WO2018009172A1 - Traitement de l'acné - Google Patents

Traitement de l'acné Download PDF

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Publication number
WO2018009172A1
WO2018009172A1 PCT/US2016/040946 US2016040946W WO2018009172A1 WO 2018009172 A1 WO2018009172 A1 WO 2018009172A1 US 2016040946 W US2016040946 W US 2016040946W WO 2018009172 A1 WO2018009172 A1 WO 2018009172A1
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Prior art keywords
formulation
amount
acid
component
acne
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PCT/US2016/040946
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English (en)
Inventor
Thomas SKÖLD
Georgia Levis
Michael J. Burns
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TetraDerm Group LLC
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Priority to PCT/US2016/040946 priority Critical patent/WO2018009172A1/fr
Publication of WO2018009172A1 publication Critical patent/WO2018009172A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/191—Carboxylic acids, e.g. valproic acid having two or more hydroxy groups, e.g. gluconic acid
    • 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
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/14—Liposomes; Vesicles
    • 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
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/36—Carboxylic acids; Salts or anhydrides thereof
    • A61K8/361—Carboxylic acids having more than seven carbon atoms in an unbroken chain; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/36—Carboxylic acids; Salts or anhydrides thereof
    • A61K8/368—Carboxylic acids; Salts or anhydrides thereof with carboxyl groups directly bound to carbon atoms of aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
    • A61K8/44—Aminocarboxylic acids or derivatives thereof, e.g. aminocarboxylic acids containing sulfur; Salts; Esters or N-acylated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • A61K8/46—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing sulfur
    • A61K8/466—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing sulfur containing sulfonic acid derivatives; Salts
    • 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
    • A61K8/553—Phospholipids, e.g. lecithin
    • 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
    • A61K8/60—Sugars; Derivatives thereof
    • 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
    • A61K8/63—Steroids; Derivatives thereof
    • 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
    • A61K8/67—Vitamins
    • A61K8/671—Vitamin A; Derivatives thereof, e.g. ester of vitamin A acid, ester of retinol, retinol, retinal
    • 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
    • A61K8/68—Sphingolipids, e.g. ceramides, cerebrosides, gangliosides
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • 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
    • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/41—Particular ingredients further characterized by their size
    • A61K2800/413—Nanosized, i.e. having sizes below 100 nm

Definitions

  • the present application relates generally to topical formulations useful for moisturizing skin or preventing, ameliorating or repairing skin damage.
  • compositions for moisturizing skin and mucosa describe a composition for moisturizing skin and mucosa. Many of the features of the composition can be used in the current invention. What is not described or suggested is that a formulation of skin barrier repair components, retinoid components, osmolytes and anti-acne acid(s) is unexpectedly effective in treating acne.
  • This invention described herein is of topical anti-acne formulations, and methods of use thereof. Included is an indexed library comprising features from the independent claims, and methods for using such libraries, substantially as shown in and/or described in connection with at least one of the figures, are disclosed. Various advantages, aspects, and features of the present disclosure, as well as details of illustrated embodiments thereof, will be more fully understood from the following description and drawings. The foregoing summary is not intended, and should not be contemplated, to describe each embodiment or every implementation of the present invention. The Detailed Description and exemplary embodiments therein more particularly exemplify the present invention.
  • FIG. 1 is an illustration of the structure of the epidermis.
  • the topical formulation comprised (1 ) three or more of the following four components a through d, or (2) component c and one or more of components a, b or d:
  • a skin barrier repair formulation comprising lipids that are fatty acid (FA), bilayer-stabilizing steroid (CH), and complex lipid (CL), wherein the skin barrier repair formulation is present in an amount that enhances skin barrier repair, wherein the weight ratio of CL to CH is from about 1 .5: 1 to about 8: 1 , and the weight ration of CL to FA is from about 4: 1 to about 1 :1 , the lipids present in an amount from about 3 % wt. to about 10 % wt.;
  • FA fatty acid
  • CH bilayer-stabilizing steroid
  • CL complex lipid
  • a natural moisturizer formulation wherein the natural moisturizers are selected from the group consisting of urea, urocanic acid (UCA), pyrrolidone-5- carboxylic acid (PCA), lactic acid and free amino acid, the natural moisturizer formulation present in a skin moisturizing amount;
  • the natural moisturizers are selected from the group consisting of urea, urocanic acid (UCA), pyrrolidone-5- carboxylic acid (PCA), lactic acid and free amino acid, the natural moisturizer formulation present in a skin moisturizing amount;
  • a skin barrier repair formulation comprising lipids that are fatty acid (FA), bilayer-stabilizing steroid (CH), and complex lipid (CL), wherein the skin barrier repair formulation is present in an amount that enhances skin barrier repair, wherein the weight ratio of CL to CH is from about 1 .5: 1 to about 8: 1 , and the weight ration of CL to FA is from about 4: 1 to about 1 :1 , the lipids present in an amount from about 3 % wt. to about 10 % wt. of the topical formulation;
  • FA fatty acid
  • CH bilayer-stabilizing steroid
  • CL complex lipid
  • a natural moisturizer formulation wherein, (v-a) comprising natural moisturizers selected from the group consisting of urea, urocanic acid (UCA), pyrrolidone-5-carboxylic acid (PCA), lactic acid and free amino acid, or (v-b) comprising glycerin, wherein the natural moisturizer formulation present in a skin moisturizing amount.
