an amount effective to reduce pigmentation.
  • the calcium sequestration or binding agent is present in the composition in an amount from about 0.1% to the solubility limit of the calcium sequestration or binding agent in the composition.
  • the calcium sequestration or binding agent is present in the composition in the amount of about 0.1% to about 25%, more preferably about 0.2% to about 10%, most preferably about 1% to about 5% by weight.
  • the pH range of any of the compositions containing a calcium sequestration or binding agent described herein is about 2.5 to about 9.0, preferably about 3.0 to about 7.0, more preferably about 4.0 to about 5.0.
  • Solutions for adjusting pH to appropriate value e.g., sodium hydroxide (NaOH), may be added to the composition of the present invention, as required.
  • the agent capable of binding or sequestering calcium ion is a phosphate agent.
  • a phosphate is defined as a form of phosphoric acid.
  • the phosphate can contain one or more of phosphorus (P) atoms as follows:
  • R1, R2 and R3 are each chosen from branched or unbranched alkyl or alkenyl groups having one or more carbon atoms.
  • phosphate does not include phosphate derivatives of ascorbic acid, such as sodium or magnesium ascorbyl phosphate, aminopropyl ascorbyl phosphate and other known phosphate derivatives of ascorbic acid with antioxidant properties.
  • the composition can be prepared contains a phosphate form substantially free of calciums such as the phosphoric acid glycerophosphoric acid (C 3 H 9 O 6 P).
  • Glycerophosphoric acid can be present in two different chemical structures, including:
  • compositions of the present invention contain the sodium salts of glycerophosphoric acid.
  • glycerophosphoric acid includes alpha-glycerophosphoric acid, beta-glycerophosphoric acid, or any mixture thereof.
  • Sodium salts of glycerophosphoric can further include the monosodium sodium salt of glycerophosphoric acid (C 3 H 8 NaO 6 P), the disodium sodium salt of glycerophosphoric acid (C 3 H 7 Na 2 O 6 P), and/or any mixture of the mono- and disodium salts.
  • Sodium salts of glycerophosphoric acid are herein referred as “sodium glycerophosphate”.
  • the sodium glycerophosphate may further contain some bound water and may be in its hydrated form.
  • the bound water is present in an amount of about 20 to about 40%; preferably between about 25 to about 35% per weight.
  • the sodium glycerophosphate in accordance to the descriptions provided in European Pharmacopoeia 6 th Ed. (2007) represents one of the preferred forms and qualities of sodium glycerophosphate.
  • the composition may be prepared with other possible salts of glycerophosphoric acid such as the potassium salts of glycerophosphoric acid, the magnesium salts of glycerophosphoric acid, the manganese salts of glycerophosphoric acid, and/or any possible combination thereof including the sodium salts of glycerophosphoric acid.
  • other possible salts of glycerophosphoric acid such as the potassium salts of glycerophosphoric acid, the magnesium salts of glycerophosphoric acid, the manganese salts of glycerophosphoric acid, and/or any possible combination thereof including the sodium salts of glycerophosphoric acid.
  • calcium glycerophosphate or any other calcium salts of phosphoric acid are not phosphates free of calcium and, therefore, are not used in the present invention.
  • compositions of the invention contain phosphate(s) in an amount effective to reduce pigmentation.
  • phosphate is present in the composition in an amount from about 0.1% to the solubility limit of the phosphate in the composition.
  • the phosphate is present in the composition in the amount of about 0.1% to about 25%, more preferably about 0.2% to about 10%, most preferably about 1% to about 5% by weight.
  • the composition is prepared with sodium glycerophosphate (C 3 H 7 Na 2 O 6 P ⁇ H 2 O according to specifications provided in European Pharmacopoeia 6 th Ed. (2007)) between about 1% to about 5% by weight.
  • sodium glycerophosphate C 3 H 7 Na 2 O 6 P ⁇ H 2 O according to specifications provided in European Pharmacopoeia 6 th Ed. (2007)
  • the present invention also provides a skin lightening composition, which is well tolerated.
  • skin lightening compositions provide less skin irritation than is commonly observed with several of the skin lightening products containing hydroquinone; in particular those skin lightening products with additionally contain chemicals with known human skin irritant properties such as retinoic acid, tretinoin, retinol, alpha hydroxy acids such as glycolic or lactic acid, beta hydroxyl acids such as salicylic acid, azelaic acid, free short chain fatty acids, free short chain fatty acid esters, ionic surfactants such as SLS or SLES.
  • Examples of skin lightening products containing hydroquinone along with chemicals with known human skin irritant properties include, but are not limited to, Tri-Luma® (from Galderma), EpiQuin® Micro (from SkinMedica), Obagi Nu-Derm® Clear and Obagi Nu-Derm® Blender (both from OMP, Inc.) and Lustra® Hydroquinone USP 4% (from TaroPharma).
  • compositions of the present invention are well tolerated and do not (or only minimally) lead to visibly noticeable skin redness (i.e., erythema, contact dermatitis) or rash (i.e., edema, contact allergy, uticaria) when used once to twice daily for a prolonged period of time (i.e., more than two weeks) under normal in use conditions typical of a skincare or dermatological product. More specifically, the compositions of the present invention provide less skin irritation as compared to skin lightening products containing hydroquinone as observed in repetitive skin irritancy patch tests in humans or animals realized according to the art-recognized models described in J. Toxicol.—Ot.
  • the present invention provides methods and compositions for skin depigmentation which are effective in concentrations not resulting in significant skin irritancy as determined by the art-recognized models described herein.
  • the present invention provides compositions which are substantially free of calcium, steroids, parabens, anti-microbial preservatives and/or formaldehyde releasers
  • the term “substantially free” as used herein means that the composition of interest (e.g., calcium) is present in the composition in an amount less than 0.1% per weight, preferably less than 0.5% by weight and most preferably less than 0.01% per weight.
  • the present invention provides compositions which are suitable for topical application, cosmetically elegant and fast absorbing.
  • compositions of the present invention do not provide sticky, oily, greasy or otherwise unpleasant feeling when applied onto skin after about one to maximum of about two minutes of application; in case applied as dose per skin area typical for skincare or dermatological products (typically less than 1 mg of composition per cm 2 ).
  • the present invention also provides stable skin lightening composition, which contain at least one calcium sequestration or binding agent, as described above, and which may further contain at least one additional active agent capable or modulating or reducing (as assessed in vitro and/or in vivo) at least one of the following steps in melanogenesis:
  • L-alanine, glycine, L-isoleucine, L-leucine, but not their D-forms were described to have hypopigmenting effects in an in vitro assay using B16F0 melanoma cells as cell model for studying melanogenesis. (See Biol Pharm Bull 30, 2007, pp. 677-681). These amino acids were shown not to function as inhibitors of tyrosinase.
  • Another compound potentially inhibiting tyrosine transport is the sulfur homologue of tyrosine 4-S-cysteinylphenol.
  • 4-S-cysteinylphenol may also act as substrate of tyrosinase and can therefore be also regarded as inhibitor of tyrosinase.
  • amino acids L-phenylalanine and L-tryptophan also compete for tyrosine transport.
  • phenylalanine is a precursor of melanin and is therefore excluded in the present invention.
  • L-Tyrosine is formed from L-phenylalanine in the presence of enzyme phenylalanine hydroxylase in melanocytes. Similarly, tryptophan is excluded in the present invention.
  • compositions of the present invention can contain at least one calcium sequestration or binding agent and can further contain L-alanine, glycine, L-isoleucine, L-leucine or a combination thereof.
  • amides R—NH(C ⁇ O)—R′
  • R from amino acid and R
  • the present composition can also contain amino acids or their respective derivatives (esters, amides, etc.) in an amount effective to reduce pigmentation or reduce the transport of L-tyrosine either into the melanocyte and/or into the melanosome.
  • the amino acid is present in the composition in an amount from about 0.001% to the solubility limit of the amino acid in the composition.
  • the amino acid is present in the composition in the amount of about 0.01% to about 10%, more preferably about 0.05% to about 5%, most preferably about 0.1% to about 2% by weight.
  • the invention provides a composition containing one or more phosphates, substantially free of calcium, and further containing L-leucine in an amount of about 0.1% to about 2% by weight.
  • the present invention provides a composition containing sodium glycerophosphate (C 3 H 7 Na 2 O 6 P ⁇ H 2 O; according to specifications provided in Ph. Eur. 6 th Ed.) in an amount of about 1% to 5% by weight and further contains L-leucine in an amount of about 0.1% to 2% by weight.
  • compositions of the present invention can contain at least one calcium sequestration or binding agent and may further contain one or more compounds capable of reducing (as assessed in vitro and/or in vivo) the turnover of L-tyrosine into L-Dopa by tyrosinase or tyrosine hydroxylase, and/or the turnover of L-Dopa into dopaquinone by tyrosinase.
  • tyrosinase inhibitors Compounds which reduce the turnover of L-tyrosine into L-Dopa and/or reduce the turnover of L-Dopa into dopaquinone are generally referred as tyrosinase inhibitors meaning that they inhibit of tyrosinase activity, tyrosinase gene expression, and/or tyrosine protein formation and/or maturation.
  • hydroquinone (1,4-benzenediol) hydroquinone (1,4-benzenediol); diphenylmethane derivatives (see WO 2004/105736; incorporated herein by reference) including but not limited to 4-(1-phenylethyl)1,3-benzenediol (phenylethyl resorcinol); kojic acid; alpha-arbutin; beta-arbutin; deoxyarbutin, L-mimosine; monobenzyl ether of hydroquinone; hydroquinone fatty esters; L-tropolone; ascorbic acid; benzoic acid; oxyresveratrol (i.e., 2,4,3′,5′-tetrahydroxystilbene); quercetin; benzaldehyde; aloesin; trans-resveratrol; anisaldehyde; cinnamic acid; gne
  • any biological precursors (pro-forms) of above chemicals can also be included in the present invention.
  • Biological precursors can be simple esters (i.e. methyl-, ethyl-, propyl-, or butyl-esters) of inhibitors with carboxy group.
  • derivatives of ascorbic acid such as aminopropyl ascorbyl phosphate, magnesium ascorbyl phosphate, alkyl esters of L-ascorbic acid such as L-ascorbyl palmitrate, L-ascorbyl isopalmitate, L-ascorbyl dipalmitate, L-ascorbyl isostearate, L-ascorbyl distearate, L-ascorbyl diisostearate, L-ascorbyl myristate, L-ascorbyl isomyristate, L-ascorbyl 2-ethylhexanoate, L-ascorbyl di-2-ethylhexanoate, L-ascorbyl oleate and L-ascorbyl dioleate; phosphates of L-ascorbic acid such as L-ascorbyl-2-phosphate and L-ascorbyl-3-phosphate; sulfates of L-as
  • the present composition may contain at least one tyrosinase inhibitor in an amount effective to reduce pigmentation or reduce the turnover of L-tyrosine into L-Dopa by tyrosinase or tyrosine hydroxylase, and/or the turnover of L-Dopa into dopaquinone by tyrosinase.
  • the tyrosinase inhibitor can be present in the composition in an amount from about 0.001% to the solubility limit of the tyrosinase inhibitor in the composition.
  • the tyrosinase inhibitor is present in the composition in the amount of about 0.01% to about 15%, more preferably about 0.05% to about 10%, most preferably about 0.1% to about 5% by weight.
  • the present invention provides a composition containing one or more phosphates, substantially free of calcium, and further containing: a) hydroquinone (1,4-benzenediol) in an amount of about 0.1% to about 10% by weight, b) 4-(1-phenylethyl)1,3-benzenediol (phenylethyl resorcinol) in an amount of about 0.1% to about 5% by weight, c) arbutin in an amount of about 0.1% to about 10% by weight, d) bearberry leaf extract in an amount of about 0.1% to about 10% by weight, e) kojic acid in an amount of about 0.1% to about 5% by weight, f) oxyresveratrol in an amount of about 0.1% to about 5% by weight, and/or g) gnetol in an amount of about 0.1% to about 5% by weight.
  • compositions of the invention may contain, in some embodiments, one or more phosphates, substantially free of calcium, and may further contain hydroquinone (1,4-benzenediol) in an amount of about 1% to about 10% by weight and/or may further contain 4-(1-phenylethyl)1,3-benzenediol (phenylethyl resorcinol) in an amount of about 0.1% to about 5% by weight
  • compositions of the present invention contain at least one calcium sequestration or binding agent and may additionally contain one or more compounds capable of reducing (as assessed in vitro and/or in vivo) the transfer of melanosmes from melanocytes to keratinocytes.
  • Inhibitors of the transfer of melanosomes from melanocytes to keratinocytes have been described previously (see Pigment Cell Res 19, 2006, pp. 550-571) and include, for example, niacinamide (vitamin B3); centaureidine; lectins; neoglycoproteins and certain inhibitors of serine proteases.
  • N-acetyl-glucosamine may also reduce melanosme transfer.
  • the present composition may contain at least one melanosme transfer inhibitor in an amount effective to reduce pigmentation or reduce the transfer of melanosmes from melanocytes to keratinocytes.
  • the melanosme transfer inhibitor can be present in the composition in an amount from about 0.001% to the solubility limit of the melanosme transfer inhibitor in the composition.
  • the melanosme transfer inhibitor is present in the composition in the amount of about 0.01% to about 12%, more preferably about 0.05% to about 6%, most preferably about 0.1% to about 3% by weight.
  • the invention provides a composition containing one or more phosphates, substantially free of calcium, and may further contain hydroquinone in an amount of about 0.1% to about 10% by weight, and further containing a melanosome transfer inhibitor in an amount of about 0.1% to about 3% by weight.
  • the present invention also provides a composition including one or more phosphates, substantially free of calcium, and also includes 4-(1-phenylethyl)1,3-benzenediol (phenylethyl resorcinol) in an amount of about 0.1% to about 5% by weight, and may also include a melanosome transfer inhibitor in an amount of about 0.1% to about 3% by weight.
  • a composition including one or more phosphates, substantially free of calcium and also includes 4-(1-phenylethyl)1,3-benzenediol (phenylethyl resorcinol) in an amount of about 0.1% to about 5% by weight, and may also include a melanosome transfer inhibitor in an amount of about 0.1% to about 3% by weight.
  • the invention additionally provides a composition containing one or more phosphates, substantially free of calcium; hydroquinone in an amount of about 0.1% to about 10% by weight; 4-(1-phenylethyl)1,3-benzenediol (phenylethyl resorcinol) in an amount of about 0.1% to about 5% by weight: and a melanosome transfer inhibitor in an amount of about 0.1% to about 3% by weight.
  • compositions of the present invention can contain at least one calcium sequestration or binding agent and can further contain one or more compounds capable of decreasing (as assessed in vitro and/or in vivo) melanocortin receptor 1 (MC1R) activity.
  • M1R melanocortin receptor 1
  • agouti signaling protein regulates skin pigmentation by antagonizing the binding of ⁇ -MSH to MC1R.
  • the signaling inhibition through the receptor results from two effects (i) a direct competition at the binding site, and (ii) a downregulation of the receptor signaling. (See Barsh et al., Pigment Cell Res., 2000, 13 Suppl. 8:48-53). As an example, undecylenoyl phenylalanine was described to have an affinity towards MC1R and was shown to act as antagonist of ⁇ -MSH in vitro.
  • the present composition contains at least one ⁇ -MSH antagonist in an amount effective to antagonizing the binding of ⁇ -MSH to MC1R.
  • the ⁇ -MSH antagonist is present in the composition in an amount from about 0.001% to the solubility limit of the ⁇ -MSH antagonist in the composition.
  • the ⁇ -MSH antagonist is present in the composition in the amount of about 0.01% to about 10%, more preferably about 0.05% to about 5%, most preferably about 0.1% to about 4% by weight.
  • the present invention provides a composition containing one or more phosphates, substantially free of calcium, and also contains hydroquinone in an amount of about 0.1% to about 10% by weight and an ⁇ -MSH antagonist in an amount of about 0.1% to about 4% by weight.
  • the ⁇ -MSH antagonist is undecylenoyl phenylalanine (with chemical structure: CH 2 ⁇ CH—(CH 2 ) 8 —CO—NH—CH(—COOH)(—CH 2 —C 6 H 5 ), as described in WO2003/061768].
  • the present invention additionally provides a composition containing one or more phosphates, substantially free of calcium; 4-(1-phenylethyl)1,3-benzenediol by weight in an amount of about 0.1% to about 5% by weight; and an ⁇ -MSH antagonist in an amount of about 0.1% to about 4% by weight.
  • the ⁇ -MSH antagonist is undecylenoyl phenylalanine.
  • the present invention also provides a composition including one or more phosphates, substantially free of calcium; hydroquinone in an amount of about 0.1% to about 10% by weight; 4-(1-phenylethyl)1,3-benzenediol by weight in an amount of about 0.1% to about 5% by weight; and an ⁇ -MSH antagonist in an amount of about 0.1% to about 4% by weight.
  • the ⁇ -MSH antagonist is undecylenoyl phenylalanine.
  • the ⁇ -MSH antagonist is undecylenoyl phenylalanine.
  • These compositions may additionally contain a melanosome transfer inhibitor in an amount of about 0.1% to about 3% by weight.
  • compositions of the present invention can include at least one calcium sequestration or binding agent and can further include one or more compounds, skincare actives or dermatology drugs and/or biologics other than calcium containing chemicals known in the arts of the treatment of skin pigmentation; general dermatology; cosmetic dermatology; skincare such as, for example skin moisturization; or rejuvenation, including but not limiting to, transforming growth factor (including TGF-beta1, TGF-beta2, TGF-beta3); collagen stimulators such as certain growth factors (e.g. PDGFs, FGFs, etc.) and/or certain peptides (e.g., Matrixyl-3000); stimulators of keratinocyte proliferation such as (e.g.
  • EGF, KGFs, etc. inhibitors of collagen degrading enzymes (e.g., natural or synthetic inhibitors of MMPs); inhibitors of elastin degrading enzymes (e.g., natural or synthetic inhibitors of elastase); appropriate antioxidants (such as vitamin C, vitamin E, ferulic acid, lipoic acid, polyphenols, ergothioneine, etc.) and their derivatives; appropriate sunscreens and/or solar UV reflectors (e.g., spheres and/or microparticles made of polymers, etc.); anti-inflammatory agents (e.g., steroids, non-steroidal anti-inflammatory agents, anti-inflammatory interleukins, IL-1ra, etc.); emollients; humectants (e.g., glycerin, urea, hyaluronic acid, natural moisturizing factors, etc.); inhibitors of neurotransmitter release; skin penetration agents (e.g., oleic acid, propylene glyco
  • any of the compositions of the present invention can contain at least one calcium sequestration or binding agent and can further contain one or more compounds capable of chemically stabilizing any of the ingredients present in the composition.
  • Compounds that help to chemically stabilize any of the ingredients may include, but are not limited to, sodium metabisulfite; sodium bisulfate; BHT; BHA; propyl gallate; disodium EDTA; lemon extract; antioxidants, including ascorbic acid (vitamin C) and its derivatives such as phosphate derivatives of ascorbic acid including sodium or magnesium ascorbyl phosphate, aminopropyl ascorbyl phosphate, and other known phosphate derivatives of ascorbic acid having antioxidant properties; and tocopherol and derivatives of tocopherol such as, sodium vitamin E phosphate (VEP), lauryl imino dipropionic acid tocopheryl phosphate, tocopheryl glucoside, tocopheryl succinate, tocophersolan (tocopheryl polyethylene glycol
  • VEP vitamin E
  • Sulfites such as sodium metabisulfite, and/or sodium bisulfate are particularly useful to stabilize hydroquinone or other chemically labile (i.e., easily being oxidized) compounds present in the said composition.
  • the compositions may contain between about 0.05 to 0.5% sulfites by weight.
  • compositions of the instant invention can be administered by any means known in the art.
  • the compositions of the present invention are formulated as a topical preparation or dosage form.
  • Topical preparations are ointments, creams, gels and lotions. The definition of these topical dosage forms is given by Bhuse L. et al. (Int J Pharm 295: 2005, 101-112) (incorporated by reference).
  • the carrier can also be a liquid, a foam, a mousse, a spray, an aerosol, an oil-in-water emulsion, a water-in-oil emulsion, a triple emulsion, a nanoemulsion, a microemulsion, a hydrogel, a solution, a paste, a jelly, a patch, a wipe, a cloth, and/or a dispersion or suspension.
  • the carrier may contain niosomes, liposomes, nanospheres, microspheres, nanoparticles, microparticles, lipid droplets, solid particles, pigments and/or water droplets.
  • the carrier is a cream.
  • the cream may be either an oil-in-water mixture, or a water-in-oil based carrier.
  • the carrier is a gel or hydrogel.
  • composition of the invention includes any composition containing one or more phosphates free of calcium in conjunction with a carrier.
  • agents can be added in any of the methods and compositions of the invention.
  • agents may include, but are not limited to, e.g., antimicrobial agents (e.g., parabens, phenoxyethanol, chlorophenesin, propylene glycol, butylene glycol, ethylhexylglycerin, imidazolidinyl urea, methylchloroisothiazolinone, potassium benzoate, DMDM hydantoin, etc.), etc.), color additives, fragrances, sensory stimulating agents, polymers, surfactants, water, oils, etc.
  • antimicrobial agents e.g., parabens, phenoxyethanol, chlorophenesin, propylene glycol, butylene glycol, ethylhexylglycerin, imidazolidinyl urea, methylchloroisothiazolinone, potassium benzoate, DMDM hydantoin, etc.
  • compositions can be found, e.g., in Volume 3: Liquid Products, Volume 4: Semisolid Products and Volume 5: Over-the-Counter Products, of the ‘Handbook of Pharmaceutical Manufacturing Formulations’ (edited by S. K. Niazi, CRC Press, Boca Raton, 2004).
  • information regarding the preparation of cosmetic or cosmeceutical compositions may be found in the formulary archive of the Happy Magazine (see http://www.happi.com/formulary).
  • formulary information for cosmetic or cosmeceutical compositions can be also obtained from diverse ingredient suppliers such as Croda, Ciba, BASF, Dow Chemicals, etc.
  • the present invention provides stable and none to little irritating (i.e., no or only limited and acceptable skin irritancy) compositions for topical application to the skin to treat skin pigmentation disorders, such as melasma, post-inflammatory hyperpigmentation, pigmentation changes due to skin aging, or any other skin conditions related with normal such as skin of color or abnormal pigmentation such as hypo- or hyper-pigmentation in humans.
