WO2022140467A1

WO2022140467A1 - Topical compositions and methods of treating skin diseases and conditions with such compositions

Info

Publication number: WO2022140467A1
Application number: PCT/US2021/064729
Authority: WO
Inventors: Manzer J. Durrani; Kirti H. Valia; Samedyar DURRANI; David Kaplan
Original assignee: Samson Pharma, Llc
Priority date: 2020-12-21
Filing date: 2021-12-21
Publication date: 2022-06-30

Abstract

A pharmaceutical composition is provided including tamibarotene or a salt or analog thereof, a solubilizer, a permeation enhancer, a polymeric emulsifier, and a surfactant. In a further preferred embodiment, the pharmaceutical composition is in the form of a gel or cream, and provides a smooth composition to apply to the skin. The invention is further directed to methods of manufacturing the pharmaceutical composition and methods of treating a patient's skin with the pharmaceutical composition.

Description

TOPICAL COMPOSITIONS AND METHODS OF TREATING SKIN DISEASES AND CONDITIONS WITH SUCH COMPOSITIONS

FIELD OF THE INVENTION

[0001] The present invention relates to topical compositions for pharmaceutical, dermatological, and cosmetic treatment of the skin. The invention is further directed to methods of manufacturing the topical compositions and methods of treating human skin and skin diseases and conditions with such compositions.

BACKGROUND

[0002] Topical pharmaceutical, dermatological, and cosmetic compositions include compositions that are applied to a person's skin. Such compositions are challenging in that it is difficult to prepare stable, homogeneous, and spreadable formulations that do not phase- separate during manufacturing, packaging, storage, and application, and are smooth and comfortable in applying to skin. These issues can be particularly challenging when dealing with relatively insoluble retinoic acid receptors (RARs) such as tamibarotene and compositions that contain oil and water components.

[0003] Tamibarotene [also known as AM80, retinobenzoic acid, Amnoid, Tamibaro] is a synthetic retinoid drug that is practically insoluble in water and can be difficult to maintain in a pharmaceutical formulation. Tamibarotene is used In a variety of oral and intravenous medical treatments. Tamibarotene has also been described for use in a topical composition for treatment of skin conditions including the effects of aging. See U.S. Published Patent Application 20160000674, published January 7, 2016.

[0004] There is a need in the art for improved pharmaceutical, dermatological, and cosmetic topical compositions to be applied to the skin, including compositions with active agents including but not limited to tamibarotene. In particular, there is a need for pharmaceutical, dermatological or cosmetic topical formulations that are more stable, homogenous, and spreadable throughout manufacturing, packaging, storage, and application to and treatment of human skin. There is also a need for formulations that are smooth and comfortable in applying to skin. [0005] There is also a need for improved treatments for acne.

SUMMARY OF THE INVENTION

[0006] One aspect of the present invention is a pharmaceutical, dermatological, or cosmetic composition comprising an active agent of tamibarotene or a salt thereof in a novel carrier. [0007] In another embodiment, is a pharmaceutical, dermatological, or cosmetic composition comprising an analog of tamibarotene or a salt thereof in a novel carrier. The composition preferably has suitable efficacy, safety and delivery features. The analog of tamibarotene may be, for example, a compound of Formula 1 or pharmaceutically acceptable salts thereof:

wherein R¹, R² R³ and R⁴ are selected from hydrogen, (C₁-C₁₂) hydrocarbon and (C₃-C₁₀) carbocycle each of which may be optionally further substituted by hydrogen or (C₁-C₆) hydrocarbon;

X is CH₂, O, S or NR²R² where R¹ and R² are defined as above;

Y is chosen independently from CO₂H, CO2R¹, CONR¹R², NR³(CO)R², CN and

Z is independently chosen from CH or NR¹ and R¹ and R² are defined as above, [0008] In a preferred embodiment, the composition comprises a compound of Formula 1, wherein R¹, R², R³ R⁴ are CH3, X is NH and Y is CO2H.

[0009] In another preferred embodiment, the composition comprises a retinoic acid receptor (RAR) ligand of Formula 1. In a further preferred embodiment, the RAR ligand is all-trans retinoic acid (ATRA), adapalene, tamibarotene, or a pharmaceutically acceptable salt thereof. In a further preferred embodiment, the RAR ligand is tamibarotene or a pharmaceutically acceptable salt thereof. [0010] In another embodiment, is a pharmaceutical, dermatological, or cosmetic composition comprising an active agent or a salt thereof in a novel carrier. The composition preferably has suitable efficacy, safety and delivery features. In a another preferred embodiment, the active agent in the composition according to the invention is a relatively or highly insoluble compound.

[0011] For all of the compositions according to the invention, the novel carrier is preferably a carrier that creates a stable ternary system wherein the active agent is encapsulated or entrapped in the system. In a further preferred embodiment, when the formulation comes in contact with the skin, the active agent may be released from the formulation to better treat a skin disease or condition.

[0012] For example, the ternary system may comprise the active agent, a polymeric emulsifier, and an aqueous phase. The active agent may be any drug that is poorly soluble in water. The active agent is preferably tamibarotene or a salt or analog thereof. The polymeric emulsifier enables the mixture of oil and water components. In a preferred embodiment, the polymeric emulsifier is an acrylates/C10-30 alkyl acrylate crosspolymer such as Pemulen* TR-l, Pemulen ’ TR-2 and/or Carbopol® 1342.

[0013] The compositions of the present invention preferably contain an emulsifier and can be prepared in a multiphase method whereby a pharmaceutical, dermatological or cosmetic composition is formed that is stable and remains in the form of a cream, ointment, lotion, paste, gel, oleogel, water-in-oil emulsion or water-in-oil foam.

[0014] In each of the preferred embodiments according to the invention, the active agent can be any active agent that is stable in the novel carrier, and preferably results in a composition that has suitable efficacy, safety and delivery features. In any of the preferred embodiments, the active agent may be tamibarotene or a salt or analog thereof.

[0015] In another preferred embodiment, is a composition comprising an active agent or salt thereof, and two or more lipids (e.g., medium-chain trigylcerides, sunflower oil, paraffin, glycerol and polyols) which differ in their polarity and solvent power. [0016] In another embodiment, the invention provides nanoemulsified topical formulations comprising an active agent or salt thereof, and curcumin as an anti-inflammatory and antioxidant agent useful in treating variety of skin conditions.

[0017] In yet another embodiment, the invention provides nanoemulsified topical formulations comprising an active agent or salt thereof, and a curcuminoid as an anti-inflammatory and antioxidant agent together with pharmaceutically acceptable or inactive ingredients useful in treating variety of skin conditions.

[0018] Specifically, an active agent or salt thereof in combination with curcumin, a naturally occurring product found in the spice turmeric, is used in present invention to treat a range of skin problems including psoriasis, acne, eczema, wounds, burns, photodamaged photoaging skin and in mucositic disorders such as oral mucositis. The nanoemulsified formulation comprising curcumin is useful as an antiinflammatory, and possibly also as anticarcinogenic. In a further aspect, the curcumin or tetrahydroxycurcumin may be replaced with curcuminoid to achieve the present invention to treat a range of skin problems including psoriasis, acne, eczema, wounds, burns, photodamaged and photoaging skin, all types of mucositic disorders.

[0019] The nanoemulsified topical formulations of the present invention can be in the form but not limiting to semi solid dosage forms, ointment/cream/gel/lotions, is preferably inexpensive, and can also be used as an effective complementary treatment in combination with one or more of the established treatments for psoriasis.

[0020] In a further aspect, the curcumin or tetrahydroxycurcumin may be replaced with curcuminoid to achieve the present invention to treat a range of skin problems including psoriasis, acne, eczema, wounds, burns, photodamaged and photoaging skin, all types of mucositic disorders.

[0021] In another aspect, the invention provides an active agent or salt thereof, in combination with curcumin or tetrahydroxycurcumin and can be administered in a form, but not limiting to topical ointment/cream in the concentration of 0.001 % to 50% preferably 0.01% to 30% and more preferably 0.1% to 20%. In a further aspect, the combination of an active agent or salt thereof and curcumin or tetrahydroxycurcumin may be replaced with curcuminoid to achieve the present invention to treat a range of skin problems including psoriasis, acne, eczema, wounds, burns, photodamaged and photoaging skin, ail types of mucositic disorders. Nanoemulsified topical formulations of the present invention can be in the form but not limiting to semi solid dosage forms, ointment or cream or gel or lotions or facemasks, plasters can aiso be used as an effective complementary treatment in combination with one or more of the established treatments for psoriasis

[0022] In a preferred embodiment, the pharmaceutical, dermatological and/or cosmetic composition is prepared by combining a first phase of an active agent or salt thereof, a solubilizer, and a permeation enhancer; and a second phase of a polymeric emulsifier. In further embodiments, the first phase may also contain a vehicle, a preservative and/or an emollient. The second phase may also contain a vehicle, a thickener, a surfactant and/or a neutralizing agent.