  • UUA urocanic acid
  • PCA pyrrolidone-5-carboxylic acid
  • lactic acid and free amino acid or
  • the alpha hydroxy acid component comprises glycolic acid in an anti-acne effective amount (meaning (a) the acid in question is effective alone or (b) it renders the other component (iv) acids more effective).
  • the beta hydroxy acid component comprises salicylic acid in an anti-effective amount.
  • compositions of the invention are believed to provide (i) equivalent or better skin (or mucosal) barrier repair and maintenance as measured by recovery and sustained improvement of transmucosal, transepithelial or transepidermal water loss (TEWL) and, in the case of the latter, including after challenge with a sodium dodecyl sulfate (SDS) formulation, as compared to a Comparator Product; and/or (ii) equivalent or better epidermal water retention as measured by epidermal electrical conductance as compared to a Comparator Product.
  • the Comparator Product can be a vehicle form of test product and/or a recognized effective moisturizer base cream found the market in the United States.
  • the Comparator Product can be, for example, Cetaphil (Galderma Laboratories, L. P. , Dallas, Texas). Comparisons for a given product of the invention will typically be against Comparator Product of comparable viscosity. E.g. , a lotion will typically be compared to a lotion, a cream to a cream.
  • the skin of the human body is comprised of the outer epidermis, and the dermis.
  • the epidermis includes the stratum corneum (outer), stratum lucidum, stratum granulosum, stratum spinosum and stratum basale. See Fig. 2.
  • Epidermal cells migrate outward from the inner stratum basale to outer stratum corneum as they mature and differentiate into to the cell types of the given layers.
  • Filaggrin derived natural moisturizers include free unaltered amino acids, urocanic acid (UCA) (derived from histidine) and pyrrolidone-5-carboxylic acid (PCA) (derived from glutamine) along with, among other things, lactates and urea. These substances are soluble in the fluids that are located both inside the skin cells and the surrounding extracellular milieu. These substances are strong humectants that help retain moisture in the stratum corneum and some are particularly useful to maintaining cellular water balance.
  • UUA urocanic acid
  • PCA pyrrolidone-5-carboxylic acid
  • osmolytes are important cytoprotectants (osmoprotectants) that play a key role in maintaining cell volume and fluid balance.
  • these transporters in particular the taurine transporter (TauT)
  • tauT taurine transporter
  • osmoprotectant osmolytes include myoinositol, glycine, alanine and taurine of which the latter is the most abundant.
  • the amount of natural moisturizers is from about 0.1 % wt. to about 10 % wt. of the formulation. Weight amounts are calculated assuming no counter-ions, and where possible no net charge. If a counter-ion containing form is used in formulation, the percent amount of the compound is calculated without the counterion.
  • Taurine is an important osmotic regulator ("Osmolyte”) for epidermal keratinocytes. To maintain cell volume homeostasis taurine is concentrated in the cells of the epidermis via active transport. The taurine transporter (TauT) regulates taurine content, and hence, the hydration of epidermal cells. [0021] In embodiments, the amount of taurine is from about 0.1 % wt. to about 5
  • vitamin-A and related retinoids are generally considered necessary to support tissue healing processes, when topically applied these entities are well known to disrupt the skin barrier and to cause dryness, irritation and flaking (Report of the Linus Pauling Institute at Oregon St. Univ. avail. at lpioregonstate.edu/infocenter/skin/vitamin ("LPI Report”)).
  • retinoids are administered to the skin in conjunction with the correct physiological ratio of intercellular lipids and/or their precursors (ceramides, cholesterol esters and fatty acids) and natural moisturizing factor constituents (such as described herein) and appropriate osmolytes (such as taurine and alanine), it is believed that they contribute positively to restoration and maintenance of epidermal cellular hydration by virtue of their ability to induce the up-regulation of critical osmolyte transporters, in particular TauT (e.g., Chesney et al., Adv. Exp. Med. Biol. 2013, 776:291 -305).