  • skin pigmentation disorders such as melasma, post-inflammatory hyperpigmentation, pigmentation changes due to skin aging, or any other skin conditions related with normal such as skin of color or abnormal pigmentation such as hypo- or hyper-pigmentation in humans.
  • Stable compositions can be obtained by (1) selecting appropriate calcium sequestration or binding agent concentration(s), (2) selecting appropriate salt form(s) of the agent other than calcium salt(s), (3) adjusting the pH of the composition, (4) selecting appropriate type of formulation (e.g., liquid, a foam, a mousse, a spray, an aerosol, an oil-in-water emulsion, a water-in-oil emulsion, a triple emulsion, a nanoemulsion, a microemulsion, a hydrogel, a solution, a paste, a jelly, a patch, a wipe, a cloth, and/or a dispersion or suspension) for the composition, (5) selecting appropriate ingredients allowing to stabilize the composition, (6) selecting and appropriate container for composition suitable for topical administration (e.g., tube, airless pump, jar, vial, monodose, etc.), and/or (7) selecting conditions allowing the preparation of a stable preparation (e.g., preparation of composition under inert gas, etc.).
  • stable when applied to the compositions of the instant invention is defined as having a comparable color when the composition is placed on a flat and inert surface (i.e., removed from its container) under normal ambient air and light conditions (i.e., air and light conditions as normally exist in the living room at home) when kept for at least one month at room temperature (about 25° C.).
  • stability of the composition may further include physical stability (e.g., viscosity, odor, appearance, texture, etc.) and chemical stability of the selected active(s) such as a drug active (e.g., calcium sequestration agent, hydroquinone, etc.). Chemical stability can be assessed using HPLC or other appropriate analytical methods.
  • physical stability e.g., viscosity, odor, appearance, texture, etc.
  • chemical stability e.g., calcium sequestration agent, hydroquinone, etc.
  • Chemical stability can be assessed using HPLC or other appropriate analytical methods.
  • the composition When the composition is placed (e.g., filled) into a suitable container (e.g., a tube, pump, jar, etc.), the composition should be chemically stable (i.e., less than a ⁇ 10% change in the content as compared to the baseline value) for at least a year under normal storage condition (i.e., room temperature; or common temperature fluctuations occurring in house/living room/bath room due to changes in season or geographical region). Stability may also be tested under accelerated conditions at elevated temperatures (e.g., 40° C. or higher) in order to predict stability of the composition at room temperature (about 25° C.).
  • a suitable container e.g., a tube, pump, jar, etc.
  • Stability may also be tested under accelerated conditions at elevated temperatures (e.g., 40° C. or higher) in order to predict stability of the composition at room temperature (about 25° C.).
  • compositions of the present invention may be applied to the entire body, including the face. These compositions may be applied as needed or alternatively, as part of a skin care routine. Preferably, the composition is applied weekly. More preferably, the composition is applied once daily at night at least half an hour before bedtime. However, it can be also applied twice daily, with the preferred mode being once in the morning and once in the evening. When compositions are applied twice daily, the compositions may be the same or different for each application. For example, the same composition may be applied twice daily or alternately, one composition may be applied in the morning and a second, different composition, may be applied in the evening.
  • the compositions can be applied to any mammal (e.g., a primate, rodent, feline, canine, domestic livestock (such as cattle, sheep, goats, horses, and pigs). Preferably, the compositions are applied to humans.
  • compositions of the present invention may further contain one or more sunscreen active agents, such as those that provide a UV-B filter and, in some embodiments, additionally a UV-A filter.
  • sunscreen active agents such as those that provide a UV-B filter and, in some embodiments, additionally a UV-A filter.
  • suitable UV-A and UV-B filters include those described in U.S. Pat. No. 7,078,022 (incorporated herein by reference).
  • compositions of the invention dry quickly and cleanly (without visible residue or significant stickiness) after application of a normal amount (i.e., 0.2 to 2 mg composition per cm 2 ) on the skin.
  • compositions of the invention are in %, w/w, based on the total weight of the composition.
  • compositions formulated in accordance with the present invention are presented in Table 19. These compositions serve as illustrative formulations which provide several of the advantageous features of the invention, namely, mildness to the skin after application with no or only limited skin irritancy; clearness and non-greasiness upon application (transparent) to face and other skin areas other than the palms and the soles; and quick-drying, particularly when the compositions are preferably formulated as water-in-oil formulations.
  • compositions were generally prepared in a clean and sanitized stainless steel vessel, which was suitable for blending products containing hydroquinone, as described herein below:
  • Example 1 The composition obtained as described in Example 1 was then filled into an airless pump container (e.g., 30 ml TopFill airless pump from MegaPlast—Mega Pumps) and then tested for physical stability (color, odor, viscosity, pH, appearance, etc.) under accelerated conditions (40 to 50° C.) for up to three months. During this period of time, the composition filled into the airless pump was stable (i.e., color, odor, viscosity, pH and appearance did not change or only changed to a limited and acceptable extent ( ⁇ 10% from baseline)).
  • an airless pump container e.g., 30 ml TopFill airless pump from MegaPlast—Mega Pumps
  • composition obtained as described in Example 1 does not leave greasy or oily residues on the skin and dries quickly and cleanly (without visible residue or significant stickiness) within one to two minutes after application on the skin.
  • compositions formulated in accordance with the present invention are presented in Table 20. Again, these compositions serve as illustrative formulations which provides the advantageous features of the invention, namely, mildness to the skin after application with no or only limited skin irritancy; clearness and non-greasiness upon application (transparent) to face and other skin areas other than the palms and the soles; and quick-drying, particularly when the compositions are preferably formulated as water-in-oil formulations.
  • compositions were generally prepared in a clean and sanitized stainless steel vessel, which was suitable for blending products containing hydroquinone, as described herein below:
  • Example 2 The composition obtained as described in Example 2 was then filled into aluminum tubes (or aluminum coated plastic tubes) and then tested for physical stability (color, odor, viscosity, pH, appearance) and chemical stability (by HPLC) of hydroquinone under accelerated conditions (40 to 50° C.) for up to three months. During this period of time, the composition filled into aluminum tubes was stable (i.e., color, odor, viscosity, pH and appearance did not change or only changed to a limited and acceptable extent ( ⁇ 10% from baseline) and the hydroquinone content remained between 3.84% to 4.24% (weight %).
  • physical stability color, odor, viscosity, pH, appearance
  • chemical stability by HPLC
  • composition obtained as described in Example 2 does not leave greasy or oily residues on the skin and dries quickly and cleanly (without visible residue or significant stickiness) within one to two minutes after application on the skin.
  • compositions formulated in accordance with the present invention are presented in Table 21. These compositions serve as illustrative formulations, which provide the advantageous features of the invention, namely, stability of the composition, mildness to the skin after application with no or only limited and acceptable skin irritancy; clearness and non-greasiness upon application (transparent) to face and other skin areas other than the palms and the soles; and quick-drying, particularly when the compositions are preferably formulated as water-in-oil formulations.
  • compositions were generally prepared in a clean and sanitized stainless steel vessel, which was suitable for blending products containing hydroquinone, as described herein below:
  • compositions obtained as described in Example 3 were then filled into aluminum tubes (or aluminum coated plastic tubes) and then tested for physical stability (color, odor, viscosity, pH, appearance) and chemical stability (by HPLC; following USP protocol for hydroquinone analysis) of hydroquinone under accelerated conditions (40 to 50° C.) for up to three months. During this period of time, the composition was stable and the hydroquinone content remained between 3.84% to 4.24% (weight %).
  • compositions do not leave greasy or oily residues on the skin and dries quickly and cleanly (without visible residue or significant stickiness) within one to two minutes following application on the skin.
  • compositions of the present invention can be evaluated by acute (1 day) or repetitive (more than one day) human irritancy patch test to assess the skin irritation potential.
  • the repetitive human irritancy patch test provides “exaggerated” irritation data since the test material is applied repetitively at a rather large dose (i.e., >20 mg per cm 2 ) under occlusive (i.e., allowing no water diffusion from skin surface to air) or semi-occlusive conditions (i.e., allowing limited water diffusion from skin surface to air). Therefore, the repetitive human irritancy patch test allows easily distinguishing skin irritation (i.e., skin irritation potential) of different compositions.
  • the composition obtained as described in Example 3 was evaluated by repetitive human irritancy patch test over a period of three weeks (with 15 observations (i.e., evaluation of patch application sites for severity of skin irritation); one observation before patch application at beginning of study followed by 14 additional observations; see below for more details) on the back of 25 subjects.
  • the test was performed according to standard irritancy patch testing by an independent contract organization specialized in consumer product testing.
  • Several currently commercialized skin lightening prescription products with 4% hydroquinone were also evaluated under identical conditions for comparison.
  • the repetitive human irritancy patch test demonstrated that the composition obtained as described in Example 3 was equally or better tolerated than a series of currently commercialized skin lightening prescription products with 4% hydroquinone. (See FIG. 1 )
  • test material was applied to the 1 inch ⁇ 1 inch absorbent pad portion of an adhesive strip. When secured to the appropriate treatment site, these dressings formed semi-occlusive patches. Each test material was applied to the appropriate treatment site Monday through Friday to maintain twenty-one (21) consecutive days of direct skin contact. Patches applied on Friday remained n place until the following Monday. Evaluations of the test sites were conducted prior to each patch application. It was noted that due to inclement weather, two of the 25 subjects were unable to report, as scheduled. They were instructed to keep their patches in place and return on the following day. If a test site had been observed to exhibit an evaluation score of a “3” or higher, the application of test material to this site would have been discontinued and the observed score of “3” (or higher) would be recorded for the remaining study days.
  • the following evaluation key was used: (0) no visible skin reaction; (+) barely perceptible or spotty erythema; (1) mild erythema covering most of the test site; (2) moderate erythema, possible presence of mild edema; (3) marked erythema, possible edema; (4) severe erythema, possible edema, vesiculation, bullae and/or ulceration.
  • the color stability was evaluated after the composition was removed from its typical (e.g., commercialized) container such as aluminum tube, aluminum coated plastic tube, or airless pump.
  • a pea size amount was placed onto a flat, inert, white surface (e.g., porcelain dish) and left under normal environmental conditions (i.e., temperature, light, air, etc.) of a room (i.e., living room) in a household for at least two weeks.
  • the color of the composition was documented by standard, digital color photography at beginning and at end of the observation period.
  • Several currently commercialized skin lightening prescription products with 4% hydroquinone were also evaluated under identical conditions for comparison.
  • compositions were removed from their typical container and placed onto porcelain dish and left under normal environmental conditions (i.e., temperature, light, air, etc.) of a room (i.e., living room) in a household for 17 days.
  • the composition of the present invention (Composition A) did not show any significant color change after 17 days as judged by photography or visually.
  • Compositions B, C and D showed all significant (i.e., clearly visible) color changes (i.e., color is changing from white to brown or brownish, or becoming darker, more brownish, or darker yellow) after 17 days. These color changes became more visible with time.
  • the color changes are mainly due to oxidation of hydroquinone, which is a constituent of Compositions B, C and D. While hydroquinone is also a constituent of Composition A, this experiment thus illustrates that the hydroquinone of Composition A is stable under the conditions of this experiment.
  • color changes described in this Example for Composition B, C and D generally occurs when the composition is placed outside its typical container, these observed color changes are not desirable, as such color changes may affect the efficacy of the product (i.e., composition being exposed to air and light after it is applied onto skin). Furthermore, thee color changes would occur after short time once some composition adheres to the outside of the container (e.g., the tube outlet or pump head) after the first and all subsequent uses of the composition. All of these factors make the composition less desirable to use, which consequently affects the patient's adherence to the recommended course of treatment (i.e., patient compliance) and therefore reduces the likelihood for an efficient treatment outcome.
  • the recommended course of treatment i.e., patient compliance
  • compositions obtained as described in Examples 1, 2, and 3 were evaluated for tolerability and efficacy in treating skin pigmentation disorders, such as melasma, post-inflammatory hyperpigmentation, pigmentation changes due to skin aging, or any other skin conditions related with normal such as skin of color or abnormal pigmentation such as hypo- or hyper-pigmentation in humans.
  • the compositions were generally applied to the affected skin area(s) either once daily in the evening (at least about half an hour before bedtime) or twice daily in the morning and in the evening.
  • a sunscreen offering at least a sun protection factor of 15 SPF15
  • SPF15 sun protection factor of 15
  • the compositions were also used at daytime, the subjects were instructed to apply the sunscreen after having applied the said compositions; preferentially at least half an hour after having applied the compositions.
  • Epidermal melasma can be treated (i.e. skin pigmentation is visibly reduced at site of application) within about one to three months, whereas dermal melasma, mixed type melasma, post-inflammatory hyperpigmentation (e.g., hyperpigmentation originating after inflammation of skin such as related to skin burns, wounds, acne, use of certain medications, dermatitis, etc.), pigmentation changes due to skin aging (e.g., freckles, age or liver spots, etc.), or any other skin conditions related with normal such as skin of color (e.g., skin of individual with Hispanic, Asian, African or American/African origins), or abnormal pigmentation such as hypo- or hyper-pigmentation in humans may require generally at least a three month treatment period to see results (i.e. skin pigmentation is visibly reduced at site of application) when using
  • Example 1 Study with Composition Described in Example 1:
  • Example 1 After a one month wash-out period where the subjects were allowed to only use JOURNÉE Bio-restorative Day Cream (offering SPF30+), the subjects applied the composition described in Example 1 twice daily (morning and evening) to their entire face after washing the face with a gentle skin cleanser (i.e., NEO-CLEANSE Gentle Cleanser by Neocutis). In the morning, they continued to use JOURNÉE Bio-restorative Day Cream.
  • a gentle skin cleanser i.e., NEO-CLEANSE Gentle Cleanser by Neocutis
  • melasma was quantified with the help of the so-called MASI index (see Arch Dermatol 130, 1994, 727-733).
  • a F forehead
  • M malar region
  • C chin
  • a F , A M , A C a numerical value
  • 0 no involvement
  • 1 less than 10% involvement
  • 2 10% to ⁇ 30%
  • 3 30% to ⁇ 50%
  • 4 50% to ⁇ 70%
  • 5 70% to ⁇ 90%
  • 6 90% to 100%.
  • Severity was based on two factors: darkness (D) of melasma compared with normal skin; and homogeneity (H) of hyperpigmentation.
  • MASI 0.3(D F +H F )A F +0.6(D M +H M )A M +0.1(D C +H C )A C . Additionally, the number of age and liver spots were counted in face. Those evaluations were performed at the beginning of study (i.e., before wash-out period), after the one month wash-out period (i.e., before starting with the treatment with composition), and at the end of the study period (i.e., after 12 weeks of use of composition), respectively.
  • Table 22 shows the efficacy of the composition described in Example 1 in treating skin pigmentation disorders and diseases.
  • the average and standard deviation in the reduction from baseline (i.e., data before wash-out) from five female subjects who completed the study is shown in percentage (%) of reduction from baseline.
  • composition leads to a reduction in melasma severity and in the number (and intensity) of age or liver spots in face.
  • the composition is effective for treating (i.e., reducing) symptoms of skin pigmentation disorders and diseases.
  • the composition was further well tolerated.
  • the use of a sunscreen i.e., JOURNÉE Bio-restorative Day Cream alone did not result in any significant reduction in symptoms of skin pigmentation disorders and diseases.
  • Example 3 The subjects applied the composition described in Example 3 once daily (evening) to either the right, or to the left side of their face (the side was randomly assigned) after washing the face with a gentle skin cleanser (i.e., Cetaphil by Galderma). In the morning, they additionally used JOURNÉE Bio-restorative Day Cream.
  • a gentle skin cleanser i.e., Cetaphil by Galderma.
  • melasma was quantified with the help of the so-called MASI index (Arch Dermatol 130, 1994, 727-733). Three areas of the face were evaluated: forehead (F), malar region (M), and chin (C) corresponding to 30%, 60% and 10% of total face; or 15%, 30% and 5% of half of the face, respectively.
  • Severity was based on two factors: darkness (D) of melasma compared with normal skin; and homogeneity (H) of hyperpigmentation. Patients were assessed on a scale from
  • the MASI score for a half-face (MASI Half-Face ) the sum of the severity rating of darkness (D) and homogeneity (H) was multiplied by the numerical value of the respective areas involved (A) and by the various percentages of the three facial areas.
  • MASI 0.15(D F +H F )A F +0.3(D M +H M )A M +0.05(D C +H C )A C .
  • Table 23 shows the efficacy of the composition described in Example 3 in treating skin pigmentation disorders and diseases.
  • the average and standard deviation in the reduction from baseline (i.e., data before starting with the treatment with composition) from ten female subjects who completed the study is shown in percentage (%) of reduction from baseline.
  • FIG. 3 is a photograph showing the reduction of pigmentation in the skin of a patient using the compounds of the present invention (e.g. the composition described in Example 3).
  • Panel A shows the hyperpigmentation of the patient's skin prior to administration of a compound of the present invention.
  • Panel B shows the reduction in skin pigmentation following 12 weeks of treatment with a composition of the present invention.
  • composition leads to a reduction in melasma severity in treated area of face.
  • the composition is effective for treating (i.e., reducing) symptoms of skin pigmentation disorders and diseases.
  • the composition was further well tolerated.
  • Example 2 Study with Composition Described in Example 2:
  • Example 2 As shown in diverse in use studies, the composition obtained as described in Example 2 was also shown to be well tolerated and efficient in treating skin pigmentation disorders, such as melasma, post-inflammatory hyperpigmentation, pigmentation changes due to skin aging, or any other skin conditions related with normal such as skin of color or abnormal pigmentation such as hypo- or hyper-pigmentation in humans. Female and male human subjects were included in this study.
  • skin pigmentation disorders such as melasma, post-inflammatory hyperpigmentation, pigmentation changes due to skin aging, or any other skin conditions related with normal such as skin of color or abnormal pigmentation such as hypo- or hyper-pigmentation in humans.
  • Female and male human subjects were included in this study.
  • compositions obtained as described in Examples 1, 2 and 3 are effective for treating (i.e., reducing) symptoms of skin pigmentation disorders and diseases and are well tolerated under in use conditions.
  • Example 3 A human study showed that the composition described in Example 3 does not cause an acnegenic/comedogenic response. Thus, the use of this composition did not result in a significant increase in the number and severity of comedones/acne.
  • Grade I Less than 10 comedones (including open: blackheads; closed: micropapules and whiteheads and/or inflammatory papulopustular lesions on one or both sides of the face.
  • Grade II 10-25 comedones (including open: blackheads; closed: micropapules and whiteheads) and/or inflammatory papulopustular lesions on one or both sides of the face.
  • Grade III severe
  • 25 comedones including open: blackheads; closed: micropapules and whiteheads
  • inflammatory papulopustular lesions on one or both sides of the face.
  • Subjects were evaluated before and after four weeks of treatment (once daily in evening) with the composition. Differences between baseline and final dermatological evaluations were considered statistically significant, if the probability of obtaining the result by chance is less than or equal to 0.05 using analysis of variance and/or appropriate t-Test statistics. All assessments of facial skin condition and lesion counts were made by a Board Certified Dermatologist. The study was performed by an independent clinical research organization.

