USOO8647671B2

(12) United States Patent (10) Patent No.: US 8,647,671 B2 Pearlman (45) Date of Patent: *Feb. 11, 2014

(54) COMPOSITIONS AND METHODS FOR THE 4,246.261 A 1/1981 Van Scott et al. TREATMENT OF SKN DISEASES 4.954,487 A 9/1990 Cooper et al. 5,486,537 A 1/1996 Farinas 5,629,006 A 5/1997 Hoang et al. (71) Applicant: Dale L. Pearlman, Menlo Park, CA 2003.0118511 A1 6/2003 Jones et al. (US) 2008. O131385 A1 6/2008 ROSo et al. 2011, 0070183 A1 3/2011 Neumann et al. (72) Inventor: Dale L. Pearlman, Menlo Park, CA (US) OTHER PUBLICATIONS (*) Notice: Subject to any disclaimer, the term of this "Guideline for Hand Hygiene in Healthcare Settings”. Centers for patent is extended or adjusted under 35 Disease Control, online Oct. 25, 2002, http://www.cdc.gov/mmwr/ U.S.C. 154(b) by 0 days. previewimmwrhtml/rrS116al.htm, retrieved Aug. 22, 2012). This patent is Subject to a terminal dis Acne Vulgaris, Medscape Reference Drugs, Diseases & Procedures, claimer. online Jun. 28, 2012, retrieved Aug. 23, 2012 Retrieved from http://emedicine.medscape.com/article/1069804-overview. (21) Appl. No.: 13/787,680 Boguniewicz, M., et al. "Atopic dermatitis: a disease of altered skin barrier and immune dysregulation.” Immunolog Rev. 2011; 24; 233 (22) Filed: Mar. 6, 2013 46. Buhse L., et al. “Topical drug classification.” International Journal of (65) Prior Publication Data Pharmaceutics 295 (2005) 101-112. US 2013/0243825A1 Sep. 19, 2013 (Continued) Related U.S. Application Data Primary Examiner — Benjamin Packard (63) Continuation-in-part of application No. 13/633,832, (74) Attorney, Agent, or Firm — Wilson, Sonsini, Goodrich filed on Oct. 2, 2012, which is a continuation-in-part of & Rosati application No. 13/466,860, filed on May 8, 2012. (60) Provisional application No. 61/612.203, filed on Mar. 16, 2012. (57) ABSTRACT Int. C. Provided herein are chemical matrices, compositions, and (51) methods for the treatment of skin diseases and disorders in an A6 IK9/32 (2006.01) individual. Said chemical matrices and compositions com (52) U.S. C. prise an alcohol selected from ethanol, isopropanol or n-pro USPC ...... 424/484 panol, at least one excipient, and, a corticosteroid, wherein (58) Field of Classification Search the alcohol is distributed within the chemical matrix as a USPC ...... 424/484 microbubble and the corticosteroid is present in less than the See application file for complete search history. standardized topical corticosteroid concentration. Addition ally, methods are described for the use of said chemical matri (56) References Cited ces and compositions for the treatment of skin diseases and U.S. PATENT DOCUMENTS disorders. 4,147,770 A 4, 1979 Sichak 4,185,100 A 1, 1980 ROvee et al. 31 Claims, 1 Drawing Sheet

Final % of Single or multi use standard corticosteroid standard | #patients |# patients success medication Corticosteroid corticosteroid in formulation amount treated successful rate Single Use (2.5:2.5:1) Desonide Ung 0.05% 0.02.1% 42% 4. 4. 100% Single Use (2.5.2.5:1) Mometasone Ung O.1% 0.042% 42% 3. 3 100% Single Use (2.5.2.5.1) TAC Ung O.1% 0.042% 42% 1 1 100% Single Use (2.5:2.5:1) TAC Cr O.1% 0.042 42% 1 1 100% Single Use (102.5.2.5) Mometasome Ung 0.1% 0.017% 17% 1 1 100% Multi Use (2.5:2.5:1 Ziplock) Desonide Ung 0.05% 0.02.1% 42% 1 1 100% Multi Use (10:2.5:2.5 Ziplock) Desonide Ung 0.05% 0.0085% 17% 2 2 100% Multi Use (10:2.5:2.5 Ziplock) Mometasone Ung O.1% 0.017% 17% 7 7 100% US 8,647,671 B2 Page 2

(56) References Cited Pagnoni A. etal. “Lack ofburning and stinging from a novel first-aid formulation applied to experimental wounds.” J. Cosmet. Sci. Mar.- OTHER PUBLICATIONS Apr. 2004: 55(2): 157-62. PCT/US2012/36966 International Search Report dated Jul 30, 2012. Psoriasis, Medscape Reference Drugs, Diseases & Procedures, Bunikowski R. etal. “Prevalence and role of serum IgE antibodies to online Aug. 6, 2012, retrieved Aug. 23, 2012 Retrieved from the Staphylococcus aureus-derived superantigens SEA and SEB in http://emedicine.medscape.com/article/1943419-overviewiao 156. children with atopic dermatitis.J. Allergy Clin. Immunol. 1999; Rafanelli A. et al. “Mometasone furoate in the treatment of atopic 103:119-24. dermatitis in children.” J. Eur: Acad. Dermatol. Venereol. 1993; 2(3): 225-230. Cho S-H... etal “Fibronectin and fibrinogen contribute to the Reginald K., et. al. “Staphylococcus aureus fibronectin-binding pro enhanced binding of Staphylococcus aureus to atopic skin' J. Allergy tein specifically binds IgE from patients with atopic dermatitis and Clin. Immunol. 2001; 108:269-74. requires antigen presentation for cellular immune responses.” J. Department of Health and Human Services, Food and Drug Admin Allergy Clin. Immunol. 2011; 128:82-91. istration “Topical Antimicrobial Drug Products for Over-the-Counter Rosacea incidence on Rise, National Rosacea Society, online Apr. Human Use; Tentative Final Monograph for Healthcare Antiseptic 1, 2010, retrieved Aug. 23, 2012 Retrieved from http://www. Drug Products”. Federal Register, vol. 59, No. 116, online Jun. 17. rosacea.org/weblog/2010/04/01/rosacea incidence on rise?in 1994 retrieved Aug. 23, 2012 Retrieved from http://www.fda.gov/ dex.php. downloads/Drugs/Development ApprovalProcess/ Trookman N.S., et al. "Randomized Controlled Trial of Desonide DevelopmentResources/Over-the-counterOTCDrugs/ Hydrogel 0.05% versus Desonide Ointment 0.05% in the treatment of StatusofCTCRulemakings/UCM1 10451.pdf. Mild-to-Moderate Atopic Dermatitis.” J. Clin Aesthet Dermatol. Hebert A.A., et al. “Safety and Efficacy of Desonide Hydrogel 0.05% Nov. 2011; 4(11): 34-38. in Pediatric Subjects with Atopic Dermatitis.” J Drugs Dermatol. Trookman N.S., et al. "Irritation and allergy patch test analysis of Feb. 2007; 6(2): 175-81. topical treatments commonly used in wound care: Evaluation on Huang J.T., et al. “Treatment of Staphylococcus aureus Colonization normal and compromised skin.”.J. Amer: Acad Dermatol. Mar. 2011; in Atopic Dermatitis Decreases Disease Severity.” Pediatrics May 64(3), Suppl 1:S16-22. 2009; 123(5): 808–814. U.S. Appl. No. 13/633,832 Office Action dated Dec. 17, 2012. Kampf, et al. “Epidemiologic Background of Hand Hygiene and US Food and Drug Administration, Drug Nomenclature Monograph, Evaluation of the Most Important Agents for Scrubs and Rubs' No. C-DRG-00201 online Jan. 30, 2009, retrieved online Aug. 22. Microbiol. Rev. (2004), 17(4), 863-93. 2012 Retrieved from http://www.fda.gov/Drugs/Development Ap Leung D.Y.M., et al. “Presence of IgE Antibodies to Staphylococcal provalProcess/FormsSubmissionRequirements/ElectronicSubmis Exotoxins on the Skin of Patients with Atopic Dermatitis' J. Clin. sions/DataStandardsManualmonographs/ucm071666.htm. Invest. 1993; 92: 1374-80. Vernon H.J., et al. "Comparison of mometasone furoate 0.1% cream Miajlovic H. et al. “Effect of filaggrin breakdown products on and hydrocortisone 1.0% cream in the treatment of childhood atopic growth of and protein expression by Staphylococcus aureus." J. dermatitis.” J. Am. Acad. Dermatol Apr. 1991; 24:603-7. Allergy Clin. Immunol. 2010; 126:1184-1190. Zollner TM et al. “Colonization with Superantigen-producing Ong P.Y., et al. “Immune Dysregulation in Atopic Dermatitis' Curr Staphylococcus aureus is associated with increased severity of atopic Allergy Asthma Rep. Sep. 2006; 6(5):384-9. dermatitis.” Clin. Exp. Allergy 2000; 30: 994-1000. U.S. Patent Feb. 11, 2014 US 8,647,671 B2

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US 8,647,671 B2 1. 2 COMPOSITIONS AND METHODS FOR THE topical corticosteroid concentration is 0.05%. Another TREATMENT OF SKN DISEASES embodiment provides the chemical matrix wherein the des onide is present in an amount of about 0.0005%, about CROSS REFERENCE 0.0025%, about 0.005%, about 0.009%, about 0.02%, or about 0.045%. Another embodiment provides the chemical This application claims the benefit of U.S. Provisional matrix wherein the desonide is present in an amount of about Application No. 61/612.203, filed Mar. 16, 2012, U.S. appli 0.0025%, about 0.005%, about 0.01%, about 0.02%, about cation Ser. No. 13/466,860, filed May 8, 2012, and U.S. 0.03%, or about 0.04%. Another embodiment provides the application Ser. No. 13/633,832, filed Oct. 2, 2012, the con chemical matrix wherein the desonide is present in an amount tents of which are hereby incorporated by reference in their 10 of about 0.005%, about 0.01%, about 0.015%, or about entireties. O.O2%. Another embodiment provides the chemical matrix BACKGROUND OF THE INVENTION wherein the corticosteroid is mometasone and the standard ized topical corticosteroid concentration is 0.1%. Another High ethanol content Sanitizer gel is known to be a very 15 embodiment provides the chemical matrix wherein the effective topical antimicrobial agent for preventing infec mometasone is present in an amount of about 0.001%, about tions. Direct application to bacterial, fungal, and viral organ 0.005%, about 0.01%, about 0.02%, about 0.04%, or about isms in the laboratory setting results in 99.99% killing within 0.09%. Another embodiment provides the chemical matrix 15 seconds of contact. This efficacy is due to its concentration wherein the mometaSone is present in an amount of about of ethyl alcohol greater than, or equal to, 60% (Federal Reg 0.005%, about 0.01%, about 0.02%, about 0.03%, about ister, Vol. 59, No. 116, Jun. 17, 1994). Similar antiseptic 0.04%, or about 0.05%. Another embodiment provides the activity has been observed for isopropanol (Federal Register, chemical matrix wherein the mometasone is present in an Vol. 47, No. 99, May 21, 1982). In current commercial for amount of about 0.01%, about 0.02%, about 0.03%, or about mulations, the ethanol containing gel typically contains spe O.04%. cial moisturizers to control dryness on users hands so they 25 Another embodiment provides the chemical matrix tolerate such a high concentration of ethyl alcohol. However, wherein the alcohol is ethanol. use of these gels containing greater than, or equal to, 60% Another embodiment provides the chemical matrix ethyl alcohol on skin damaged with cracks, tears and/or fis wherein the ointment is selected from AQUAPHORR), white Sures results in a pronounced stinging sensation (Guideline petrolatum USP, white ointment USP hydrophilic petrolatum for Hand Hygiene in Health-care Settings, Centers for Dis 30 USP or hydrophilic ointment USP ease Control. Another embodiment provides the chemical matrix wherein the chemical matrix comprises from about 2% to SUMMARY OF THE INVENTION about 10% ethanol by volume. Another embodiment provides the chemical matrix wherein the chemical matrix comprises One embodiment disclosed herein provides a means of 35 from about 10% to about 20% ethanol by volume. Another applying ethanol to the skin without stinging. Another embodiment provides the chemical matrix wherein the embodiment disclosed herein provides a chemical matrix that chemical matrix comprises from about 20% to about 30% allows for the use of corticosteroids at lower concentrations ethanol by volume. than previously employed while maintaining efficacy. Other One embodiment provides a chemical matrix comprising embodiments disclosed herein provide methods that allow for 40 from about 2% to about 30% of an alcohol by volume, a the use of corticosteroids at lower concentrations than previ therapeutically effective amount of a corticosteroid and at ously employed while maintaining efficacy. least one excipient, wherein the chemical matrix is an oint One embodiment provides a chemical matrix comprising ment Suitable for topical administration, the alcohol is prima from about 2% to about 30% of an alcohol by volume, a rily dispersed into the chemical matrix in the form of corticosteroid and at least one excipient, wherein the chemi 45 microbubbles, the alcohol is selected from ethanol, isopro cal matrix is an ointment Suitable for topical administration, panol, or n-propanol, or combinations thereof, and the thera the alcohol is primarily dispersed into the chemical matrix in peutically effective amount of a corticosteroid is between the form of microbubbles, the alcohol is selected from etha about 1% and about 91% of the standardized topical corticos nol, isopropanol, or n-propanol, or combinations thereof, and teroid concentration. the corticosteroid is present in a concentration between about 50 Another embodiment provides the chemical matrix 1% and about 91% of the standardized topical corticosteroid wherein the therapeutically effective amount of a corticoster concentration. oid is about 1%, about 5%, about 10%, about 15%, about Another embodiment provides the chemical matrix 25%, about 35%, about 50%, about 65%, about 75%, about wherein the corticosteroid is present in a concentration of 85%, or about 91% of the standardized topical corticosteroid about 1%, about 5%, about 10%, about 15%, about 25%, 55 concentration. about 35%, about 50%, about 65%, about 75%, about 85%, or Another embodiment provides the chemical matrix about 91% of the standardized topical corticosteroid concen wherein the therapeutically effective amount of a corticoster tration. Another embodiment provides the chemical matrix oid is presentina concentration between about 1%, about 5%, wherein the corticosteroid is present in a concentration of about 10%, about 15%, or about 25% of the standardized about 1%, about 5%, about 10%, about 15%, or about 25% of 60 topical corticosteroid concentration. Another embodiment the standardized topical corticosteroid concentration. provides the chemical matrix wherein the therapeutically Another embodiment provides the chemical matrix wherein effective amount of a corticosteroid is present in a concentra the corticosteroid is present in a concentration of about 10%, tion between about 10%, about 15%, about 25%, or about about 15%, about 25%, or about 35% of the standardized 35% of the standardized topical corticosteroid concentration. topical corticosteroid concentration. 65 Another embodiment provides the chemical matrix Another embodiment provides the chemical matrix wherein the corticosteroid is desonide and the standardized wherein the corticosteroid is desonide and the standardized topical corticosteroid concentration is 0.05%. Another US 8,647,671 B2 3 4 embodiment provides the chemical matrix wherein the des costeroid concentration is 0.05%. Another embodiment pro onide is present in an amount of about 0.0005%, about vides the method wherein the desonide is present in the for 0.0025%, about 0.005%, about 0.009%, about 0.02%, or mulation in an amount of about 0.0005%, about 0.0025%, about 0.045%. Another embodiment provides the chemical about 0.005%, about 0.009%, about 0.02%, or about 0.045%. matrix wherein the desonide is present in an amount of about Another embodiment provides the method wherein the des 0.0025%, about 0.005%, about 0.01%, about 0.02%, about onide is present in the formulation in an amount of about 0.03%, or about 0.04%. Another embodiment provides the 0.0025%, about 0.005%, about 0.01%, about 0.02%, about chemical matrix wherein the desonide is present in an amount 0.03%, or about 0.04%. Another embodiment provides the of about 0.005%, about 0.01%, about 0.015%, or about method wherein the desonide is present in an amount of about O.O2%. 