  • TauT critical osmolyte transporters
  • Retinoic acid and retinoids in general are associated with skin dryness, and thus contraindicated for maintaining hydrated skin.
  • retinoid dermatitis also referred to as retinoid irritation or retinoid reaction.
  • Retinoid dermatitis is characterized by erythema, scaling, dryness, and pruritus.
  • Topical retinoids induce changes in the epidermis that lead to increased proliferation and altered differentiation of keratinocytes (see Photoaging); this in turn disrupts the barrier of the skin and contributes to the features of retinoid dermatitis.” It is therefore counterintuitive to incorporate retinoic acid or a derivative in a product intended to moisturize the skin. Nonetheless, it serves to cause activation of the TauT with the consequence that the osmoprotectant taurine is actively transported, along with water, into the keratinocyte thus increasing keratinocyte hydration.
  • Vitamin-A related retinoids include without limitation, retinoic acids (such as, all-trans retinoic acid or 13-cis retinoic acid), retinols (such as all-trans retinol (Tretinoin), 13-cis retinol or 9-cis retinol), comparable retinals (retinaldehydes), hydroxypinacolone retinoate (HPR)(binds directly to retinoic acid receptors), Fenretinide, the retinoids recited in W01996-029069 (as described therein and in U.S.
  • Patents 4,739,098 and 4,326,055 ; European Patent Application 176034 A, published April 2, 1986 and PCT Patent Applications WO 93/25530 and WO 94/17796, all of which are incorporated herein by reference on their teachings of retinoids), tricyclic retinoids (such as described in W01996020914, incorporated herein by reference on its teachings of retinoids), adapalene (6-[3-(1 -adamantyl)-4-methoxy-phenyl] naphthalene- 2-carboxylic acid), tazarotene (ethyl 6-[2-(4,4-dimethyl-3,4-dihydro-2H-1 - benzothiopyran-6-yl)ethynyl]pyridine-3-carboxylate), or the like.
  • the amount of retinoid is from about 0.01 % wt. to about
  • the retinoid component comprises one or more retinols in an amount from about 0.1 % wt. to about 5 % wt. of the formulation.
  • the amount of retinoid varies with the particular retinoid employed. Those of skill will recognize that higher portions of the range may be used for example with retinol palimate, and lower portions used for example with tretinoin (all-trans retinoic acid).
  • the acid of (iv) can be any with anti-acne effect, whether through moisturizing action, keratolytic action, bacteriostatic action, or otherwise.
  • Notable examples are alpha hydroxy and beta hydroxy acids.
  • Another example is azelaic acid (nonanedioic acid).
  • the amount can be, for example, from about 0.3 % to about 20% by weight in the overall formulation. While termed an "acid", it should be understood that all or a portion of an acid can be present in the formulation as a salt, such as ammonium lactate. The amount is normalized to the weight of the corresponding acid.
  • Glycolic acid can favorably be present in an amount from about 3 % to about 20% by weight, or from about 5% to about 7%.
  • Salicylic acid can favorably be present in an amount from about 0.3 % to about 20% by weight, or from about 2% to about 3%.
  • complex lipids are phospholipids, ceramides, sphingomyelins, glycosphingolipids, and combinations thereof in a form that can be incorporated in lipid bilayers.
  • phospholipids comprise about 90 mole % or more of the complex lipid, or about 95 mole % or more, or about 97 mole % or more, or about 98 mole % or more, or about 99 mole % or more.
  • the phospholipid can be a mixture of different phospholipid types, including minor amounts of lysophospholipids. In certain embodiments, about 5 mole % or more of the phospholipid has a head group with no net charge.
  • the phospholipid can be made up of phosphatidylcholine or phosphatidylethanolamine.
  • the bilayer stabilizing steroid or steroid analog is typically cholesterol, a fatty acyl ester of cholesterol, or an analog thereof, such as ergosterol, cholestanol, 7-dehydrocholesterol, lanosterol, or the like. Any steroid or steroid analog that stabilizes the bilayer of the vesicles can be used, though steroids or analogs with substantial hormone activity are typically avoided unless intended for use as the bioactive agent.
  • the fatty acid can, for example, be of any composition found in a natural source, including hydrolysis of esterified fatty acids.
  • the fatty acid component can be hydrogenated to remove substantially all or a portion of any unsaturation.
  • the fatty acid component is selected such that 50 mole % or more is C12 or higher, or C14, or C16 or higher.
  • the fatty acid component is selected such that 50 mole % or more is C22 or lower, or C20 or lower, or C18 or lower.
  • 75 mole % or more of the fatty acid component is from C12 or C14 or C16 to C22 or C20 or C18.