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Abstract

The present invention provides compositions containing one or more calcium sequestration agents and methods for topical application of such compositions to the skin to treat skin pigmentation disorders, such as melasma, post-inflammatory hyperpigmentation, pigmentation changes due to skin aging, or any other skin conditions related with normal such as skin of color or abnormal pigmentation such as hypo- or hyper-pigmentation in humans.

Description

    RELATED APPLICATIONS
  • This application is a continuation of U.S. patent application Ser. No. 12/688,107, filed Jan. 15, 2010 which claims priority to U.S. Ser. No. 61/145,325, filed Jan. 16, 2009, both of which are herein incorporated by reference in their entirety.
    • FIELD OF THE INVENTION
  • The invention relates generally to compositions containing one or more calcium sequestration agents and methods for topical application to the skin to treat skin pigmentation disorders, such as melasma, post-inflammatory hyperpigmentation, pigmentation changes due to skin aging, or any other skin conditions related with normal such as skin of color or abnormal pigmentation such as hypo- or hyper-pigmentation in humans.
    • BACKGROUND OF THE INVENTION
  • In humans, skin color arises from a complex series of cellular processes that are carried out within a group of cells known as melanocytes. Melanocytes are located in the lower part of the epidermis and their function is to synthesize a pigment, melanin, which protects the body from the damaging effects of ultraviolet radiation. Melanin is a biopolymer originating from conversions of the amino acids phenylalanine or tyrosine.
  • The mechanism by which the skin pigment melanin is formed (melanin formation=melanogenesis) and skin ultimately gets its color (skin color=skin pigmentation) is a multi-step process and involves the following main steps:
      • 1) Uptake (active transport via transporter) of amino acid precursors (L-tyrosine, L-phenylalanine) into melanocytes promoted by active transport mechanism
      • 2) Conversion (turnover) of phenylalanine into tyrosine catalyzed by enzyme phenylalanine hydroxylase in melanocytes
      • 3) Uptake (active transport via transporter) of amino acid precursors L-tyrosine into melanosmes located in melanocytes promoted by active transport mechanism
      • 4) Conversion (turnover) of L-tyrosine into L-Dopa by enzyme tyrosinase in melanosme
      • 5) Conversion (turnover) of L-Dopa into dopaquinone by enzyme tyrosinase in melanosme
      • 6) Conversion (turnover) of dopaquinone into two different types of melanin called eumelanin (i.e., darker melanin) and phaeomelanin (i.e., lighter melanin) by various biochemical pathways in melanosme. The amount of each type of melanin determines the color and degree of pigmentation in a person's skin
      • 7) Once melanin is produced, transfer of melanosme with melanin from melanocytes to keratinocytes (which are found in the upper layers of the epidermis) via the melanocyte dendrites.
  • In spite of the fact that the chemical and enzymatic basis of melanogenesis and skin pigmentation are rather well-documented, their regulation at the cellular and biochemical level is only partially understood. For instance, it is well known that the activity of tyrosinase is promoted by the action of alpha-melanocyte stimulating hormone (α-MSH) and UV rays. However, the processes of melanosome maturation and melanosome transfer into the keratinocyte are currently far less studied and not yet understood.
  • Typically, the more melanin is formed, the darker (or more tanned) the skin. However, melanogenesis and skin pigmentation can be disturbed or disorder, which may lead to undesirable pigmentation patterns. Examples of pigmentation disorders (i.e., disorders where pigmentation is disturbed or disordered) include age spots, liver spots, melasma, hyperpigmentation, etc. This has lead to research to find compounds that will inhibit melanogenesis and reduce skin pigmentation. One of the targets of this research is tyrosinase, the enzyme which catalyses the initial steps in the generation of melanin.
  • Skin pigmentation has been of concern to human beings for many years. In particular, the ability to remove hyperpigmentation (i.e., areas of darker skin color than the surrounding or adjacent, normal pigmented skin), such as found in age spots, freckles or aging skin generally, is of interest to individuals desiring a uniform skin color, skin complexion, or skin tone. In certain areas of the world, general body whitening is desirable.
  • There are also hypopigmentation (i.e., areas of less dark skin color than the surrounding or adjacent, normal pigmented skin) and hyperpigmentation disorders that are desirable to treat. Likewise, the ability to generate a tanned appearance without incurring photodamage due to solar radiation is important to many individuals.
  • Many methods proposed to accomplish depigmentation (i.e., reduction or limitation of skin pigmentation or skin color). For example, arbutin, kojic acid, hydroquinone, retinoids, and other chemical compounds have been used for depigmentation. Chemicals that allow depigmentation of skin are also called skin lighteners, skin brighteners, skin whiteners, skin bleachers or actives with skin lightening, skin brightening, skin whitening or skin bleaching properties.
  • Many of these previous examples were not acceptable or were of limited efficacy in treating skin pigmentation. Most of these compounds have been described to address only a few steps of the multiple steps leading to melanin formation and ultimately skin pigmentation, which may result their limited efficacy. For instance, most chemicals used for depigmentation are described as inhibitors of tyrosinase. Although tyrosinase production and activity is a key factor in melanin formation, melanogenesis is a multi-step process and involves other important and rate-limiting steps than tyrosinase catalyzed conversion of L-tyrosine and L-Dopa and Dopa-quinone. In addition, many of these compounds have been found to be irritating to the skin and, therefore, undesirable for use. Also, precise application of all these compounds may be necessary in order to achieve the desired result and to avoid distinct line of demarcation between the areas of skin to which such previous compositions have been applied.
  • Accordingly, there is a need for compositions which inhibit melanogenesis and reduce skin pigmentation by modulating one or more of the multiple steps involved in melanogenesis and skin pigmentation. At the same time, there is also a need for compositions that allow skin depigmentation without irritation. The compositions and methods of the present invention address these long felt needs in the art.
    • SUMMARY OF THE INVENTION
  • The present invention provides compositions containing at least one calcium sequestering or calcium binding agent for treating or ameliorating at least one symptom of a skin pigmentation disorder or condition, in a subject in need thereof. Preferably, the calcium sequestering or binding agent is a phosphate. More preferably, the phosphate is glycerophosphoric acid or a, non-calcium, salt thereof. Most preferably, the phosphate is sodium glycerophosphate. The calcium sequestering or binding agent is present in the composition in the amount of about 0.1% to about 25%. When the calcium sequestering or binding agent is phosphate it is preferably present in the composition in the amount of about 1% to about 5% by weight.
  • The compositions for treating or ameliorating at least one symptom of a skin pigmentation disorder or condition in a subject in need thereof can contain a calcium sequestering or binding agent and can further contain one or more of the following agents, which modulate or regulate at least one step of melanogenesis: L-alanine, glycine, L-isoleucine, L-leucine, hydroquinone, 4-(1-phenylethyl)1,3-benzenediol, arbutin, bearberry leaf extract, kojic acid, oxyresveratrol, gnetol, retinoic acid or retinol, melanosome transfer inhibitor, or α-MSH antagonist.
  • Also provided are compositions that include at least one additional agent selected from the group consisting of skin moisturization or skin rejuvenation agents. For example, the skin moisturization or skin rejuvenation agents may be ascorbic acid, vitamin E, jojoba oil, shea butter, human fibroblast lysate, retinoic acid, retinol, and/or any derivatives thereof.
  • The compositions for treating, or ameliorating at least one symptom of, a skin pigmentation disorder or condition, in a subject in need thereof, are formulated for topical administration. By way of non-limiting example, the compositions of the invention can be in the form of a solution, an oil-in-water emulsion, a water-in-oil emulsion, a gel, an ointment, a patch, a paste, a liquid, a foam, a mousse, a spray, an aerosol, a triple emulsion, a nanoemulsion, a microemulsion, a hydrogel, a jelly, a dispersion, a suspension, and/or a tape. The compositions are stable, substantially free of calcium, do not cause an acnegenic/comedogenic response, and/or produce only minor skin irritation upon administration.
  • Also provided herein are methods of treating or ameliorating a skin pigmentation disorder comprising administering an effective amount of any of the compositions of the invention to a patient suffering therefrom. For example, the skin pigmentation disorder can include, but is not limited to, melasma, post-inflammatory hyperpigmentation, pigmentation changes due to skin aging, age or liver spots, freckles, or any other skin conditions related with normal such as skin of color or abnormal pigmentation such as hypo- or hyper-pigmentation. Preferably, administration of the compound reduces skin pigmentation. The subject can be any mammal, preferably a human.
  • The invention also provides pharmaceutical formulations containing any of the compositions described herein and at least one pharmaceutically acceptable carrier. Similarly, the invention also provides cosmetic formulations containing any of the compositions described herein an at least one cosmetically acceptable carrier. In other embodiments, the invention provides kits including, in one or more containers, these pharmaceutical or cosmetic formulations. Those skilled in the art will recognize that such kits may optionally contain instructions for use of the pharmaceutical or cosmetic formulations in the treatment or amelioration of said skin pigmentation disorder or condition.
  • The invention also includes unit dosage forms containing therapeutically effective amounts of any of the compositions and/or pharmaceutical formulations described herein.
  • Any of the compositions or formulations described herein can be used in methods of reducing skin pigmentation in a patient by administering an effective amount of the composition and/or formulation to the patient. In such methods, the effective amount of the composition is administered topically to the patient.
  • Also provided are compositions for treating or ameliorating at least one symptom of a skin pigmentation disorder or condition that include 59.68% (by weight) water, 0.1% (by weight) disodium EDTA, 0.3% (by weight) xanthan gum, 0.3% (by weight) chlorphenesisn, 0.6% (by weight) phenoxyethanol, 0.5% (by weight) undecylenoyl phenylalanine, 3.00% (by weight) sodium glycerophosphate, 1.00% (by weight) leucine, 6.00% (by weight) cetearyl alcohol/ceteareth-20, 6.00% (by weight) glyceryl stearate, 3.00% (by weight) diisopropyl adipate, 3.00% (by weight) caprylyl methicone, 1.00% (by weight) dimethicone, 1.00% (by weight) simmondsia chinensis (jojoba) seed oil, 1.00% (by weight) butryospermum parkii shea butter), 0.2% (by weight) DL-alpha tocopheryl acetate, 1.92% (by weight) citric acid 50% solution, 4.00% (by weight) hydroquinone, 0.4% (by weight) sodium metabisulfite, 2.00% (by weight) glycerin, 0.5% (by weight) phenylethyl resorcinol, 0.5% (by weight) aminopropyl ascorbyl phosphate, and 4.00% (by weight) hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer isohexadecane polysorbate 60. For example, such a composition can be formulated as a water-in-oil emulsion.
  • Finally, the invention further provides a composition for treating or ameliorating at least one symptom of a skin pigmentation disorder or condition containing 63.41% (by weight) water, 0.1% (by weight) disodium EDTA, 0.3% (by weight) xanthan gum, 0.3% (by weight) chlorphenesisn, 0.6% (by weight) phenoxyethanol, 0.5% (by weight) undecylenoyl phenylalanine, 3.00% (by weight) sodium glycerophosphate, 1.00% (by weight) leucine, 1.92% (by weight) citric acid 50% solution, 8.25% (by weight) cetearyl alcohol/ceteareth-20, 6.00% (by weight) glyceryl stearate, 5.00% (by weight) diisopropyl adipate, 3.00% (by weight) caprylyl methicone, 1.00% (by weight) dimethicone, 1.00% (by weight) simmondsia chinensis (jojoba) seed oil, 1.00% (by weight) butryospermum parkii shea butter), 0.2% (by weight) DL-alpha tocopheryl acetate, 2.00% (by weight) glycerin, 0.5% (by weight) phenylethyl resorcinol, 0.5% (by weight) aminopropyl ascorbyl phosphate, and 0.42% (by weight) hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer/isohexadecane/polysorbate 60. For example, such a composition can be formulated as a water-in-oil emulsion.
  • Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.
  • Other features and advantages of the invention will be apparent from the following detailed description.
    • BRIEF DESCRIPTION OF THE DRAWINGS
  • FIG. 1 is a graph showing skin irritation of a composition of the present invention (see Example 3, infra) as compared to other known compositions (e.g.: Compositions A to D), which are not part of this invention. This graph, which represents a “survival” type curve, shows the percentage of subjects who did not show any irritancy reaction reaching an evaluation score of “3” or higher as a function of time (i.e., observation) during the repetitive human irritancy patch test of three weeks (21 days) duration. As judged during this test (by providing “exaggerated” irritation data), the composition of the present invention was better tolerated (i.e., fewer subjects reached an evaluation score of “3” or higher with continued, prolonged application of patch with test material) as compared to Compositions A to D).
  • FIG. 2 shows the color stability of a composition of the present invention (Composition A) as compared to other, control compositions (e.g.: Compositions B, C and D), which are not part of this invention.
  • FIG. 3 is a photograph showing the reduction of pigmentation in the skin of a patient using the compounds of the present invention (i.e., the composition described in Example 3, infra). Panel A shows the hyperpigmentation of the patient's skin prior to administration of a compound of the present invention. Panel B shows the reduction in skin pigmentation following 12 weeks of treatment with a composition of the present invention.
    •  DETAILED DESCRIPTION
  • The present invention is directed to modulating (increasing or decreasing) various steps of melanogenesis (melanin formation) and to reduce skin pigmentation (skin color). More specifically, the present invention provides compositions for treating or ameliorating a symptom of a pigmentation disorder or condition involving a single active agent which modulates more than one step in the multi-step process of melanin formation and skin pigmentation. The present invention also provides compositions which contain at least two active agents (e.g., 2, 3, 4, 5, or more), where each active agent can target at least one step in the multi-step process of melanin formation. These multiple agents decrease melanin formation and skin pigmentation. By targeting multiple steps of melanogenesis and skin pigmentation, the compositions of present invention provide superior properties as compared to hypopigmentation products currently known in the art.
    • Calcium Sequestration or Binding Agents
  • Calcium (Ca2+) may be an important regulator of some steps in melanogenesis and skin pigmentation. For instance, increase in calcium is believed to promote active transport of L-phenylalanine and its turnover via phenylalanine hydroxylase to L-tyrosine to significantly increase the pool of this substrate for melanogenesis. (See Dermatol Clin 25, 2007, pp. 283-291). Further, there is some evidence from in vitro studies that calcium impacts the melanosome transfer. (See Pigment Cell Res 20, 2007, pp. 380-384). This study, which used melanocyte-keratinocyte co-cultures, implied that melanin transfer was inhibited when intracellular calcium in keratinocytes was bound (chelated) with calcium chelator 1,2-bis-(o-aminophenoxy)-ethane-N,N,N′,N′-tetraacetic acid tetra-acetoxymethyl ester (BAPTA-AM).
  • Thus, the present invention provides compositions and methods for skin depigmentation which interferes one or more steps in the melanogenesis and skin pigmentation process where calcium is involved by administering a composition suitable for topical application containing at least one calcium sequestration or binding agent.
  • Examples of calcium sequestering or binding agents include either inorganic, organic (or a combination thereof, or organo-metallics) derived molecules. Preferably, the agents are calcium-free oxoanions of any or all possible oxidation states, achiral or chiral, selected from phosphates, phosphate esters, phosphonates, phosphonate esters, phosphoramidites, sulfates, sulfate esters, sulfonates, sulfonate esters, sulfites, siloxanes, carbonates, boronates, borinates, borinate esters, siloxanes, siloxane esters, polysiloxanes, sulfoxides, sulfonamides, sulfinic acids, sulfinimides, thiol esters, thioureas, and tosylates. Preferably the organic agents would possess calcium free anionic or neutral Lewis Base donors, achiral or chiral selected from carboxylic acids, polycarboxylates, carboxylic esters, nitriles, isocyanates, hydrazines, hydrazones, ureas, carboxylic esters, oximes, amides, amidines, thioethers, ethers, amines, alcohols, alkoxides, thiols, thiolates.
  • Table 1 recites non-limiting, representative, examples of carboxylic acids, boronic acids, amines, sulfates suitable to be utilized as calcium sequestration or binding agents
  • TABLE 1
    Product Code & Pack Size Product Name CAS Structure MF MW
    AC10430DA   AC10430EA
     1 GR    10 GR  25.00 USD 189.00 USD Amino- phenylboronic acid 0.5 ulfate 66472- 86-4
    Figure US20160030321A1-20160204-C00001
         		C6H8BNO2•0.5 H2O4S 185.98176 (136.94502)
    Figure US20160030321A1-20160204-C00002
    AC10702EA   AC10702EE  10 GR    50 GR  19.00 USD  42.00 USD 5-bromo- 2-furoic acid 585- 70-6
    Figure US20160030321A1-20160204-C00003
         		C5H3BrO3 190.98102
    AC10728DA   AC10728EA
     1 GR    10 GR  19.00 USD 102.00 USD 4-bromo- phenylboronic acid 5467- 74-3
    Figure US20160030321A1-20160204-C00004
         		C6H6BBrO2 200.82644
    AC11546EA   AC11546EE
     10 GR    50 GR  21.00 USD  33.00 USD 3,5- dimethoxy- benzoic acid 1132- 21-4
    Figure US20160030321A1-20160204-C00005
         		C9H10O4 182.176
    AC11968DA  1 GR  59.00 USD 2-amino- 3-(5-fluoro- 1H-indol-3- yl)propanoic acid 154-08- 5
    Figure US20160030321A1-20160204-C00006
         		C11H11FN2O2 222.218943
    SEW01633CB   SEW01633DA   SEW01633DE 250 MG    1 GR    5 GR  93.00 USD 270.00 USD 761.00 USD Thieno[2,3- b]thiophene- 2-carboxylic acid 14756- 75-3
    Figure US20160030321A1-20160204-C00007
         		C7H4O2S2 184.22756
    AC12788DA   AC12788EA
     1 GR    10 GR  48.00 USD 155.00 USD 5-methyl-2- thiophene- carboxylic acid 1918- 79-2
    Figure US20160030321A1-20160204-C00008
         		C6H6O25 142.17244
    AC13036EA   AC13036EE
     10 GR    50 GR  29.00 USD 117.00 USD Phenyl- boronic acid 98-80- 6
    Figure US20160030321A1-20160204-C00009
         		C6H7BO2 121.93038
    AC13196EA  10 GR  74.00 USD Pyridine- 3-ylacetic acid hydro- chloride 6419- 36-9
    Figure US20160030321A1-20160204-C00010
         		C7H7NO2•HCl 173.59902 (137.13808)
    AC13366DA   AC13366EA  1 GR    10 GR  33.00 USD  65.00 USD 2- piperazine- carboxylic acid dihydro- chloride 3022-15- 9
    Figure US20160030321A1-20160204-C00011
         		C5H10N2O2•2 HCl 203.06848 (130.1466)
    AC14674CB   AC14674DA 250 MG    1 GR 179.00 USD 522.00 USD 2-Amino- 3-(6-fluoro- 1H-indol-3- yl)-propanoic acid 7730- 20-3
    Figure US20160030321A1-20160204-C00012
         		C11H11FN2O2 222.218943

    Table 2 recites non-limiting, representative, examples of phosphates suitable to be utilized as calcium sequestration or binding agents.
  • TABLE 2
    Figure US20160030321A1-20160204-C00013
         		1-Naphthyl phosphate
    Figure US20160030321A1-20160204-C00014
         		1-Naphthyl phosphate calcium salt trihydrate
    Figure US20160030321A1-20160204-C00015
         		2,4-Diamino-6,7- diisopropylpteridine phosphate salt
    Figure US20160030321A1-20160204-C00016
         		2-Cyanoethyl phosphate barium salt dihydrate
    Figure US20160030321A1-20160204-C00017
         		2-Naphthyl phosphate disodium salt
    Figure US20160030321A1-20160204-C00018
         		3,9-Bis(2,4- dicumylphenoxy)- 2,4,8,10-tetraoxa-3,9- diphosphasphiro[5.5] undecane
    Figure US20160030321A1-20160204-C00019
         		6-Benzoyl-2-naphthyl phosphate disodium salt
    Figure US20160030321A1-20160204-C00020
         		Anilinium hypophosphite

    Table 3 recites non-limiting, representative, examples of phosphonates or phosphinates suitable to be utilized as calcium sequestration or binding agents.
  • TABLE 3
    Figure US20160030321A1-20160204-C00021
         		Dimethyl thiophosphonate
    Figure US20160030321A1-20160204-C00022
         		Ethyl methylphosphonate
    Figure US20160030321A1-20160204-C00023
         		Dimethyl vinylphosphonate
    Figure US20160030321A1-20160204-C00024
         		Trimethyl phosphonoformate
    Figure US20160030321A1-20160204-C00025
         		Diethyl (trichloromethyl) phosphonate
    Figure US20160030321A1-20160204-C00026
         		Diethyl cyanophosphonate
    Figure US20160030321A1-20160204-C00027
         		O,O′-Diethyl methylphosphonothioate
    Figure US20160030321A1-20160204-C00028
         		Diethyl vinylphosphonate
    Figure US20160030321A1-20160204-C00029
         		Triethyl phosphonoformate