[0023] In another embodiment, the pharmaceutical or cosmetic composition is prepared by combining a first phase comprising an active agent or salt thereof, a solubilizer, a preservative, and a permeation enhancer; and a second phase comprising a vehicle, a polymeric emulsifier, a thickener, a surfactant, and a neutralizing agent.

[0024] In another preferred embodiment, the pharmaceutical or cosmetic composition is prepared by combining a first phase of an active agent or salt thereof, a solubilizer, a preservative, an emollient, a vehicle and a solubilizer; a second phase comprising a vehicle, a permeation enhancer, and a moisturizer; and a third phase comprising an emulsifier and a neutralizing agent.

[0025] In a further preferred embodiment, the solubilizer is one or more polyethylene glycols (e.g., PEG 300, PEG 400, PEG 600, PEG 700, PEG 800, PEG 900).

[0026] In another preferred embodiment, the preservative is one or more parabens, such as methyl paraben and/or propyl paraben.

[0027] In another preferred embodiment, the permeation enhancer is isopropyl myristate. [0028] In another preferred embodiment, the emulsifier is a polymeric emulsifier. Preferably, the polymeric emulsifier is an acrylates/C10-30 alkyl acrylate crosspolymer such as Pemulen® TR-1, Pemulen* TR-2 and/or Carbopol 1342.

[0029] In another preferred embodiment, the surfactant is Tween 80.

[0030] In another preferred embodiment, the neutralizing agent is tris amino or triethanolamine.

[0031] The compositions and methods according to the invention, particularly those where the active agent is tamibarotene or a salt or analog thereof, can be used for treatment of a wide range of skin diseases and conditions, including but not limited to wrinkled skin, dry skin, rough skin, aging skin, discolored skin, acne, psoriasis, eczema, rosacea, vitiligo, dermatitis, burns, photodamaged and photoaging skin, skin cancer, alopecia, and all types of mucositic disorders. [0032] The compositions and methods according to the invention can contain one or more antibacterial, antiviral, or antifungal agents, so that the composition can further treat skin diseases and conditions caused by exposure to bacteria, viruses, or fungi. Compositions with bacterial agents may be used to treat bacterial infections including impentigo, forunculosis, cellulitis, and folliculitis. Compositions with antiviral agents may be used to treat viral infections including coronaviruses (e.g., Covid-19), genital and perianal warts, Herpes simplex infections and cold sores. Compositions with antifungal agents may be used to treat tinea pedis, cruris, corporis, unguium and candidiasis.

[0033] In another embodiment, the composition according to the invention has a viscosity that is spreadable and provides for smooth application to the patient's skin. For example, a viscosity modifier or thickener such as Methocel E4M may be added in an appropriate amount to adjust the viscosity of the composition. Preferably, the compositions according to the invention have a viscosity in the range of 10,000 - 200,000 cps; 20,000 to 150,000 cps; or more preferably 50,000 to 100,000 cps. Viscosity may be measured, for example, at 20 rpm, 1 min, Brookfield DV2T Viscometer, Model RV, spindle #07.

[0034] In another preferred embodiment, the composition further comprises isopropyl myristate, which can have a wide impact on formulation physical stability. As permeation enhancer, isopropyl myristate plays an important role in drug penetration through the skin. Formulation droplet size and, consequently, physical stability are highly dependent on homogenization rate. Isopropyl myristate and homogenization rate interaction can significantly influence formulation droplet size and tamibarotene release.

[0035] In another embodiment according to the invention, the active agent may be used at a relatively small amount due to the properties of the composition.

[0036] Further preferably, the composition enables tamibarotene, a salt thereof, or an analog thereof, to be employed at a concentration to provide a benefit of reduced cost and/or reduced sensitivity. For example, the concentration of the tamibarotene, a salt thereof, or an analog thereof may be 10% or less, 5% or less, 2% or less, 1% or less, 0.5% or less, 0.1% or less, 0.05% or less, 0.025% or less by weight of the composition. Alternatively, the concentration of the tamibarotene, a salt thereof, or an analog thereof may be between about 0.025% and 1.0%, between about 0.05% to 1,0%, between about 0.1 to 1.0%, between about 0.05% and 0.5%, or between about 0.1 and 0.5% by weight of the composition.

[0037] In another embodiment of the invention is a formulation and method for treating acne with a combination of a retinoid, Pemulen®, and an antimicrobial ingredient benzoyl peroxide.

DETAILED DESCRIPTION

[0038] The present invention is directed to a pharmaceutical, dermatological, or cosmetic composition containing an active agent or a salt thereof and a novel carrier, in a preferred embodiment, the active agent is tamibarotene or a salt thereof.

[0039] In another embodiment, the invention is directed to a pharmaceutical, dermatological, or cosmetic composition containing an analog of tamibarotene or a salt thereof. In another embodiment, the active agent is an analog of tamibarotene or salt thereof that has suitable efficacy, safety and delivery features, in a novel carrier. The analog of tamibarotene may be, for example, a compound of Formula 1 or pharmaceutically acceptable salts thereof:

wherein R¹, R² R³ and R⁴ are selected from hydrogen, (C₁-C₁₂) hydrocarbon and (C3-C10) carbocycle each of which may be optionally further substituted by hydrogen or (C₁-C₆) hydrocarbon;

X is CH2, O, S or NR^XR² where R¹ and R^z are defined as above;

Y is chosen independently from CO2H, CO2R¹, CONR^lR²; NRⁱ(CO)R², CN and

Z is independently chosen from CH or NR¹ and R³ and R² are defined as above.

[0040] In a preferred embodiment, the composition comprises a compound of Formula 1, wherein R¹, R², R³ R⁴ are CH₃, X is NH and Y is CO₂H.

[0041] In another preferred embodiment, the composition comprises a retinoic acid receptor (RAR) ligand. In a further preferred embodiment, the RAR ligand is all-trans retinoic acid (ATRA), adapalene, tamibarotene, tretinoin, tazarotene, alitretinoin, bexarotene or a pharmaceutically acceptable salt thereof, in a further preferred embodiment, the RAR ligand is tamibarotene or a pharmaceutically acceptable salt thereof.

[0042] In another embodiment, is a pharmaceutical, dermatological, or cosmetic composition comprising an active agent or a salt thereof in a novel carrier. The composition preferably has suitable efficacy, safety and delivery features. In a another preferred embodiment, the active agent in the composition according to the invention is a relatively or highly insoluble compound.

[0043] For all of the compositions according to the invention, the novel carrier is preferably a carrier that creates a stable ternary system wherein the active agent is encapsulated or entrapped in the system. In a further preferred embodiment, when the formulation comes in contact with the skin, the active agent may be released from the formulation to better treat a skin disease or condition. [0044] For example, the ternary system may comprise the active agent, a polymeric emulsifier, and an aqueous phase. The active agent may be a drug that is poorly soluble in water. The polymeric emulsifier enables the mixture of oil and water components. Preferred polymeric emulsifiers are an acrylates/C10-30 alkyl acrylate crosspolymer such as Pemulen® TR-1, Pemulen® TR-2 and/or Carbopol 1342.

[0045] The compositions of the present invention preferably contain an emulsifier and can be prepared in a multiphase method whereby a pharmaceutical, dermatological or cosmetic composition is formed that is stable and remains in the form of a cream, ointment, lotion, paste, gel, oleogel, water-in-oil emulsion or water-in-oil foam.

[0046] In a preferred embodiment, the pharmaceutical, dermatological, or cosmetic composition is prepared by combining a first phase of an active agent or salt thereof, a solubilizer, and a permeation enhancer; and a second phase of a polymeric emulsifier. In further embodiments, the first phase may also contain a vehicle, a preservative and/or an emollient. The second phase may also contain a vehicle, a thickener, a surfactant and/or a neutralizing agent. The active agent is preferably tamibarotene or a salt or analog thereof. [0047] In one embodiment, the pharmaceutical or cosmetic composition is prepared by combining a first phase comprising an active agent or salt thereof, a solubilizer, a preservative, and a permeation enhancer; and a second phase comprising a vehicle, a polymeric emulsifier, a thickener, a surfactant, and a neutralizing agent. The active agent is preferably tamibarotene or a salt or analog thereof.

[0048] For example, a pharmaceutical or cosmetic composition may be prepared by combining a first phase of tamibarotene or a salt or analog thereof, a solubilizer of a polyethylene glycol (e.g., PEG 300 and/or PEG 400), a preservative of one or more parabens (e.g., methylparaben and/or propylparaben), a permeation enhancer of isopropyl myristate; and a second phase of a vehicle of water, a polymeric emulsifier (e.g., Pemulin TR-1, Pemulin TR-2, and/or Carbopol 1342), a surfactant of Tween SO, and a neutralizing agent of tris amino. [0049] In a two-phase preparation of the pharmaceutical or cosmetic composition., the two phases may be prepared separately and then mixed together until a homogeneous composition is formed.