10 0.005%, about 0.01%, about 0.015%, or about 0.02%. Another embodiment provides the chemical matrix Another embodiment provides the method wherein the wherein the corticosteroid is mometasone and the standard corticosteroid is mometasone and the standardized topical ized topical corticosteroid concentration is 0.1%. Another corticosteroid concentration is 0.1%. Another embodiment embodiment provides the chemical matrix wherein the provides the method wherein the mometasone is present in an mometasone is present in an amount of about 0.001%, about 15 amount of about 0.001%, about 0.005%, about 0.01%, about 0.005%, about 0.01%, about 0.02%, about 0.04%, or about 0.02%, about 0.04%, or about 0.09%. Another embodiment 0.09%. Another embodiment provides the chemical matrix provides the method wherein the mometasone is present in an wherein the mometaSone is present in an amount of about amount of about 0.005%, about 0.01%, about 0.02%, about 0.005%, about 0.01%, about 0.02%, about 0.03%, about 0.03%, about 0.04%, or about 0.05%. Another embodiment 0.04%, or about 0.05%. Another embodiment provides the provides the method wherein the mometasone is present in an chemical matrix wherein the mometasone is present in an amount of about 0.01%, about 0.02%, about 0.03%, or about amount of about 0.01%, about 0.02%, about 0.03%, or about O.04%. O.04%. Another embodiment provides the method wherein the Another embodiment provides the chemical matrix alcohol is ethanol. wherein the alcohol is ethanol. 25 Another embodiment provides the method wherein the Another embodiment provides the chemical matrix ointment is selected from AQUAPHORR), white petrolatum wherein the ointment is selected from AQUAPHORR), white USP, white ointment USP hydrophilic petrolatum USP or petrolatum USP, white ointment USP hydrophilic petrolatum hydrophilic ointment USP. USP or hydrophilic ointment USP Another embodiment provides the method wherein the Another embodiment provides the chemical matrix 30 chemical matrix comprises from about 2% to about 10% wherein the chemical matrix comprises from about 2% to ethanol by volume. Another embodiment provides the about 10% ethanol by volume. Another embodiment provides method wherein the chemical matrix comprises from about the chemical matrix wherein the chemical matrix comprises 10% to about 20% ethanol by volume. Another embodiment from about 10% to about 20% ethanol by volume. Another provides the method wherein the chemical matrix comprises embodiment provides the chemical matrix wherein the 35 from about 20% to about 30% ethanol by volume. chemical matrix comprises from about 20% to about 30% Another embodiment provides the method wherein the ethanol by volume. skin disease or disorder is eczema. Another embodiment pro One embodiment provides a method of treating a skin vides the method wherein the skin disease or disorder is disease or disorder in an individual in need thereof compris atopic dermatitis. ing topical application to the individual of a chemical matrix 40 One embodiment provides a method of treating a skin comprising from about 2% to about 30% of an alcohol by disease or disorder in an individual in need thereof compris Volume, a corticosteroid and at least one excipient, wherein ing topical application to the individual of a chemical matrix the chemical matrix is an ointment Suitable for topical admin comprising from about 2% to about 30% of an alcohol by istration, the alcohol is primarily dispersed into the chemical volume, a therapeutically effective amount of a corticosteroid matrix in the form of microbubbles, the alcohol is selected 45 and at least one excipient, wherein the chemical matrix is an from ethanol, isopropanol, or n-propanol, or combinations ointment Suitable for topical administration, the alcohol is thereof, and the corticosteroid is present in a concentration primarily dispersed into the chemical matrix in the form of between about 1% and about 91% of the standardized topical microbubbles, the alcohol is selected from ethanol, isopro corticosteroid concentration. panol, or n-propanol, or combinations thereof, and the thera Another embodiment provides the method wherein the 50 peutically effective amount of a corticosteroid is between corticosteroid is present in a concentration of about 1%, about about 1% and about 91% of the standardized topical corticos 5%, about 10%, about 15%, about 25%, about 35%, about teroid concentration. 50%, about 65%, about 75%, about 85%, or about 91% of the standardized topical corticosteroid concentration. INCORPORATION BY REFERENCE Another embodiment provides the method wherein the 55 corticosteroid is present in a concentration between about 1% All publications, patents, and patent applications men and about 85% of the standardized topical corticosteroid con tioned in this specification are herein incorporated by refer centration. ence to the same extent as if each individual publication, Another embodiment provides the method wherein the patent, or patent application was specifically and individually corticosteroid is present in a concentration of about 1%, about 60 indicated to be incorporated by reference. 5%, about 10%, about 15%, or about 25% of the standardized topical corticosteroid concentration. Another embodiment BRIEF DESCRIPTION OF THE DRAWINGS provides the method wherein the corticosteroid is present in a concentration of about 10%, about 15%, about 25%, or about The novel features of the invention are set forth with par 35% of the standardized topical corticosteroid concentration. 65 ticularity in the appended claims. A better understanding of Another embodiment provides the method wherein the the features and advantages of the present invention will be corticosteroid is desonide and the standardized topical corti obtained by reference to the following detailed description US 8,647,671 B2 5 6 that sets forth illustrative embodiments, in which the prin The term “comedogenic” describes the tendency of some ciples of the invention are utilized, and the accompanying dermatological products, such as oils, lotions, ointments, drawings of which: creams, and gels to block the pores of the skin. Noncome FIG. 1 provides a summary of the effect on treatment dogenic products are less likely to clog pores and lead to outcome of the method of preparation of the matrices and 5 formation of blackheads (open comedones), whiteheads compositions provided herein as described in example 2-18. (closed comedones), red bumps (inflammatory papules) and red, Swollen, pussy red bumps and lumps (inflammatory pus DETAILED DESCRIPTION OF THE INVENTION tules, nodules, and cysts) in patients’ skin. Comedogenic ingredients of many commercially available skin care prod New treatments are needed for many dermatologic dis 10 ucts include isopropyl myristate, cocoa butter, coconut oils, eases because current treatments lack efficacy, exhibit side and wheat germ oil. effects, or are so unpleasant to use that patients are discour The term “subjective irritation” describes burning, sting aged from using them. In a series of clinical trials it has been ing, or itching without detectable visible or microscopic found that, in comparison to current treatments, use of the 15 changes in the skin. compositions described herein produces clinical outcomes The term “non-homogeneous” describes the lack of a uni characterized by equal or higher efficacy, while exhibiting form phase throughout the bulk, or entirety, of the composi minimal side effects and good patient compliance. tion. The terms “non-homogeneous” and "heterogeneous It has been discovered that certain topical compositions are synonymous and can be used interchangeably. As used (lotions, creams, ointments, emulsions and dispersions) that herein, the terms “non-homogeneous” and "heterogeneous' contain ethanol or certain other alcohols distributed non refer to the bulk, or entirety, of the composition as employed homogenously have the unexpected benefit of effectively by the patient or caregiver. treating a variety of dermatologic diseases and disorders. The term "semisolid describes a material that has the Whereas previously known only for maintaining hygiene on properties of a solid and of a liquid. healthy skin, now it is possible to use topical compositions 25 The term “gel' describes a semisolid dosage form that containing ethanol or certain other alcohols to treat diseases contains a gelling agent to provide stiffness to a solution or and disorders of the skin wherein the skin is damaged, broken, colloidal dispersion (US FDA Drug Nomenclature Mono torn, or marked by fissures. These skin diseases and disorders graph, number C-DRG-002.01). A gel optionally contains range from infections (bacterial or fungal) to inflammatory suspended particles. Further, a gel optionally contains >50% diseases (dermatitis, psoriasis, acne Vulgaris, or rosacea). It 30 water and other volatiles (Buhse L, et. al. International Jour has been also discovered that the topical compositions nal of Pharmaceutics; 295: 101-112). A gel offers non-greasy described herein can be safely used on the face. Effective medication delivery. treatments are achieved, in some cases, through use of the The term “oil” describes an unctuous, combustible sub topical compositions described herein wherein ethanol or stance which is liquid, or easily liquefiable, on warming, and another alcohol is the sole active ingredient. Further advan 35 is soluble in ether but insoluble in water. Oils are classified as tages are obtained by incorporating into said compositions at animal, mineral or vegetable oils, depending on their origin least one additional therapeutic active agent. One distinguish (US FDA Drug Nomenclature Monograph, number C-DRG ing feature of these compositions is the non-homogenous 002.01). nature of the formulation. In particular, it has been found that The term "emulsion” describes a dosage form consisting of when the ethanol or other alcohol is distributed in a non 40 a two-phase system comprised of at least two immiscible homogenous fashion throughout the composition into liquids, one of which is dispersed as droplets (internal or bubble-like regions of locally high concentration, where the dispersed phase) within the other liquid (external or continu approximate effective concentration of the ethanol or other ous phase) generally stabilized with one or more emulsifying alcohol in the bubble-like regions is about 60% to about 80%, agents (US FDA Drug Nomenclature Monograph, number a beneficial effect is observed upon topical application to 45 C-DRG-00201). damaged skin but without a stinging sensation. This result is The term “lotion” describes an emulsion liquid dosage striking when compared to the well-known stinging sensation form. This dosage form is generally for external application to observed upon application of commercially available high the skin (US FDA Drug Nomenclature Monograph, number ethanol content sanitizers gels to damaged skin. C-DRG-00201). A lotion optionally contains moisturizing Definitions 50 agents which help increase skin moisture. Further a lotion As used herein, amelioration of the symptoms of a particu optionally contains Small amounts of alcoholic preservatives lar disease, disorder or condition by administration of a par to prevent microbial growth during product life. ticular compound or pharmaceutical composition refers to The term “cream describes an emulsion semisolid dosage any lessening of severity, delay in onset, slowing of progres form, usually containing >20% water and volatiles and/or Sion, or shortening of duration, whether permanent or tem 55 <50% hydrocarbons, waxes or polyols as the vehicle. A cream porary, lasting or transient that can be attributed to or associ is more viscous than a lotion. This dosage form is generally ated with administration of the compound or composition. for external application to the skin or mucous membranes (US The terms “treat,” “treating or “treatment, as used herein, FDA Drug Nomenclature Monograph, number C-DRG include alleviating, abating or ameliorating a disease or con 00201). A cream optionally contains moisturizing agents dition symptoms, preventing additional symptoms, amelio 60 which help increase skin moisture. Further a cream optionally rating or preventing the underlying metabolic causes of contains alcoholic preservatives to prevent microbial growth symptoms, inhibiting the disease or condition, e.g., arresting during product life. the development of the disease or condition, relieving the The term “ointment describes a semisolid dosage form, disease or condition, causing regression of the disease or usually containing <20% water and volatiles and/or >50% condition, relieving a condition caused by the disease or 65 hydrocarbons, waxes or polyols as the vehicle. This dosage condition, or stopping the symptoms of the disease or condi form is generally for external application to the skin or tion either prophylactically and/or therapeutically. mucous membranes (US FDA Drug Nomenclature Mono US 8,647,671 B2 7 8 graph, number C-DRG-00201). An ointment offers a dense, press the bacteria. The oral agent 13-cis-retinoic acid (Accu occlusive covering which increases hydration of dry skin taneTM) seeks to reduce oil production and resolve clogging of rashes. the pores. The term “solution' describes a clear, homogeneous liquid In some embodiments, the compositions and methods dosage form that contains one or more chemical Substances described herein are useful for the treatment of acne Vulgaris. dissolved in a solvent or mixture of mutually miscible sol In some embodiments, the compositions and methods vents (US FDA Drug Nomenclature Monograph, number described herein are an excellent first line treatment for mild C-DRG-00201). to moderate, and some cases, severe pustular acne seen in The term “high ethanol content describes a composition teenagers. The compositions and methods described herein 10 are optionally used independently, or in combination with comprising throughout the bulk or entirety of the composi over-the-counter and/or prescription dispensed therapeuti tion, greater than or equal to 60% ethyl alcohol content. cally active agents to address all types of acne lesions. In Commercially available hand sanitizer gels are one example Some embodiments, the compositions disclosed herein of a high ethanol content composition (Federal Register, Vol. include at least one comedolytic agent. In some embodi 59, No. 116, Jun. 17, 1994). 