    Table 4 recites non-limiting, representative, examples of phosphonic/phosphoric acids suitable to be utilized as calcium sequestration or binding agents.
  • TABLE 4
    Figure US20160030321A1-20160204-C00030
         		Methylphosphonic acid
    Figure US20160030321A1-20160204-C00031
         		(Aminomethyl)phosphonic acid
    Figure US20160030321A1-20160204-C00032
         		Methylenediphosphonic acid
    Figure US20160030321A1-20160204-C00033
         		Vinylphosphonic acid
    Figure US20160030321A1-20160204-C00034
         		Phosphonoacetic acid
    Figure US20160030321A1-20160204-C00035
         		Dimethylphosphinic acid
    Figure US20160030321A1-20160204-C00036
         		Ethylphosphonic acid
    Figure US20160030321A1-20160204-C00037
         		2-Aminoethylphosphonic acid

    Table 5 recites non-limiting, representative, examples of amidines suitable to be utilized as calcium sequestration or binding agents.
  • TABLE 5
    Product Code & Pack Size Product Name CAS Structure MF MW
    CC12331DA   CC12331EA
     1 GR    10 GR 121.00 USD 443.00 USD 1-benzothiophene-3- carboxamidamidine hydrochloride 465515-36-0
    Figure US20160030321A1-20160204-C00038
         		C9H8N2S•HCl 212.69686 (176.23592)
    MO07267DA   MO07267EA  1 GR    10 GR  70.00 USD 270.00 USD N-Hydroxy- butyramidine 27620-10-6
    Figure US20160030321A1-20160204-C00039
         		C4H10N2O 102.1362
    RF00749DA   RF00749EA
     1 GR    10 GR  42.00 USD 328.0 USD 3,5- Bis(trifluoromethyl) benzamidine hydrochloride 97603-94-6
    Figure US20160030321A1-20160204-C00040
         		C9H6F6N2•HCl 292.611398 (256.150458)
    RF01501DA   RF10501EA   RF01501EB  1 GR    10 GR    25 GR  25.00 USD 225.00 USD 358.00 USD 2,2-dimethyl- propanimidamide 18202-73-8
    Figure US20160030321A1-20160204-C00041
         		C5H12N2•HCl 136.62452 (100.16368)
    MO07766D   MO07766EA   MO07766EB  1 GR    10 GR    25 GR  33.00 USD 270.00 USD 490.00 USD Pyridine-3- carboxamidine hydrochloride 0.5 hydrate 7356-60-7
    Figure US20160030321A1-20160204-C00042
         		C6H7N3•HCl•0.5 H2O 166.61026 (121.14168)
    CC39931CB   CC29931DA 250 MG    1 GR 104.00 USD 260.00 USD Tetrahydropyran-4- carboxamidine hydrochloride 426828-34-4
    Figure US20160030321A1-20160204-C00043
         		C6H12N2O•ClH 164.63502 (128.17408)

    Table 6 recites non-limiting, representative, examples of boronic acids suitable to be utilized as calcium sequestration or binding agents.
  • TABLE 6
    Product Code & Pack Size Product Name CAS Structure MF MW
    AC10430DA   AC10430EA
     1 GR   10 GR  25.00 USD 189.00 USD 3-amino- phenyl boronic acid 0.5 sulfate 66472- 86-4
    Figure US20160030321A1-20160204-C00044
         		C6H8BN02•0.5 H2O4S 185.98176 (136.94502)
    AC10728DA   AC10728EA  1 GR   10 GR  19.00 USD 102.00 USD 4- bromophenyl- boronic acid 5467- 74-3
    Figure US20160030321A1-20160204-C00045
         		C6H6BBrO2 200.82644
    AC13036EA   AC13036EE
    10 GR   50 GR  29.00 USD 117.00 USD Phenylboronic acid 98-80-6
    Figure US20160030321A1-20160204-C00046
         		C6H7BO2 121.93038
    AC30926DA   AC30926EA
     1 GR   10 GR  19.00 USD 157.00 USD 2- methylphenyl- boronic acid 16419- 60-6
    Figure US20160030321A1-20160204-C00047
         		C7H9BO2 135.95726
    AC30948DA   AC30948EA
     1 GR   10 GR  81.00 USD 430.00 USD 4-methoxy- phenylboronic 5720- 07-0
    Figure US20160030321A1-20160204-C00048
         		C9H9BO3 151.95666
    AC34441DA   AC3RRR1E   AC34441EE  1 GR   10 GR   50 GR  48.00 USD 155.00 USD 577.00 USD 4-chlorophenyl- boronic acid 1679- 18-1
    Figure US20160030321A1-20160204-C00049
         		C6H6BClO2 156.37544
    AC34443DA
     1 GR  25.00 USD 4-methylphenyl- boronic acid 5720- 05-8
    Figure US20160030321A1-20160204-C00050
         		C7H9BO2 135.95726
    AC34465DA   AC34465EA
     1 GR   10 GR  33.00 USD 187.00 USD Hexylboronic acid 16343- 08-1
    Figure US20160030321A1-20160204-C00051
         		C6H15BO2 129.9939
    AC34468DA   AC34468EA
     1 GR   10 GR  19.00 USD 117.00 USD 4- (methylsulfanyl) phenylboronic acid 98546- 51-1
    Figure US20160030321A1-20160204-C00052
         		C7H9BO2S 168.01726
    AC34469DA   AC34469E
     1 GR   10 GR  19.00 USD 151.00 USD 1-naphthyl- boronic acid 13922- 41-3
    Figure US20160030321A1-20160204-C00053
         		C10H9BO2 171.99026
    AC35883DA   AC35883EA
     1 GR 10 GR  19.00 USD 151.00 USD 3-acetylphenyl- boronic acid 204841- 19-0
    Figure US20160030321A1-20160204-C00054
         		C8H9BO3 163.96766

    Table 7 recites non-limiting, representative, examples of esters or alcohols suitable to be utilized as calcium sequestration or binding agents.
  • TABLE 7
    Product Code & Pack Size Product Name CAS Structure MF MW
    CC03622DA CC03622EA
     1 GR    10 GR 102.00 USD 537.00 USD 1-Methyl-1H- imidazole-4- carboxylic acid methyl ester 17289- 19-9
    Figure US20160030321A1-20160204-C00055
         		C6H8N2O2 140.14172
    CC04940DA  1 GR 106.00 USD Isoquinoline-4- boronic acid 2,2- dimethyl- propanedial- 1,3-cyclic ester 844891- -01-6
    Figure US20160030321A1-20160204-C00056
         		C14H16BN02 241.09654
    CC19422DA  1 GR 159.00 USD 3-(2-Methyl- thiazol-4-yl)- benzoic acid methyl ester 850375- -07-4
    Figure US20160030321A1-20160204-C00057
         		C12H11NO2S 233.28484
    MO07248CD   MO07248DA 250 MG    1 GR  78.00 USD 161.00 USD 3-(5-Bromo- pyridin-3-yl)- [1,2,4] oxadiazole- 5-carboxylic acid ethyl ester 850375- 34-7
    Figure US20160030321A1-20160204-C00058
         		C10H8BrN3O3 298.09582
    MO07285DA   MO07285EA
     1 GR   471.00 GR  66.00 USD 471.00 USD (4-Hydroxy- emethyl- benzyl)- carbamic acid tert-butyl ester 123986- 64-1
    Figure US20160030321A1-20160204-C00059
         		C13H19NO3 237.29876
    MO07286CB   MO07286DA   MO07286DE 250 MG    1 GR    5 GR  78.00 USD 200.00 USD 546.00 USD (3-Hydroxy- methyl- benzyl)- carbamic acid tert- butyl ester 226070- 69-5
    Figure US20160030321A1-20160204-C00060
         		C13H19NO3 237.29876
    MO07352CB   MO07352DA   MO07352EA 250 MG    1 GR    10 GR  48.00 USD  95.00 USD 706.00 USD 3-Amino- methyl- benzoic acid methyl ester hydrochloride 17841- 68-8
    Figure US20160030321A1-20160204-C00061
         		C9H11NO2•HCl 201.65278 (165.19184)
    RDP00077DA   RDP00077EA   RPD00077EB  1 GR    10 GR    25 GR  42.00 USD  65.00 USD 115.00 USD (S)-tryptophan ethyl ester hydrochloride 7479- 05-2
    Figure US20160030321A1-20160204-C00062
         		C13H16N2O2•ClH 268.74318 (232.28224)
    BTB06937EE   BTB06937FA  50 GR   100 GR  36.00 USD  65.00 USD 4-methoxy-4- oxobutanoic acid 3878- 55-5
    Figure US20160030321A1-20160204-C00063
         		C5H8O4 132.11612
    SB01817EA   SB01817EB  10 GR    25 GR  55.00 USD  83.00 USD Methyl propiolate 922- 67-8
    Figure US20160030321A1-20160204-C00064
         		C4H4O2 84.07456

    Table 8 recites non-limiting, representative, examples of isocyanates suitable to be utilized as calcium sequestration or binding agents.
  • TABLE 8
    Product Code & Pack Size Product Name CAS Structure MF MW
    AC29669EA   AC29669EB
     10 GR    25 GR  31.00 USD  59.00 USD 2-nitrophenyl isocyanante 3320-86-3
    Figure US20160030321A1-20160204-C00065
         		C7H4N2O3 164.12036
    AC29670EA   AC29670EB
     10 GR    25 GR  65.00 USD  70.00 USD 4-nitrophenyl isocyanate 100-28-7
    Figure US20160030321A1-20160204-C00066
         		C7H4N2O3 164.12036
    AC30815DA
     1 GR  31.00 USD 2,6-difluorophenyl isocyanate 65295-69-4
    Figure US20160030321A1-20160204-C00067
         		C7H3F2NO 155.10372
    AC30913DA  1 GR  19.00 USD 4-chloro-3- (trifluoromethyl)phenyl isocyanate 327-78-6
    Figure US20160030321A1-20160204-C00068
         		C8H3ClF3NO 221.566129
    AC30914DA   AC30914EA
     1 GR    10 GR  27.00 USD 217.00 USD 2,5-difluorophenyl isocyanate 39718-32-6
    Figure US20160030321A1-20160204-C00069
         		C7H3H2NO 155.103726
    AC31411DA   AC31411EA
     1 GR    10 GR  19.00 USD 155.00 USD [1,1′-biphenyl]-2-yl isocyanate 17337-13-2
    Figure US20160030321A1-20160204-C00070
         		Cl3H9NO 195.22056
    AC31419DA   AC31419E   AC31419EB  1 GR    10 GR    25 GR  19.00 USD  74.00 177.00 USD 4-(methylsulfanyl)phenyl isocyanate 1632-84-4
    Figure US20160030321A1-20160204-C00071
         		C8H7NOS 165.20968
    AC31420DA  1 GR  19.00 USD 2-ethylphenyl isocyanate 40411-25-4
    Figure US20160030321A1-20160204-C00072
         		C9H9NO 147.17656
    AC31427EA   AC31427EB
     10 GR    25 GR  81.00 USD 181.00 USD 4-methyl-3- nitrophenyl isocyanate 13471-69-7
    Figure US20160030321A1-20160204-C00073
         		C8H6N2O3 178.14724
    AC31429DA   AC31429EA   AC31429EB  1 GR    10 GR    25 GR  19.00 USD  95.00 USD 177.00 USD 2,4-dimethoxyphenyl isocyanate 84370-87-6
    Figure US20160030321A1-20160204-C00074
         		C9H9NO3 179.17536
    AC31435DA   AC31435EA
     1 GR    10 GR  25.00 USD 198.00 USD 4- (chloromethyl)phenyl isocyanate 29173-65-7
    Figure US20160030321A1-20160204-C00075
         		C8H6ClNO 167.59474
    AC31931CB 250 MG  55.00 2-fluoro-5- methylphenyl isocyanate 190774-50-6
    Figure US20160030321A1-20160204-C00076
         		C8H6FNO 151.140143

    Table 9 recites non-limiting, representative, examples of oximes suitable to be utilized as calcium sequestration or binding agents.
  • TABLE 9
    Product Code & Pack Size Product Name CAS Structure MF MF
    CD11194DA   CD11194EA
     1 GR    10 GR  81.00 USD 432.00 USD Azepan-2- one axime 19214-08-5
    Figure US20160030321A1-20160204-C00077
         		C6H12N2O 128.17408
    SPB04865DA   SPB04865EA   SPB04865EB  1 GR    10 GR    25 GR  51.00 USD  76.00 USD 142.00 USD 2,4- dichloro- benzaldehyde oxime 56843-28-8
    Figure US20160030321A1-20160204-C00078
         		C7H5C12NO 190.0288
    SPB04935EA   SPB04935FA
     10 GR   100 GR 321.00 USD 801.00 USD 3,4- dichloro- benzaldehyde oxime 5331-92-0
    Figure US20160030321A1-20160204-C00079
         		C7H5C12NO 190.0288
    CD00359DA   CD00359EA   CD00359EE  1 GR    10 GR    50 GR  42.00 USD  65.00 USD 232.00 USD 2-furaldehyde oxime 1121-47-7
    Figure US20160030321A1-20160204-C00080
         		C5H5NO2 111.1002
    SPB05555DA   SPB05555EA
     1 GR    10 GR  55.00 USD 332.00 USD 4- (trifluoro- methoxy) benzaldehyde oxime 150162- 39-3
    Figure US20160030321A1-20160204-C00081
         		C8H6F3NO2 205.136349
    SPB05820DA   SPB05820EA SPB05820EE  1 GR    10 GR    50 GR  42.00 USD  65.00   232.00 USD 2,6-dichloro- benzaldehyde oxime 25185-95-9
    Figure US20160030321A1-20160204-C00082
         		C7H5Cl2NO 190.0288
    END00218DA  1 GR  53.00 USD 4-phenylbut- 3-en-2-one oxime 2887-98-1
    Figure US20160030321A1-20160204-C00083
         		C10H11NO 161.20344
    SPB08294DA   SPB08294EA   SPB08294EB  1 GR    10 GR   25 GR  19.00 USD 147.00 USD   275.00 USD 2-chloro-5- fluoro- benzaldehyde oxime 443-33-4
    Figure US20160030321A1-20160204-C00084
         		C7H5ClFNO 173.574203
    SPB08414DA   SPB08414EA
     1 GR    10 GR  53.00 USD 321.00 USD 3,5-dibromo-4- hydroxy- benzaldehyde oxime 25952-74-3
    Figure US20160030321A1-20160204-C00085
         		C7H5Br2NO2 294.9302
    MO00284CB MO00284DA 250 MG    1 GR  68.00   134.00 USD 2-bromo- 1-phenyl-1- ethanone oxime 14181-72-7
    Figure US20160030321A1-20160204-C00086
         		C8H8BrNO 214.06162
    KM08088DA  1 GR  53.00 USD 4-(3-hydroxy-3- methylbut-1-yn- yl)benzaldehyde oxime 175203-57-3
    Figure US20160030321A1-20160204-C00087
         		Cl2H13NO2 203.24072
    TL00712DA   TL00712EA   TL00712EB  1 GR  10 GR    25 GR  57.00 USD 337.00 USD 426.00 USD (1E)-1-(5,6,7,8- tetrahydro- napthalen-2- yl)ethanone oxime 7357-12- 2
    Figure US20160030321A1-20160204-C00088
         		C12H15NO 189.2572
    BTB09548DA   BTB09548EA   BTB09548EB  1 GR    10 GR    25 GR  29.00 USD  65.00 USD  81.00 USD 3-phenyl- acrylaldehyde oxime 13372-81-1
    Figure US20160030321A1-20160204-C00089
         		C9H9NO 147.17656

    Table 10 recites non-limiting, representative, examples of sulfites suitable to be utilized as calcium sequestration or binding agents.
  • TABLE 10
    Product Code & Pack Size Product Name CAS Structure MF MF
    AC27651DA
     1 GR  70.00 USD 1-methyl-1H- benzimidazole- 2- sulfonic acid 5533- 38-0
    Figure US20160030321A1-20160204-C00090
         		C8H9N2O3S 212.223312
    AC40114CA   AC40114CB 100 MG 250 MG  74.00 USD 255.00 USD Ammonium 7-chloro- 2,1,3- benzoxa- diazole- 4-sulfonate 81377- 14-2
    Figure US20160030321A1-20160204-C00091
         		C6H2ClN2O4S•H4N 251.64434 (233.60588)
    MO000766DA   MO00766DE  1 GR  5 GR 142.00 USD 403.00 USD 6-chloro- imidazo[2,1- b]thiazole- 5-sulfonic acid amide 112582- 89-5
    Figure US20160030321A1-20160204-C00092
         		C5H4ClN3O2S2 237.67866
    BTB06262DA   BTB06262EA   BTB06262EB  1 GR  10 GR  25 GR  23.00 USD  65.00 USD 115.00 USD 8-chloro- naphthalene- 1-sulfonic acid 145-74- 4
    Figure US20160030321A1-20160204-C00093
         		C10H7ClO3S 242.67678
    BTB09138DA  1 GR  55.00 USD 2- {[amino(imino) methyl]amino}- ethane-1- sulfonic acid 543-18- 0
    Figure US20160030321A1-20160204-C00094
         		C3H9N3O3S 167.18276
    BTB13613DA   BTB13613EA
     1 GR  10 GR  53.00 USD 321.00 USD 2-(4- aminophenyl)- 6-methyl-1,3- benzothiazole- 7- sulfonic acid 130-17- 6
    Figure US20160030321A1-20160204-C00095
         		C14H12N2O3S2 320.38088
    RJC04098DA   RJC04098EA
     1 GR  10 GR  53.00 USD 321.00 USD 2,5-dichloro- 4-(5- hydroxy-3- methyl-1H- pyrazol-1-yl) benzenesulfonic acid dihydrate 306935- 68-2
    Figure US20160030321A1-20160204-C00096
         		C10H8Cl2NO204S•2H2O 359.18108 (323.15052)
    SB01747DA   SB01747EA   SB01747EB  1 GR  10 GR  25 GR  42.00 USD  65.00 USD 115.00 USD 3-amino-4- hydroxy-5- nitobenzene-1- sulfonic acid hydrate 175278- 60-1
    Figure US20160030321A1-20160204-C00097
         		C6H6N2O6S•H2O 252.19872 (234.18344)

    Table 11 recites non-limiting, representative, examples of sulfates suitable to be utilized as calcium sequestration or binding agents.
  • TABLE 11
    Product
    Product Code & Pack Size Name CAS Structure MF MF
    AC10430DA   AC10430EA
     1 GR    10 GR  25.00 USD 189.00 USD 3-amino- phenyl- boronic acid 0.5 sulfate 66472-86-4
    Figure US20160030321A1-20160204-C00098
         		C6H8BNO2•0.5 H2O4S 185.98176 (136.94502)
    AC33706CB 250 MG  27.00 USD Potassium 1H- indol-3-yl sulfate 2642-37-7
    Figure US20160030321A1-20160204-C00099
         		C8H6NO4S•K 251.29824 (212.19994)