[0050] In another preferred embodiment, the pharmaceutical or cosmetic composition is prepared by combining a first phase of an active agent or salt thereof, a solubilizer, a preservative, an emollient, a vehicle and a solubilizer; a second phase comprising a vehicle, a permeation enhancer, and a moisturizer; and a third phase comprising an emulsifier and a neutralizing agent. The active agent is preferably tamibarotene or a salt or analog thereof. [0051] For example, a pharmaceutical, dermatological, or cosmetic composition may be prepared by combining a first phase of tamibarotene or a salt or analog thereof, a solubilizer of a polyethylene glycol (e.g., PEG 300 and/or PEG 400), a preservative of one or more parabens (e.g., methyiparaben and/or propylparaben), an emollient of glycerin, and a vehicle of water; a second phase of a vehicle of water, a permeation enhancer of isopropyl palmitate myristate, and a moisturizer of dimethicone and/or petrolatum; and a third phase of a polymeric emulsifier (e.g., Pemulin TR-1, Pemulin TR-2, and/or Carbopol 1342), and a neutralizing agent of triethanolamine.

[0052] In a three-phase preparation of the pharmaceutical or cosmetic composition, the three phases may be prepared separately and then mixed together until a homogeneous composition is formed.

[0053] In a further preferred embodiment, the solubilizer used in the compositions and methods according to the invention is one or more polyethylene glycols (e.g., PEG 300, PEG 400, PEG 600, PEG 700, PEG 800, PEG 900, PEG 1000, PEG 1450, PEG 7500, PEG 8000, PEG 10,000-16000, and PEG 20,000, and/or combinations of two or more PEG grades aforementioned.

[0054] In another preferred embodiment, the preservative used in the compositions and methods according to the invention is one or more parabens, such as methyl paraben and/or propyl paraben. [0055] In another preferred embodiment, the permeation enhancer used in the compositions and methods according to the invention is isopropyl myristate.

[0056] In another preferred embodiment, the emulsifier used in the compositions and methods according to the invention is a polymeric emulsifier. Preferably, the polymeric emulsifier is an acrylates/C10-30 alkyl acrylate crosspolymer such as Pemulen® TR-1, Pemulen’® TR-2 and/or Carbopol 1342.

[0057] in another preferred embodiment, the surfactant used in the compositions and methods according to the invention is Tween 80.

[0058] In another preferred embodiment, the neutralizing agent used in the compositions and methods according to the invention is tris amino or triethanolamine.

[0059] An additional embodiment of the invention is a method for treating skin. The methods and compositions of the invention may be applied to any dermatological disease or condition. Skin conditions may including but are not limited to wrinkled skin, dry skin, rough skin, aging skin, discolored skin, acne, psoriasis, eczema, rosacea, vitiligo, dermatitis, burns, photodamaged and photoaging skin, skin cancer, alopecia, and all types of mucositic disorders. [0060] In another embodiment, the composition according to the invention has a viscosity that is spreadable and provides for smooth application to a patient's skin. For example, a viscosity modifier or thickener such as Methocel E4M may be added in an appropriate amount to adjust the viscosity of the composition.

[0061] Preferably, the compositions according to the invention have a viscosity in the range of 10,000 ~ 200,000 cps; 20,000 to 150,000 cps; or more preferably 50,000 to 100,000 cps as preferred viscosity ranges Viscosity may be measured, for example, at 20 rpm, 1 min, Brookfield DV2T Viscometer, Model RV, spindle #07.

[0062] In a preferred embodiment, the composition forms an Interpenetrating Polymer Network (IPN ), a unique matrix in which Tamibarotene is solubilized in Carbopol 974P which can be combined with Carbopol 971P, sodium carboxymethyl cellulose (CMC-Na), or hydroxypropyl methyl cellulose (HPMC K100M). In a preferred embodiment, Carbopol 974P is blended with HPMC, further preferably at Carbopol 974P to HPMC blend ratios of 1:1 and 2:1. This provides a controlled or sustained release topical gel which is obtained at a Carbopol 974P to HPMC ratio of 2.5:1. This tamibarotene gel containing 2.5% Carbopol 974P combined with 1% HPMC.

[0063] In another embodiment according to the invention, the active agent or sait thereof may be used at a relatively smali amount due to the properties of the composition.

[0064] Further preferably, the composition enables the tamibarotene or a salt or analog thereof to be employed at a lower concentration to provide a benefit of reduced cost of tamibarotene and/or reduced sensitivity to tamibarotene. For example, the concentration of the tamibarotene may be 10% or iess, 5% or less, 4% or less, 3% or iess, 2% or less, 1% or less, 0.5% or less, 0.1% or less, 0.05% or less, 0.025% or less by weight of the composition.

Alternatively, the concentration of the tamibarotene or a salt or analog thereof may be between about 0.025% and 1.0%, between about 0.05% to 1.0%, between about 0.1 to 1.0%, between about 0.05% and 0.5%, or between about 0.1 and 0.5% by weight of the composition. [0065] The compositions of the invention are preferably in the form of a topical ointment, lotion, cream or a gel.

[0066] Additional excipients and active agents, including additional tamibarotene salts or analogs, may be added to the compositions of the invention. For example, fragrances, sunscreen, antioxidants, other anti-aging agents, other skin treatment agents, moisturizing agents (including ammonium lactate), anti-irritants, other retinoids, may be added to the formulations.

[0067] In a preferred embodiment, the invention is directed to a pharmaceutical composition comprising an active agent of tamibarotene or a salt or analog thereof, a solubilizer, a permeation enhancer, and a polymeric emulsifier, wherein the solubilizer is a polyethylene glycol, the permeation enhancer is isopropyl myristate, and the polymeric emulsifier is an acryiates/C10-30 alkyl acrylate crosspolymer, in one embodiment, the active agent is tamibarotene or a salt thereof. In another embodiment, the active agent is tamibarotene. In another embodiment, the active agent is a tamibarotene analog or a salt thereof. The solubilizer comprises polyethylene glycol 400 and/or polyethylene glycol 300, The composition further comprises a preservative, preferably a paraben such as methylparaben and/or propylparaben. The polymeric emulsifier is Pemulin TR-1 or Carbopal 1342. The composition may further comprise a surfactant, for example, Tween 80. In a further preferred embodiment, the composition further comprises a neutralizing agent, such as tris amino or sodium hydroxide. In another preferred embodiment, the composition further comprises water.

[0068] In another preferred embodiment, the composition according to the invention has a viscosity between about 20,000 to about 200,000. The concentration of tamibarotene or salt or analog thereof is preferably 1% or less, 0.5% or less, 0.1% or less, 0.05% or less or 0.025% or less.

[0069] The composition according to the invention is preferably in the form of a gel or cream. [0070] In another preferred embodiment is a method of using the composition of the invention to treat a skin condition, for example, wherein the skin condition is wrinkled skin, dry skin, rough skin, aging skin, discolored skin, acne, psoriasis, eczema, rosacea, vitiligo, dermatitis, burns, photodamaged and photoaging skin, skin cancer, alopecia, or a mucositic disorders, in a preferred embodiment, the composition according to the invention is used in a method to treat acne.

[0071] In another embodiment of the invention is an acne treatment using a composition of one or more retinoids in combination with one or more Pemulen’- components and an antimicrobial benzoyl peroxide. Acne is characterized by primary lesions on the face, chest, and back, and by a variety of other signs and symptoms. Acne, inflammatory lesions result from Propionibacterium acnes colonization and are of relevance as they can cause permanent scarring. Acne also causes significant psychological morbidity in affected patients. Products currently available for the treatment of acne include systemic and topical treatments. As these products can cause severe side effects, new, innovative therapies are needed, in this invention, a novel combination of a retinoid, Pemulen', and an anti-microbial ingredient benzoyl peroxide are to function synergistically. Pemulen* products are emulsifiers that are high molecular weight copolymers of acrylic acid and C10-C30 alkyl acrylate crosslinked with allyl pentaerythritol. These pharmaceutical excipients provide effective sterically stabilized emulsification properties to form stable oil-in-water emulsions solubilizing highly insoluble retinoids such as tamibarotene in a binary combination with a hydrophilic therapeutic agent benzoyl peroxide.