15 ments, the compositions disclosed herein include at least one The term “standardized topical corticosteroid concentra anti-inflammatory agent. In some embodiments, the compo tion” means, for a particular corticosteroid, the United States sitions disclosed herein include at least one antibiotic agent. Food and Drug Administration (US FDA) approved concen Rosacea (Adult Acne') tration for topical use. The standardized topical corticosteroid In this disorder, adults, usually 25 years and older, develop concentrations are provided in the United States Pharma a triad of distinctive features separating it from acne Vulgaris copeia, which is hereby incorporated by reference in its (“teenage acne). The triad consists of: entirety. For some corticosteroids, there is more than one a) central facial increased redness and increased Surface standardized topical corticosteroid concentrations approved blood vessels; for use by the US FDA due to factors such as different form of b) central facial inflammatory red papules, pustules, and nod formulation (for example, cream vs. ointment) and the like. 25 ules; Skin Diseases and Disorders c) tendency to easy facial flushing and blushing in response to Acne Vulgaris (“Teenage Acne') trigger factors including certain psychological states (em Acne is a common skin disease that affects 60-70% of barrassment or anger), exercise during workouts, con Americans at Some time during their lives. In some embodi sumption of alcoholic drinks and hot coffee/tea. ments teenagers need ongoing treatment from age 12 to 23 30 The condition can last for many years and gradually worsen. Patients are usually motivated to seek treatment years old. because of the disfigurement of the skin disorder. Acne Vulgaris is characterized by the onset around puberty In a recent study, Dr. Maeve McAleer and colleagues at the of comedones and inflammatory lesions on the face, neck, School of Public Health and Population Science, University chest, and back. It tends to resolve on average around age 23 35 College, Dublin, found that 14.4 percent of 1,000 subjects years of age. The pathogenesis is multifactorial. There is examined in Ireland had rosacea. Moreover, in a 1989 study increased oil production by increasingly active skin oil glands of 800 office workers in Sweden, the prevalence of rosacea under the influence of puberty associated hormones. An was 10 percent—including 14 percent in women and 6 per obstruction of the secretory tubules (“pores') which connect cent in men. the gland to the skin Surface leads to accumulation of oil 40 The specific pathogenesis of rosacea is not known. The under the skin Surface. As the Volume increases the lumps same bacteria found infecting acne Vulgaris lesions has not called comedones become visible. Bacteria then proliferate in been found in rosacea. There are no plugged up pores (come the oil leading to further inflammation in the skin causing the dones) present in rosacea patients. There are many hypoth formation of the visible red papules, pustules, nodules, and eses for rosacea causation revolving around a postulated bac cysts typically seen in acne Vulgaris. The specific bacteria 45 teria which infects the skin leading to the inflammation So infecting these lesions has been identified as Proprionobac characteristic of the condition. terium acnes. These lesions can be uncomfortable or tender, Treatment of rosacea involves the use of topical and oral can create disfigurement of the teenager compared to his agents. peers, leading to embarrassment in affected boys and girls. Topical Agents: Thus teenagers frequently seek treatment to minimize this 50 a) Antimicrobial agents: metronidazole, Sulfa/sulfur combi disorder. nations, clindamycin, benzoyl peroxide; Treatment is based on agents which seek to correct the b) Anti-inflammatory agents of uncertain mechanism: aZelaic fundamental pathologic events creating acne lesions. acid. Topical treatments fall into several classes: Oral Agents: a) “Comedolytic agents' dissolve the secretory tubule 55 a) Antibacterial agents: These include oral antibiotics (tetra obstruction thus allowing drainage of the trapped oil. Topical cycline family, erythromycin macrollide family, amplicillin agents of this type include: Sulfur, resorcinol, Salicyclic acid, penicillin family) which suppress growth of bacteria and/ glycolic acid, retinoids such as tretinoin, adapaline and taZ or kill bacteria. arotene, and benzoyl peroxide. Use of the compositions and methods described herein is a b) “Antibacterial agents' Suppress the bacterial population. 60 very effective topical treatment for red bumps and pussy Topical agents of this class include: benzoyl peroxide, anti bumps of rosacea. The treatment produces clinical improve biotics (erythromycin, clindamycin), and astringents, and ment noticeable to the patients within a week of starting nonspecific mechanism agents like azelaic acid. treatment. Of equal significance is that this treatment rapidly c) “Cleansers' seek to dissolve surface oil, dissolve reduces central facial redness. This is not true of topical clogged pores, and remove bacteria. Oral treatments: These 65 FinaceaTM or MetrogelTM which are the current standard of include oral antibiotics (tetracycline family, erythromycin care for this indication. Advantages of the compositions and macrollide family, amplicillin penicillin family) which Sup methods disclosed herein for the treatment of rosacea over US 8,647,671 B2 10 current topical treatments. Such as Finacea and Metrogel, biotics treat bacterial infection. Sedative antihistamines can include faster onset of relief, reliably reduces redness, no enable sleep and rest. For moderate to severe cases, photo stinging, less costly, and reduced environmental impact. therapy can be used. Advantages of the compositions and methods disclosed The latest scientific understanding of the causes of eczema herein for the treatment of rosacea over current oral include 5 highlight the unmet medical need satisfied by the methods, no concerns about safety of oral antibiotics, no upset stomach compositions and devices disclosed herein. In patients with or Sun sensitization issues, no impact on use of oral contra eczema, the skin is drier thanusual withouter layer cracks and ceptives, no issue of vaginal yeast infections, and reduced fissures which facilitate easy colonization by a particular environmental impact. In some embodiments, the composi bacterium, Staphylococcus aureus (Boguniewicz M, Leung tions and methods described herein are useful for the treat 10 DYM. Atopic dermatitis: a disease of altered skin barrier and ment of rosacea. In some embodiments the compositions immune dysregulation. Immunolog Rev. 2011; 24:233-46). disclosed herein include at least one anti-inflammatory agent. The staphylococcal population density in the skin rises In some embodiments, the compositions disclosed herein greatly because the patients are deficient in Some of the usual include at least one antibiotic agent. factors required to defend against them (Miajlovic H. Fallon Dermatitis 15 PG, Irvine A D, Foster T. J. Effect of filaggrin breakdown Dermatitis, or eczema, is a common, very uncomfortable, products on growth of and protein expression by Staphyllo frequently very itchy, rash characterized by red, scaly, coccus aureus. J. Allergy Clin. Immunol. 2010; 126:1184 patches in the skin. The redness, Swelling, and discharge are 1190; Cho S-H, Strickland I, Boguniewicz M, et. al. all signs of inflammation of an allergic type process. The Fibronectin and fibrinogen contributes to the enhanced bind classification of the dermatitis is determined by the appear ing of S. aureus to atopic skin. J. Allergy Clin. Immunol. 2001; ance and distribution of the patches and the demographics of 108:269-74; Bunikowski R, Mielke M, Skarabis H, et al. the patient. For example, atopic dermatitis is characterized by Prevalence and role of serum IgE antibodies to the Staphylo rash patches located typically in the fronts of the elbows and coccus aureus-derived superantigens SEA and SEB in chil behind the knees in young children. Nummular dermatitis is dren with atopic dermatitis.J. Allergy Clin. Immunol. 1999; characterized by round rash patches scattered randomly on 25 103:119-24: Leung DYM, Harbeck R. Bina Petal. Presence the trunk and limbs of adults. Contact dermatitis is character of IgE antibodies to staphylococcal exotoxins on the skin of ized by linear shaped swollen patches on the trunk or limbs at patients with atopic dermatitis: evidence for a new group of any age. allergens. J. Clin. Invest. 1993; 92:1374-80; Zollner T M. Prior to the discovery of the methods, compositions and Wichelhaus T A. Hartung A, et al. Colonization with super devices disclosed herein, the use of high ethanol content gels 30 antigen-producing Staphylococcus aureus is associated with in the treatment of eczema was complicated by a stinging increased severity of atopic dermatitis. Clin. Exp. Allergy sensation upon topical application. This stinging occurs 2000: 30: 994-1000). The staphylococci worsen the eczema because the acute phase of the rash is characterized by many by an immune mechanism which up-regulates inflammation Small cracks and fissures in the skin. By using the methods, culminating in the symptoms and appearance of the visible compositions and devices disclosed herein to treat the acute 35 eczema rash (Reginald K, Westritschnig K. Linhard B. phase of eczematous lesions topical application of the com Focke-Tekl M, et. al. Staphylococcus aureus fibronectin position does not cause a stinging sensation. Maintenance binding protein specifically binds IgE from patients with therapy employing the methods, compositions and devices atopic dermatitis and requires antigen presentation for cellu disclosed herein to Suppress the recurrence of eczematous lar immune responses. J. Allergy Clin. Immunol. 2011; 128: lesions is provided by application of the composition, Such 40 82–91). that topical application of the composition does not cause a Measures which decrease this bacterial population are gen Stinging sensation. erally found to help resolve eczema. Oral and topical antibi During the Sub-acute phase (rash but no fissures) the com otics currently are used for this purpose. Previously, high position disclosed herein is well tolerated and increases effi ethanol content gels were to be avoided due to the Stinging cacy of concomitant or Subsequent topical steroid therapy in 45 sensation upon topical application as the stinging sensation resolving the remaining rash. Once the eczema is resolved, would lead to a lack of patient compliance. ongoing use of the compositions as disclosed herein that do While the use of “bleach baths’ has recently been shown to not contain corticosteroid helps Sustain the disease-free improve eczema by lowering the S. aureus skin population remission period. The addition of moisturizing ingredients to (Huang JT, Abrams M, Tlougan B. Rademaker A, Paller A.S. the compositions disclosed herein keep the skin moist. 50 Treatment of Staphylococcus aureus colonization in atopic In Some embodiments, the compositions and methods dermatitis decreases disease severity. Pediatrics May 2009: described herein are useful for the treatment of dermatitis. In 123(5): 808–814) caregivers are reluctant to use this treatment Some embodiments the compositions disclosed herein because of the time and effort required. This effort includes include at least one anti-inflammatory agent. preparing the bath, cleaning up afterwards, ventilating the Atopic Dermatitis 55 bathroom to remove the bleach odor, and trying to avoid Atopic dermatitis occurs in approximately 10-20% of chil bleaching bathroom linens. dren and 2% of adults (Ong PY. Leung DY. Immune dys Use of the compositions as described herein is a significant regulation in atopic dermatitis. Curr Allergy Asthma Rep. advance for topical therapy in eczema. Caregivers find apply September 2006; 6(5):384-9). ing the compositions described herein to be an easy and In the developed countries of North America and Europe, 60 familiar way of treating skin problems. The caregiver applies children from ages 2 to 8 years commonly suffer from this a single composition that contains a secondary topical medi itching, unattractive rash. The discomfort and sleep depriva cation. This single composition is formulated to cause no tion are a major burden for patients and their families. irritation to the skin, such as a stinging sensation. Preferred Treatment of eczema is difficult and often requires a multi dosage forms of this composition include non-homogenous faceted approach. Moisturizers are administered to relieve 65 ointments, lotions, creams and other emulsions or dispersions dry skin. Cold compresses can relieve itch. Corticosteroid and where the ethanol can be suspended or dispersed in the non topical calcineurin inhibitors can reduce inflammation. Anti aqueous component to avoida Stinging sensation upon topical US 8,647,671 B2 11 12 application. In some embodiments, the compositions and Current treatments include methods to hydrate the skin methods described herein are useful for the treatment of (use of a humidifier, use of moisturizers) and the use of topical atopic dermatitis. In some embodiments the compositions and/or oral medications (corticosteroids, antibiotics, antihis disclosed herein include at least one anti-inflammatory agent. tamine). In some embodiments the compositions disclosed herein In some embodiments, the compositions and methods include at least one corticosteroid. described herein are useful for the treatment of nummular Contact Dermatitis dermatitis. Irritant contact dermatitis can occur after brief exposure to Neurodermatitis (Eczema) a strong irritant or frequent exposure to a mild irritant. When Neurodermatitis develops when nerve endings in the skin contact with the irritant damages the skin faster than the skin 10 become irritated, triggering a severe itch-scratch-itch cycle. can repair itself, irritant contact dermatitis can develop. Common causes of nerve irritation include an insect bite and Allergic contact dermatitis usually develops within hours emotional stress. after the allergen makes skin contact. Nearly 3000 allergens Neurodermatitis occurs more frequently in people who are known to cause allergic contact dermatitis. Common 15 have psoriasis or contact dermatitis, people who have an allergens include fragrances, metals, plants, clothing and atopic condition (atopic dermatitis, hayfever, asthma), shoes. females, and people between 30 and 50 years of age. Current treatments include avoidance of the irritant or Current treatments include administration of a topical cor allergen, frequent use of topical moisturizers, application of ticosteroid, a topical or oral antibiotic, a topical keratolytic, topical corticosteroid to reduce inflammation and administra and a sedative/tranquilizer. tion of antibiotics should an infection develop. Phototherapy In some embodiments, the compositions