    Table 12 recites non-limiting, representative, examples of hydrazines suitable to be utilized as calcium sequestration or binding agents.
  • TABLE 12
    Figure US20160030321A1-20160204-C00100
         		3-Fluorophenyl- hydrazine hydrochloride
    Figure US20160030321A1-20160204-C00101
         		4-Fluorophenyl- hydrazine hydrochloride
    Figure US20160030321A1-20160204-C00102
         		4-Iodophenyl- hydrazine
    Figure US20160030321A1-20160204-C00103
         		2-Nitrophenyl- hydrazine
    Figure US20160030321A1-20160204-C00104
         		3-Nitrophenyl- hydrazine hydrochloride
    Figure US20160030321A1-20160204-C00105
         		4-Nitrophenyl- hydrazine
    Figure US20160030321A1-20160204-C00106
         		Phenylhydrazine
    Figure US20160030321A1-20160204-C00107
         		Phenylhydrazine hydrochloride
    Figure US20160030321A1-20160204-C00108
         		Diethyl 1,2- hydrazine- dicarboxylate
  • Table 13 recites non-limiting, representative, examples of carboxylic acids suitable to be utilized as calcium sequestration or binding agents.
  • TABLE 13
    Figure US20160030321A1-20160204-C00109
    Figure US20160030321A1-20160204-C00110
    Catalog Catalog
    Brand Number MW Brand Number MW
    ALDRICH 2355
    Figure US20160030321A1-20160204-P00899
    		 85.59 ALDRICH 2461
    Figure US20160030321A1-20160204-P00899
    		 86.11
    Figure US20160030321A1-20160204-C00111
    Figure US20160030321A1-20160204-C00112
    Figure US20160030321A1-20160204-C00113
    Figure US20160030321A1-20160204-C00114
    Catalog Catalog
    Brand Number MW Brand Number MW
    ALDRICH
    Figure US20160030321A1-20160204-P00899
    36838    		 100.12 ALDRICH 277827 136.95
    Figure US20160030321A1-20160204-C00115
    Figure US20160030321A1-20160204-C00116
    Figure US20160030321A1-20160204-P00899
    indicates data missing or illegible when filed
  • Table 14 recites non-limiting, representative, examples of aryl carboxylic acids suitable to be utilized as calcium sequestration or binding agents.
  • TABLE 14
    Figure US20160030321A1-20160204-C00117
    Figure US20160030321A1-20160204-C00118
    Catalog Catalog
    Brand Number MW Brand Number MW
    ALDRICH
    Figure US20160030321A1-20160204-P00899
    		 132.42 ALDRICH
    Figure US20160030321A1-20160204-P00899
    		 25.11
    Figure US20160030321A1-20160204-C00119
    Figure US20160030321A1-20160204-C00120
    Figure US20160030321A1-20160204-C00121
    Figure US20160030321A1-20160204-C00122
    Catalog Catalog
    Brand Number MW Brand Number MW
    ALDRICH
    Figure US20160030321A1-20160204-P00899
    		 122.11 ALDRICH
    Figure US20160030321A1-20160204-P00899
    		 120.10
    Figure US20160030321A1-20160204-C00123
    Figure US20160030321A1-20160204-C00124
    Figure US20160030321A1-20160204-C00125
    Figure US20160030321A1-20160204-C00126
    Catalog Catalog
    Brand Number MW Brand Number MW
    ALDRICH P06609 120.10 ALDRICH P13823 526.33
    Figure US20160030321A1-20160204-C00127
    Figure US20160030321A1-20160204-C00128
    Figure US20160030321A1-20160204-C00129
    Figure US20160030321A1-20160204-C00130
    Catalog Catalog
    Brand Number MW Brand Number MW
    ALDRICH P3404 196.18 ALDRICH A2244 149.12
    Figure US20160030321A1-20160204-C00131
    Figure US20160030321A1-20160204-C00132
    Figure US20160030321A1-20160204-C00133
    Figure US20160030321A1-20160204-C00134
    Catalog Catalog
    Brand Number MW Brand Number MW
    ALDRICH 41894 540.10 ALDRICH 182780 149.98
    Figure US20160030321A1-20160204-C00135
    Figure US20160030321A1-20160204-C00136
    Figure US20160030321A1-20160204-C00137
    Figure US20160030321A1-20160204-C00138
    Catalog Catalog
    Brand Number MW Brand Number MW
    ALDRICH 813886 159.14 ALDRICH
    Figure US20160030321A1-20160204-P00899
    		 182.43
    Figure US20160030321A1-20160204-C00139
    Figure US20160030321A1-20160204-C00140
    Figure US20160030321A1-20160204-P00899
    indicates data missing or illegible when filed
  • Table 15 recites non-limiting, representative, examples of cycloalkyl carboxylic acids suitable to be utilized as calcium sequestration or binding agents.
  • TABLE 15
    Figure US20160030321A1-20160204-C00141
    Figure US20160030321A1-20160204-C00142
    Catalog Catalog
    Brand Number MW Brand Number MW
    ALDRICH
    Figure US20160030321A1-20160204-P00899
    		 924.94 ALDRICH P24606 10839
    Figure US20160030321A1-20160204-C00143
    Figure US20160030321A1-20160204-C00144
    Figure US20160030321A1-20160204-C00145
    Figure US20160030321A1-20160204-C00146
    Catalog Catalog
    Brand Number MW Brand Number MW
    ALDRICH O1493 124.95 ALDRICH
    Figure US20160030321A1-20160204-P00899
    		 158.52
    Figure US20160030321A1-20160204-C00147
    Figure US20160030321A1-20160204-C00148
    Figure US20160030321A1-20160204-C00149
    Figure US20160030321A1-20160204-C00150
    Catalog Catalog
    Brand Number MW Brand Number MW
    ALDRICH 34847 115.12 ALDRICH 725803 126.23
    Figure US20160030321A1-20160204-C00151
    Figure US20160030321A1-20160204-C00152
    Figure US20160030321A1-20160204-C00153
    Figure US20160030321A1-20160204-C00154
    Catalog Catalog
    Brand Number MW Brand Number MW
    ALDRICH 56.034 126.17 ALDRICH 28085 129.12
    Figure US20160030321A1-20160204-C00155
    Figure US20160030321A1-20160204-C00156
    Figure US20160030321A1-20160204-C00157
    Figure US20160030321A1-20160204-C00158
    Catalog Catalog
    Brand Number MW Brand Number MW
    ALDRICH 81533 122.49 ALDRICH 12802 125.16
    Figure US20160030321A1-20160204-C00159
    Figure US20160030321A1-20160204-C00160
    Figure US20160030321A1-20160204-C00161
    Figure US20160030321A1-20160204-C00162
    Catalog Catalog
    Brand Number MW Brand Number MW
    ALDRICH 104950 129.18 ALDRICH 29055 148.39
    Figure US20160030321A1-20160204-C00163
    Figure US20160030321A1-20160204-C00164
    Figure US20160030321A1-20160204-P00899
    indicates data missing or illegible when filed
  • Table 16 recites non-limiting, representative, examples of heteroaryl and biaryl acids suitable to be utilized as calcium sequestration or binding agents.
  • TABLE 16
    Figure US20160030321A1-20160204-C00165
    Figure US20160030321A1-20160204-C00166
    Catalog Catalog
    Brand Number MW Brand Number MW
    ALDRICH 814654 186.58 ALDRICH 831588 158.19
    Figure US20160030321A1-20160204-C00167
    Figure US20160030321A1-20160204-C00168
    Figure US20160030321A1-20160204-C00169
    Figure US20160030321A1-20160204-C00170
    Catalog Catalog
    Brand Number MW Brand Number MW
    ALDRICH 813483 588.47 ALDRICH 834152 100.22
    Figure US20160030321A1-20160204-C00171
    Figure US20160030321A1-20160204-C00172
    Figure US20160030321A1-20160204-C00173
    Figure US20160030321A1-20160204-C00174
    Catalog Catalog
    Brand Number MW Brand Number MW
    ALDRICH 054829 188.72 ALDRICH 10847 279.96
    Figure US20160030321A1-20160204-C00175
    Figure US20160030321A1-20160204-C00176
    Figure US20160030321A1-20160204-C00177
    Figure US20160030321A1-20160204-C00178
    Catalog Catalog
    Brand Number MW Brand Number MW
    ALDRICH 107926 258.25 ALDRICH 109337 258.25
    Figure US20160030321A1-20160204-C00179
    Figure US20160030321A1-20160204-C00180
  • Table 17 recites non-limiting, representative, examples of ureas suitable to be utilized as calcium sequestration or binding agents.
  • TABLE 17
    Figure US20160030321A1-20160204-C00181
         		Urea
    Figure US20160030321A1-20160204-C00182
         		Hydroxyurea
    Figure US20160030321A1-20160204-C00183
         		Semicarbazide hydrochloride
    Figure US20160030321A1-20160204-C00184
         		1-Cyanoisourea sodium salt
    Figure US20160030321A1-20160204-C00185
         		Biuret
    Figure US20160030321A1-20160204-C00186
         		N-Methylurea
    Figure US20160030321A1-20160204-C00187
         		o-Methylisourea bisulfate
  • Table 18 recites non-limiting, representative, examples of hydrazones suitable to be utilized as calcium sequestration or binding agents.
  • TABLE 18
    Figure US20160030321A1-20160204-C00188
         		Glyoxal mono- dimethyl- hydrazone
    Figure US20160030321A1-20160204-C00189
         		Benz- aldehyde semi- carbazone
    Figure US20160030321A1-20160204-C00190
         		Benz- aldehyde p- nitrophenyl- hydrazone
    Figure US20160030321A1-20160204-C00191
         		Benzo- phenone hydrazone
    Figure US20160030321A1-20160204-C00192
         		2-Hydroxy- benz- aldehyde phenyl- hydrazone
    Figure US20160030321A1-20160204-C00193
         		Benzil mono- hydrazone
    Figure US20160030321A1-20160204-C00194
         		2-Nitro- benz- aldehyde tosyl- hydrazone
    Figure US20160030321A1-20160204-C00195
         		2′- Amino- aceto- phenone phenyl- hydrazone
    Figure US20160030321A1-20160204-C00196
         		Valero- phenone tosyl- hydrazone
  • The “calcium sequestration agent” or “calcium binding agent” of the present invention is any agent capable of binding or sequestering calcium ion (CaII) such that the bound or sequestered calcium ion is prevented or inhibited (i.e., reduced) from interacting with other binding agents. In the context of the present invention, the calcium sequestration or binding agent, when administered to the skin of a patient in need of such treatment, binds or sequesters calcium ion in the local area of topical administration and regulates or modulates (i.e., prevents, limits, or inhibits) calcium from acting as a regulator in several (i.e., at least two) steps of melanogenesis and skin pigmentation.
  • The present composition contain a calcium sequestration or binding agent in an amount effective to reduce pigmentation. For example, the calcium sequestration or binding agent is present in the composition in an amount from about 0.1% to the solubility limit of the calcium sequestration or binding agent in the composition. Preferably, the calcium sequestration or binding agent is present in the composition in the amount of about 0.1% to about 25%, more preferably about 0.2% to about 10%, most preferably about 1% to about 5% by weight.
  • The pH range of any of the compositions containing a calcium sequestration or binding agent described herein is about 2.5 to about 9.0, preferably about 3.0 to about 7.0, more preferably about 4.0 to about 5.0. Solutions for adjusting pH to appropriate value, e.g., sodium hydroxide (NaOH), may be added to the composition of the present invention, as required.
  • Preferably, the agent capable of binding or sequestering calcium ion is a phosphate agent. A phosphate is defined as a form of phosphoric acid. The phosphate can contain one or more of phosphorus (P) atoms as follows:
      • i) one phosphorus atom (i.e., orthophosphates) such as H3PO4, any possible salts of H3PO4, or esters of H3PO4 as shown in FIG. 1
      • ii) two phosphorus atoms (i.e., pyrophosphates) such as H4P2O7, any possible salts of H4P2O7, or esters of H4P2O7
      • iii) three phosphorus atoms (i.e., tripolyphosphates) such H5P3O10, any possible salts of H5P3O10, or esters of H5P3O10
      • iv) more than three phosphorus atoms (i.e., polyphosphates) such as H(n+4)(PO3)(n+2), any possible salts of H(n+4)(PO3)(n+2), or esters of H(n+4)(PO3)(n+2)
  • The structural formula of orthophosphate esters is shown in Formula I, where R1, R2 and R3 are each chosen from branched or unbranched alkyl or alkenyl groups having one or more carbon atoms.
  • Figure US20160030321A1-20160204-C00197
  • As used herein, the terms “phosphate” or “phosphates” does not include phosphate derivatives of ascorbic acid, such as sodium or magnesium ascorbyl phosphate, aminopropyl ascorbyl phosphate and other known phosphate derivatives of ascorbic acid with antioxidant properties.
  • Preferably, the composition can be prepared contains a phosphate form substantially free of calciums such as the phosphoric acid glycerophosphoric acid (C3H9O6P). Glycerophosphoric acid can be present in two different chemical structures, including:
      • i) alpha-glycerophosphoric acid (also known as 3-glycerophosphate, 1-glycerophosphate, 3-phosphoglycerol, alpha-phosphoglycerol, glycerol-3-phosphate, glycerol 1-phosphate, glycerol-3-P, glycerophosphoric acid, 1-glycerophosphoric acid, alpha-glycerophosphate), and
      • ii) beta-glycerophosphoric acid (also known as glycerol 2-phosphate, beta-glycerol phosphate, beta-GP, 2-glycerophosphoric acid, glycerophosphoric acid II).
  • More preferably, the compositions of the present invention contain the sodium salts of glycerophosphoric acid. The term “glycerophosphoric acid” includes alpha-glycerophosphoric acid, beta-glycerophosphoric acid, or any mixture thereof. Sodium salts of glycerophosphoric can further include the monosodium sodium salt of glycerophosphoric acid (C3H8NaO6P), the disodium sodium salt of glycerophosphoric acid (C3H7Na2O6P), and/or any mixture of the mono- and disodium salts. Sodium salts of glycerophosphoric acid are herein referred as “sodium glycerophosphate”.
  • The sodium glycerophosphate may further contain some bound water and may be in its hydrated form. The bound water is present in an amount of about 20 to about 40%; preferably between about 25 to about 35% per weight. For the present invention, the sodium glycerophosphate in accordance to the descriptions provided in European Pharmacopoeia 6th Ed. (2007) represents one of the preferred forms and qualities of sodium glycerophosphate.
  • Excluding any calcium salts of glycerophosphoric acid, the composition may be prepared with other possible salts of glycerophosphoric acid such as the potassium salts of glycerophosphoric acid, the magnesium salts of glycerophosphoric acid, the manganese salts of glycerophosphoric acid, and/or any possible combination thereof including the sodium salts of glycerophosphoric acid. Those skilled in the art will recognize that calcium glycerophosphate or any other calcium salts of phosphoric acid are not phosphates free of calcium and, therefore, are not used in the present invention.
  • The compositions of the invention contain phosphate(s) in an amount effective to reduce pigmentation. For example, phosphate is present in the composition in an amount from about 0.1% to the solubility limit of the phosphate in the composition. Preferably, the phosphate is present in the composition in the amount of about 0.1% to about 25%, more preferably about 0.2% to about 10%, most preferably about 1% to about 5% by weight.
  • Preferably, the composition is prepared with sodium glycerophosphate (C3H7Na2O6P×H2O according to specifications provided in European Pharmacopoeia 6th Ed. (2007)) between about 1% to about 5% by weight.
  • The present invention also provides a skin lightening composition, which is well tolerated. Preferably, such skin lightening compositions provide less skin irritation than is commonly observed with several of the skin lightening products containing hydroquinone; in particular those skin lightening products with additionally contain chemicals with known human skin irritant properties such as retinoic acid, tretinoin, retinol, alpha hydroxy acids such as glycolic or lactic acid, beta hydroxyl acids such as salicylic acid, azelaic acid, free short chain fatty acids, free short chain fatty acid esters, ionic surfactants such as SLS or SLES. Examples of skin lightening products containing hydroquinone along with chemicals with known human skin irritant properties, include, but are not limited to, Tri-Luma® (from Galderma), EpiQuin® Micro (from SkinMedica), Obagi Nu-Derm® Clear and Obagi Nu-Derm® Blender (both from OMP, Inc.) and Lustra® Hydroquinone USP 4% (from TaroPharma).
  • Specifically, the compositions of the present invention are well tolerated and do not (or only minimally) lead to visibly noticeable skin redness (i.e., erythema, contact dermatitis) or rash (i.e., edema, contact allergy, uticaria) when used once to twice daily for a prolonged period of time (i.e., more than two weeks) under normal in use conditions typical of a skincare or dermatological product. More specifically, the compositions of the present invention provide less skin irritation as compared to skin lightening products containing hydroquinone as observed in repetitive skin irritancy patch tests in humans or animals realized according to the art-recognized models described in J. Toxicol.—Ot. & Ocular Toxicol., 1(2); 109-115. 1982; Contact Dermatitis, 20(1); 3-9. 1989; Lanman, B. M., E. B. Elvers, and C. J. Howard, 1968, “The Role of Human Patch Testing in a Product Development Program,” Joint Conference on Cosmetic Sciences, The Toilet Goods Association (currently, the Cosmetic, Toiletry and Fragrance Association), Washington, D.C., Apr. 21-23, 1968 and Patel, S. M., E. Patrick, and H. I. Maibach, 1976, “Animal, Human, and In Vitro Test Methods for Predicting Skin Irritation,” Dermatotoxicology, Chpt. 33, 5th Ed., Eds. F. N. Marzulli, H. I. Maibach, Taylor, and Frances) (each of which are incorporated herein by reference).
  • Preferably, the present invention provides methods and compositions for skin depigmentation which are effective in concentrations not resulting in significant skin irritancy as determined by the art-recognized models described herein. Preferably, the present invention provides compositions which are substantially free of calcium, steroids, parabens, anti-microbial preservatives and/or formaldehyde releasers The term “substantially free” as used herein means that the composition of interest (e.g., calcium) is present in the composition in an amount less than 0.1% per weight, preferably less than 0.5% by weight and most preferably less than 0.01% per weight. Preferably, the present invention provides compositions which are suitable for topical application, cosmetically elegant and fast absorbing. That is, the compositions of the present invention do not provide sticky, oily, greasy or otherwise unpleasant feeling when applied onto skin after about one to maximum of about two minutes of application; in case applied as dose per skin area typical for skincare or dermatological products (typically less than 1 mg of composition per cm2).
    • Additional Active Agents
  • The present invention also provides stable skin lightening composition, which contain at least one calcium sequestration or binding agent, as described above, and which may further contain at least one additional active agent capable or modulating or reducing (as assessed in vitro and/or in vivo) at least one of the following steps in melanogenesis:
  • i) uptake of L-tyrosine into melanocytes, and/or
  • ii) uptake of L-phenylalanine into melanocytes, and/or
  • iii) turnover of phenylalanine into tyrosine by phenylalanine hydroxylase, and/or
  • iv) uptake of L-tyrosine into melanosmes, and/or
  • v) turnover of L-tyrosine into L-Dopa by tyrosinase or tyrosine hydroxylase, and/or
  • vi) turnover of L-Dopa into dopaquinone by tyrosinase, and/or
  • vii) transfer of melanosme from melanocytes to keratinocytes.
  • Several compounds can be described as compounds capable of competing with the transport (active uptake into cell or cell organelle) of L-tyrosine into melanocytes and/or into melanosmes, what may result in a reducing or limiting pool of L-tyrosine for melanogenesis.
    • Amino Acids
  • Several amino acids are known competitively inhibit the uptake of L-tyrosine into melanocytes and/or melanosmes. Amino acids L-alanine, glycine, L-isoleucine, L-leucine, but not their D-forms, were described to have hypopigmenting effects in an in vitro assay using B16F0 melanoma cells as cell model for studying melanogenesis. (See Biol Pharm Bull 30, 2007, pp. 677-681). These amino acids were shown not to function as inhibitors of tyrosinase.
  • Another compound potentially inhibiting tyrosine transport is the sulfur homologue of tyrosine 4-S-cysteinylphenol. (See Biochem J 280, 1991, pp. 721-725). 4-S-cysteinylphenol may also act as substrate of tyrosinase and can therefore be also regarded as inhibitor of tyrosinase. There is some evidence that amino acids L-phenylalanine and L-tryptophan also compete for tyrosine transport. (See Biochem J 280, 1991, pp. 721-725; J Biol Chem 271, 1996, pp. 4002-4008). However, phenylalanine is a precursor of melanin and is therefore excluded in the present invention. L-Tyrosine is formed from L-phenylalanine in the presence of enzyme phenylalanine hydroxylase in melanocytes. Similarly, tryptophan is excluded in the present invention.
  • Thus, the compositions of the present invention can contain at least one calcium sequestration or binding agent and can further contain L-alanine, glycine, L-isoleucine, L-leucine or a combination thereof. L-alanine, glycine, L-isoleucine, L-leucine can also include esters (e.g. R—COOR′ with R=from amino acid and R′=branched or not branched alky/aryl side chain consisting of up to 18 carbons), amides (R—NH(C═O)—R′), with R=from amino acid and R′=branched or not branched alky/aryl side chain consisting of up to 18 carbons) or both to increase their skin bioavailability. These amino acids also include zwitterions with a sodium or potassium as positive ion (cation).
  • The present composition can also contain amino acids or their respective derivatives (esters, amides, etc.) in an amount effective to reduce pigmentation or reduce the transport of L-tyrosine either into the melanocyte and/or into the melanosome. For example, the amino acid is present in the composition in an amount from about 0.001% to the solubility limit of the amino acid in the composition. Preferably, the amino acid is present in the composition in the amount of about 0.01% to about 10%, more preferably about 0.05% to about 5%, most preferably about 0.1% to about 2% by weight.
  • In one embodiment, the invention provides a composition containing one or more phosphates, substantially free of calcium, and further containing L-leucine in an amount of about 0.1% to about 2% by weight. Preferably, the present invention provides a composition containing sodium glycerophosphate (C3H7Na2O6P×H2O; according to specifications provided in Ph. Eur. 6th Ed.) in an amount of about 1% to 5% by weight and further contains L-leucine in an amount of about 0.1% to 2% by weight.
    • Tyrosinase Inhibitors
  • The compositions of the present invention can contain at least one calcium sequestration or binding agent and may further contain one or more compounds capable of reducing (as assessed in vitro and/or in vivo) the turnover of L-tyrosine into L-Dopa by tyrosinase or tyrosine hydroxylase, and/or the turnover of L-Dopa into dopaquinone by tyrosinase. Compounds which reduce the turnover of L-tyrosine into L-Dopa and/or reduce the turnover of L-Dopa into dopaquinone are generally referred as tyrosinase inhibitors meaning that they inhibit of tyrosinase activity, tyrosinase gene expression, and/or tyrosine protein formation and/or maturation.
  • For example, the following compounds have been described to act as tyrosinase inhibitors as assessed in diverse in vitro enzymatic and cellular assays (see Journal of Medicinal Chemistry 42 (2007) 1370-1381 [including supporting information mentioned under Appendix A]; Pigment Cell Res 19, 2006, pp. 550-571) (incorporated herein by reference) and are therefore suitable to be incorporated, either alone or in combination, into the compositions described herein: hydroquinone (1,4-benzenediol); diphenylmethane derivatives (see WO 2004/105736; incorporated herein by reference) including but not limited to 4-(1-phenylethyl)1,3-benzenediol (phenylethyl resorcinol); kojic acid; alpha-arbutin; beta-arbutin; deoxyarbutin, L-mimosine; monobenzyl ether of hydroquinone; hydroquinone fatty esters; L-tropolone; ascorbic acid; benzoic acid; oxyresveratrol (i.e., 2,4,3′,5′-tetrahydroxystilbene); quercetin; benzaldehyde; aloesin; trans-resveratrol; anisaldehyde; cinnamic acid; gnetol; dihydrognetol; 3,3′,4-hydroxy-trans-stilbene; 3,3′,4,4′-hydroxy-trans-stilbene; 3-amino-L-tyrosine, 2-aminophenol; isoliquiritigenin; 4-hydroxychalcone; butein; 4′-hydroxychalcone; 2′,4′-dihydroxychalcone; 2′,4-dihydroxychalcone; trans-4-azobenzene carboxylic acid; cis-4-azobenzene carboxylic acid; trans-4,4′-azobenzene dicarboxylic acid; cis-4,4′-azobenzene dicarboxylic acid; castanospermine; deosynojirimycin; Ko-YGC; Ko-YGV; Ko-YGE; Ko-YGT; Ko-YGL; Ko-YGW; Ko-YGF; Ko-YGH; Ko-YGN; Ko-YGD; Ko-YGG; Ko-YIG; Ko-YYG; Ko-YSG; Ko-YMG; Ko-YQG; Ko-YRG; Ko-YHG; Ko-YNG; Ko-YDG; Ko-FIY; Ko-FRY; Ko-FYY; Ko-FWY; Ko-FFY; Ko-KWY; Ko-KRY; Ko-KKY; Ko-KIY; Ko-FWW; Ko-FWF; Ko-FWI; Ko-FWD; Ko-WWY; glabridin; N-cyclopenthyl-N-nitrosohydroxyl-amine; N-benzyl-N-nitrosohydroxylamine; N-benzyl-N-nitrosohydroxylamine; N-cyclopenthyl-N-nitrosohydroxyl-amine; 3,5-dihydroxy-4′-methoxystilbene; 3,4′-dimethoxy-5-hydroxystilbene; piceid; rhapontigenin; rhaponticin; kurarinone; kushnol F; 4-hydroxyanisol; 2-hydroxy-4-methoxy benzaldehyde; cuminaldehyde; artocarbene; norartocarpanone; 4-propylresorcinol; 3,4-dihydroxybenzonitrile; 3,4,2,4-trans-stilbene; artogomezianol; andalasin; crocusatins H; crocin-1; crocin-3; 3,4-dihydroxycinnamic acid; 4-hydroxy-3-methoxycinnamic acid; anisic acid; 2-methoxycinnamic acid; 3-methoxycinnamic acid; 4-methoxycinnamic acid; kaempferol; glabrene; pyridoxine; Pyridoxamine; Pyridoxal; Pyridoxamine 5′-phosphate; Protocatechuic acid methyl ester; Protocatechuic acid; m-coumaric acid; 3-caffeoylquinic acid; 4-caffeoylquinic acid; 5-caffeoylquinic acid; 3,4-dicaffeoylquinic acid; Caffeic acid; Fisetin; 3,7,4′-trihydroxyflavone; Morin; Luteolin; Apigenin; Galangin; Diethyldithiocarbamate; Phenylthiourea; Phloroglucinol; Eckstolonol; Eckol; Phlorofucofuroeckol; Dieckol; HPABS; Gluthatione; B-Mercaptoethanol; Protocatechualdehyde; 8′-epi-cleomiscosin A; 3,4-Dihydroxybenzaldoxime; 3-Hydroxy-4-methoxybenzaldoxime; 3,4,5-Trihydroxybenzaldoxime; 4-Hydroxy-3-methoxy benzaldoxime; 3-Ethoxy-4-hydroxy benzaldoxime; 4-Hydroxybenzaldoxime; 3,4-Dihydroxy-benzaldehyde-O-ethyloxime; 3,4-Dihydroxybenzaldehyde-O-(4-methylbenzyl)-oxime; 3-Hydroxy-4-methoxy benzaldehyde-O-ethyloxime; 3,4,5-Trihydroxybenzaldehyde-O-ethyloxime; 4-Hydroxy-3-methoxybenzaldehyde-O-ethyloxime; 3-Ethoxy-4-hydroxybenzaldehyde-O-ethyloxime; 4-Hydroxybenzaldehyde-O-ethyloxime; 4-Hydroxy-3-methylbenzaldehyde-O-ethyloxime; 3,5-Dimethyl-4-hydroxybenzaldehyde-O-ethyloxime; (+)-Androst-4-ene-3,17-dione; Androsta-1,4-diene-3,17-dione; 17β-Hydroxyandrosta-1,4-dien-3-one; 11α-Hydroxyandrost-4-ene-3,17-dione; 17β, 11α-Dihydroxyandrost-4-en-3-one; Esculetin; Lappaconitine; Stigmast-5-ene-3β,26-diol; Stigmast-5-ene-3β-ol; Campesterol; arctostaphylos uva ursi (bearberry) leaf extract; glycyrrhiza glabra (licorice) extract; sanguisorba officinalis (burnet) extract; scutellaria baicalensis root (skull cap) extract; and morus alba (mulberry) extract; pinosylvin, dihydropinosylvin; gallic acid; gentisic acid; methyl gentisate; epigallocatechin-3-O-gallate; epigallocatechin; green tea leave extract; ellagic acid; pyognol; myrica rubra leave extract; and/or octadecenedioic acid.