[0072] Pemulen® polymer excipients contain both hydrophilic and hydrophobic portions and serve as excellent gel-forming polymers, creating a network around suspended oil droplets and providing exceptional emulsion stability, often without the need for additional surfactants. Pemulen® polymers help create low irritancy creams and lotions, providing optimal aesthetics, feel, and drug penetration into the membrane, as well as efficacious, non-irritating emulsion eye drops. Pemulen® acrylic acid polymer excipients also provide viscosity building and high yield value to allow for suspension and stabilization of insoluble particulates.

[0073] In a preferred embodiment, Pemulen® polymers containing tamibarotene and benzoyl peroxide in a ternary system are used as film formers to provide a long-acting film coating encapsulating on skin. Tamibarotene and benzoyl peroxide thereby contact skin lesions to treat mild and moderate acne.

[0074] In a further preferred embodiment, a ternary system works as a triangular or three-part combination of composition of matter in unison as a stable system design. Each component at the 3 vertices of a triangle interacts synergistically. Each vertex represents an element of the composition of matter. The drugs tamibarotene and benzoyl peroxide and/or clindamycin are at the apex of the triangle, base 1 of the triangle is either Pemulen® TR-1 or Pemulen® TR-2, and base 2 of the triangle is the human skin.

[0075] Topical retinoids include retinol, tretinoin, adapalene, tazarotene, alitretinoin, and bexarotene. These retinoics can be formulated into creme, gel, and liquid forms and can be prescribed for mild to moderate acne.

[0076] The combination of a retinoid such as tamibarotene with an anti-microbial benzoyl peroxide in a Pemulen® matrix drug delivery system provides a synergistic ternary combination of tamibarotene, Pemulen® polymers, and benzoyl peroxide, which is a powerful antimicrobial agent which destroys both surface and ductal bacterial organisms and yeasts. [0077] Benzoyl peroxide has lipophilic properties which permit penetration of the pilosebaceous duct, and its efficacy is largeiy against superficial inflammatory lesions. Once applied to the skin, benzoyl peroxide decomposes to release free oxygen radicals, which have potent bactericidal activity in the sebaceous follicles and anti-inflammatory action, it also has effects on noninflammatory lesions by reducing follicular hyperkeratosis to a degree. Benzoyl peroxide, as with topical retinoids, like tamibarotene, do not affect sebum production.

[0078] In a further preferred embodiment, is a composition for treating acne in which at least one retinoid and benzoyl peroxide in a formulation with an aqueous gel comprising Pemulen® TR-1 and/or TR-2. A combination of active agent may also be used, which include, for example, tamibarotene and tazarotene, tamibarotene and tretinoin, tamibarotene and adapalene. In a further preferred embodiment, the Pemulen® component ensures the stability of the two incompatible active ingredients.

EXAMPLES

[0079] Example 1 - 1% Tamibarotene Cream

Procedure:

Forming Phase I

(1) Add 60 g of Polyethylene Glycol 300 (PEG 300) in a 8 oz glass jar.

(2) Add 2.0 g Tamibarotene to step 1 and mix until dissolve.

(3) Add 0.30 g of methylparaben to step 2 and mix.

(4) Add 0.20 g of Propylparaben to step 3 while stirring and mix.

(5) Add 20,0 g of Isopropyl Palmitate to step 4 while stirring and mix.

Forming Phase II

(6) Add 114.2 g of purified water in a 8 oz glass jar. (7) Add slowly 1.2 g of Methocel E4M to step 6 while mixing.

(8) Mix until it is homogenous.

(9) Add 0.6 g of Pemulen TR-1 to step 7 while mixing.

(10) Mix until it is homogenous.

(11) Add 1.0 g of Tween 80 to step 9 while mixing.

(12) Mix until it is homogenous.

Phase I + Phase II

(13) Add slowly Phase I to Phase II while mixing. Mix continuously for 10 minutes.

(14) Mix until it is homogenous.

(15) Add slowly sufficient amount of 18% Sodium Hydroxide solution to step 14 to pH between 5.0 to 6.0

(16) Once the mixture is homogenous, measure the pH. Record pH 5.79

(17) Measure the pH after 24 hours. Record pH 5.70

(18) Record Viscosity: 25,180 cps; 20 rpm, 1 mln, Brookfield DV2T Viscometer, Model RV, Spindle# 06

[0080] Example 2 - 0.50% Tamibarotene Cream

Procedure:

Forming Phase I

(1) Add 60 g of Polyethylene Glycol 300 (PEG 300) in a 8 oz glass jar.

(2) Add 1.00 g Tamibarotene to step 1 and mix until dissolve.

(3) Add 0.30 g of methylparaben to step 2 and mix until dissolve.

(4) Add 0.20 g of propylparaben to step 3 while stirring and mix until dissolve. (5) Add 20.0 g of Isopropyl Palmitate to step 4 while stirring and mix.

Forming Phase 11

(5) Add 114.1 g of purified water in a 8 oz glass jar.

(6) Add slowly 2.4 g of Methocel E4M to step 5 while mixing.

(7) Mix until it is homogenous.

(8) Add 0.6 g of Pemulen TR-1 to step 6 while mixing.

(9) Mix until it is homogenous.

(10) Add 1.0 g of Tween 80 to step 8 while mixing.

(11) Mix until it is homogenous, measure the pH. Record pH 3.74

Phase I + Phase II

(12) Add slowly Phase I to Phase II while mixing. Mix continuously for 10 minutes.

(13) Mix until it is homogenous, measure the pH. Record pH 4.28

(14) Add slowly sufficient amount of 18% Sodium Hydroxide solution to step 13 to pH between 5.0 to 6.0

(15) Once the mixture is homogenous, measure the pH. Record pH 5.89

[0081] Example 3 - 0.10% Tamibarotene cream

Isopropyl Palmitate, Croda, CRODAMOL IPP- Permeation LQ, Lot# 0001438350 Enhancer 10.00 20.00 20.013

Phase II

Purified Water, USP,

RICCA, Lot# 2906896 Vehicle 57.550 115.100 115.150

Pemulen® TR-l , Lubrizol, Lot# 0102227754 (Acrylates/C10-30 alkyl Polymeric acrylate crosspolymer) Emulsifier 0.30 0.600 0.605

Methocel E4M Premium HPMC, Dow/DuPont, Lot# Thickner, Rheology 0180J3S011 Modifier 1.20 2.40 2.405

Tween 80, Croda,

TWEEN 80-LQ-(MH),

Lot# 0001584082 Surfactant 0.50 1.00 1.009

18% Sodium Hydroxide, Spectrum, Lot# 2IG0028, 18 g IN 100 5 drops to pH mL Neutralizing Agent 0.10 0.200 between 5 to 6

Total 100.000 200.000 200.10

Procedure:

Forming Phase I

(1) Add 60 g of Polyethylene Glyco! 300 (PEG 300) in 3 8 oz glass jar.

(2) Add 0.200 g Tamibarotene to step 1 and mix until dissolve.

(3) Add 0.30 g of methylparaben to step 2 and mix until dissolve.

(4) Add 0.20 g of propylparaben to step 3 while stirring and mix until dissolve.

(5) Add 20.0 g of Isopropyl Palmitate to step 4 while stirring and mix.

Forming Phase H

(5) Add 115.15 g of purified water in a 8 oz glass jar. (6) Add slowly 2.4 g of Methocel E4M to step 5 while mixing.

(7) Mix until it is homogenous.

(8) Add 0.6 g of Pemulen TR-1 to step 6 while mixing.

(9) Mix until it is homogenous.

(10) Add 1.0 g of Tween 80 to step 8 while mixing.

(11) Mix until it is homogenous, measure the pH. Record pH 3.73

Phase I + Phase II

(13) Mix until it is homogenous, measure the pH. Record pH 4.38

(15) Once the mixture is homogenous, measure the pH. Record pH 5.78

[0082] Example 4 - 0.05% Tamibarotene cream

Procedure:

Forming Phase I

(1) Add 60 g of Polyethylene Glycol 300 (PEG 300) in a 8 oz glass jar.

(2) Add 0.100 g Tamibarotene to step 1 and mix until dissolve.

(3) Add 0.30 g of methylparaben to step 2 and mix until dissolve.

(5) Add 20,0 g of Isopropyl Palmitate to step 4 while stirring and mix. Forming Phase II

(5) Add 115.20 g of purified water in a 8 oz glass jar. (6) Add slowly 2.4 g of Methocel E4M to step 5 while mixing.

(7) Mix until it is homogenous.

(8) Add 0.6 g of Pemulen TR-1 to step 6 while mixing.

(9) Mix until it is homogenous.

(10) Add 1.0 g of Tween 80 to step 8 while mixing.

(11) Mix until it is homogenous, measure the pH. Record pH

3.78

Phase I + Phase II

(13) Mix until it is homogenous, measure the pH. Record pH

4.38

(15) Once the mixture is homogenous, measure the pH. Record pH 5.81

[0083] Example 5 - 0.025% Tamibarotene cream

Procedure:

Forming Phase I

(1) Add 60 g of Polyethylene Glycol 300 (PEG 300) in a 8 oz glass jar.