and methods can be used in severe cases to Suppress the overactive immune described herein are useful for the treatment of neuroderma response. titis. In Some embodiments, the compositions and methods Stasis Dermatitis (Eczema) described herein are useful for the treatment of contact der 25 Stasis dermatitis, also known as gravitational dermatitis, matitis. venous dermatitis, or venous stasis dermatitis, develops in the Dyshidrotic Dermatitis (Hand Eczema) lower legs when circulation becomes sluggish. Poor blood Dyshidrotic dermatitis, also known as hand eczema, pom flow leads to fluid build-up. The legs swell, causing the devel pholyx, Vesicular eczema, or vesicular palmoplantar eczema, opment of a rash that usually itches, painful sores and discol occurs only on the palms of the hands, sides of fingers and 30 ored thinning skin. soles of the feet. It typically causes a burning, itching sensa In the United States, about 15-20 million people over 50 tion and ablistering rash. Patients with dyshidrotic dermatitis years of age have stasis dermatitis. are typically between 20 and 40 years of age. Risk factors Current treatments include methods to increase blood flow include stress and pre-existing conditions (atopic condition, 35 in the legs as well as the administration of topical and/or oral contact dermatitis, infection). medications (corticosteroids, antibiotics). Current treatments include the use of topical corticosteroid In some embodiments, the compositions and methods and cold compresses, antibiotics, topical medications to described herein are useful for the treatment of stasis derma relieve pain and itch, and topical calcineurin inhibitors to titis. reduce inflammation as well as drainage of large blisters to 40 Hand Dermatitis (Eczema) relieve pain. Hand dermatitis is not one specific type of eczema but In Some embodiments, the compositions and methods rather any type of eczema that develops on the hands. described herein are useful for the treatment of dyshidrotic Estimates indicate that between 2% and 10% of Americans dermatitis. have some form of hand dermatitis. Hand dermatitis may Seborrheic Dermatitis (Seborrheic Eczema) 45 account for 80% of all job-related skin conditions. People in Seborrheic dermatitis, also known as cradle cap, seborrhea, occupations that involve frequent hand immersion in water or dandruff, usually begins on the scalp as oily, waxy patches are more susceptible to the development of hand dermatitis. and can sometimes spread to the face and beyond. Symptoms Current treatments include administration of topical or oral can also include flaking skin; reddish, somewhat Swollen corticosteroids and/or antibiotics, topical tars, and topical skin; and constant itchiness. In some cases, seborrheic der 50 calcineurin inhibitors as well as the use of phototherapy or matitis is thought to be triggered by the microorganism botulinum toxin type A injections. malassezia. In some embodiments, the compositions and methods Current treatments include administration of a topical mild described herein are useful for the treatment of hand derma corticosteroid and topical anti-fungal medication, such as titis. ketoconazole, as well as the use of a specific shampoo regi 55 Occupational Dermatitis (Eczema) C. Occupational dermatitis is not one specific type of eczema In Some embodiments, the compositions and methods but rather any type of eczema that is caused by a person’s described herein are useful for the treatment of seborrheic workplace. dermatitis. Estimates indicate that 5% of men and 10% of women in Nummular Dermatitis (Eczema) 60 the workforce develop eczema on their hands from workplace Nummular dermatitis presents itself as unique, coin exposure. Often, the eczema is the result of an irritant (irritant shaped or oval lesions. contact dermatitis) or an allergic reaction (allergic contact Approximately 2 out of every 1000 people in the United dermatitis). Occupational dermatitis can also occur on the States develop nummular eczema. Men develop it more fre face and forearms. quently, with the first incident occurring between 55 and 65 65 Current treatments include avoidance of the irritant/aller years of age. Women tend to develop nummular dermatitis gen, frequent use of topical moisturizers, application of topi between 15 and 25 years of age. cal corticosteroid to reduce inflammation and administration US 8,647,671 B2 13 14 of antibiotics should an infection develop. Phototherapy can In this fungal infection of the soles, there are dry pink to tan be used in severe cases to Suppress the overactive immune scaly patches which gradually expand to cover the sole and response. the web spaces between the toes. Often cracks occur due to In Some embodiments, the compositions and methods the dryness causing decreased skin flexibility. Symptoms described herein are useful for the treatment of occupational often range from mild to severeitching from the inflammation dermatitis. of the skin and mild to severe discomfort due to the cracks. Secondarily Infected Dermatitis Typically it begins in teen years and can last through adult Due to the marked itchiness of rashes, dermatitis patients hood. Sometimes painful blisters can occur due to the intense frequently scratch the affected skin disrupting its integrity inflammation induced by the immune defense response to the and providing a "portal of entry” for bacteria to infect the 10 skin. Thus a rash which began with only inflammation soon fungal infection. becomes so called “secondarily infected with bacteria. This Current standard of treatment includes administration of colonization of the rash with an overgrowth of abnormal topical agents and/or the use of oral agents. Topical treatment bacteria (often Staphylococcus aureus) further contributes to include antifungal agents such as terbenafine, econazole, skin irritation. Thus, because a secondary infection has 15 miconazole, clotrimazole, butenafine, tolnaftate, or salicylic occurred, effective treatment of the rash must suppress both acid. All of these agents typically take 2-4 weeks to improve inflammation and infection. the rash. Oral agents used for the treatment of tinea pedis Treatment of dermatitis employs several classes of thera include griseofulvin, terbenafine, itraconazole, or flucona peutic agents. Zole. While effective, these pose risks of toxicity including Topical Treatment: blood, liver, and heart injury. a) Immunosuppressive agents to reduce inflammation include In some embodiments, the compositions and methods corticosteroids such as hydrocortisone and many other described herein are useful for the treatment of tinea pedis. In related molecules, and immunomodulating agents such as Some embodiments the compositions disclosed herein tacrolimus and pimecrolimus. include at least one anti-fungal agent. b) Antibacterial agents to Suppress bacterial infection include 25 Tinea Versicolor mupirocin, retapamulin, neomycin, bacitractin, poly Tinea Versicolor is a chronic fungal infection of the skin myxin, and Sulfa. and is characterized as a rash in humans known to be caused Oral Treatment: by pitryosporum and two species of malassezia genus yeast: a) Immunosuppressive agents to reduce inflammation include malassezia globosa and malassezia furfur (Crespo-ErchigaV. corticosteroids like prednisone 30 Florencio V. D. Malassezia yeasts and pityriasis versicolor. b) Antibiotics to suppress bacterial infection include tetracy Curr Opin Infect Dis. April 2006: 19(2):139-47: Gaitanis G, cline family, erythromycin macrollide family, penicillin Velegraki A, Alexopoulos E. C. Chasapi V. Tsigonia A, Kat family, cephalosporin family, ciprofloxacin family, and sambas A. Distribution of Malassezia species in pityriasis clindamycin. versicolor and seborrhoeic dermatitis in Greece. Typing of the c) oral antihistamines to reduce the itch and Swelling of 35 major pityriasis versicolor isolate M. globosa. Br J. Dermatol. inflammation. May 2006: 154(5):854-9; Morishita N. Sei Y. Sugita T. Use of compositions as described herein dramatically Molecular analysis of malassezia microflora from patients improves the efficacy oftopical steroids while eliminating the with pityriasis versicolor. Mycopathologia. February 2006; need for topical and oral antibiotics. This simpler treatment 161(2):61-5; Rincon S. Celis A, Sopo L, Motta A, Cepero de means better compliance and better Success in treatment. 40 Garcia MC. Malassezia yeast species isolated from patients In Some embodiments, the compositions and methods with dermatologic lesions. Biomedica. June 2005; 25(2): 189 described herein are useful for the treatment of secondarily 95; Krisanty RI, Bramono K, Made Wisnu I. Identification of infected dermatitis. In some embodiments, the compositions Malassezia species from pityriasis versicolor in Indonesia disclosed herein include at least one immunosuppressive and its relationship with clinical characteristics. Mycoses. agent. In some embodiments, the compositions disclosed 45 May 2009; 52(3):257-62). Treatment consists of applying herein include at least one antimicrobial agent. antifungal medicines to the skin. These medications include Pitted Keratolysis clotrimazole, ketoconazole, and miconazole. Pitted keratolysis is a distinctive non-inflammatory bacte In some embodiments, the compositions and methods rial infection of the soles of the feet that is characterized by described herein are useful for the treatment of tinea versi appearance of pits on the soles. It usually occurs in teenagers 50 color. In some embodiments, the methods described herein and young adults with Sweat soaked skin due to athletic are useful for the treatment of tinea versicolor. In some activities and not changing to dry socks. This wet condition embodiments, the compositions disclosed herein include at leads to maceration and breakdown of the outer skin layer least one anti-fungal agent. creatingaportal of entry for a specific bacteria: Erythromyces Psoriasis minitussitum. It is foul Smelling and gives a “Swiss cheese' 55 According to the National Institutes of Health (NIH), appearance to the soles of the feet. approximately 2.2% of the United States population have Current standard of treatment includes topical application psoriasis. of agents to decrease Sweating to dry the feet (aluminum Psoriasis is characterized by red scaly elevated plaques which chloride) and antibacterial agents to suppress the bacterial are often located on elbows and knees but can be extensively infection (erythromycin, or clindamycin). 60 spread out on the skin of the trunk, limbs, and Scalp. This is a In Some embodiments, the compositions and methods chronic, often recurrent, condition which usually begins in described herein are useful for the treatment of pitted kera early adulthood and lasts the lifetime. Sometimes children are tolysis. affected. The rash can be uncomfortable, unsightly, and Athlete's Foot (Tinea Pedis) embarrassing. Tinea pedis is thought to be the world's most common 65 The pathogenesis of psoriasis is not well understood. Cur dermatophytosis. Reportedly, 70% of the population will be rent understanding Suggests immune system activation lead infected with tinea pedis at Some time. ing to inflammatory changes in the skin. Current methods of US 8,647,671 B2 15 16 treatment seek to reverse the inflammatory changes and was prepared by sequential tape stripping prior to topical reduce the overgrowth thickening of the affected skin areas. application of the materials in the study. Topical treatment includes use of anti-inflammatory agents Methods of Treatment (such as corticosteroids to reduce the inflammation in the One embodiment provides a method of treating a skin skin) and antiproliferative agents (such as calcipotriene to disease or disorder in an individual comprising topical appli reduce the skin overgrowth). Topical agents often have lim cation to the skin of a Subject in need thereof of a pharma ited effectiveness due to inadequate percutaneous drug deliv ceutical composition Suitable for topical administration com ery through the thickened psoriatic skin. To overcome this prising from about 2% to no more than 59.9% of an alcohol by obstacle, a topical agent can be covered over with an air Volume and at least one excipient wherein said composition is impermeable plastic sheet (Saran WrapTM) to increase percu 10 a non-homogeneous semisolid and the alcohol is selected taneous drug delivery. While effective, it is very uncomfort from ethanol, isopropanol, or n-propanol. One embodiment able to wear leading to poor compliance and thus inadequate provides a method of treating a skin disease or disorder in an efficacy. individual comprising topical application of a pharmaceutical Oral or systemic agents include anti-inflammatory agents composition Suitable for topical administration comprising (such as methotrexate, or cyclosporine), and tumor necrosis 15 from about 2% to no more than 59.9% ethanol by volume, and factor inhibitors (etenercept, infliximab, and similar others). at least one excipient wherein the composition is a non While effective they can damage blood and liver and pose homogeneous semisolid. Another embodiment provides the risks of severe toxicity including death. Other modes of method wherein the composition is a non-homogenous semi therapy include ultraviolet light treatment to suppress epider solid dispersion. One embodiment provides a method of treat mal growth (however, one drawback of this treatment is the ing a skin disease or disorder in an individual comprising potential to cause cancer of the skin) and corticosteroid injec topical application to the skin of a subject in need thereof of tions into patch Suppresses inflammation locally (this is very a pharmaceutical composition Suitable for topical adminis uncomfortable and can lead to unsightly thinning where tration comprising from about 2% to no more than 59.9% of injected). an alcohol by Volume and at least one excipient wherein said In Some embodiments, the compositions and methods 25 composition is a non-homogeneous emulsion and the alcohol described herein are useful for the treatment of psoriasis. In is selected from ethanol, isopropanol, or n-propanol. Another Some embodiments the compositions disclosed herein embodiment provides the method wherein the composition is include at least one anti-inflammatory agent. In some a non-homogenous semisolid emulsion. Another embodi embodiments the compositions disclosed herein include at ment provides the method wherein the composition is a non least one anti-proliferative agent. 