  • In addition to these recited tyrosinase inhibitors, any biological precursors (pro-forms) of above chemicals can also be included in the present invention. Biological precursors can be simple esters (i.e. methyl-, ethyl-, propyl-, or butyl-esters) of inhibitors with carboxy group. Also included are derivatives of ascorbic acid, such as aminopropyl ascorbyl phosphate, magnesium ascorbyl phosphate, alkyl esters of L-ascorbic acid such as L-ascorbyl palmitrate, L-ascorbyl isopalmitate, L-ascorbyl dipalmitate, L-ascorbyl isostearate, L-ascorbyl distearate, L-ascorbyl diisostearate, L-ascorbyl myristate, L-ascorbyl isomyristate, L-ascorbyl 2-ethylhexanoate, L-ascorbyl di-2-ethylhexanoate, L-ascorbyl oleate and L-ascorbyl dioleate; phosphates of L-ascorbic acid such as L-ascorbyl-2-phosphate and L-ascorbyl-3-phosphate; sulfates of L-ascorbic acid such as L-ascorbyl-2-sulfate and L-acorbyl-3-sulfate; as well as their sodium, potassium, magnesium and/or manganese salts.
  • The present composition may contain at least one tyrosinase inhibitor in an amount effective to reduce pigmentation or reduce the turnover of L-tyrosine into L-Dopa by tyrosinase or tyrosine hydroxylase, and/or the turnover of L-Dopa into dopaquinone by tyrosinase. For example, the tyrosinase inhibitor can be present in the composition in an amount from about 0.001% to the solubility limit of the tyrosinase inhibitor in the composition. Preferably, the tyrosinase inhibitor is present in the composition in the amount of about 0.01% to about 15%, more preferably about 0.05% to about 10%, most preferably about 0.1% to about 5% by weight. The present invention provides a composition containing one or more phosphates, substantially free of calcium, and further containing: a) hydroquinone (1,4-benzenediol) in an amount of about 0.1% to about 10% by weight, b) 4-(1-phenylethyl)1,3-benzenediol (phenylethyl resorcinol) in an amount of about 0.1% to about 5% by weight, c) arbutin in an amount of about 0.1% to about 10% by weight, d) bearberry leaf extract in an amount of about 0.1% to about 10% by weight, e) kojic acid in an amount of about 0.1% to about 5% by weight, f) oxyresveratrol in an amount of about 0.1% to about 5% by weight, and/or g) gnetol in an amount of about 0.1% to about 5% by weight.
  • The compositions of the invention may contain, in some embodiments, one or more phosphates, substantially free of calcium, and may further contain hydroquinone (1,4-benzenediol) in an amount of about 1% to about 10% by weight and/or may further contain 4-(1-phenylethyl)1,3-benzenediol (phenylethyl resorcinol) in an amount of about 0.1% to about 5% by weight
    • Melanosome Transfer Inhibitors
  • In some embodiments, the compositions of the present invention contain at least one calcium sequestration or binding agent and may additionally contain one or more compounds capable of reducing (as assessed in vitro and/or in vivo) the transfer of melanosmes from melanocytes to keratinocytes. Inhibitors of the transfer of melanosomes from melanocytes to keratinocytes have been described previously (see Pigment Cell Res 19, 2006, pp. 550-571) and include, for example, niacinamide (vitamin B3); centaureidine; lectins; neoglycoproteins and certain inhibitors of serine proteases. In addition, N-acetyl-glucosamine may also reduce melanosme transfer.
  • The present composition may contain at least one melanosme transfer inhibitor in an amount effective to reduce pigmentation or reduce the transfer of melanosmes from melanocytes to keratinocytes. For example, the melanosme transfer inhibitor can be present in the composition in an amount from about 0.001% to the solubility limit of the melanosme transfer inhibitor in the composition. Preferably, the melanosme transfer inhibitor is present in the composition in the amount of about 0.01% to about 12%, more preferably about 0.05% to about 6%, most preferably about 0.1% to about 3% by weight.
  • The invention provides a composition containing one or more phosphates, substantially free of calcium, and may further contain hydroquinone in an amount of about 0.1% to about 10% by weight, and further containing a melanosome transfer inhibitor in an amount of about 0.1% to about 3% by weight.
  • For example, the present invention also provides a composition including one or more phosphates, substantially free of calcium, and also includes 4-(1-phenylethyl)1,3-benzenediol (phenylethyl resorcinol) in an amount of about 0.1% to about 5% by weight, and may also include a melanosome transfer inhibitor in an amount of about 0.1% to about 3% by weight.
  • In one embodiments, the invention additionally provides a composition containing one or more phosphates, substantially free of calcium; hydroquinone in an amount of about 0.1% to about 10% by weight; 4-(1-phenylethyl)1,3-benzenediol (phenylethyl resorcinol) in an amount of about 0.1% to about 5% by weight: and a melanosome transfer inhibitor in an amount of about 0.1% to about 3% by weight.
    • Melanocortin Receptor 1 Inhibitors
  • The compositions of the present invention can contain at least one calcium sequestration or binding agent and can further contain one or more compounds capable of decreasing (as assessed in vitro and/or in vivo) melanocortin receptor 1 (MC1R) activity. For instance, agouti signaling protein regulates skin pigmentation by antagonizing the binding of α-MSH to MC1R. (See Abdel-Malek et al., J. Cell Sci. 2001, 114 (Pt.5):1019-24; Jordan and Jackson, Bioessays. 1998, 20(8):603-606; Voisey and Van Daal, Pigment Cell Res. 2002; 15(1):10-18; Wolff, Pigment Cell Res. 2003, 16(1):2-15). The signaling inhibition through the receptor results from two effects (i) a direct competition at the binding site, and (ii) a downregulation of the receptor signaling. (See Barsh et al., Pigment Cell Res., 2000, 13 Suppl. 8:48-53). As an example, undecylenoyl phenylalanine was described to have an affinity towards MC1R and was shown to act as antagonist of α-MSH in vitro.
  • In some embodiments, the present composition contains at least one α-MSH antagonist in an amount effective to antagonizing the binding of α-MSH to MC1R. For example, the α-MSH antagonist is present in the composition in an amount from about 0.001% to the solubility limit of the α-MSH antagonist in the composition. Preferably, the α-MSH antagonist is present in the composition in the amount of about 0.01% to about 10%, more preferably about 0.05% to about 5%, most preferably about 0.1% to about 4% by weight.
  • In one embodiment, the present invention provides a composition containing one or more phosphates, substantially free of calcium, and also contains hydroquinone in an amount of about 0.1% to about 10% by weight and an α-MSH antagonist in an amount of about 0.1% to about 4% by weight. By way of non-limiting example, the α-MSH antagonist is undecylenoyl phenylalanine (with chemical structure: CH2═CH—(CH2)8—CO—NH—CH(—COOH)(—CH2—C6H5), as described in WO2003/061768].
  • Preferably, the present invention additionally provides a composition containing one or more phosphates, substantially free of calcium; 4-(1-phenylethyl)1,3-benzenediol by weight in an amount of about 0.1% to about 5% by weight; and an α-MSH antagonist in an amount of about 0.1% to about 4% by weight. By way of non-limiting example, the α-MSH antagonist is undecylenoyl phenylalanine.
  • Alternatively, the present invention also provides a composition including one or more phosphates, substantially free of calcium; hydroquinone in an amount of about 0.1% to about 10% by weight; 4-(1-phenylethyl)1,3-benzenediol by weight in an amount of about 0.1% to about 5% by weight; and an α-MSH antagonist in an amount of about 0.1% to about 4% by weight. Preferably, the α-MSH antagonist is undecylenoyl phenylalanine.
  • Also provided are compositions containing one or more phosphates, substantially free of calcium; hydroquinone in an amount of about 0.1% to about 10% by weight; 4-(1-phenylethyl)1,3-benzenediol by weight in an amount of about 0.1% to about 5% by weight; and an α-MSH antagonist in an amount of about 0.1% to about 4% by weight. For example, the α-MSH antagonist is undecylenoyl phenylalanine. These compositions may additionally contain a melanosome transfer inhibitor in an amount of about 0.1% to about 3% by weight.
    • Dermatological Drugs, Biologics and Skin Care Additives
  • Any of the compositions of the present invention can include at least one calcium sequestration or binding agent and can further include one or more compounds, skincare actives or dermatology drugs and/or biologics other than calcium containing chemicals known in the arts of the treatment of skin pigmentation; general dermatology; cosmetic dermatology; skincare such as, for example skin moisturization; or rejuvenation, including but not limiting to, transforming growth factor (including TGF-beta1, TGF-beta2, TGF-beta3); collagen stimulators such as certain growth factors (e.g. PDGFs, FGFs, etc.) and/or certain peptides (e.g., Matrixyl-3000); stimulators of keratinocyte proliferation such as (e.g. EGF, KGFs, etc.); inhibitors of collagen degrading enzymes (e.g., natural or synthetic inhibitors of MMPs); inhibitors of elastin degrading enzymes (e.g., natural or synthetic inhibitors of elastase); appropriate antioxidants (such as vitamin C, vitamin E, ferulic acid, lipoic acid, polyphenols, ergothioneine, etc.) and their derivatives; appropriate sunscreens and/or solar UV reflectors (e.g., spheres and/or microparticles made of polymers, etc.); anti-inflammatory agents (e.g., steroids, non-steroidal anti-inflammatory agents, anti-inflammatory interleukins, IL-1ra, etc.); emollients; humectants (e.g., glycerin, urea, hyaluronic acid, natural moisturizing factors, etc.); inhibitors of neurotransmitter release; skin penetration agents (e.g., oleic acid, propylene glycol, etc.); skin protectants (e.g., allantoin, calamine, coca butter, cod liver oil, colloidal oatmeal, dimethicone, glycerin, hard fat, kaolin, lanolin, mineral oil, petrolatum, topical starch, white petrolatum, etc.); vitamins (e.g., vitamin B3, vitamin B5, vitamin B6, vitamin D, vitamin F, etc.) and derivatives thereof; keratolytic agents (e.g., urea, alpha-hydroxyl acids (e.g., lactic acid, glycolic acid, citric acid, etc.), beta-hydroxyl acids (e.g., salicylic acid, etc.), and polyhydroxyacids, etc.)); external analgesic agents (e.g., benzocaine, butamben picrate, dibuccaine, diemethisoquin, dyclonine, lidocaine, pramoxine, tetracaine, etc.) and their respective salts; antipruritic agents; cell metabolism stimulants (e.g., pantothenic acid, niacin, nicotinic acid esters, etc.); appropriate anti-acne agents; astringents; counter irritants; antihistamine agents; azelaic acid; retinoic acid, retinol and/or derivatives; natural oils (e.g., jojoba oil, shea butter, etc.); appropriate biological components (e.g., cell lysate, human dermal fibroblast lysate, conditioned cell culture medium, stem cell components, etc.); mixtures of growth factors (e.g., PSP® from Neocutis Inc, Nouricel-MD® from SkinMedica Inc., etc.); and/or wound healing agents.
    • Formulations and Modes of Administration
  • Those skilled in the art will recognize that any of the compositions of the present invention can contain at least one calcium sequestration or binding agent and can further contain one or more compounds capable of chemically stabilizing any of the ingredients present in the composition. Compounds that help to chemically stabilize any of the ingredients may include, but are not limited to, sodium metabisulfite; sodium bisulfate; BHT; BHA; propyl gallate; disodium EDTA; lemon extract; antioxidants, including ascorbic acid (vitamin C) and its derivatives such as phosphate derivatives of ascorbic acid including sodium or magnesium ascorbyl phosphate, aminopropyl ascorbyl phosphate, and other known phosphate derivatives of ascorbic acid having antioxidant properties; and tocopherol and derivatives of tocopherol such as, sodium vitamin E phosphate (VEP), lauryl imino dipropionic acid tocopheryl phosphate, tocopheryl glucoside, tocopheryl succinate, tocophersolan (tocopheryl polyethylene glycol 1000 succinate), disodium lauriminodipropionate tocopheryl phosphates, tocophereth-5,10,12,18, and 50 (polyethylene glycol (PEG) tocopheryl ethers. Sulfites such as sodium metabisulfite, and/or sodium bisulfate are particularly useful to stabilize hydroquinone or other chemically labile (i.e., easily being oxidized) compounds present in the said composition. In general, the compositions may contain between about 0.05 to 0.5% sulfites by weight.
  • The compounds, compositions and formulations of the instant invention can be administered by any means known in the art. Preferably, the compositions of the present invention are formulated as a topical preparation or dosage form. Topical preparations are ointments, creams, gels and lotions. The definition of these topical dosage forms is given by Bhuse L. et al. (Int J Pharm 295: 2005, 101-112) (incorporated by reference). The carrier can also be a liquid, a foam, a mousse, a spray, an aerosol, an oil-in-water emulsion, a water-in-oil emulsion, a triple emulsion, a nanoemulsion, a microemulsion, a hydrogel, a solution, a paste, a jelly, a patch, a wipe, a cloth, and/or a dispersion or suspension. The carrier may contain niosomes, liposomes, nanospheres, microspheres, nanoparticles, microparticles, lipid droplets, solid particles, pigments and/or water droplets.
  • In one preferred embodiment, the carrier is a cream. In various embodiments, the cream may be either an oil-in-water mixture, or a water-in-oil based carrier. In another preferred embodiment, the carrier is a gel or hydrogel.
  • Those skilled in the art will recognize that any reference herein to a composition of the invention includes any composition containing one or more phosphates free of calcium in conjunction with a carrier.
  • Those skilled in the art will also recognize that additional agents can be added in any of the methods and compositions of the invention. These agents may include, but are not limited to, e.g., antimicrobial agents (e.g., parabens, phenoxyethanol, chlorophenesin, propylene glycol, butylene glycol, ethylhexylglycerin, imidazolidinyl urea, methylchloroisothiazolinone, potassium benzoate, DMDM hydantoin, etc.), etc.), color additives, fragrances, sensory stimulating agents, polymers, surfactants, water, oils, etc. Information regarding the preparation of compositions, can be found, e.g., in Volume 3: Liquid Products, Volume 4: Semisolid Products and Volume 5: Over-the-Counter Products, of the ‘Handbook of Pharmaceutical Manufacturing Formulations’ (edited by S. K. Niazi, CRC Press, Boca Raton, 2004). Moreover, information regarding the preparation of cosmetic or cosmeceutical compositions may be found in the formulary archive of the Happy Magazine (see http://www.happi.com/formulary). In addition, formulary information for cosmetic or cosmeceutical compositions can be also obtained from diverse ingredient suppliers such as Croda, Ciba, BASF, Dow Chemicals, etc.
  • The present invention provides stable and none to little irritating (i.e., no or only limited and acceptable skin irritancy) compositions for topical application to the skin to treat skin pigmentation disorders, such as melasma, post-inflammatory hyperpigmentation, pigmentation changes due to skin aging, or any other skin conditions related with normal such as skin of color or abnormal pigmentation such as hypo- or hyper-pigmentation in humans.
  • Stable compositions can be obtained by (1) selecting appropriate calcium sequestration or binding agent concentration(s), (2) selecting appropriate salt form(s) of the agent other than calcium salt(s), (3) adjusting the pH of the composition, (4) selecting appropriate type of formulation (e.g., liquid, a foam, a mousse, a spray, an aerosol, an oil-in-water emulsion, a water-in-oil emulsion, a triple emulsion, a nanoemulsion, a microemulsion, a hydrogel, a solution, a paste, a jelly, a patch, a wipe, a cloth, and/or a dispersion or suspension) for the composition, (5) selecting appropriate ingredients allowing to stabilize the composition, (6) selecting and appropriate container for composition suitable for topical administration (e.g., tube, airless pump, jar, vial, monodose, etc.), and/or (7) selecting conditions allowing the preparation of a stable preparation (e.g., preparation of composition under inert gas, etc.).
  • The term “stable” when applied to the compositions of the instant invention is defined as having a comparable color when the composition is placed on a flat and inert surface (i.e., removed from its container) under normal ambient air and light conditions (i.e., air and light conditions as normally exist in the living room at home) when kept for at least one month at room temperature (about 25° C.).
  • Other than the above-defined color stability, stability of the composition may further include physical stability (e.g., viscosity, odor, appearance, texture, etc.) and chemical stability of the selected active(s) such as a drug active (e.g., calcium sequestration agent, hydroquinone, etc.). Chemical stability can be assessed using HPLC or other appropriate analytical methods. When the composition is placed (e.g., filled) into a suitable container (e.g., a tube, pump, jar, etc.), the composition should be chemically stable (i.e., less than a ±10% change in the content as compared to the baseline value) for at least a year under normal storage condition (i.e., room temperature; or common temperature fluctuations occurring in house/living room/bath room due to changes in season or geographical region). Stability may also be tested under accelerated conditions at elevated temperatures (e.g., 40° C. or higher) in order to predict stability of the composition at room temperature (about 25° C.).
  • The compositions of the present invention may be applied to the entire body, including the face. These compositions may be applied as needed or alternatively, as part of a skin care routine. Preferably, the composition is applied weekly. More preferably, the composition is applied once daily at night at least half an hour before bedtime. However, it can be also applied twice daily, with the preferred mode being once in the morning and once in the evening. When compositions are applied twice daily, the compositions may be the same or different for each application. For example, the same composition may be applied twice daily or alternately, one composition may be applied in the morning and a second, different composition, may be applied in the evening. The compositions can be applied to any mammal (e.g., a primate, rodent, feline, canine, domestic livestock (such as cattle, sheep, goats, horses, and pigs). Preferably, the compositions are applied to humans.
  • In some embodiments, a sunscreen formulation offering a SPF 15 or higher is used in addition during day time in order to protect skin from sun exposure or damage. Additionally, the compositions of the present invention may further contain one or more sunscreen active agents, such as those that provide a UV-B filter and, in some embodiments, additionally a UV-A filter. Examples of suitable UV-A and UV-B filters include those described in U.S. Pat. No. 7,078,022 (incorporated herein by reference).
  • Preferably, the compositions of the invention dry quickly and cleanly (without visible residue or significant stickiness) after application of a normal amount (i.e., 0.2 to 2 mg composition per cm2) on the skin.
  • The examples as set forth herein are meant to exemplify the various aspects of carrying out the invention and are not intended to limit the invention in any way. Unless otherwise specified, it is to be understood that the concentrations of the component ingredients in the compositions of the invention are in %, w/w, based on the total weight of the composition.
    • Example 1
  • Exemplary compositions formulated in accordance with the present invention are presented in Table 19. These compositions serve as illustrative formulations which provide several of the advantageous features of the invention, namely, mildness to the skin after application with no or only limited skin irritancy; clearness and non-greasiness upon application (transparent) to face and other skin areas other than the palms and the soles; and quick-drying, particularly when the compositions are preferably formulated as water-in-oil formulations.
  • TABLE 19
    INGREDIENT % BY
    NO. PHASE (TRADE NAME) INCI DESIGNATION SUPPLIER WEIGHT
    1 A DEIONIZED WATER WATER (AQUA) 63.310
    2 A NA2EDTA DISODIUM EDTA AKZO/DEWOLF 0.100
    3 A KELTROL CG-T XANTHAN GUM CP KELCO/ 0.300
    UNIVAR
    4 B LIPOWAX D CETEARYL ALCOHOL LIPO 8.250
    CETEARETH-20
    5 B LIPO GMS 450 GLYCERYL STEARATE LIPO 6.000
    6 B CERAPHYL 230 DIISOPROPYL ADIPATE ISP SUTTON 5.000
    7 B DC TORAY FZ-3196 CAPRYLYL METHICONE DOW CORNING/ 3.000
    UNIVAR
    8 B DC 200 FLUID 100 CST DIMETHICONE DOW CORNING/ 1.000
    UNIVAR
    9 B LIPOVOL J SIMMONDSIA LIPO 1.000
    CHINENSIS (JOJOBA)
    SEED OIL
    10 B SHEA BUTTER HMP BUTYROSPERMUM EARTH SUPPLIED 1.000
    PARKII (SHEA BUTTER) PRODUCTS
    11 B VITAMIN E ACETATE OIL DL-ALPHA BASF/ 0.200
    (USP, FCC) TOCOPHERYL ACETATE CHEMCENTRAL
    12 C DEIONIZED WATER WATER (AQUA) 0.100
    13 C ELESTAB CPN ULTRA PURE CHLORPHENESIN COGNIS 0.300
    14 C PHENOXETOL PHENOXYETHANOL CLARIANT 0.600
    15 C SEPIWHITE MSH UNDECYLENOYL SEPPIC 0.500
    PHENYLALANINE
    16 C SODIUM GLYCEROPHOSPHATE SODIUM DR. PAUL 3.000
    (Ph. Eur. 6 Ed, Item# 500012045500) GLYCEROPHOSPHATE LOHMANN
    17 C L-LEUCINE LEUCINE AJINOMOTO 1.000
    18 C1 CITRIC ACID 50% SOLUTION CITRIC ACID PCI 1.920
    (TO pH 4.5-5.0)
    19 C2 GLYCERIN 99.7% (USP) GLYCERIN ACME-HARDESTY 2.000
    20 C2 SYMWHITE 377 PHENYLETHYL KAH/SYMRISE 0.500
    RESORCINOL
    21 C2 VITAGEN AMINOPROPYL BASF 0.500
    ASCORBYL PHOSPHATE
    22 D SIMULGEL INS 100 HYDROXYETHYL SEPPIC 0.420
    ACRYLATE/SODIUM
    ACRYLOYLDIMETHYL
    TAURATE COPOLYMER
    ISOHEXADECANE
    POLYSORBATE
    60
    TOTAL 100.00
  • Such compositions (e.g., Table 19) were generally prepared in a clean and sanitized stainless steel vessel, which was suitable for blending products containing hydroquinone, as described herein below:
    • PHASE A: DISPERSE KELTROL IN WATER, MIX UNTIL ALL HYDRATES;
      • ADD REMAINING PHASE A INGREDIENTS, HEAT TO ABOUT 75° C. WHILE MIX UNTIL ALL DISSOLVES.
    • PHASE B: COMBINE PHASE B INGREDIENTS IN A SEPARATE VESSEL AND MIX WHILE HEATING TO 75° C.; ONCE ALL WAXES MELT AND PHASE IS AT TEMP AND UNIFORM, SLOWLY ADD TO PHASE A; COOL TO 35° C.
    • PHASE C: COMBINE PHASE C INGREDIENTS WITH MECHANICAL STIRRING UNIT AND MIX WITH MODERATE AGITATION
    • PHASE C1: USE PHASE C1 TO ADJUST pH OF PHASE C TO 4.0-4.5
    • PHASE C2: COMBINE PHASE C2 AND MIX WHILE HEATING SLIGHTLY TO 40° C.; CONTINUE MIXING UNTIL POWDERS DISSOLVE THEN ADD TO PHASE C; ADD PHASE C TO BATCH WITH MODERATE AGITATION
    • PHASE D: ADD PHASE D TO BATCH, MIX UNTIL UNIFORM;
      • HOMOGENIZE THE BATCH AT 3500 RPM FOR 5 MINUTES; SWITCH TO IMPELLER MIXING; COOL TO ROOM TEMPERATURE.
  • The composition obtained as described in Example 1 was then filled into an airless pump container (e.g., 30 ml TopFill airless pump from MegaPlast—Mega Pumps) and then tested for physical stability (color, odor, viscosity, pH, appearance, etc.) under accelerated conditions (40 to 50° C.) for up to three months. During this period of time, the composition filled into the airless pump was stable (i.e., color, odor, viscosity, pH and appearance did not change or only changed to a limited and acceptable extent (±10% from baseline)).
  • The composition obtained as described in Example 1 does not leave greasy or oily residues on the skin and dries quickly and cleanly (without visible residue or significant stickiness) within one to two minutes after application on the skin.
    • Example 2
  • Additional compositions formulated in accordance with the present invention are presented in Table 20. Again, these compositions serve as illustrative formulations which provides the advantageous features of the invention, namely, mildness to the skin after application with no or only limited skin irritancy; clearness and non-greasiness upon application (transparent) to face and other skin areas other than the palms and the soles; and quick-drying, particularly when the compositions are preferably formulated as water-in-oil formulations.
  • TABLE 20
    INGREDIENT % BY
    NO. PHASE (TRADE NAME) INCI DESIGNATION SUPPLIER WEIGHT
    1 A DEIONIZED WATER WATER (AQUA) 59.680
    2 A NA2EDTA DISODIUM EDTA AKZO 0.100
    3 A KELTROL CG-T XANTHAN GUM CP KELCO 0.300
    4 A ELESTAB CPN ULTRA PURE CHLORPHENESIN COGNIS 0.300
    5 A PHENOXETOL PHENOXYETHANOL CLARIANT 0.600
    6 A SEPIWHITE MSH UNDECYLENOYL SEPPIC 0.500
    PHENYLALANINE
    7 A SODIUM GLYCEROPHOSPHATE SODIUM DR. PAUL 3.000
    (Ph. Eur. 6 Ed, Item# 500012045500) GLYCEROPHOSPHATE LOHMANN
    8 A L-LEUCINE LEUCINE AJINOMOTO 1.000
    9 B LIPOWAX D CETEARYL ALCOHOL LIPO 6.000
    CETEARETH-20
    10 B LIPO GMS 450 GLYCERYL STEARATE LIPO 6.000
    11 B CERAPHYL 230 DIISOPROPYL ADIPATE ISP SUTTON 3.000
    12 B DC TORAY FZ-3196 CAPRYLYL METHICONE DOW CORNING 3.000
    13 B DC 200 FLUID 100 CST DIMETHICONE DOW CORNING/ 1.000
    UNIVAR
    14 B LIPOVOL J SIMMONDSIA LIPO 1.000
    CHINENSIS (JOJOBA)
    SEED OIL
    15 B SHEA BUTTER HMP BUTYROSPERMUM EARTH SUPPLIED 1.000
    PARKII (SHEA BUTTER) PRODUCTS
    16 B VITAMIN E ACETATE OIL DL-ALPHA BASF/ 0.200
    (USP, FCC) TOCOPHERYL ACETATE CHEMCENTRAL
    17 C CITRIC ACID 50% SOLUTION CITRIC ACID PCI 1.920