(2) Add 0.050 g Tamibarotene to step 1 and mix until dissolve.

(3) Add 0.30 g of methylparaben to step 2 and mix until dissolve. (4) Add 0,20 g of propylparaben to step 3 while stirring and mix until dissolve.

(5) Add 20.0 g of isopropyl Palmitate to step 4 while stirring and mix.

Forming Phase II

(5) Add 115.70 g of purified water in a 8 oz glass jar.

(6) Add slowly 2.0 g of Methocel E4M to step 5 while mixing.

(7) Mix until it is homogenous.

(8) Add 0.6 g of Pemulen TR-1 to step 6 while mixing.

(9) Mix until it is homogenous.

(10) Add 1.0 g of Tween 80 to step 8 while mixing.

(11) Mix until it is homogenous, measure the pH, Record pH

3.75

Phase I + phase II

(13) Mix until it is homogenous, measure the pH. Record pH

4.32

(15) Once the mixture is homogenous, measure the pH. Record pH 5.47

(16) Record Viscosity: 40,670 cps; 20 rpm, 1 min, Brookfield DV2T Viscometer, Model RV, Spindle#

07 [0084] Example 6-1% Tamlbarotene Cream

Procedure:

Forming Phase I

(1) Add 60 g of Polyethylene Glyco! 400 (PEG 400) in a 8 oz glass jar.

(2) Add 2.0 g Tamibarotene to step 1 and mix until dissolve.

(3) Add 0.30 g of methylparaben to step 2 and mix.

(4) Add 0.20 g of Propylparaben to step 3 while stirring and mix.

(5) Add 20.0 g of Isopropyl Myristate to step 4 while stirring and mix.

Forming Phase il

(6) Add 112.4 g of purified water in a 8 oz glass jar.

(7) Add slowly 2.0 g of Carbopol 1342 to step 6 while mixing.

(8) Once the mixture is homogenous, measure the pH. Record pH 3.07

(9) Add 0.6 g of Pemulen TR-1 to step 7 while mixing.

(10) Once the mixture is homogenous, measure the pH. Record pH 2.87

(11) Add 1.0 g of Tween 80 to step 9 while mixing.

(12) Once the mixture is homogenous, measure the pH. Record pH 2.96

Phase I + Phase II

(14) Once the mixture is homogenous, measure the pH. Record pH 3.58

(15) Add slowly sufficient amount of 40% Tris Amino solution in water (about 1.5 g) to step 14 to pH between 5.0 to 6.0 and allowed to mix.

(16) Once the mixture is homogenous, measure the pH. Record pH 5.44 (17) Measure the pH after 24 hours. Record pH 5,40

(18) Record Viscosity: 71,600 cps; 20 rpm, 1 min, Brookfield DV2T Viscometer, Model RV, Spindle#

07

[0085] Example 7 - 0.50% Tamibarotene cream

Procedure:

Forming Phase I

(1) Add 60 g of Polyethylene Glycol 300 (PEG 300) in a 8 oz glass jar.

(2) Add 1.0 g Tamibarotene to step 1 and mix until dissolve.

(3) Add 0.30 g of methylparaben to step 2 and mix until dissolve.

(5) Once the mixture Is homogenous, measure the pH. Record pH 4.88

(6) Add 20.0 g of Isopropyl Myristate to step 4 while stirring and mix.

Forming Phase II

(7) Add 113.5 g of purified water in a 8 oz glass jar.

(8) Add slowly 2.0 g of Carbopol 1342 to step 7 while mixing.

(9) Once the mixture is homogenous, measure the pH. Record pH 3.05

(10) Add 0.6 g of Pemulen TR-1 to step 8 while mixing.

(11) Once the mixture is homogenous, measure the pH. Record pH 2.93

(12) Add 1.0 g of Tween 80 to step 10 while mixing.

(13) Once the mixture is homogenous, measure the pH. Record pH 3.02 Phase I + Phase II

(14) Add slowly Phase I to Phase II while mixing. Mix continuously for 10 to 15 minutes.

(15) Once the mixture is homogenous, measure the pH. Record pH 3.56

(16) Add slowly sufficient amount of 40% Tris Amino solution in water (about

2.2 g) to step 15 to pH between 5.0 to 6.0 and allowed to mix.

(17) Once the mixture is homogenous, measure the pH. Record pH 5.29

[0086] Example 8 - 0.10% Tamibarotene cream

Procedure:

Forming Phase I

(1) Add 60 g of Polyethylene Glycol 300 (PEG 300) in a 8 oz glass jar.

(2) Add 0.20 g Tamibarotene to step 1 and mix until dissolve.

(3) Add 0.30 g of methylparaben to step 2 and mix until dissolve.

(5) Add 20.0 g of Isopropyl Myristate to step 4 while stirring and mix.

Forming Phase II

(6) Add 112.7 g of purified water in a 8 oz glass jar.

(7) Add slowly 2.0 g of Carbopol 1342 to step 6 while mixing.

(8) Add 0.6 g of Pemulen TR-1 to step 7 while mixing. (9) Add 1,0 g of Tween 80 to step 8 while mixing.

(10) Once the mixture is homogenous, measure the pH. Record pH 3.03

Phase I + Phase II

(11) Add siowly Phase I to Phase II while mixing. Mix continuously for 10 to 15 minutes.

(12) Once the mixture is homogenous, measure the pH. Record pH 3.53

(13) Add slowly sufficient amount of 40% Tris Amino solution in water (about

2.2 g) to step 12 to pH between 5.0 to 6.0 and allowed to mix.

(14) Once the mixture is homogenous, measure the pH. Record pH 5.15

[0087] Example 9 ~ 0.05% Tamibarotene cream

Procedure:

Forming Phase 1

(1) Add 60 g of Polyethylene Glyco! 300 (PEG 300) in a 8 oz glass jar.

(2) Add 0.10 g Tamibarotene to step 1 and mix until dissolve.

(3) Add 0.30 g of methylparaben to step 2 and mix until dissolve.

(5) Add 20.0 g of Isopropyl Myristate to step 4 while stirring and mix.

Forming Phase H

(6) Add 113.6 g of purified water in a 8 oz glass jar. (7) Add slowly 2.0 g of Carbopol 1342 to step 6 while mixing.

(8) Add 0.6 g of Pemulen TR-1 to step 7 while mixing.

(9) Add 1.0 g of Tween 80 to step 8 while mixing.

(10) Once the mixture is homogenous, measure the pH. Record pH 3.05

Phase I + Phase II

(11) Add slowly Phase I to Phase II while mixing. Mix continuously for 10 to 15 minutes.

(12) Once the mixture is homogenous, measure the pH. Record pH 3.63

(13) Add slowly sufficient amount of 40% Tris Amino solution in water (about

2.2 g) to step 12 to pH between 5.0 to 6,0 and allowed to mix.

(14) Once the mixture is homogenous, measure the pH. Record pH 5.39

[0088] Example 10 - 0.025% Tamibarotene cream

Procedure:

Forming Phase I

(1) Add 60 g of Polyethylene Glycol 300 (PEG 300) in a 802 glass jar.

(2) Add 0.050 g Tamibarotene to step 1 and mix until dissolve.

(3) Add 0.30 g of methylparaben to step 2 and mix until dissolve.

(5) Add 20.0 g of Isopropyl Myristate to step 4 while stirring and mix. Forming Phase II

(6) Add 113.64 g of purified water in a 8 oz glass jar.

(7) Add slowly 2.0 g of Carbopol 1342 to step 6 while mixing.

(8) Add 0.6 g of Pemulen TR-1 to step 7 while mixing.

(9) Add 1.0 g of Tween 80 to step 8 while mixing.

(10) Once the mixture is homogenous, measure the pH. Record pH 2.94

Phase I + Phase II

(12) Once the mixture is homogenous, measure the pH. Record pH 3.58

(13) Add slowly sufficient amount of 40% Tris Amino solution in water (about

2.2 g) to step 12 to pH between 5.0 to 6.0 and allowed to mix.

(14) Once the mixture is homogenous, measure the pH. Record pH 5.60

[0089] Example 11 ~ Carrier for Cream Formulation

Procedure;

Forming Component (a) - Part 1

(1) Add 20 g of Polyethylene Glycol 300 (PEG 300) in a 8 oz glass jar.

(2) Add 2.0 g Tamibarotene to step 1 and mix until dissolve.

(3) Add 0.30 g of methylparaben to step 2 and mix.

(4) Add 0.20 g of propylparaben to step 3 while stirring and mix.

(5) Add 4.0 g of Glycerin to step 4 while stirring and mix.

(6) Add 126.20 g of purified water to another 8 oz glass jar.