  • lipid components of skin barrier repair formulation are present in the form of the aggregates structures of lipid vesicles (as defined below) or lipid particles, with about 10% wt. or more present in lipid vesicles and about 10% wt. or more present in lipid particles.
  • the formulations of the invention can be presented as, for example, emulsions, liquid suspensions, creams, gels, lotions or foams.
  • Some embodiments of the invention can be in the form of an emulsion.
  • Emulsions contain both a dispersed and a continuous phase, with the boundary between the phases called the "interface".
  • An emulsion is a mixture of two or more liquids that are normally immiscible (nonmixable or unblendable).
  • emulsifiers are generally surfactants, co-surfactants or co-solvents, such as cetearyl alcohol, polysorbate 20 and ceteareth 20 or polyethylene glycol, and others as known by skilled artisans.
  • the topical formulation can be applied to skin or mucosa.
  • Mucosal tissues with which the topical formulation can be used include for example nasal (including olfactory), vaginal, anorectal, penile, oral, buccal and bronchial tissue.
  • the skin barrier repair formulation may have added PEGylated lipids or other lipids conjugated with hydrophilic polymer in amounts that stabilize these aggregate forms.
  • the formulation pH is from about 3.2 to about 5.5, such as about 3.5 to about 5, or such as about 4 to about 5.
  • the formulation can include anti-acne medicaments of additional classes, such as antibiotic agents, anti-inflammatory agents, anti-androgen agents (for women), oxygen-generating agents (such as benzoyl peroxide) and nitric oxide generating agents (such as nitrite salt, nitroglycerin, nitroprusside, S-nitroso-N- acetylpenicillamine, isosorbide dinitrate, and the like).
  • Antibiotic agents include for example Clindamycin, Erythromycin, Minocycline, Doxycycline, Sodium sulfacetamide, and the like.
  • Anti-inflammatory agents include for example Dapsone (though an antibiotic in other contexts) and Sodium sulfacetamide.
  • These medicaments can be delivered separately. Separate treatments include oral antibiotic, oral contraceptives and oral Sprironolactone.
  • Useful treatment regimens include application to the affected skin twice to three times a day.
  • the treatment amount can be, for example about 1 g formulation per 10 cm 2 .
  • a moisturizer is any substance or mixtures of chemical agents specially designed to make the external layers of the skin or epidermis softer and more pliable, by increasing their hydration or water content.
  • a humectant is any substance that is hygroscopic and can absorb water from the air. Humectants are usually molecules with one or more hydrophilic groups attached to them.
  • hydrophilic groups can either be amines (-NH3) such as urea or amino acids, carboxyl groups (-COOH) such as fatty acids or alpha hydroxy acids, or hydroxyl groups (-OH) such as glycerin, sorbitol and butylene glycol or other glycols.
  • amines -NH3
  • carboxyl groups -COOH
  • fatty acids or alpha hydroxy acids or hydroxyl groups (-OH) such as glycerin, sorbitol and butylene glycol or other glycols.
  • hydroxyl groups glycerin, sorbitol and butylene glycol or other glycols.
  • Osmolytes are compounds affecting osmosis. They are soluble in the fluids within a cell, or in the surrounding extracellular environment e.g. as plasma osmolytes. They play a role in maintaining cell volume and fluid balance. For example, when a cell swells due to external osmotic pressure, membrane channels open and allow efflux of osmolytes which carry water with them, restoring normal cell volume. Osmolytes also contribute to protein folding.
  • Natural osmolytes that can act as osmoprotectants include trimethylamine N-oxide (TMAO), dimethylsulfoniopropionate, trimethylglycine, sarcosine, betaine, glycerophosphorylcholine, myo-inositol, taurine, glycine, alanine and others.
  • TMAO trimethylamine N-oxide
  • dimethylsulfoniopropionate trimethylglycine
  • sarcosine betaine
  • glycerophosphorylcholine trimethylglycine
  • myo-inositol taurine
  • taurine glycine
  • alanine alanine
  • Humectants include ingredients such as glycerin, urea, pyrrolidone carboxylic acid (PCA), hyaluronic acid, or the like. These materials function by attracting water outward to the stratum corneum (SC) from the dermis below and binding that water in the SC. Glycerin, for instance, frequently is used due to its low cost and high efficacy. However, the tacky feeling imparted to skin by high levels of humectants is one of the drawbacks to formulating with them. Thus, when optimizing skin formulations, cosmetic chemists often are challenged to reduce these negative properties. Certain amino acids such as alanine are humectants. In certain embodiments, hyaluronic acid or a salt thereof is included, such as for example in an amount from about 0.1 % by weight to about 5%.