30 homogenous cream or a non-homogenous ointment. Another Test for Stinging embodiment provides the method wherein the composition is An assessment of stinging can be made using a Superficial a non-homogenous cream. Another embodiment provides the skin abrasion model. When the skin is disrupted by superficial method wherein the composition is a non-homogenous oint wounds, Subsequently applied materials can sting, burn, and ment. Another embodiment provides the method wherein the irritate. To measure the stinging, standardized wounds can be 35 composition is a non-homogeneous emulsion. Another created in the skin, typically on the forearm, by sequential embodiment provides the method wherein the composition is tape Stripping repeated until the glistening layer is reached. a non-homogenous dispersion. Another embodiment pro This glistening layer corresponds to the skin's dermal layer vides the method wherein the composition is a non-homog where nerves are located. Materials to be tested on the super enous cream or a non-homogenous lotion. Another embodi ficial wounds would include a positive control material. Such 40 ment provides the method wherein the composition is a non 70% ethanol solution, a negative control, such as the formu homogenous lotion. lation vehicle without active agents, and the test Another embodiment provides a method of treating a skin formulation(s). Each material is applied to a single site on the disease or disorder in an individual comprising topical appli abraded forearm for a short duration of time, such as 15 cation of a pharmaceutical composition Suitable for topical seconds. The study subject is then asked to rate the intensity 45 administration comprising from about 2% to no more than of stinging/burning using a predesignated multi-point scale. 59.9% ethanol by volume, and at least one excipient wherein Thus, stinging as well as burning sensations can be assessed the composition is a non-homogeneous semisolid and the by this method. method is for maintenance therapy. Another embodiment pro For example, in a study of novel first aid formulation for vides the method wherein the composition is a non-homog wounds, standardized wounds were created by sequential 50 enous semisolid dispersion. Another embodiment provides tape stripping repeated until the glistening layer was reached the method wherein the composition is a non-homogenous (Pagnoni A, Spinelli G, Berger RS, Bowman J. Garreffa S. semisolid emulsion. Another embodiment provides the Snoddy AM. Lack of burning and stinging from a novel first method wherein the composition is a non-homogenous cream aid formulation applied to experimental wounds. J. Cosmet. or a non-homogenous ointment. Another embodiment pro Sci. March-April 2004: 55(2): 157-62). Each material to be 55 vides the method wherein the composition is a non-homog tested was applied to a wound for 15 seconds. The 24 subjects enous cream. Another embodiment provides the method in the study reported the intensity of the stinging/burning wherein the composition is a non-homogenous ointment. sensation. The tested materials included 70% isopropyl alco Another embodiment provides the method wherein the com hol (sting/burn control), sterile 0.9% sodium chloride solu position is a non-homogeneous emulsion. Another embodi tion (no Sting/no burn control) and the novel formulation. It 60 ment provides the method wherein the composition is a non was found that the alcohol stung while the novel formulation homogenous dispersion. Another embodiment provides the stung no more than the saline solution. method wherein the composition is a non-homogenous cream In another example, irritation of Superficial wounds by or a non-homogenous lotion. Another embodiment provides topical agents commonly used in wound care was assessed the method wherein the composition is a non-homogenous using this Superficial skin abrasion model (Trookman NS, 65 lotion. Rizer R L. Weber T. J. Amer: Acad. Dermatol. March 2011; Another embodiment provides a method of treating a skin 64(3), Suppl 1:S16-22). As in the previous example, the skin disease or disorder in an individual comprising topical appli US 8,647,671 B2 17 18 cation of a pharmaceutical composition Suitable for topical a non-homogenous cream or a non-homogenous lotion. administration comprising from about 2% to no more than Another embodiment provides the method wherein the com 59.9% ethanol by volume, and at least one excipient wherein position is a non-homogenous lotion. the composition is a non-homogeneous semisolid and the Another embodiment provides a method of treating a skin method is for preventive treatment of the skin disease or disease or disorder in an individual comprising topical appli disorder. Another embodiment provides the method wherein cation of a pharmaceutical composition Suitable for topical the composition is a non-homogenous semisolid dispersion. administration comprising from about 2% to no more than Another embodiment provides the method wherein the com 59.9% ethanol by volume, at least one moisturizing ingredi position is a non-homogenous semisolid emulsion. Another ent and at least one excipient, wherein the composition is a embodiment provides the method wherein the composition is 10 non-homogeneous semisolid. Another embodiment provides a non-homogenous cream or a non-homogenous ointment. the method wherein the composition is a non-homogenous Another embodiment provides the method wherein the com semisolid dispersion. Another embodiment provides the position is a non-homogenous cream. Another embodiment method wherein the composition is a non-homogenous semi provides the method wherein the composition is a non-ho solid emulsion. Another embodiment provides the method mogenous ointment. Another embodiment provides the 15 wherein the composition is a non-homogenous cream or a method wherein the composition is a non-homogeneous non-homogenous ointment. Another embodiment provides emulsion. Another embodiment provides the method wherein the method wherein the composition is a non-homogenous the composition is a non-homogenous dispersion. Another cream. Another embodiment provides the method wherein embodiment provides the method wherein the composition is the composition is a non-homogenous ointment. Another a non-homogenous cream or a non-homogenous lotion. embodiment provides the method wherein the composition is Another embodiment provides the method wherein the com a non-homogeneous emulsion. Another embodiment pro position is a non-homogenous lotion. vides the method wherein the composition is a non-homog Another embodiment provides a method of treating a skin enous dispersion. Another embodiment provides the method disease or disorder in an individual comprising topical appli wherein the composition is a non-homogenous cream or a cation of a pharmaceutical composition Suitable for topical 25 non-homogenous lotion. Another embodiment provides the administration comprising from about 2% to no more than method wherein the composition is a non-homogenous 59.9% ethanol by volume, and at least one excipient wherein lotion. Non-limiting examples of moisturizing ingredients the composition is a non-homogeneous semisolid and the include glycerin, hydrogenated polyisobutene, cetearyl alco method is for prophylactic treatment of the skin disease or hol, macadamia nut oil, dimethicone, tocopheryl acetate, disorder. Another embodiment provides the method wherein 30 Stearoxytrimethylsilane, Stearyl alcohol, and panthenol. the composition is a non-homogenous semisolid dispersion. Another embodiment provides the method wherein the Another embodiment provides the method wherein the com composition comprises from about 2% to about 10% ethanol position is a non-homogenous semisolid emulsion. Another by volume. Another embodiment provides the method embodiment provides the method wherein the composition is wherein the composition comprises about 2% ethanol by a non-homogenous cream or a non-homogenous ointment. 35 volume. Another embodiment provides the method wherein Another embodiment provides the method wherein the com the composition comprises about 3% ethanol by volume. position is a non-homogenous cream. Another embodiment Another embodiment provides the method wherein the com provides the method wherein the composition is a non-ho position comprises about 4% ethanol by volume. Another mogenous ointment. Another embodiment provides the embodiment provides the method wherein the composition method wherein the composition is a non-homogeneous 40 comprises about 5% ethanol by volume. Another embodi emulsion. Another embodiment provides the method wherein ment provides the method wherein the composition com the composition is a non-homogenous dispersion. Another prises about 6% ethanol by volume. Another embodiment embodiment provides the method wherein the composition is provides the method wherein the composition comprises a non-homogenous cream or a non-homogenous lotion. about 7% ethanol by volume. Another embodiment provides Another embodiment provides the method wherein the com 45 the method wherein the composition comprises about 8% position is a non-homogenous lotion. ethanol by volume. Another embodiment provides the Another embodiment provides a method of treating a skin method wherein the composition comprises about 9% ethanol disease or disorder in an individual comprising topical appli by volume. Another embodiment provides the method cation of a pharmaceutical composition Suitable for topical wherein the composition comprises about 10% ethanol by administration comprising from about 2% to no more than 50 volume. Another embodiment provides the method wherein 59.9% ethanol by volume, and at least one excipient wherein the composition comprises from about 6% to about 10% the composition is a non-homogeneous semisolid and the ethanol by volume. Another embodiment provides the method is for treatment of acute or Sub-acute skin disease or method wherein the composition comprises from about 5% to disorder. Another embodiment provides the method wherein about 10% ethanol by volume. the composition is a non-homogenous semisolid dispersion. 55 Another embodiment provides the method wherein the Another embodiment provides the method wherein the com composition comprises from about 10% to about 20% ethanol position is a non-homogenous semisolid emulsion. Another by volume. Another embodiment provides the method embodiment provides the method wherein the composition is wherein the composition comprises about 11% ethanol by a non-homogenous cream or a non-homogenous ointment. volume. Another embodiment provides the method wherein Another embodiment provides the method wherein the com 60 the composition comprises about 12% ethanol by volume. position is a non-homogenous cream. Another embodiment Another embodiment provides the method wherein the com provides the method wherein the composition is a non-ho position comprises about 13% ethanol by volume. Another mogenous ointment. Another embodiment provides the embodiment provides the method wherein the composition method wherein the composition is a non-homogeneous comprises about 14% ethanol by volume. Another embodi emulsion. Another embodiment provides the method wherein 65 ment provides the method wherein the composition com the composition is a non-homogenous dispersion. Another prises about 15% ethanol by volume. Another embodiment embodiment provides the method wherein the composition is provides the method wherein the composition comprises US 8,647,671 B2 19 20 about 16% ethanol by volume. Another embodiment provides Another embodiment provides a method of treating a skin the method wherein the composition comprises from about disease or disorder in an individual comprising topical appli 10% to about 15% ethanol by volume. Another embodiment cation of a pharmaceutical composition Suitable for topical provides the method wherein the composition comprises administration comprising from about 2% to no more than from about 10% to about 16% ethanol by volume. Another 5 59.9% isopropanol by volume, and at least one excipient embodiment provides the method wherein the composition wherein the composition is a non-homogeneous semisolid. comprises from about 10% to about 21% ethanol by volume. Another embodiment provides the method wherein the com Another embodiment provides the method wherein the position is a non-homogenous semisolid dispersion. Another composition comprises from about 20% to about 30% ethanol embodiment provides the method wherein the composition is 10 a non-homogenous semisolid emulsion. Another embodi by volume. Another embodiment provides the method ment provides the method wherein the composition is a non wherein the composition comprises from about 21% to about homogenous cream or a non-homogenous ointment. Another 31% ethanol by volume. Another embodiment provides the embodiment provides the method wherein the composition is method wherein the composition comprises about 25% etha a non-homogenous cream. Another embodiment provides the nol by volume. Another embodiment provides the method 15 method wherein the composition is a non-homogenous oint wherein the composition comprises about 30% ethanol by ment. Another embodiment provides the method wherein the volume. Another embodiment provides the method wherein composition is a non-homogeneous emulsion. Another the composition comprises about 31% ethanol by volume. embodiment provides the method wherein the composition is Another embodiment provides the method wherein the com a non-homogenous dispersion. Another embodiment pro position comprises about 32% ethanol by volume. Another vides the method wherein the composition is a non-homog embodiment provides the method wherein the composition enous cream or a non-homogenous lotion. Another embodi comprises from about 25% to about 30% ethanol by volume. ment provides the method wherein the composition is a non Another embodiment provides the method wherein the com homogenous lotion. Another embodiment provides the position comprises from about 30% to about 35% ethanol by method wherein the composition comprises from about 2% to volume. Another embodiment provides the method wherein 25 about 10% isopropanol by volume. Another embodiment pro the composition comprises from about 30% to about 40% vides the method wherein the composition comprises from ethanol by volume. Another embodiment provides the about 10% to about 20% isopropanol by volume. Another method wherein the composition comprises from about 40% embodiment provides the method wherein the composition to about 50% ethanol by volume. Another embodiment pro comprises from about 20% to about 30% isopropanol by vides the method wherein the composition comprises from 30 volume. Another embodiment provides the method wherein about 50% to about 55% ethanol by volume. the composition comprises from about 30% to about 40% Another embodiment provides the method wherein the isopropanol by volume. Another embodiment provides the composition is non-comedogenic. method wherein the composition comprises from about 40% Another embodiment provides the method wherein the to about 50% isopropanol by volume. Another embodiment skin disease or disorder is acne, rosacea, dermatitis, second 35 provides the method wherein the composition comprises arily infected dermatitis, bacterial skin infection, or fungal from about 50% to about 59.9% isopropanol by volume. skin infection. Another embodiment provides the method Methods of Treatment with a Second Active Ingredient wherein the skin disease or disorder is dermatitis or eczema. One embodiment provides a means of applying ethanol to Another embodiment provides the method wherein the skin the skin without stinging. disease or disorder is atopic dermatitis. 