(7) Add 2 g of Polyethylene Glycol 1540 (PEG 1540) to step 6 and mix until dissolve.

(8) Add slowly PEG 1540 dissolved in water from step 7 to step 5 while mixing.

Forming Component (b) - Part 2

(9) Add 31.50 g of purified water to a 8 oz glass jar.

(10) Add 5.0 g of Isopropyl palmitate in step 9 while mixing.

(11) Add 5.0 g of Dimethicone in step 10 while mixing.

(12) Add 2.0 g of White Petrolatum in step 11 while mixing.

Component (a) - Part 1 + Component (b) -

Part 2

(13) Add slowly Component ( b) - Part 2 to Component (a) - Part 1 while mixing.

(14) Mix Part 1 + Part 2 for 15 minutes.

Addition of Pemulen

TR-1 (15) Add slowly 3.0 g of Pemulen TR-1 to step 14 while stirring with over head mixer.

(16) Mix until Pemulen TR-1 is uniformly suspended. Stir for 30 minutes.

(17) Record pH 4.12

(18) Add sufficient amount of Triethanolamine to step 16 to pH between 5.0 to 6.0

(19) Record pH 5.27

(20) Record Viscosity: 69,270 cps; 20 rpm, 1 min, Brookfield DV2T Viscometer, Model RV, Spindle#

07

[0090] Example 12 - 1.00% Tamibarotene cream

Component (b) - Part 2

Purified Water, USP,

RICCA, Lot# 2906896 Vehicle 15.75 31.50 31.605

Permeation Enhancer 2.50 5.00 5.006

Dow Corning TI-1050

Fluid 30,000 Cst (Dimethicone), Lot#

H033J5P018 Moisturizer 2.50 5.00 5.041

CROLATUM V-SO, White Petrolatum, Croda, Lot# Lot# 000160269 Moisturizer 1.00 2.00 2.011

Total 21.75 43.50 43.66

Component (c) - Part 3

Pemulen® TR-l , NF, Lubrizol, Lot# 0102227754 (Acrylates/C10-30 alkyl Polymeric acrylate crosspolymer) Emulsifier 1.50 3.000 3.006

Triethanolamine, NF, to pH between 5.0

Spectrum, Lot# 1IJ0158 Neutralizing Agent 0.40 0.800 to 6.0

1.90 3.80 3.01

Total 100.00 200.00 199.50

Procedure:

Forming Component (a) - Part 1

(1) Add 20 g of Polyethylene Glycol 300 (PEG 300) in a 8 oz glass jar.

(2) Add 2.0 g Tamibarotene to step 1 and mix until dissolve.

(3) Add 0.30 g of methylparaben to step 2 and mix.

(4) Add 0.20 g of propylparaben to step 3 while stirring and mix.

(5) Add 4.0 g of Glycerin to step 4 while stirring and mix.

(6) Add 126.20 g of purified water to another 8 oz glass jar. (7) Add 2 g of Polyethylene Glycol 1540 (PEG 1540) to step 6 and mix until dissolve.

(8) Add slowly PEG 1540 dissolved in water from step 7 to step 5 while mixing.

Forming Component (b) - Part 2

(9) Add 31.50 g of purified water to a 8 oz glass jar.

(10) Add 5.0 g of Isopropyl palmitate in step 9 while mixing.

(11) Add 5.0 g of Dimethicone in step 10 while mixing.

(12) Add 2.0 g of White Petrolatum in step 11 while mixing.

Component (a) - Part 1 + Component (b) - Part 2

(13) Add slowly Component (b) - Part 2 to Component (a) - Part 1 while mixing.

(14) Mix Part 1 + Part 2 for 15 minutes.

Addition of Pemulen TR-1

(15) Add slowly 3.0 g of Pemulen TR-1 to step 14 while stirring with over head mixer.

(16) Mix until Pemulen TR-1 is uniformly suspended. Stir for 30 minutes.

(17) Record pH 4.12

(18) Add sufficient amount of Triethanolamine to step 16 to pH between 5.0 to

6.0

(19) Record pH 5.27

(20) Record Viscosity: 69,270 cps; 20 rpm, 1 min, Brookfield DV2T Viscometer, Model RV, Spindle# 07

[0091] Example 13 - 1.00% Tamibarotene cream

Procedure:

Forming Phase 1

(1) Add 20 g of Polyethylene Glycol 300 (PEG 300) in a 8 oz glass jar.

(2) Add 2.0 g Tamibarotene to step 1 and mix until dissolve.

(3) Add 0.30 g of methylparaben to step 2 and mix.

(4) Add 0.20 g of sorbic acid to step 3 while stirring and mix.

(5) Add 10.0 g of Glycerin to step 4 while stirring and mix.

(6) Add 106.90 g of purified water to step 5 and mix.

(7) Add slowly 0.40 g of Pemulen TR-1 while mixing.

(8) Once the mixture is homogenous, measure the pH. Record pH 3.72

(9) Add sufficient amount of triethanolamine to step 8 to pH between 5.0 to 6.0 and allowed to mix.

(10) Record pH 5.49

(11) Heat the mixture to 50°C and maintain at 50°C.

Forming Phase II

(12) Add 17.0 g of Gelot 64 to another 8 oz glass jar.

(13) Add 17.0 g of Compritol 888 in step

13.

(14) Add 17.0 g of Geleol Mono and Diglycerides in step 14.

(15) Add 10.00 g of Mineral Oil, Heavy in step 15.

(16) Heat the mixture to 70°C, mix until homogenous and maintain at

70°C.

Phase I + Phase II

(17) Add slowly Phase II to Phase I while mixing. Stop heating and mix continuously.

(18) Once the cream is formed and it is homogenous, stop mixing and allow to cool.

(19) Record pH 5.49 (20) Record Viscosity: 343,100 cps; 5 rpm, 1 min, Brookfield DV2T Viscometer, Model RV, Spindle#

07

[0092] Example 14 - Tamibarotene Cream Formulations at Different Viscosities

[0093] Tamibarotene cream formulations of different viscosities were prepare and evaluated.

Formulations of 0.025% tamibarotene cream were varied In the amount of 0.6, 1.0, 1.2 and

1.5% Methocel E4M. The viscosity was measured and is compared in Tables 1-4.

[0094] Table 1

0.025% Tamibarotene Cream Lot # 02092020-HA-0.025%

Spindle: RV-07 Methocel E4M - 1.0% lpt/10 sec , 6 pts

Duration: 1 min total

[0095] Table 2

0.025% Tamibarotene Cream Lot # 03092020-HA-0.025%

Spindle: RV-07 Methocel E4M - 1.2% lpt/10 sec , 6 pts

Duration: 1 min total

[0096] Table 3

Methocel E4M 1,0% vs 1.2%

Lot # 02092020-HA-0.025% vs Lot # 03092020-HA-

0.025%

Spindle: RV-07 and RV-06 lpt/10 sec , 6 pts

Duration: 1 min total

[0097] Table 4

Methocel E4M 0.6,% 1.0% , 1.2% and 1.5% lpt/10 sec , 6 pts

Duration: 1 min total

[0098] A shown in the above data, the viscosity of a tamibarotene cream formulation can be modified by the addition of Methocell E4M. An increase in the % Methocel! E4M results in an increase in the viscosity.

[0099] Example 15 - 1.00% Tamibarotene Gel Formulation

Procedure;

1. Weigh 20 g of alcohol 95% in 4 oz jar.

2. Add 0.5 g of Tamibarotene in aicohoi and mix to dissoive.

3. Add 0.075 g of methylparaben and 0.050 g of propylparaben in alcohol and mix to dissolve.

4. Add 5 g of polyethylene glycol 300 in step 2 and mix to dissolve.

5. Add 5 g of glycerin in step 3 and mix to dissolve.

6. Add 16.925 g of purified water in step 4 and mix to dissolve,

7. Add slowly 1.25 g of Pemulen TR-1 in step 5 while mixing with IKA overhead mixer.

8. Mix it for at least 15 minutes until Pemulen TR-1 is uniformly suspended.

9. Measure and record pH 3.66

10. Once Pemulen TR-1 is uniformly suspended in water, add 1.2 g of IN sodium hydroxide.

11. Measure and record pH 5.08

12. Allow 24 hours to form uniform gel formulation.

13. Measure and record the pH of the gel product.

14. pH of Formulation E, Lot# 28012020-E; pH is 5.16

11. Appearance; Opaque/Translucent Gel [0100] Example 16 - 0.50% Tamibarotene Gel Formulation

Procedure:

1. Weigh 20 g of alcohol 95% in 4 oz jar,

2. Add 0.25 g of Tamibarotene in alcohol and mix to dissolve.

4. Add 5 g of polyethylene glycol 300 in step 2 and mix to dissolve. 5. Add 5 g of glycerin in step 3 and mix to dissolve.