    (TO pH 4.5-5.0)
    18 D EASTMAN ™ HYDROQUINONE HYDROQUINONE EASTMAN/ 4.000
    (USP GRADE) CHEMPOINT
    19 E SODIUM METABISULFITE SODIUM UPI 0.400
    (NF/FCC) METABISULFITE
    20 F GLYCERIN 99.7% (USP) GLYCERIN ACME-HARDESTY 2.000
    21 F SYMWHITE 377 PHENYLETHYL KAH/SYMRISE 0.500
    RESORCINOL
    22 F VITAGEN AMINOPROPYL BASF 0.500
    ASCORBYL PHOSPHATE
    23 G SIMULGEL INS 100 HYDROXYETHYL SEPPIC 4.000
    ACRYLATE/SODIUM
    ACRYLOYLDIMETHYL
    TAURATE COPOLYMER
    ISOHEXADECANE
    POLYSORBATE
    60
    TOTAL 100.00
  • Such compositions (e.g., Table 20) were generally prepared in a clean and sanitized stainless steel vessel, which was suitable for blending products containing hydroquinone, as described herein below:
    • PHASE A: DISPERSE KELTROL IN WATER, MIX UNTIL ALL HYDRATES; ADD EDTA, MIX UNTIL ALL DISSOLOVES;
      • ADD REMAINING PHASE A INGREDIENTS, HEAT TO 75° C. WHILE MIX UNTIL ALL DISSOLVES.
    • PHASE B: COMBINE PHASE B INGREDIENTS, HEAT TO 75° C., MIX UNTIL ALL MELTED AND UNIFORM;
      • WHEN BOTH PHASE A AND PHASE B AT 75° C., ADD PHASE B INTO PHASE A WITH AGITATION MIX FOR 10 MINUTES, START COOLING TO 50° C.
    • PHASE C: ADJUST pH WITH PHASE C TO pH 4.5-5.0, COOL TO 45° C.
    • PHASE D: ADD PHASE D TO BATCH WITH MIX, MIX UNTIL ALL DISSOLVES AND UNIFORM.
    • PHASE E: ADD PHASE E TO BATCH WITH MIXING, MIX UNTIL ALL DISSOLVES.
    • PHASE F: COMBINE PHASE F INGREDIENTS, SLIGHTLY HEAT AND MIX UNTIL ALL DISSOLVES, ADD TO THE BATCH.
    • PHASE G: ADD PHASE G TO BATCH, MIX UNTIL UNIFORM;
      • HOMOGENIZE THE BATCH AT 3500 RPM FOR 5 MINUTES, SWITCH TO IMPELLER MIXER, MIX;
      • ADJUST pH WITH PHASE C TO pH 4.5-5.0 IF NECESSARY.
  • The composition obtained as described in Example 2 was then filled into aluminum tubes (or aluminum coated plastic tubes) and then tested for physical stability (color, odor, viscosity, pH, appearance) and chemical stability (by HPLC) of hydroquinone under accelerated conditions (40 to 50° C.) for up to three months. During this period of time, the composition filled into aluminum tubes was stable (i.e., color, odor, viscosity, pH and appearance did not change or only changed to a limited and acceptable extent (±10% from baseline) and the hydroquinone content remained between 3.84% to 4.24% (weight %).
  • The composition obtained as described in Example 2 does not leave greasy or oily residues on the skin and dries quickly and cleanly (without visible residue or significant stickiness) within one to two minutes after application on the skin.
    • Example 3
  • Additional compositions formulated in accordance with the present invention are presented in Table 21. These compositions serve as illustrative formulations, which provide the advantageous features of the invention, namely, stability of the composition, mildness to the skin after application with no or only limited and acceptable skin irritancy; clearness and non-greasiness upon application (transparent) to face and other skin areas other than the palms and the soles; and quick-drying, particularly when the compositions are preferably formulated as water-in-oil formulations.
  • TABLE 21
    INGREDIENT % BY
    NO. PHASE (TRADE NAME) INCI DESIGNATION WEIGHT
    1 A DEIONIZED WATER WATER (AQUA) 59.680
    2 A NA2EDTA DISODIUM EDTA 0.100
    3 A KELTROL CG-T XANTHAN GUM 0.300
    4 A ELESTAB CPN ULTRA PURE CHLORPHENESIN 0.300
    5 A PHENOXETOL PHENOXYETHANOL 0.600
    6 A SEPIWHITE MSH UNDECYLENOYL PHENYLALANINE 0.500
    7 A SODIUM GLYCEROPHOSPHATE (Ph. SODIUM GLYCEROPHOSPHATE 3.000
    Eur. 6 Ed, Item# 500012045500)
    8 A L-LEUCINE LEUCINE 1.000
    9 B CITRIC ACID 50% SOLUTION CITRIC ACID 1.920
    (TO pH 4.5-5.0)
    10 C LIPOWAX D CETEARYL ALCOHOL CETEARETH-20 6.000
    11 C LIPO GMS 450 GLYCERYL STEARATE 6.000
    12 C CERAPHYL 230 DIISOPROPYL ADIPATE 3.000
    13 C DC TORAY FZ-3196 CAPRYLYL METHICONE 3.000
    14 C DC 200 FLUID 100 CST DIMETHICONE 1.000
    15 C LIPOVOL J SIMMONDSIA CHINENSIS (JOJOBA) SEED OIL 1.000
    16 C SHEA BUTTER HMP BUTYROSPERMUM PARKII (SHEA BUTTER) 1.000
    17 C VITAMIN E ACETATE OIL DL-ALPHA TOCOPHERYL ACETATE 0.200
    (USP, FCC)
    18 D EASTMAN ™ HYDROQUINONE (USP HYDROQUINONE 4.000
    GRADE)
    19 E SODIUM METABISULFITE (NF/FCC) SODIUM METABISULFITE 0.400
    20 F GLYCERIN 99.7% (USP) GLYCERIN 2.000
    21 F SYMWHITE 377 PHENYLETHYL RESORCINOL 0.500
    22 F VITAGEN AMINOPROPYL ASCORBYL PHOSPHATE 0.500
    23 G SIMULGEL INS 100 HYDROXYETHYL ACRYLATE/SODIUM 4.000
    ACRYLOYLDIMETHYL TAURATE
    COPOLYMER ISOHEXADECANE
    POLYSORBATE
    60
    TOTAL 100.00
  • Such compositions (e.g., Table 21) were generally prepared in a clean and sanitized stainless steel vessel, which was suitable for blending products containing hydroquinone, as described herein below:
    • PHASE A: WEIGHT WATER AND HEAT TO 70° C.
      • DISPERSE KELTROL IN WATER, MIX UNTIL ALL HYDRATES; ADD EDTA, MIX UNTIL ALL DISSOLOVES;
      • THEN ADD REMAINING PHASE A INGREDIENTS ONE BY ONE; MIX UNTIL ALL DISSOLVES.
    • PHASE B: ADD CITRIC ACID 50% SOLUTION TO PHASE A; MIX WELL; CHECK pH OF BATCH; pH SHOULD BE BETWEEN 4.5-5.0
    • PHASE C: COMBINE PHASE C INGREDIENTS;
      • HEAT TO 60° C., MIX UNTIL ALL MELTED AND UNIFORM;
      • WHEN BOTH, COMBINED PHASES A & B AND PHASE C ARE AT 60° C., ADD PHASE C INTO COMBINED PHASES A & B WITH AGITATION MIX FOR 10 MINUTES; START COOLING TO 45° C.
    • PHASE D: ADD PHASE D TO BATCH WITH MIX, MIX UNTIL ALL DISSOLVES AND UNIFORM.
    • PHASE E: ADD PHASE E TO BATCH WITH MIXING, MIX UNTIL ALL DISSOLVES.
    • PHASE F: COMBINE PHASE F INGREDIENTS, SLIGHTLY HEAT AND MIX UNTIL ALL DISSOLVES, ADD TO THE BATCH.
    • PHASE G: ADD PHASE G TO BATCH, MIX UNTIL UNIFORM;
      • HOMOGENIZE THE BATCH AT 3500 RPM FOR 5 MINUTES, SWITCH TO IMPELLER MIXER, MIX FOR 5 to 10 MINUTES;
      • CHECK FINAL pH;
      • ADJUST pH WITH PHASE B TO pH 4.5-5.0 IF NECESSARY.
  • Compositions obtained as described in Example 3 were then filled into aluminum tubes (or aluminum coated plastic tubes) and then tested for physical stability (color, odor, viscosity, pH, appearance) and chemical stability (by HPLC; following USP protocol for hydroquinone analysis) of hydroquinone under accelerated conditions (40 to 50° C.) for up to three months. During this period of time, the composition was stable and the hydroquinone content remained between 3.84% to 4.24% (weight %).
  • These compositions do not leave greasy or oily residues on the skin and dries quickly and cleanly (without visible residue or significant stickiness) within one to two minutes following application on the skin.
    • Example 4
  • The results of skin tolerability testing (e.g., no or only limited and acceptable skin irritancy) of the compositions formulated in accordance with the present invention are presented below.
  • The compositions of the present invention can be evaluated by acute (1 day) or repetitive (more than one day) human irritancy patch test to assess the skin irritation potential. The repetitive human irritancy patch test provides “exaggerated” irritation data since the test material is applied repetitively at a rather large dose (i.e., >20 mg per cm2) under occlusive (i.e., allowing no water diffusion from skin surface to air) or semi-occlusive conditions (i.e., allowing limited water diffusion from skin surface to air). Therefore, the repetitive human irritancy patch test allows easily distinguishing skin irritation (i.e., skin irritation potential) of different compositions.
  • The composition obtained as described in Example 3 was evaluated by repetitive human irritancy patch test over a period of three weeks (with 15 observations (i.e., evaluation of patch application sites for severity of skin irritation); one observation before patch application at beginning of study followed by 14 additional observations; see below for more details) on the back of 25 subjects. The test was performed according to standard irritancy patch testing by an independent contract organization specialized in consumer product testing. Several currently commercialized skin lightening prescription products with 4% hydroquinone were also evaluated under identical conditions for comparison. The repetitive human irritancy patch test demonstrated that the composition obtained as described in Example 3 was equally or better tolerated than a series of currently commercialized skin lightening prescription products with 4% hydroquinone. (See FIG. 1)
  • As shown in FIG. 1, the following compositions were evaluated:
      • i) Composition described in Example 3
      • ii) Composition A: composition with 4% hydroquinone and further containing sodium lauryl sulfate and lactic acid (OBAGI NU-DERM® Blender® (PM 5) by OMP Inc., Long Beach, CA 90802; Lots: 6K2423 and 8E1677)
      • iii) Composition B: composition with 4% hydroquinone and further containing sodium lauryl sulfate and lactic acid (OBAGI-C RX SYSTEM™ C-Therapy Night Cream (PM) by OMP Inc., Long Beach, CA 908020; Lot: 8E1440)
      • iv) Composition C: composition with 4% hydroquinone and further containing glycolic acid (LUSTRA® Hydroquinone USP 4% by Taro Pharmaceuticals U.S.A, Hawthorne, NY 10532; Lot: H8114)
      • v) Composition D: composition with 4% hydroquinone and further containing sodium lauryl sulfate (GLYTONE Skin Bleaching/Clarifying Cream Hydroquinone USP 4% by Pierre Fabre/Genesis Pharmaceutical Inc., Parsippany N.J. 07054; Lot: 1058/01)
        The following standard method was used to assess skin irritation:
  • The upper back between the scapulae served as treatment area. Approximately 0.2 grams of each test material was applied to the 1 inch×1 inch absorbent pad portion of an adhesive strip. When secured to the appropriate treatment site, these dressings formed semi-occlusive patches. Each test material was applied to the appropriate treatment site Monday through Friday to maintain twenty-one (21) consecutive days of direct skin contact. Patches applied on Friday remained n place until the following Monday. Evaluations of the test sites were conducted prior to each patch application. It was noted that due to inclement weather, two of the 25 subjects were unable to report, as scheduled. They were instructed to keep their patches in place and return on the following day. If a test site had been observed to exhibit an evaluation score of a “3” or higher, the application of test material to this site would have been discontinued and the observed score of “3” (or higher) would be recorded for the remaining study days.
  • The following evaluation key was used: (0) no visible skin reaction; (+) barely perceptible or spotty erythema; (1) mild erythema covering most of the test site; (2) moderate erythema, possible presence of mild edema; (3) marked erythema, possible edema; (4) severe erythema, possible edema, vesiculation, bullae and/or ulceration.
    • Example 5
  • The results of color stability of the compositions formulated in accordance with the present invention are presented below. In Examples 1, 2 and 3, the color of the compositions of the present invention is described as being stable (e.g., characteristic white color of compositions does not significantly change for up to three months at elevated temperatures as evaluated visually with the naked eye) when the composition is placed (i.e., filled) into an adequate container.
  • In this Example, the color stability was evaluated after the composition was removed from its typical (e.g., commercialized) container such as aluminum tube, aluminum coated plastic tube, or airless pump. A pea size amount was placed onto a flat, inert, white surface (e.g., porcelain dish) and left under normal environmental conditions (i.e., temperature, light, air, etc.) of a room (i.e., living room) in a household for at least two weeks. The color of the composition was documented by standard, digital color photography at beginning and at end of the observation period. Several currently commercialized skin lightening prescription products with 4% hydroquinone were also evaluated under identical conditions for comparison.
  • As shown in FIG. 2, the following compositions were evaluated:
      • i) Composition A: composition described in Example 3
      • ii) Composition B: composition with 4% hydroquinone and further containing retinol (EpiQuin® Micro by SkinMedica, Carlsbad, Calif. 92010)
      • iii) Composition C: composition with 4% hydroquinone and further containing 0.01% fluocinolone acetonide and 0.05% tretinoin (Tri-Luma® Cream by Galderma Laboratories, Fort Worth, Tex. 76177)
      • iv) Composition D: composition with 4% hydroquinone and further containing sodium lauryl sulfate and lactic acid (OBAGI NU-DERM® Blender® (PM 5) by OMP Inc., Long Beach, CA 90802)
  • The compositions were removed from their typical container and placed onto porcelain dish and left under normal environmental conditions (i.e., temperature, light, air, etc.) of a room (i.e., living room) in a household for 17 days. The composition of the present invention (Composition A) did not show any significant color change after 17 days as judged by photography or visually. However, Compositions B, C and D showed all significant (i.e., clearly visible) color changes (i.e., color is changing from white to brown or brownish, or becoming darker, more brownish, or darker yellow) after 17 days. These color changes became more visible with time. The color changes are mainly due to oxidation of hydroquinone, which is a constituent of Compositions B, C and D. While hydroquinone is also a constituent of Composition A, this experiment thus illustrates that the hydroquinone of Composition A is stable under the conditions of this experiment.
  • Although the color changes described in this Example for Composition B, C and D generally occurs when the composition is placed outside its typical container, these observed color changes are not desirable, as such color changes may affect the efficacy of the product (i.e., composition being exposed to air and light after it is applied onto skin). Furthermore, thee color changes would occur after short time once some composition adheres to the outside of the container (e.g., the tube outlet or pump head) after the first and all subsequent uses of the composition. All of these factors make the composition less desirable to use, which consequently affects the patient's adherence to the recommended course of treatment (i.e., patient compliance) and therefore reduces the likelihood for an efficient treatment outcome.
    • Example 6
  • The compositions obtained as described in Examples 1, 2, and 3 were evaluated for tolerability and efficacy in treating skin pigmentation disorders, such as melasma, post-inflammatory hyperpigmentation, pigmentation changes due to skin aging, or any other skin conditions related with normal such as skin of color or abnormal pigmentation such as hypo- or hyper-pigmentation in humans. The compositions were generally applied to the affected skin area(s) either once daily in the evening (at least about half an hour before bedtime) or twice daily in the morning and in the evening. A sunscreen offering at least a sun protection factor of 15 (SPF15) (e.g., JOURNÉE Bio-restorative Day Cream by Neocutis Inc., San Francisco, Calif. 94123) was used during daytime to protect skin from sun. In case the compositions were also used at daytime, the subjects were instructed to apply the sunscreen after having applied the said compositions; preferentially at least half an hour after having applied the compositions.
  • The studies lasted at least three months (i.e., 12 weeks) and were continued over a longer period of time depending on severity of the skin pigmentation disorder. Epidermal melasma can be treated (i.e. skin pigmentation is visibly reduced at site of application) within about one to three months, whereas dermal melasma, mixed type melasma, post-inflammatory hyperpigmentation (e.g., hyperpigmentation originating after inflammation of skin such as related to skin burns, wounds, acne, use of certain medications, dermatitis, etc.), pigmentation changes due to skin aging (e.g., freckles, age or liver spots, etc.), or any other skin conditions related with normal such as skin of color (e.g., skin of individual with Hispanic, Asian, African or American/African origins), or abnormal pigmentation such as hypo- or hyper-pigmentation in humans may require generally at least a three month treatment period to see results (i.e. skin pigmentation is visibly reduced at site of application) when using compositions formulated in accordance with the present invention; eventually in combination with the use of a sunscreen product.
  • Results demonstrating the efficacy of the compositions formulated in accordance with the present invention are presented in FIG. 3.
  • Study with Composition Described in Example 1:
  • After a one month wash-out period where the subjects were allowed to only use JOURNÉE Bio-restorative Day Cream (offering SPF30+), the subjects applied the composition described in Example 1 twice daily (morning and evening) to their entire face after washing the face with a gentle skin cleanser (i.e., NEO-CLEANSE Gentle Cleanser by Neocutis). In the morning, they continued to use JOURNÉE Bio-restorative Day Cream.
  • Assessment of global melasma severity was performed by the investigator according to the following 4-point visual scoring system: 0=absent (color of the melasma lesions is close to that of surrounding skin; 1=mild (color is slightly darker than that of normal skin); 2=moderate (color is moderately darker); and 3=severe (color is markedly darker than surrounding normal skin). In addition, melasma was quantified with the help of the so-called MASI index (see Arch Dermatol 130, 1994, 727-733).
  • Three areas of the face were evaluated: forehead (F), malar region (M), and chin (C) corresponding to 30%, 60% and 10% of total face The involvement of melasma in the area of forehead, malar region, and chin were given a numerical value (AF, AM, AC): 0=no involvement; 1=less than 10% involvement; 2=10% to <30%; 3=30% to <50%; 4=50% to <70%; 5=70% to <90%; 6=90% to 100%. Severity was based on two factors: darkness (D) of melasma compared with normal skin; and homogeneity (H) of hyperpigmentation. Patients were assessed on a scale from 0 through to 4 as follows; the darkness (D) scale: 0=absent; 1=slight; 2=mild; 3=marked; 4=maximum; and the homogeneity (H) scale: 0=minimal; 1=slight; 2=mild; 3=marked; 4=maximum. To calculate the MASI score, the sum of the severity rating of darkness (D) and homogeneity (H) was multiplied by the numerical value of the respective areas involved (A) and by the various percentages of the three facial areas. These values were added to obtain the MASI score as follows: MASI=0.3(DF+HF)AF+0.6(DM+HM)AM+0.1(DC+HC)AC. Additionally, the number of age and liver spots were counted in face. Those evaluations were performed at the beginning of study (i.e., before wash-out period), after the one month wash-out period (i.e., before starting with the treatment with composition), and at the end of the study period (i.e., after 12 weeks of use of composition), respectively.
  • TABLE 22
    Reduction in Global Reduction in Reduction in
    Melasma Severity as Melasma as total Number
    assessed by Investiga- assessed by of Age/Liver
    tor Global Assessment MASI-Scoring Spots
    After one month 0 ± 0% 2 ± 3% 0 ± 0%
    wash-out period
    After 12 weeks 20 ± 27% 56 ± 33% 55 ± 22%
    of use of
    composition
  • Table 22 shows the efficacy of the composition described in Example 1 in treating skin pigmentation disorders and diseases. The average and standard deviation in the reduction from baseline (i.e., data before wash-out) from five female subjects who completed the study is shown in percentage (%) of reduction from baseline.
  • This study shows that the composition leads to a reduction in melasma severity and in the number (and intensity) of age or liver spots in face. Thus, the composition is effective for treating (i.e., reducing) symptoms of skin pigmentation disorders and diseases. The composition was further well tolerated. As further shown in this study, the use of a sunscreen (i.e., JOURNÉE Bio-restorative Day Cream) alone did not result in any significant reduction in symptoms of skin pigmentation disorders and diseases.
  • Study with Composition Described in Example 3:
  • The subjects applied the composition described in Example 3 once daily (evening) to either the right, or to the left side of their face (the side was randomly assigned) after washing the face with a gentle skin cleanser (i.e., Cetaphil by Galderma). In the morning, they additionally used JOURNÉE Bio-restorative Day Cream.
  • Assessment of global melasma severity was performed by the investigator according to the following 4-point visual scoring system: 0=absent (color of the melasma lesions is close to that of surrounding skin; 1=mild (color is slightly darker than that of normal skin); 2=moderate (color is moderately darker); and 3=severe (color is markedly darker than surrounding normal skin). In addition, melasma was quantified with the help of the so-called MASI index (Arch Dermatol 130, 1994, 727-733). Three areas of the face were evaluated: forehead (F), malar region (M), and chin (C) corresponding to 30%, 60% and 10% of total face; or 15%, 30% and 5% of half of the face, respectively. The involvement of melasma in the area of forehead, malar region, and chin were given a numerical value (AF, AM, AO: 0=no involvement; 1=less than 10% involvement; 2=10% to <30%; 3=30% to <50%; 4=50% to <70%; 5=70% to <90%; 6=90% to 100%. Severity was based on two factors: darkness (D) of melasma compared with normal skin; and homogeneity (H) of hyperpigmentation. Patients were assessed on a scale from
  • through to 4 as follows; the darkness (D) scale: 0=absent; 1=slight; 2=mild; 3=marked; 4=maximum; and the homogeneity (H) scale: 0=minimal; 1=slight; 2=mild; 3=marked; 4=maximum. To calculate the MASI score for a half-face (MASIHalf-Face), the sum of the severity rating of darkness (D) and homogeneity (H) was multiplied by the numerical value of the respective areas involved (A) and by the various percentages of the three facial areas. These values were added to obtain the MASI score as follows: MASI=0.15(DF+HF)AF+0.3(DM+HM)AM+0.05(DC+HC)AC. Those evaluations were performed at the beginning of study (i.e., before starting with the treatment with composition), and at the end of the study period (i.e., after 12 weeks of use of composition), respectively.
  • TABLE 23
    Reduction in Global Reduction in
    Melasma Severity as Melasma as
    assessed by Investigator assessed by
    Global Assessment MASI-Scoring
    After 12 weeks of 38 ± 37% 74 ± 20%
    use of composition
  • Table 23 shows the efficacy of the composition described in Example 3 in treating skin pigmentation disorders and diseases. The average and standard deviation in the reduction from baseline (i.e., data before starting with the treatment with composition) from ten female subjects who completed the study is shown in percentage (%) of reduction from baseline.
  • FIG. 3 is a photograph showing the reduction of pigmentation in the skin of a patient using the compounds of the present invention (e.g. the composition described in Example 3). Panel A shows the hyperpigmentation of the patient's skin prior to administration of a compound of the present invention. Panel B shows the reduction in skin pigmentation following 12 weeks of treatment with a composition of the present invention.
  • The results of this study show that the composition leads to a reduction in melasma severity in treated area of face. Thus, the composition is effective for treating (i.e., reducing) symptoms of skin pigmentation disorders and diseases. The composition was further well tolerated.
  • Study with Composition Described in Example 2:
  • As shown in diverse in use studies, the composition obtained as described in Example 2 was also shown to be well tolerated and efficient in treating skin pigmentation disorders, such as melasma, post-inflammatory hyperpigmentation, pigmentation changes due to skin aging, or any other skin conditions related with normal such as skin of color or abnormal pigmentation such as hypo- or hyper-pigmentation in humans. Female and male human subjects were included in this study.
  • These studies demonstrated that the compositions obtained as described in Examples 1, 2 and 3 are effective for treating (i.e., reducing) symptoms of skin pigmentation disorders and diseases and are well tolerated under in use conditions.
    • Example 7
  • A human study showed that the composition described in Example 3 does not cause an acnegenic/comedogenic response. Thus, the use of this composition did not result in a significant increase in the number and severity of comedones/acne.
  • Prior to initiation of the study, each subject was examined and the facial skin condition, including counts of non-inflammatory and inflammatory lesions, were recorded. Severity of comedones/acne were determined by the following lesion count categories:
  • Grade I (mild)=Less than 10 comedones (including open: blackheads; closed: micropapules and whiteheads and/or inflammatory papulopustular lesions on one or both sides of the face.
  • Grade II (moderate)=10-25 comedones (including open: blackheads; closed: micropapules and whiteheads) and/or inflammatory papulopustular lesions on one or both sides of the face.
  • Grade III (severe)=More than 25 comedones (including open: blackheads; closed: micropapules and whiteheads) and/or inflammatory papulopustular lesions on one or both sides of the face.
  • Subjects were evaluated before and after four weeks of treatment (once daily in evening) with the composition. Differences between baseline and final dermatological evaluations were considered statistically significant, if the probability of obtaining the result by chance is less than or equal to 0.05 using analysis of variance and/or appropriate t-Test statistics. All assessments of facial skin condition and lesion counts were made by a Board Certified Dermatologist. The study was performed by an independent clinical research organization.
    • OTHER EMBODIMENTS
  • While the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims (21)