  • Occlusive Agents increase moisture levels in skin by providing a physical barrier to epidermal water loss.
  • Ingredients with occlusive properties include petrolatum, waxes, oils and silicones. Some occlusive agents like petrolatum can leave a heavy feeling on skin; thus they often are combined with other ingredients like emollients to improve consumer appeal.
  • Emollients provide some occlusivity and improve the appearance of the skin by smoothing flaky skin cells. Many different types of emollient esters and oils are available to formulators. Emollients generally are grouped by their ability to spread on the skin.
  • emollients By combining emollients with the different spread rates, formulators can tailor the skin feel of a moisturizer. One can test for these differences by using different emollients in a standard base lotion or other composition. Additionally, emollient lipids similar to those naturally found in the skin may also increase the rate of barrier repair, for example as ceramides, steroids, sterol esters or fatty acids. Emollients are often polymeric, and include silicone compounds, but further include petrolatum.
  • Embodiments of the invention can include one or both of two types of lipid aggregates, lipid particles and lipid vesicles, defined below. These are typically produced separately, and can be combined for use. The fraction used to create the vesicles can be termed the "ultra-fine fraction.”
  • bilayer-enclosed vesicles can be made typically with methods that direct sufficient oscillatory energy or other means (e.g. mechanical or thermal) per unit volume - at once or by serially applying such energy to different sub-volumes.
  • Sonicating devices for example, can be used.
  • appropriate high pressure homogenizers can be used, such as of a Rannie homogenizer from Invensys APV (Fluid Handling & Homogenisers, Lake Mills, Wl).
  • the pressure of the homogenizer can be set, for example, from about 10,000 to 40,000 psi, such as 21 ,756 psi (1500 bar).
  • An example of a sonicator is Soniprep 150, manufactured by Sanyo Gallencamp Pic. Ultrasound radiation is transmitted by high frequency vibrations via a titanium alloy probe from a transducer that converts electrical energy to mechanical energy.
  • the diameter of the probe tip can vary.
  • An example of a diameter of a probe tip is about 9.5 mm.
  • the amplitude at which the sonication can be performed can vary.
  • An example of an amplitude is 10 microns for 30 minutes.
  • the vesicle formation is typically conducted at a relatively elevated temperature, such as a temperature of 45 °C or more, or 50 °C or more, or 55 °C or more, or 60 °C or more, or 65 °C or more.
  • the temperature can, for example, be 75 °C or less, or 70 °C or less, or 65 °C or less.
  • the bioactive agent(s) may affect the choice of temperature, with the temperature moderated for more labile bioactive agents.
  • the pH obtained from the vesicle formation can be selected in view of the properties of the bioactive agent.
  • the use of smaller vesicles with associated bioactive agent can provide faster initial uptake of the bioactive agent.
  • the amount and size of the vesicles can be varied.
  • more energy has to be applied to the production process.
  • the Rannie homogenizer it may be appropriate to pass the production suspension two or more times through a homogenization cycle. Delays and cooling between the applications of energy can minimize excess heating.
  • the average vesicle size can be, for example,
  • the average vesicle size can be, for example, 20 nm or more, or 30 nm more, or 40 nm more, or 45 nm more, or 50 nm more, or 75 nm more, or 100 nm more, or 150 nm more, or 200 nm more. Size determination can be by light scattering, using a Malvern Autosizer (Malvern Instruments Ltd. , Malvern, Worcestershire, UK), or a device calibrated to give comparable results.
  • Electron-microscopic analysis shows that the predominate morphology of lipid aggregates is unilamellar vesicles.
  • the vesicles can comprise fatty acid (FA), bilayer-stabilizing steroid (CH), and complex lipid (CL).
  • FA fatty acid
  • CH bilayer-stabilizing steroid
  • CL complex lipid
  • the fraction used to create the lipid particles can be termed the "disperse fraction.”
  • the lipid particles can be made by passing aqueous suspensions of the lipid components through dispersing equipment, such as the Dispermix device from Ystral GmbH (Ballrechten-Dottingen, Germany). These particles typically have a wide size distribution, which is typically of sizes larger than found in the ultra-fine fraction, such as from 1000 nm (1 micron). In some embodiments, the upper sizes may be as high as 20 or 30 microns. Average size can be determined by measuring an appropriate sampling by microscope. [0058] Particle formation is typically conducted at a relatively elevated temperature, such as a temperature of 45 °C or more, or 50 °C or more, or 55 °C or more, or 60 °C or more, or 65 °C or more.
  • the temperature can, for example, be 75 °C or less, or 70 °C or less, or 65 °C or less.
  • the bioactive agent(s) may affect the choice of temperature, with the temperature moderated for more labile bioactive agents.