6. Add 17,175 g of purified water in step 4 and mix to dissolve.

8. Mix it for at least 15 minutes until Pemulen TR-1 is uniformly suspended,

9. Once Pemulen TR-1 is uniformly suspended in water, add 1,2 g of IN sodium hydroxide.

10. Allow 24 hours to form uniform gel formulation.

11. Measure and record the pH of the gel product.

12. pH of Formulation F, Lot# 28012020-F; pH is 5.43

13. Appearance: Clear

Gel

[0101] Example 17 - 0.50% Tamibarotene Gel Formulation

Procedure:

1. Weigh 40 g of alcohol 95% in 4 oz jar.

2. Add 0.5 g of Tamibarotene in alcohol and mix to dissolve.

3. Add 0.150 g of methylparaben and 0.100 g of propylparaben in alcohol and mix to dissolve.

4. Add 10 g of polyethylene glycol 300 in step 3 and mix to dissolve.

5. Add 10 g of glycerin in step 4 and mix to dissolve.

6. Add 36,45 g of purified water in step 5 and mix to dissolve.

7. Add slowly 2.50 g of Pemulen TR-1 in step 6 while mixing with I KA overhead mixer.

8. Mix it for at least 15 minutes until Pemulen TR-1 is uniformly suspended.

9. Measure and record pH 3.81

10. Once Pemulen TR-1 is uniformly suspended in water, add 0.3 g (8 drops) of Triethanolamine

11. Allow 24 hours to form uniform gel formulation.

12. Measure and record the pH of the gel product. pH of Formulation I is5.47 13. Appearance: Clear Gel

[0102] Example 18 - 1.00% Tamibarotene Gel Formulation

Procedure:

1. Weigh 30 g of alcohol 95% in 4 oz jar,

2. Add 20 g of Transcutol HP in step 1 and mix to dissolve.

3. Add 1.0 g of Tamibarotene in step 2 and mix to dissolve,

4. Add 0.150 g of Methylparaben and 0.100 g of Propylparaben in step 3 and mix to dissolve.

5. Add 10 g of polyethylene glycol 300 in step 4 and mix to dissolve.

6. Add 10 g of glycerin in step 5 and mix to dissolve.

7. Add 23.450 g of purified water in step 6 and mix to dissolve. Measure and record pH 4.30

8. Add 1.0 g of Polyethylene glycol 1540 in step 7 and mix and dissolve.

9. Add slowly 0.200 g of Pemulen TR-1 in step 8 while mixing with IKA overhead mixer.

10. Mix it for at least for 15 minutes until Pemulen TR-1 is uniformly suspended.

110. Measure and record pH 5.54

12. Once Pemulen TR-1 is uniformly suspended in water, add 0.100 g (2 drops) of Triethanolamine.

13. Add 4.0 g of Hydroxyethylcellulose in 11 and mix.

14. Allow 24 hours to form uniform gel formulation. Measure and record pH

5.55 15. Appearance: Clear

Gel

16. Brookfield LV DV-ll+Pro, Spindle# 64, 5 RPM, 2 min, Viscosity: 6,863.cps

[0103] Example 19 - 3.00% Tamibarotene Gel Composition

Procedure:

1. Weigh 30 g of alcohol 95% in 4 oz jar.

2. Add 20 g of Transcutol HP in step 1 and mix to dissolve.

3. Add 3.0 g of Tamibarotene in step 2 and mix to dissolve.

5. Add 10 g of polyethylene glycol 300 in step 4 and mix to dissolve.

6. Add 10 g of glycerin in step 5 and mix to dissolve.

7. Add 19.250 g of purified water in step 6 and mix to dissolve.

8. Add 1.0 g of Polyethylene glycol 1540 in step 7 and mix and dissolve. Record pH 4.04

9. Add slowly 0.200 g of Pemulen TR-1 in step 8 while mixing with I KA overhead mixer.

11. Measure and record pH 4.06

12. Once Pemulen TR-1 is uniformly suspended in water, add 0.300 g (6 drops) of Triethanolamine.

13. Measure and record pH 5.41

14. Add 6.0 g of Hydroxyethylcellulose in 12 and mix. 15. Allow 24 hours to form uniform gel formulation. Measure and record pH

5.47

16. Appearance: Clear

Gel

17. Brookfield LV DV-IH-Pro, Spindle# 64, 5 RPM, 2 min, Viscosity: 7,198 cps

[0104] Example 20 » 5.00% Tamibarotene Gel Formulation

Procedure:

1. Weigh 20 g of alcohol 95% in 4 oz jar.

2. Add 30 g of Transcutol HP in step 1 and mix to dissolve.

3. Add 5.0 g of Tamibarotene in step 2 and mix to dissolve.

5. Add 10 g of polyethylene glycol 300 in step 4 and mix to dissolve.

6. Add 10 g of glycerin in step 5 and mix to dissolve.

7. Add 13,250 g of purified water in step 6 and mix to dissolve.

8. Add 1.0 g of Polyethylene glycol 1540 in step 7 and mix and dissolve. Record pH 4.06

11. Measure and record pH 4.01 12. Once Pemulen TR-1 is uniformly suspended in water, add 0.400 g (8 drops) of Triethanolamine.

13. Measure and record pH 5.45

14. Add 10.0 g of Hydroxyethylcellulose in 12 and mix.

15. Allow 24 hours to form uniform gel formulation. Measure and record pH

5.5

16. Appearance: Clear

Gel

17. Brookfield IV DV-ll+Pro, Spindle# 64, 5 RPM, 2 min, Viscosity: 2,783 cps

[0105] Example 21 - Topical Preparations of Tamibarotene and Benzoyl Peroxide in Pemulen

TR-1 Hydrogels

[0106] Example 22 - Topical Preparation of Tamibarotene and Benzoyl Peroxide in Pemulen®

TR-2 Hydrogels

[0107] Example 23 - Preparation of Ternary System

[0108] The foilowing is a method of making a ternary formulation of tamibarotene, comprising: a. forming a first part: i. adding demineralized water to a 1000 ml beaker ii. stirring or agitation at 600 rpm; iii. adding Clindamycin {0.5-2 percent} and Benzoyl Peroxide {5 percent} iv. adding glycerin v. adding tamibarotene; vii. increasing stirring rate or agitation to 1500 rpm. b. forming a second part i. adding demineralized water to an 800 ml beaker ii. stirring or agitating at 600 rpm iii. adding isopropyl palmitate iv. adding dimethicone v. adding white petrolatum vi. adding gingko biloba vii. increasing agitation or stirring to 1500 rpm vii*. mix part 1 and part 2 for 30 minutes ix. slow agitation or stirring down on part 1 to 600 rpm and blend part 2 into part 1 increase agitation of the combined formulation to 1,800 rpm for 30 minutes. c. forming a third part by: i. slow agitation of combined formulation of the second part to 600 rpm ii. adding Pemulen® TR-1 or TR-2 very slowly iii. increasing stirring speed to 1,800 rpm for 30 minutes to disperse all of Pemulen®TR-1 or Pemulen®TR-2 iii. increasing agitation to 2,800 rpm and until the emulsion Is smooth and creamy without any of the oils floating on the surface iv. slowing agitation down to 600 rpm and adding a fragrance; and vi. mixing well and placing in a proper vessel.

[0109] Example 24 - Preparation of Pemulen® TR -1 and Pemulen® TR-2 Stock Gels for the Incorporation of Active Topical Medicaments

[0110] Prepare stock gel at pH 6.0

[0111] Example 25 - Preparation of Formulations

[0112] Once diluted to 1 percent an oil soluble active, e.g., Tamibarotene, Tamibarotene - Tazarotene, Tamibarotene-Tretinoin, Tamibarotene-Adapalene can be emulsified into the Pemulen® TR -1 & Pemulen® TR-2 Stock Gels.

[0113] pH 6.0 Suspend 4g Pemulen TR-1 into 100 ml deionized water, stir until uniform and a clear dispersion is formed.

[0114] Dissolve 4.5g (4.0 ml) triethanolamine (Tris-Amino, TEA) into 95 mL water

[0115] Stir vigorously mix Pemulen® TR-l or TR-2 dispersion with the TEA solution adjust to pH 6,0 with the additional TEA or additional Pemulen® dispersion, and qs 200 ml (final volume)

[0116] Tamibarotene -Tretinoin

[0117] Tamibarotene-Tazarotene

[0118] Tamibarotene-Adapalene

[0119] Example 26 - Tamibarotene Creams

[0120] Tamibarotene cream of the present invention is characterized in that a cream is used as a base, and a composition in which tamibarotene is dissolved as an active ingredient is encapsulated in the base.