40 One embodiment provides a method of treating a skin Another embodiment provides the method wherein topical disease or disorder in an individual in need thereof compris application of the pharmaceutical composition does not irri ing topical application to the individual of a chemical matrix tate the skin. Another embodiment provides the method comprising from about 2% to about 30% of an alcohol by wherein topical application of the pharmaceutical composi Volume, a corticosteroid and at least one excipient, wherein tion does not cause subjective irritation of the skin. Another 45 the chemical matrix is an ointment Suitable for topical admin embodiment provides the method wherein topical application istration, the alcohol is primarily dispersed into the chemical of the pharmaceutical composition does not cause a stinging matrix in the form of microbubbles, the alcohol is selected sensation. from ethanol, isopropanol, or n-propanol, or combinations Another embodiment provides a method of treating a skin thereof, and the corticosteroid is present in a concentration disease or disorder in an individual by killing or inhibiting the 50 between about 1% and about 91% of the standardized topical growth of microorganisms. Another embodiment provides corticosteroid concentration. Another embodiment provides the method wherein the microorganisms are bacteria. the method wherein the corticosteroid is present in a concen Examples of such bacteria include Gram positive and Gram tration between about 1% and about 85% of the standardized negative aerobic and anaerobic bacteria. Non-limiting topical corticosteroid concentration. Another embodiment examples of Such bacteria include Acinetobacter baumannii, 55 provides the method wherein the corticosteroid is present in a Acinetobacter johnsonii, Acinetobacter l'offi, Corynebacte concentration between about 1% and about 75% of the stan rium spp., Enterobacter agglomerans, Enterobacter cloacae, dardized topical corticosteroid concentration. Another Klebsiella pneumoniae, Propionibacterium acnes, embodiment provides the method wherein the corticosteroid Pseudomonas aeruginosa, Staphylococcus aureus, Staphyllo is present in a concentration between about 1% and about coccus epidermidis, Staphylococcus warneri, Streptococcus 60 65% of the standardized topical corticosteroid concentration. mitis, and Streptococcus pyogenes. Another embodiment pro Another embodiment provides the method wherein the corti vides the method wherein the microorganisms are fungi. costeroid is present in a concentration between about 1% and Non-limiting examples of Such fungi include Candida albi about 55% of the standardized topical corticosteroid concen cans, Trichophyton mentagrophytes, Trichophyton rubrum, tration. Another embodiment provides the method wherein Epidermophyton floccosum, Microsporum audouinii, 65 the corticosteroid is present in a concentration between about Microsporum canis, Microsporum filvum, Microsporum 1% and about 45% of the standardized topical corticosteroid gypseum, and Pityrosporum ovale. concentration. Another embodiment provides the method US 8,647,671 B2 21 22 wherein the corticosteroid is present in a concentration 50%, about 65%, about 75%, about 85%, or about 91% of the between about 1% and about 35% of the standardized topical standardized topical corticosteroid concentration. corticosteroid concentration. Another embodiment provides Another embodiment provides the method wherein the corti the method wherein the corticosteroid is present in a concen costeroid is present in a concentration of about 1%, about 5%, tration between about 1% and about 25% of the standardized about 10%, about 15%, or about 25% of the standardized topical corticosteroid concentration. Another embodiment topical corticosteroid concentration. Another embodiment provides the method wherein the corticosteroid is present in a provides the method wherein the corticosteroid is present in a concentration between about 1% and about 15% of the stan concentration of about 10%, about 15%, about 25%, or about dardized topical corticosteroid concentration. Another 35% of the standardized topical corticosteroid concentration. embodiment provides the method wherein the corticosteroid 10 is present in a concentration between about 10% and about Another embodiment provides the method wherein the 91% of the standardized topical corticosteroid concentration. corticosteroid is desonide and the standardized topical corti Another embodiment provides the method wherein the corti costeroid concentration is 0.05%. Another embodiment pro costeroid is present in a concentration between about 10% vides the method wherein the desonide is present in the for and about 85% of the standardized topical corticosteroid con 15 mulation in an amount of about 0.0005%, about 0.0025%, centration. Another embodiment provides the method about 0.005%, about 0.009%, about 0.02%, or about 0.045%. wherein the corticosteroid is present in a concentration Another embodiment provides the method wherein the des between about 10% and about 75% of the standardized topi onide is present in the formulation in an amount of about cal corticosteroid concentration. Another embodiment pro 0.0025%, about 0.005%, about 0.01%, about 0.02%, about vides the method wherein the corticosteroid is present in a 0.03%, or about 0.04%. Another embodiment provides the concentration between about 10% and about 65% of the stan method wherein the desonide is present in an amount of about dardized topical corticosteroid concentration. Another 0.005%, about 0.01%, about 0.015%, or about 0.02%. embodiment provides the method wherein the corticosteroid Another embodiment provides the method wherein the is present in a concentration between about 10% and about corticosteroid is mometasone and the standardized topical 55% of the standardized topical corticosteroid concentration. 25 corticosteroid concentration is 0.1%. Another embodiment Another embodiment provides the method wherein the corti provides the method wherein the mometasone is present in an costeroid is present in a concentration between about 10% amount of about 0.001%, about 0.005%, about 0.01%, about and about 45% of the standardized topical corticosteroid con 0.02%, about 0.04%, or about 0.09%. Another embodiment centration. Another embodiment provides the method provides the method wherein the mometasone is present in an wherein the corticosteroid is present in a concentration 30 amount of about 0.005%, about 0.01%, about 0.02%, about between about 10% and about 35% of the standardized topi 0.03%, about 0.04%, or about 0.05%. Another embodiment cal corticosteroid concentration. Another embodiment pro provides the method wherein the mometasone is present in an vides the method wherein the corticosteroid is present in a amount of about 0.01%, about 0.02%, about 0.03%, or about concentration between about 10% and about 25% of the stan O.04%. dardized topical corticosteroid concentration. Another 35 Another embodiment provides the chemical matrix embodiment provides the method wherein the corticosteroid wherein the alcohol is ethanol. Another embodiment provides is present in a concentration between about 10% and about the chemical matrix wherein the alcohol is isopropanol. 15% of the standardized topical corticosteroid concentration. Another embodiment provides the chemical matrix wherein Another embodiment provides the method wherein the corti the alcohol is n-propanol. costeroid is present in a concentration between about 20% 40 Another embodiment provides the method wherein the and about 91% of the standardized topical corticosteroid con ointment is selected from AQUAPHORR), white petrolatum centration. Another embodiment provides the method USP, white ointment USP hydrophilic petrolatum USP or wherein the corticosteroid is present in a concentration hydrophilic ointment USP. between about 20% and about 85% of the standardized topi Another embodiment provides the method wherein the cal corticosteroid concentration. Another embodiment pro 45 chemical matrix comprises from about 2% to about 10% vides the method wherein the corticosteroid is present in a ethanol by volume. Another embodiment provides the concentration between about 20% and about 75% of the stan method wherein the chemical matrix comprises from about dardized topical corticosteroid concentration. Another 10% to about 20% ethanol by volume. Another embodiment embodiment provides the method wherein the corticosteroid provides the method wherein the chemical matrix comprises is present in a concentration between about 20% and about 50 from about 20% to about 30% ethanol by volume. 65% of the standardized topical corticosteroid concentration. Another embodiment provides the method wherein the Another embodiment provides the method wherein the corti skin disease or disorder is eczema. Another embodiment pro costeroid is present in a concentration between about 20% vides the method wherein the skin disease or disorder is and about 55% of the standardized topical corticosteroid con atopic dermatitis. centration. Another embodiment provides the method 55 One embodiment provides a method of treating a skin wherein the corticosteroid is present in a concentration disease or disorder in an individual in need thereof compris between about 20% and about 45% of the standardized topi ing topical application to the individual of a chemical matrix cal corticosteroid concentration. Another embodiment pro comprising from about 2% to about 30% of an alcohol by vides the method wherein the corticosteroid is present in a volume, a therapeutically effective amount of a corticosteroid concentration between about 20% and about 35% of the stan 60 and at least one excipient, wherein the chemical matrix is an dardized topical corticosteroid concentration. Another ointment Suitable for topical administration, the alcohol is embodiment provides the method wherein the corticosteroid primarily dispersed into the chemical matrix in the form of is present in a concentration between about 20% and about microbubbles, the alcohol is selected from ethanol, isopro 25% of the standardized topical corticosteroid concentration. panol, or n-propanol, or combinations thereof, and the thera Another embodiment provides the method wherein the 65 peutically effective amount of a corticosteroid is between corticosteroid is present in a concentration of about 1%, about about 1% and about 91% of the standardized topical corticos 5%, about 10%, about 15%, about 25%, about 35%, about teroid concentration. US 8,647,671 B2 23 24 One embodiment provides a method of treating a skin costeroid is present in a concentration between about 20% disease or disorder in an individual in need thereof compris and about 91% of the standardized topical corticosteroid con ing topical application to the individual of a chemical matrix centration. Another embodiment provides the method comprising from about 2% to about 30% of an alcohol by wherein the corticosteroid is present in a concentration Volume, a corticosteroid and at least one excipient, wherein 5 between about 20% and about 85% of the standardized topi the chemical matrix is a cream Suitable for topical adminis cal corticosteroid concentration. Another embodiment pro tration, the alcohol is primarily dispersed into the chemical vides the method wherein the corticosteroid is present in a matrix in the form of microbubbles, the alcohol is selected concentration between about 20% and about 75% of the stan from ethanol, isopropanol, or n-propanol, or combinations dardized topical corticosteroid concentration. Another thereof, and the corticosteroid is present in a concentration 10 between about 1% and about 91% of the standardized topical embodiment provides the method wherein the corticosteroid corticosteroid concentration. Another embodiment provides is present in a concentration between about 20% and about the method wherein the corticosteroid is present in a concen 65% of the standardized topical corticosteroid concentration. tration between about 1% and about 85% of the standardized Another embodiment provides the method wherein the corti topical corticosteroid concentration. Another embodiment 15 costeroid is present in a concentration between about 20% provides the method wherein the corticosteroid is present in a and about 55% of the standardized topical corticosteroid con concentration between about 1% and about 75% of the stan centration. Another embodiment provides the method dardized topical corticosteroid concentration. Another wherein the corticosteroid is present in a concentration embodiment provides the method wherein the corticosteroid between about 20% and about 45% of the standardized topi is present in a concentration between about 1% and about cal corticosteroid concentration. Another embodiment pro 65% of the standardized topical corticosteroid concentration. vides the method wherein the corticosteroid is present in a Another embodiment provides the method wherein the corti concentration between about 20% and about 35% of the stan costeroid is present in a concentration between about 1% and dardized topical corticosteroid concentration. Another about 55% of the standardized topical corticosteroid concen embodiment provides the method wherein the corticosteroid tration. Another embodiment provides the method wherein 25 is present in a concentration between about 20% and about the corticosteroid is present in a concentration between about 25% of the standardized topical corticosteroid concentration. 1% and about 45% of the standardized topical corticosteroid Another embodiment provides the method wherein the concentration. Another embodiment provides the method corticosteroid is present in a concentration of about 1%, about wherein the corticosteroid is present in a concentration 5%, about 10%, about 15%, about 25%, about 35%, about between about 1% and about 35% of the standardized topical 30 50%, about 65%, about 75%, about 85%, or about 91% of the corticosteroid concentration. Another embodiment provides standardized topical corticosteroid concentration. Another the method wherein the corticosteroid is present in a concen embodiment provides the method wherein the corticosteroid tration between about 1% and about 25% of the standardized is present in a concentration of about 1%, about 5%, about topical corticosteroid concentration. Another embodiment 10%, about 15%, or about 25% of the standardized topical provides the method wherein the corticosteroid is present in a 35 corticosteroid concentration. Another embodiment provides concentration between about 1% and about 15% of the stan the method wherein the corticosteroid is present in a concen dardized topical corticosteroid concentration. Another tration of about 10%, about 15%, about 25%, or about 35% of embodiment provides the method wherein the corticosteroid the standardized topical corticosteroid concentration. is present in a concentration between about 10% and about Another embodiment provides the method wherein the 91% of the standardized topical corticosteroid concentration. 