  • the pH obtained from the particle formation can be selected in view of the properties of the bioactive agent.
  • Lipid components can be selected such that both the ultra-fine fraction and the disperse fraction can be formed from substantially the same lipids.
  • the disperse fraction and the ultra-fine fraction can be mixed to form the delivery system.
  • care can be taken to avoid temperatures above a given boundary, such as 35 °C.
  • the amount of bioactive agent in each of the lipid fractions, and the relative amount of the lipid components of the fractions can be varied as indicated by empirical studies of the resulting pharmacokinetic profile.
  • compositions of the invention have been found to incorporate into mucosal tissue, in contrast to a number of topical lotions or creams, that cake when applied to such tissue.
  • topical lotions or creams that cake when applied to such tissue.
  • incorporation it is meant that when a moisturizing useful amount is applied to mucosal tissue, any caking (agglomeration, undispersed product) disappears within about 5 seconds.
  • a conjugate of a lipid-phase anchoring hydrophobic moiety and a flexible, soluble polymer can be, for example, a conjugate of a type A lipid and a polymer such as polyethylene glycol. Other hydrophobic materials can be used to anchor the polymer to a lipid or bilayer phase, so long as the association is sufficiently stable.
  • One exemplary conjugate is distearoyl-phosphatidylethanolamine-polyethylene glycol (DSPE-PEG).
  • the conjugated polyethylene glycol can have an average molecular weight of, for example 2000.
  • the average molecular weight of the flexible, soluble polymer is 500 or more, 750 or more, or 1000 or more.
  • the average molecular weight of the polymer is 5000 or less, 4000 or less, or 3000 or less.
  • the contribution of the lipid anchor portion of the conjugate to the overall aggregate-forming lipid is typically relatively low, such as 10 mole % or less. In certain embodiments using the conjugate, the contribution is 9 mole % or less, or, 8 mole % or less, or, 7 mole % or less, or, 6 mole % or less, or, 5.5 mole % or less, or, 5 mole % or less. In certain embodiments using the conjugate, the contribution is 1 mole % or more, or, 2 mole % or more, or, 3 mole % or more, or, 4 mole % or more, or, 4.5 mole % or more, or, 5 mole % or more.
  • polymers besides polyethylene glycol can be used, provided sufficient biocompatibility, flexibility and water solubility. Without being bound to theory, it is believed that the polymer stabilizes the lipid aggregates by physically keeping them separate, thereby limiting fusions that change the properties of the lipid aggregates.
  • Other flexible, soluble polymers can include polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), monosial ganglioside, and the like.
  • the conjugate while stabilizing the lipid aggregates in the composition before use, also help adhere lipid aggregates to the skin or mucosal membrane as the composition spreads along such skin or membrane.
  • This latter function can be substituted, to some degree, with optional non-anchored hydrophilic polymer, such as PEG or PVP or PVA. This latter function can be applied in the absence of substantial amounts of vesicles and lipid particles.
  • a bioactive agent is a substance such as a chemical that can act on a cell, virus, tissue, organ or organism, including but not limited to drugs (i.e. , pharmaceuticals) to create a change in the functioning of the cell, virus, organ or organism to achieve a pharmaceutical or therapeutic effect.
  • drugs i.e. , pharmaceuticals
  • the bioactive agent is an agent separate from those components.
  • a cell surface disruptor is (a) a detergent or (b) an organic solvent; wherein such detergent is (a) a micelle-forming detergent that is stronger than phospholipid, ceramide(s), sphingomyelin(s) or glucocerebroside(s) (in a form typically found in cell membrane) and (b) not a fatty acid or salt thereof that is C8 or higher.
  • a "modified cell-surface disruptor" is not a fatty acid or salt thereof that is C10 or higher.
  • a composition is essentially lacking cell-surface disruptors if the amount present is zero or less than the amount that can cause irritation by cell- surface disruption.
  • a cell-surface disruptor might be present due to its use in facilitating the formulation of the composition (such as a carrier for a component that will be substantially diluted), but the amount in the final composition will be of no consequence as a cell-surface disruptor.
  • a flexible, soluble polymer is a polymer effective to, when positioned on and linked to the outside of a bi layer-enclosed vesicle, to increase the stability of the vesicle.
  • Lipid particles are the result from melting the lipid fraction (described above) in conjunction with mild homogenization and letting it to cool. Lipid particles may thus be relatively heterogeneous, containing for example large or small particles, micro scale lumps, crystals, bilayer fragments and or multilamellar vesicles of different sizes and lamillarity, or the like. They are aggregates of lipid that contain a contiguous segment of lipid, or are substantially multilamellar (i.e., can by microscopic examination be estimated to have 80% of its lipid content weight in multilamellar structures).