[0121] In the tamibarotene cream of the present invention, preferably, the oil component is a propylene glycol fatty acid ester or polyethylene glycol, and preferably 0.1 to 50 mg of the oil component with the tamibarotene as an active ingredient. Preferably, the polyethylene glycols have an average molecular weight of 200 to 1500.

[0122] The tamibarotene cream of the present invention is cream or may be either a soft cream or a hard cream.

[0123] The tamibarotene cream of the present invention comprises a cream as a base, and a composition in which tamibarotene is dissolved as an active ingredient is encapsulated in the base.

[0124] Tamibarotene as an active ingredient of the present invention is 4-[(5,6,7,8-tetrahydro- 5,5,8,8"tetramethyl-2-naphthalenyl) carbamoyl] benzoic acid.

[0125] Since tamibarotene of the present invention uses tamibarotene in a dispersion state, it is not necessary to consider crystal polymorphism, and the manufacture of the drug substance is easy. [0126] Specifically, these oily components include one or more selected from the group consisting of esters of fatty acids and polyhydric alcohols, polyethylene glycols, animal and vegetable oils, surfactants, and low molecular weight bases.

[0127] Example 27 - Tamibarotene Cremes

[0128] In the tamibarotene cream of the present invention, the fatty acid and polyhydric alcohol esters may be any liquid if they are dispersed into the cream. Propylene glycol fatty acid esters, sucrose fatty acid esters, sorbitan fatty acid esters and fatty acid triglycerides are preferred.

[0129] In the tamibarotene creams of the present Invention, propylene glycol fatty acid esters include all fatty acids. From the solubility of tamibarotene and the marketability of propylene glycol fatty acid esters, monooleate, di (capryl, caprin) Acid) esters and related fatty acid esters are preferred,

[0130] Moreover, in the tamibarotene cream of the present invention, the fatty acid triglycerides are preferably C8-C12 medium chain fatty acid triglycerides, such as l-caprylyl-2,3- dilaurin glyceride, Trinona Noin glyceride, tricaprin glyceride, l-lauro-2,3-dicaprin glyceride, 2- lauro-l,3-dicapurine glyceride, l-capryl-2,3-dilaurin glyceride, 2-capryl-l,3-dilaurin glyceride, trilaurin A glyceride etc.

[0131] Example 28 - Tamibarotene Creme

[0132] In the tamibarotene cream of the present invention, the oil component is preferably propylene glycol fatty acid esters and may be polyethylene glycols.

[0133] In the tamibarotene creams of the present invention, polyethylene glycols include polyethylene glycol and methoxy polyethylene glycol.

[0134] Moreover, in the tamibarotene cream of the present invention, it is preferable that polyethylene glycols are essential components, and the polyethylene glycols preferably have an average molecular weight of 200 to 1500 to solubilize tamibarotene.

[0135] Specifically, polyethylene glycol (macrogol) 200, 300, 400, 600, 1000, 1500, 1540 described in US Pharmacopoeia and US Pharmacopoeia Pharmaceutical Ingredient Standards are shown. Polyethylene glycol having an average molecular weight of 300, 400, 600, 1000, 1540 are preferred.

[0136] Although the description herein contains many details, these should not be construed as limiting the scope of the disclosure but as merely providing illustrations of some of the presently preferred embodiments. Therefore, it will be appreciated that the scope of the disclosure fully encompasses other embodiments which may become obvious to those skilled in the art.

[0137] In the context of the present invention, it is to be understood that this invention is not limited to particular embodiments described, as such may, of course, vary, it is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

[0138] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.

[0139] Certain ranges are presented herein with numerical values being preceded by the term "about." The term "about" is used herein to provide literal support for the exact number that it precedes, as well as a number that is near to or approximately the number that the term precedes. In determining whether a number is near to or approximately a specifically recited number, the near or approximating unrecited number may be a number which, in the context in which it is presented, provides the substantial equivalent of the specifically recited number. [0140] Unless defined otherwise, 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 any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, representative illustrative methods and materials are now described.

[0141] All publications and patents cited in this specification are herein incorporated by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference and are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.

[0142] It is noted that, as used herein and in the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as "solely," "only" and the like in connection with the recitation of claim elements, or use of a "negative" limitation.

[0143] As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present invention. Any recited method can be carried out in the order of events recited or in any other order that is logically possible.

Claims

1. A pharmaceutical composition comprising:

(i) an active agent of tamibarotene or a salt or analog thereof;

(it) a solubilizer;

(hi) a permeation enhancer; and

(iv) a polymeric emulsifier; wherein the solubilizer is a polyethylene glycol, the permeation enhancer is isopropyl myristate, and the polymeric emulsifier is an acrylates/C10-30 alkyl acrylate crosspolymer.

2. The composition of claim 1, wherein the active agent is tamibarotene or a salt thereof.

3. The composition of claim 1, wherein the active agent is tamibarotene.

4. The composition of claim 1, wherein active agent Is a tamibarotene analog or a salt thereof.

5. The composition of claim 4., wherein the tamibarotene analog is a compound of Formula 1:

wherein R¹, R² R³ and R⁴ are selected from hydrogen., (C₁-C₁₂) hydrocarbon and (C₃-C₁₀) carbocyde each of which may be optionally further substituted by hydrogen or (C₁-C₆) hydrocarbon;

X is CH2, O, S or NR²R² where R¹ and R² are defined as above;

Y is chosen independently from CO₂H, CO2R¹, CONR¹R²; NR¹(CO)R², CN and

Z Is independently chosen from CH or NR¹ and R¹ and R² are defined as above.

6. The composition of claim 1, wherein the solubilizer comprises polyethylene glycol 400 and/or polyethylene glycol 300.

7. The composition of claim 1, wherein the composition further comprises a preservative,

8. The composition of claim 7 , wherein the preservative is methylparaben and/or propylparaben.

9. The composition of claim 1, wherein the polymeric emulsif ier is Pemulin TR-1, Pemulin TR-2 or Carbopol 1342.

10. The composition of claim 1, wherein the composition further comprises a surfactant.

11. The composition of claim 10, wherein the surfactant is Tween 80.

12. The composition of claim 1, wherein the composition further comprises a neutralizing agent.

13. The composition of claim 12, wherein the neutralizing agent is tris amino or sodium hydroxide.

14. The composition of claim 1_? wherein the composition further comprises water.

15. The composition of claim 1, wherein the viscosity of the composition is between about 20,000 to about 200,000.

16. The composition of claim 1, wherein the concentration of tamibarotene or salt or analog thereof is 1% or less.

17. The composition of claim 1, wherein the concentration of tamibarotene or salt or analog thereof is 0.5% or less.

18. The composition of claim 1, wherein the concentration of tamibarotene or salt or analog thereof is 0.1% or less.

19. The composition of claim 1, wherein the concentration of tamibarotene or salt or analog thereof is 0.05% or less.

20. The composition of claim 1, wherein the concentration of tamibarotene or salt or analog thereof is 0.025% or less.

21. The composition of claim 1, wherein the composition is in the form of a gel.

22. The composition of claim 1, wherein the composition is in the form of a cream.

23. A method of using the composition of claim 1 to treat a skin condition.

24. The method of using the composition of claim 23, wherein the skin condition is wrinkled skin, dry skin, rough skin, aging skin, discolored skin, acne, psoriasis, eczema, rosacea, vitiligo, dermatitis, burns, photodamaged and photoaging skin, skin cancer, alopecia, or a mucositic disorders.

25. A method of using the composition of claim 1 to treat acne.

26. A topical composition comprising:

(v) an active agent of tamibarotene or a salt or analog thereof;

(vi) benzoyl peroxide; and

(vii) a polymeric emulsifier; wherein the polymeric emulsifier is an acrylates/C10-30 alkyl acrylate crosspolymer.

27. The composition of claim 26, wherein the active agent is tamibarotene or a salt thereof.

28. The composition of claim 26, wherein the active agent is tamibarotene.

29. The composition of claim 26, wherein active agent is a tamibarotene analog or a salt thereof.

30. The composition of claim 26, wherein the pharmaceutical composition further comprises a second active agent of tretinoin, tazarotene, and/or adapalene.

31. A method of treating acne, comprising applying to the skin a composition comprising:

(i) an active agent of tamibarotene or a salt or analog thereof;

(li) benzoyl peroxide; and

(iii) a polymeric emulsifier; wherein the polymeric emulsifier is an acrylates/C10-30 alkyl acrylate crosspolymer.

32. The method of claim 31, wherein the active agent is tamibarotene or a salt thereof.

33. The method of claim 31, wherein the active agent is tamibarotene.

34. The method of claim 31, wherein active agent is a tamibarotene analog or a salt thereof.

35. The method of claim 31, wherein the pharmaceutical composition further comprises a second active agent of tretinoin, tazarotene, and/or adapalene.