What is claimed is:
1. A composition for treating or ameliorating at least one symptom of a skin pigmentation disorder or condition comprising at least one calcium sequestering or calcium binding agent.
2. The composition of claim 1, wherein the at least one calcium sequestering or calcium binding agent is a phosphate free of calcium.
3. The composition of claim 2, wherein the phosphate is glycerophosphoric acid or a non-calcium salt thereof.
4. The composition of claim 3, wherein the phosphate is sodium glycerophosphate.
5. The composition of claim 1, wherein the at least one calcium sequestering or calcium binding agent is present in an amount of about 0.1% to about 25% by weight.
6. The composition of claim 2, wherein the phosphate free of calcium is present in an amount of about 1% to about 5% by weight.
7. The composition of claim 1, wherein the composition further comprises at least one additional agent that modulates or regulates at least one step of melanogenesis.
8. The composition of claim 7, wherein the at least one additional agent is selected from the group consisting of L-alanine, glycine, L-isoleucine, L-leucine, hydroquinone, 4-(1-phenylethyl) 1,3-benzenediol, arbutin, bearberry leaf extract, kojic acid, oxyresveratrol, gnetol, a melanosome transfer inhibitor, and an α-MSH antagonist.
9. The composition of claim 1, wherein the composition further comprises at least one skin moisturization and skin rejuvenation agent.
10. The composition of claim 9, wherein the skin moisturization and skin rejuvenation agent is selected from the group consisting of ascorbic acid, vitamin E, jojoba oil, shea butter, human fibroblast lysate, retinoic acid, retinol, and any derivatives thereof.
11. The composition of claim 1, wherein said composition is suitable for topical administration to a subject in need thereof.
12. The composition of claim 1, wherein said composition is in the form of a solution, an oil-in-water emulsion, a water-in-oil emulsion, a gel, an ointment, a patch, a paste, a liquid, a foam, a mousse, a spray, an aerosol, a triple emulsion, a nanoemulsion, a microemulsion, a hydrogel, a jelly, a dispersion, a suspension, and a tape.
13. The composition of claim 1, wherein said composition is substantially free of calcium.
14. The composition of claim 1, wherein said composition is stable, does not cause an acnegenic or comedogenic response, and produces minimal skin irritation in said subject.
15. A method of treating or ameliorating a skin pigmentation disorder comprising administering an effective amount of the composition of claim 1 to a patient suffering therefrom.
16. The method of claim 15, wherein the skin pigmentation disorder is selected from the group consisting of melasma, post-inflammatory hyper-pigmentation, pigmentation changes due to skin aging, age or liver spots, freckles, hypo-pigmentation, and hyper-pigmentation.
17. The method of claim 15, wherein the patient is a human.
18. The method of claim 15, wherein the composition is administered to the patient topically.
19. The method of claim 15, wherein, following administration, the composition reduced skin pigmentation in the patient.
20. A pharmaceutical formulation comprising the composition of claim 1 and at least one pharmaceutically acceptable carrier.
21-32. (canceled)
US14/794,462 2009-01-16 2015-07-08 Calcium sequestration compositions and methods of treating skin pigmentation disorders and conditions Abandoned US20160030321A1 (en)

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US20100189795A1 (en) 2010-07-29
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CN102281863A (en) 2011-12-14
WO2010083368A2 (en) 2010-07-22
JP5781443B2 (en) 2015-09-24
EP2381918A2 (en) 2011-11-02
KR20110122124A (en) 2011-11-09
TWI442940B (en) 2014-07-01
CA2748375C (en) 2017-08-01
TW201036645A (en) 2010-10-16
US9326930B2 (en) 2016-05-03
CA2748375A1 (en) 2010-07-22
CN102281863B (en) 2015-08-19

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