40 corticosteroid is desonide and the standardized topical corti Another embodiment provides the method wherein the corti costeroid concentration is 0.05%. Another embodiment pro costeroid is present in a concentration between about 10% vides the method wherein the desonide is present in the for and about 85% of the standardized topical corticosteroid con mulation in an amount of about 0.0005%, about 0.0025%, centration. Another embodiment provides the method about 0.005%, about 0.009%, about 0.02%, or about 0.045%. wherein the corticosteroid is present in a concentration 45 Another embodiment provides the method wherein the des between about 10% and about 75% of the standardized topi onide is present in the formulation in an amount of about cal corticosteroid concentration. Another embodiment pro 0.0025%, about 0.005%, about 0.01%, about 0.02%, about vides the method wherein the corticosteroid is present in a 0.03%, or about 0.04%. Another embodiment provides the concentration between about 10% and about 65% of the stan method wherein the desonide is present in an amount of about dardized topical corticosteroid concentration. Another 50 0.005%, about 0.01%, about 0.015%, or about 0.02%. embodiment provides the method wherein the corticosteroid Another embodiment provides the method wherein the is present in a concentration between about 10% and about corticosteroid is mometasone and the standardized topical 55% of the standardized topical corticosteroid concentration. corticosteroid concentration is 0.1%. Another embodiment Another embodiment provides the method wherein the corti provides the method wherein the mometasone is present in an costeroid is present in a concentration between about 10% 55 amount of about 0.001%, about 0.005%, about 0.01%, about and about 45% of the standardized topical corticosteroid con 0.02%, about 0.04%, or about 0.09%. Another embodiment centration. Another embodiment provides the method provides the method wherein the mometasone is present in an wherein the corticosteroid is present in a concentration amount of about 0.005%, about 0.01%, about 0.02%, about between about 10% and about 35% of the standardized topi 0.03%, about 0.04%, or about 0.05%. Another embodiment cal corticosteroid concentration. Another embodiment pro 60 provides the method wherein the mometasone is present in an vides the method wherein the corticosteroid is present in a amount of about 0.01%, about 0.02%, about 0.03%, or about concentration between about 10% and about 25% of the stan O.04%. dardized topical corticosteroid concentration. Another Another embodiment provides the chemical matrix embodiment provides the method wherein the corticosteroid wherein the alcohol is ethanol. Another embodiment provides is present in a concentration between about 10% and about 65 the chemical matrix wherein the alcohol is isopropanol. 15% of the standardized topical corticosteroid concentration. Another embodiment provides the chemical matrix wherein Another embodiment provides the method wherein the corti the alcohol is n-propanol. US 8,647,671 B2 25 26 Another embodiment provides the method wherein the ethanol by volume, the corticosteroid is selected from des chemical matrix comprises from about 2% to about 10% onide or mometasone, and the corticosteroid comprises from ethanol by volume. Another embodiment provides the about 0.1% (w/w) to about 0.0001% (w/w) of the chemical method wherein the chemical matrix comprises from about matrix. Another embodiment provides the method wherein 10% to about 20% ethanol by volume. Another embodiment the chemical matrix comprises from about 20% to about 30% provides the method wherein the chemical matrix comprises ethanol by volume, the corticosteroid is selected from des from about 20% to about 30% ethanol by volume. onide or mometasone, and the corticosteroid comprises from Another embodiment provides the method wherein the about 0.1% (w/w) to about 0.0001% (w/w) of the chemical skin disease or disorder is eczema. Another embodiment pro matrix. vides the method wherein the skin disease or disorder is 10 Another embodiment provides the method wherein the atopic dermatitis. skin disease or disorder is dermatitis. Another embodiment One embodiment provides a method of treating a skin provides the method wherein the skin disease or disorder is disease or disorder in an individual in need thereof compris eczema. Another embodiment provides the method wherein ing topical application to the individual of a chemical matrix the skin disease or disorder is atopic dermatitis. comprising from about 2% to about 30% of an alcohol by 15 Another embodiment provides the method wherein the volume, a therapeutically effective amount of a corticosteroid alcohol is 1-propanol or 2-propanol. Another embodiment and at least one excipient, wherein the chemical matrix is a provides the method wherein the corticosteroid is selected cream Suitable for topical administration, the alcohol is pri from desonide or mometasone. Another embodiment pro marily dispersed into the chemical matrix in the form of vides the method wherein the chemical matrix comprises microbubbles, the alcohol is selected from ethanol, isopro from about 2% to about 10% alcohol by volume. Another panol, or n-propanol, or combinations thereof, and the thera embodiment provides the method wherein the chemical peutically effective amount of a corticosteroid is between matrix comprises from about 10% to about 20% alcohol by about 1% and about 91% of the standardized topical corticos volume. Another embodiment provides the method wherein teroid concentration. the chemical matrix comprises from about 20% to about 30% One embodiment provides a method of treating a skin 25 alcohol by volume. Another embodiment provides the disease or disorder in an individual in need thereof compris method wherein the corticosteroid is selected from desonide ing topical application to the individual of a chemical matrix or mometasone. Another embodiment provides the method comprising from about 2% to about 30% of an alcohol by wherein the skin disease or disorder is dermatitis. Another Volume, a corticosteroid and at least one excipient, wherein embodiment provides the method wherein the skin disease or the chemical matrix is an ointment Suitable for topical admin 30 disorder is eczema. Another embodiment provides the istration, the alcohol is primarily dispersed into the chemical method wherein the skin disease or disorder is atopic derma matrix in the form of microbubbles, and the alcohol is titis. selected from ethanol, isopropanol, or n-propanol. One embodiment provides a method of treating a skin Another embodiment provides the method wherein the disease or disorder in an individual comprising topical appli alcohol is ethanol. Another embodiment provides the method 35 cation of a pharmaceutical composition Suitable for topical wherein the chemical matrix comprises from about 2% to administration comprising from about 2% to no more than about 10% ethanol by volume. Another embodiment provides 59.9% of an alcohol by volume, a second active ingredient, the method wherein the chemical matrix comprises from and at least one excipient wherein the composition is a non about 10% to about 20% ethanol by volume. Another embodi homogeneous semisolid and the alcohol is selected from ment provides the method wherein the chemical matrix com 40 ethanol, isopropanol, or n-propanol. One embodiment pro prises from about 20% to about 30% ethanol by volume. vides a method of treating a skin disease or disorder in an Another embodiment provides the method wherein the individual comprising topical application of a pharmaceutical ointment is selected from AQUAPHORR), white petrolatum composition Suitable for topical administration comprising USP, white ointment USP hydrophilic petrolatum USP or from about 2% to no more than 59.9% ethanol by volume, a hydrophilic ointment USP. 45 second active ingredient, and at least one excipient wherein Another embodiment provides the method wherein the the composition is a non-homogeneous semisolid. Another corticosteroid is selected from desonide or mometasone. embodiment provides the method wherein the composition is Another embodiment provides the method wherein the corti a non-homogenous semisolid dispersion. Another embodi costeroid comprises from about 0.1% (w/w) to about ment provides the method wherein the composition is a non 0.0001% (w/w) of the chemical matrix. Another embodiment 50 homogenous semisolid emulsion. Another embodiment pro provides the method wherein the chemical matrix comprises vides the method wherein the composition is a non from about 2% to about 10% ethanol by volume and the homogenous cream or a non-homogenous ointment. Another corticosteroid is selected from desonide or mometasone. embodiment provides the method wherein the composition is Another embodiment provides the method wherein the a non-homogenous cream. Another embodiment provides the chemical matrix comprises from about 10% to about 20% 55 method wherein the composition is a non-homogenous oint ethanol by volume and the corticosteroid is selected from ment. desonide or mometaSone. Another embodiment provides the One embodiment provides a method of treating a skin method wherein the chemical matrix comprises from about disease or disorder in an individual comprising topical appli 20% to about 30% ethanol by volume and the corticosteroid is cation of a pharmaceutical composition Suitable for topical selected from desonide or mometaSone. 60 administration comprising from about 2% to no more than Another embodiment provides the method wherein the 59.9% of an alcohol by volume, a second active ingredient, chemical matrix comprises from about 2% to about 10% and at least one excipient wherein the composition is a non ethanol by volume, the corticosteroid is selected from des homogeneous emulsion and the alcohol is selected from etha onide or mometasone, and the corticosteroid comprises from nol, isopropanol, or n-propanol. Another embodiment pro about 0.1% (w/w) to about 0.0001% (w/w) of the chemical 65 vides a method of treating a skin disease or disorder in an matrix. Another embodiment provides the method wherein individual comprising topical application of a pharmaceutical the chemical matrix comprises from about 10% to about 20% composition Suitable for topical administration comprising US 8,647,671 B2 27 28 from about 2% to no more than 59.9% ethanol by volume, a embodiment provides the method wherein the composition second active ingredient, and at least one excipient wherein comprises from about 25% to about 30% ethanol by volume. the composition is a non-homogeneous emulsion. Another Another embodiment provides the method wherein the com embodiment provides the method wherein the composition is position comprises from about 30% to about 35% ethanol by a non-homogenous dispersion. Another embodiment pro volume. Another embodiment provides the method wherein vides the method wherein the composition is a non-homog the composition comprises from about 30% to about 40% enous cream or a non-homogenous lotion. Another embodi ethanol by volume. Another embodiment provides the ment provides the method wherein the composition is a non method wherein the composition comprises from about 40% homogenous cream. Another embodiment provides the to about 50% ethanol by volume. Another embodiment pro method wherein the composition is a non-homogenous 10 vides the method wherein the composition comprises from lotion. about 50% to about 55% ethanol by volume. Another embodiment provides the method wherein the Another embodiment provides the method wherein the composition comprises from about 2% to about 10% ethanol composition is non-comedogenic. by volume. Another embodiment provides the method Another embodiment provides the method wherein the wherein the composition comprises about 2% ethanol by 15 skin disease or disorder is acne, rosacea, dermatitis, second volume. Another embodiment provides the method wherein arily infected dermatitis, bacterial skin infection, or fungal the composition comprises about 3% ethanol by volume. skin infection. Another embodiment provides the method Another embodiment provides the method wherein the com wherein the skin disease or disorder is dermatitis or eczema. position comprises about 4% ethanol by volume. Another Another embodiment provides the method wherein the skin embodiment provides the method wherein the composition disease or disorder is atopic dermatitis. comprises about 5% ethanol by volume. Another embodi Another embodiment provides the method wherein the ment provides the method wherein the composition com second active ingredient is a corticosteroid selected from prises about 6% ethanol by volume. Another embodiment 21-acetoxypregnenolone, alclometaSone, algestone, amcino provides the method wherein the composition comprises nide, beclomethasone, betamethasone, budesonide, chloro about 7% ethanol by volume. Another embodiment provides 25 prednisone, clobetasol, clobetaSone, clocortolone, clopred the method wherein the composition comprises about 8% nol, corticosterone, cortisone, cortivaZol, deflazacort, ethanol by volume. Another embodiment provides the desonide, desoximetaSone, dexamethasone, diflorasone, method wherein the composition comprises about 9% ethanol diflucortolone, difluprednate, enoxolone, fluazacort, fluclo by volume. Another embodiment provides the method ronide, flumethasone, flunisolide, fluocinolone acetonide, wherein the composition comprises about 10% ethanol by 30 fluocinonide, fluocortin butyl, fluocortolone, fluo volume. Another embodiment provides the method wherein rometholone, fluperolone acetate, fluprednidene acetate, flu the composition comprises from about 6% to about 10% prednisolone, flurandrenolide, fluticasone propionate, for ethanol by volume. Another embodiment provides the mocortal, halcinonide, halobetasol propionate, method wherein the composition comprises from about 5% to halometaSone, halopredone acetate, hydrocortamate, hydro about 10% ethanol by volume. 