  • a lipid-phase anchoring hydrophobic moiety is used as a covalent conjugate with a flexible, soluble polymer.
  • the lipid-phase anchoring hydrophobic moiety associates, for example, with the bilayer of a vesicle with sufficient stability to keep conjugated polymer predominantly anchored to lipid and positioned to increase the stability of the vesicles.
  • ⁇ lipid vesicles
  • Lipid vesicles are lipid aggregates that are unilamellar vesicles. These can include minor amounts ( ⁇ about 20% by lipid content weight) of unilamellar vesicles that incorporate 1 -8 other unilamellar vesicles (separately within, or serially inclusive in nesting doll fashion).
  • Treating" a disease, disorder or condition includes ameliorating the symptoms of the disease, disorder or condition, or delaying or ameliorating the progression or initiation of disease, disorder or condition, including symptoms or complications thereof.
  • any animal can be treated, including mammals such as humans.
  • a “skin moisturizing amount” is an amount of a component or subformulaton that, if added to a base formulation of the invention lacking the same, increases TEWL after challenge (measured as described below) at one or more of the 0.5, 1 , 2 or 3 hour timepoints.
  • ranges recited herein include ranges therebetween, and can be inclusive or exclusive of the endpoints.
  • Optional included ranges are from integer values therebetween (or inclusive of one original endpoint), at the order of magnitude recited or the next smaller order of magnitude.
  • the lower range value is 0.2
  • optional included endpoints can be 0.3, 0.4, ... 1 .1 , 1 .2, and the like, as well as 1 , 2, 3 and the like;
  • optional included endpoints can be 7, 6, and the like, as well as 7.9, 7.8, and the like.
  • One-sided boundaries, such as 3 or more similarly include consistent boundaries (or ranges) starting at integer values at the recited order of magnitude or one lower.
  • 3 or more includes 4 or more, or 3.1 or more.
  • Protocol for measuring transepidermal water loss (TEWL) after challenge with drying agent or irritant surfactant such as SDS For humans, the subject will clean the left forearm prior to visit without scrubbing. The patient will acclimate to the office environment for 30 min prior to baseline measurement and application of a skin drying agent and prospective treatment compositions (such as creams). The volar surface of the left forearm will be marked using a sharpie with 4 circles about the size of a quarter. The TEWL meter will measure all areas (circle 1 , 2, 3, 4 and 5) as a baseline after the 30 min acclimation period.
  • the forearm circled areas 2, 3, and 4 will be treated with a drying agent such as 1 % SLS on an applicator tip.
  • the closest circle to the hand (circle 1 ) will serve as an untreated control.
  • Circle 2 will receive SLS only.
  • SLS circles 3, 4 and 5 will receive the positive control, test composition and test composition minus taurine and retinoid, respectively.
  • Circle 3 will receive a positive control product such as cetaphil restoraderm.
  • the forth circle (circle 4) will receive the test composition.
  • Circle 5 (if used) will receive the test composition formulated without retinoid and without taurine (Tminus Composition).
  • compositions (circles 3 - 5) will be applied and rubbed into the marked area until absorbed onto the skin (about a minute).
  • the moisture meter will measure all circles at 30 min 1 , 2, and 3 hrs post treatment. In embodiments, measurements are continued, such as for intervals including 48 hrs.
  • a formulation pursuant to Example 4 was compared to Proactive® in treating acne.
  • the study was with 10 subjects (male & female) with acne, ages 16 - 40, each with more than 10 papules or pustules, and no concomitant acne medications.
  • the study used a split-face design, with the test formulation ("Formulation A") applied to the right side, and Proactive applied to the left side. Treatments were applied twice daily.
  • Example 1 The study protocol of Example 1 is conducted with a composition of the invention ("Formulation A1 ") compared to one or more formulations that are the same except lacking one or more of (a) one or more of the anti-acne acids, (b) retinoid, (c) the component (iii) compounds.
  • Formulaulation A1 a composition of the invention compared to one or more formulations that are the same except lacking one or more of (a) one or more of the anti-acne acids, (b) retinoid, (c) the component (iii) compounds.
  • Formulation A1 compared to one or more formulations that are the same except lacking one or more of (a) one or more of the anti-acne acids, (b) retinoid, (c) the component (iii) compounds.
  • the study utilizes the Protocol for measuring transepidermal water loss (TEWL) after challenge with drying agent or irritant surfactant such as SDS.
  • TEWL transepidermal water loss
  • SDS drying agent or irritant surfactant
  • the study can be split face or split arms, or the like.
  • An exemplary formulation of the invention is as follows (by weight):
  • Hyaluronic acid (or, e.g., a salt 0-5
  • An appropriate thickening agent such as hydroxyethyl cellulose can be added for the purposes of adjusting viscosity so that dosing forms ranging including but not limited liquids, lotions, gels, creams and ointments.
  • the formulation is to be a foam
  • an appropriate foaming agent such as laureth-4, is added.
  • Embodiment 1 A topical formulation comprising: (i) a skin barrier repair formulation comprising lipids that are fatty acid (FA), bilayer-stabilizing steroid (CH), and complex lipid (CL), wherein the skin barrier repair formulation is present in an amount that enhances skin barrier repair, wherein the weight ratio of CL to CH is from about 1 .5: 1 to about 8: 1 , and the weight ration of CL to FA is from about 4: 1 to about 1 : 1 , the lipids present in an amount from about 3 % wt. to about 10 % wt.
  • FA fatty acid
  • CH bilayer-stabilizing steroid
  • CL complex lipid
  • the topical formulation comprises (ii) one or more retinoids in an amount from about 0.01 % wt. to about 10 % wt. of the topical formulation; (iii) myoinositol, glycine, alanine, taurine or a combination thereof in an amount from about 0.1 % wt. to about 5 % wt of the topical formulation; and (iv) one or more of one or more anti-acne acids cumulatively in an anti-acne effective amount.
  • Embodiment 2 The formulation of Embodiment 1 , further comprising (v-a) natural moisturizers selected from the group consisting of urea, urocanic acid (UCA), pyrrolidone-5-carboxylic acid (PCA), lactic acid and free amino acid, the natural moisturizers present in a skin moisturizing amount.
  • v-a natural moisturizers selected from the group consisting of urea, urocanic acid (UCA), pyrrolidone-5-carboxylic acid (PCA), lactic acid and free amino acid, the natural moisturizers present in a skin moisturizing amount.
  • Embodiment 3 The formulation of Embodiment 1 , further comprising (v-b) glycerol present in a skin moisturizing amount
  • Embodiment 4 The formulation of one of the foregoing Embodiments, wherein component (iv) comprises glycolic acid in an anti-acne effective amount.
  • Embodiment 5 The formulation of one of the foregoing Embodiments, wherein component (iv) comprises salicylic acid in an anti-acne effective amount.
  • Embodiment 6 The formulation of one of Embodiments 1 - 5, wherein component (i) comprises vesicles of average size from about 20 to about 500 nm.
  • Embodiment 7 The formulation of one of Embodiments 1 - 5, wherein component (i) comprises lipid particles of average size from about 1 to about 30 microns.
  • Embodiment 8 The formulation of one of Embodiments 1 - 5, wherein component (i) comprises (i) vesicles of average size from about 20 to about 500 nm and (ii) lipid particles of average size from about 1 to about 30 microns.
  • Embodiment 9 A method of treating acne, comprising periodically applying the formulation of one of the foregoing Embodiments.
  • This invention described herein is of a topical formulation, and methods of delivering a bioactive agent to skin or mucosa, or systemically using the same.

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Abstract

L'invention concerne, entre autres, une formulation topique qui comprend : (i) une formulation de réparation de la barrière cutanée comprenant des lipides qui sont des acides gras (FA), un stéroïde stabilisant la bicouche (CH) et un lipide complexe (CL), la formulation de réparation de la barrière cutanée étant présente à hauteur d'une quantité qui améliore la réparation de la barrière cutanée, le rapport pondéral entre CL et CH variant d'environ 1,5/1 à environ 8/1, et le rapport pondéral entre CL et FA variant d'environ 4/1 à environ 1/1, les lipides étant présents à hauteur d'environ 3 % en poids à environ 10 % en poids de la formulation topique ; (ii) un ou plusieurs rétinoïdes à hauteur d'environ 0,01 % en poids à environ 10 % en poids de la formulation topique ; (iii) du myoinositol, de la glycine, de l'alanine, de la taurine ou une combinaison de ceux-ci à hauteur d'environ 0,1 % en poids à environ 5 % en poids de la formulation topique ; et (iv) un ou plusieurs acides anti-acné (tels qu'un alphahydroxy acide ou un bêtahydroxy acide) présents en quantités cumulées telles à se révéler efficaces contre l'acné.
PCT/US2016/040946 2016-07-05 2016-07-05 Traitement de l'acné WO2018009172A1 (fr)

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RU2804182C1 (ru) * 2022-12-26 2023-09-26 Федеральное государственное бюджетное образовательное учреждение высшего образования "Сибирский государственный медицинский университет" Министерства здравоохранения Российской Федерации Способ профилактики ретиноидного дерматита у пациентов с акне

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