35 cortisone, loteprednol etabonate, maZipredone, medrysone, Another embodiment provides the method wherein the meprednisone, methylprednisolone, mometaSone furoate, composition comprises from about 10% to about 20% ethanol paramethasone, prednicarbate, prednisolone, prednisolone by volume. Another embodiment provides the method 25-diethylamino-acetate, prednisolone sodium phosphate, wherein the composition comprises about 11% ethanol by prednisone, prednival, prednylidene, rimexolone, tiXocortol, volume. Another embodiment provides the method wherein 40 triamcinolone, triamcinolone acetonide, triamcinolone bene the composition comprises about 12% ethanol by volume. tonide, triamcinolone diacetonide, and triamcinolone hexac Another embodiment provides the method wherein the com etonide; and a pharmaceutically acceptable salt thereof, or position comprises about 13% ethanol by volume. Another phosphate prodrug thereof, or ester prodrug thereof. embodiment provides the method wherein the composition Another embodiment provides the method wherein the comprises about 14% ethanol by volume. Another embodi 45 second active ingredient is a corticosteroid selected from ment provides the method wherein the composition com hydrocortisone, desonide, mometaSone, betamethasone, flu prises about 15% ethanol by volume. Another embodiment ticasone, fluocinolone, triamcinolone, triamcinolone provides the method wherein the composition comprises acetonide, triamcinolone diacetonide, or clobetasol, and a about 16% ethanol by volume. Another embodiment provides pharmaceutically acceptable Salt thereof, or phosphate pro the method wherein the composition comprises from about 50 drug thereof, or ester prodrug thereof. Another embodiment 10% to about 15% ethanol by volume. Another embodiment provides the pharmaceutical composition wherein the second provides the method wherein the composition comprises active ingredient is a corticosteroid selected from hydrocor from about 10% to about 16% ethanol by volume. Another tisone, desonide, mometasone, triamcinolone, triamcinolone embodiment provides the method wherein the composition acetonide, triamcinolone diacetonide, fluocinolone or fluti comprises from about 10% to about 21% ethanol by volume. 55 casone; and a pharmaceutically acceptable salt thereof, or Another embodiment provides the method wherein the phosphate prodrug thereof, or ester prodrug thereof. Another composition comprises from about 20% to about 30% ethanol embodiment provides the pharmaceutical composition by volume. Another embodiment provides the method wherein the second active ingredient is hydrocortisone or a wherein the composition comprises from about 21% to about pharmaceutically acceptable Salt thereof, or phosphate pro 31% ethanol by volume. Another embodiment provides the 60 drug thereof, or ester prodrug thereof. Another embodiment method wherein the composition comprises about 25% etha provides the pharmaceutical composition wherein the second nol by volume. Another embodiment provides the method active ingredient is desonide, or a pharmaceutically accept wherein the composition comprises about 30% ethanol by able salt thereof, or phosphate prodrug thereof, or ester pro volume. Another embodiment provides the method wherein drug thereof. Another embodiment provides the pharmaceu the composition comprises about 31% ethanol by volume. 65 tical composition wherein the second active ingredient is Another embodiment provides the method wherein the com mometasone. Another embodiment provides the pharmaceu position comprises about 32% ethanol by volume. Another tical composition wherein the second active ingredient is US 8,647,671 B2 29 30 fluticasone, or a pharmaceutically acceptable salt thereof, or method wherein the composition is a non-homogenous phosphate prodrug thereof, or ester prodrug thereof. Another cream. Another embodiment provides the method wherein embodiment provides the pharmaceutical composition the composition is a non-homogenous ointment. Another wherein the second active ingredient is fluocinolone. Another embodiment provides the method wherein the composition is embodiment provides the pharmaceutical composition 5 a non-homogeneous emulsion. Another embodiment pro wherein the second active ingredient is triamcinolone. vides the method wherein the composition is a non-homog Another embodiment provides the method wherein the enous dispersion. Another embodiment provides the method second active ingredient is a corticosteroid. Another embodi wherein the composition is a non-homogenous cream or a ment provides the method wherein the second active ingre non-homogenous lotion. Another embodiment provides the dient is a corticosteroid selected from 21-acetoxypreg 10 nenolone, alclometasone, algestone, amcinonide, method wherein the composition is a non-homogenous beclomethasone, betamethasone, budesonide, chloropred lotion. Another embodiment provides the method wherein the nisone, clobetasol, clobetaSone, clocortolone, cloprednol, composition comprises from about 2% to about 10% isopro corticosterone, cortisone, cortivaZol, deflazacort, desonide, panol by volume. Another embodiment provides the method desoximetasone, dexamethasone, diflorasone, diflucor 15 wherein the composition comprises from about 10% to about tolone, difluprednate, enoXolone, fluazacort, flucloronide, 20% isopropanol by volume. Another embodiment provides flumethasone, flunisolide, fluocinolone acetonide, fluocino the method wherein the composition comprises from about nide, fluocortin butyl, fluocortolone, fluorometholone, flu 20% to about 30% isopropanol by volume. Another embodi perolone acetate, fluprednidene acetate, fluprednisolone, flu ment provides the method wherein the composition com randrenolide, fluticasone propionate, formocortal, prises from about 30% to about 40% isopropanol by volume. halcinonide, halobetasol propionate, halometasone, halopre Another embodiment provides the method wherein the com done acetate, hydrocortamate, hydrocortisone, loteprednol position comprises from about 40% to about 50% isopro etabonate, maZipredone, medrysone, meprednisone, methyl panol by volume. Another embodiment provides the method prednisolone, mometasone furoate, paramethasone, predni wherein the composition comprises from about 50% to about carbate, prednisolone, prednisolone 25-diethylamino-ac 25 59.9% isopropanol by volume. etate, prednisolone sodium phosphate, prednisone, prednival, In some of the methods of treatment disclosed herein, the prednylidene, rimexolone, tiXocortol, triamcinolone, triamci ratio of ethanol to the second active ingredient in the non nolone acetonide, triamcinolone benetonide, and triamcino homogeneous composition is fixed during the course of treat lone hexacetonide, or a phosphate or ester prodrug thereof. ment. In some of the methods of treatment disclosed herein, Another embodiment provides the method wherein the 30 the ratio of ethanol to the second active ingredient in the second active ingredient is a corticosteroid selected from non-homogeneous composition varies as directed by a phy hydrocortisone, desonide, mometasone, betamethasone, flu sician during the course of treatment. Topical application of ticasone, triamcinolone, fluocinolone or clobetasol. Another the non-homogeneous composition can occur one to four embodiment provides the method wherein the second active times a day or as directed by a physician. The duration of ingredient is a corticosteroid selected from hydrocortisone, 35 treatment can vary from one to four weeks or as directed by a desonide, mometasone, fluocinolone, triamcinolone or fluti physician. In some of the methods of treatment disclosed casone. Another embodiment provides the method wherein herein, a non-homogeneous composition comprising ethanol the second active ingredient is hydrocortisone. Another and a second active ingredient is topically applied during the embodiment provides the method wherein the second active initial course of treatment prior to replacement with another ingredient is desonide. Another embodiment provides the 40 non-homogeneous composition comprising ethanol as main method wherein the second active ingredient is mometasone. tenance therapy. The course of treatment can optionally Another embodiment provides the method wherein the sec include pre-treatment of the area with Soap and water and/or ond active ingredient is fluticasone. Another embodiment occlusion of the treatment area Subsequent to application of provides the method wherein the second active ingredient is the non-homogeneous composition described herein. fluocinolone. Another embodiment provides the method 45 One embodiment provides the method of treating a skin wherein the second active ingredient is triamcinolone. disease or disorder in an individual comprising topical appli Another embodiment provides the method wherein topical cation of a non-homogeneous pharmaceutical composition application of the pharmaceutical composition does not irri suitable for topical administration from one to four times a tate the skin. Another embodiment provides the method day comprising a fixed ratio of the ethanol and the second wherein topical application of the pharmaceutical composi 50 active ingredient during the duration of treatment. Another tion does not cause subjective irritation of the skin. Another embodiment provides the method wherein the duration of embodiment provides the method wherein topical application treatment is two weeks. Another embodiment provides the of the pharmaceutical composition does not cause a stinging method wherein the duration of treatment is three weeks. sensation. Another embodiment provides the method wherein the dura Another embodiment provides a method of treating a skin 55 tion of treatment is four weeks. Another embodiment pro disease or disorder in an individual comprising topical appli vides the method wherein the topical administration is once a cation of a pharmaceutical composition Suitable for topical day. Another embodiment provides the method wherein the administration comprising from about 2% to no more than topical administration is twice a day. Another embodiment 59.9% isopropanol by volume, a second active ingredient, provides the method wherein the topical administration is and at least one excipient wherein the composition is a non 60 three times a day. Another embodiment provides the method homogeneous semisolid. Another embodiment provides the wherein the topical administration is four times a day. method wherein the composition is a non-homogenous semi Another embodiment provides the method of treating a skin solid dispersion. Another embodiment provides the method disease or disorder in an individual comprising topical appli wherein the composition is a non-homogenous semisolid cation of a pharmaceutical composition Suitable for topical emulsion. Another embodiment provides the method wherein 65 administration as directed by a physician comprising a fixed the composition is a non-homogenous cream or a non-ho ratio of the ethanol and the second active ingredient during mogenous ointment. Another embodiment provides the the duration of treatment. US 8,647,671 B2 31 32 Another embodiment provides the method wherein the embodiment provides the method wherein the initial percent non-homogeneous composition comprising a fixed ratio of age of ethanol is 7% and the final percentage of ethanol is the ethanol and the second active ingredient contains 5% 31% during the duration of treatment. Another embodiment ethanol by volume. Another embodiment provides the provides the method wherein the initial percentage of ethanol method wherein the non-homogeneous composition com is 10% and the final percentage of ethanol is 31% during the prising a fixed ratio of the ethanol and the second active duration of treatment. Another embodiment provides the ingredient contains 6% ethanol by volume. Another embodi method wherein the initial percentage of ethanol is about 5% ment provides the method wherein the non-homogeneous to about 10% and the final percentage of ethanol is 31% composition comprising a fixed ratio of the ethanol and the during the duration of treatment. second active ingredient contains 7% ethanol by Volume. 10 Compositions for the Treatment of Skin Diseases and Disor Another embodiment provides the method wherein the non ders homogeneous composition comprising a fixed ratio of the The compositions and chemical matrices described herein ethanol and the second active ingredient contains 10% etha are non-homogenous. In particular, it has been found that nol by volume. Another embodiment provides the method when the alcohol, selected from ethanol, propanol, or iso wherein the non-homogeneous composition comprising a 15 propanol, is distributed in a non-homogenous fashion fixed ratio of the ethanol and the second active ingredient throughout the bulk of the composition or matrix into bubble contains 12% ethanol by volume. Another embodiment pro like regions of locally high concentration, referred to herein vides the method wherein the non-homogeneous composi as microbubbles, wherein the approximate effective concen tion comprising a fixed ratio of the ethanol and the second tration of the alcohol inside the microbubbles is about 60% to active ingredient contains 16% ethanol by volume. Another about 80%, a beneficial effect is observed upon topical appli embodiment provides the method wherein the non-homoge cation to damaged skin but without a stinging sensation. In neous composition comprising a fixed ratio of the ethanol and the compositions described herein, a key aspect is the role of the second active ingredient contains 21% ethanol by Volume. the alcohol. The alcohol, selected from ethanol, propanol, or Another embodiment provides the method wherein the non iso-propanol, functions as an active ingredient of the compo homogeneous composition comprising a fixed ratio of the 25 sition having an antiseptic activity and not merely as a solvent ethanol and the second active ingredient contains 31% etha or excipient. nol by volume. One embodiment provides a chemical matrix comprising Another embodiment provides the method of treating a from about 2% to about 30% of an alcohol by volume, a skin disease or disorder in an individual comprising topical corticosteroid and at least one excipient, wherein the chemi application of a non-homogeneous pharmaceutical composi 30 cal matrix is an ointment Suitable for topical administration, tion suitable for topical administration from one to four times the alcohol is primarily dispersed into the chemical matrix in a day as part of a progressive ratio therapy in which the the form of microbubbles, the alcohol is selected from etha percentage of ethanol is increased every 2-3 days during the nol, isopropanol, or n-propanol, or combinations thereof, and duration of treatment. Another embodiment provides the the corticosteroid is present in a concentration between about method wherein the duration of treatment is two weeks. 35 1% and about 91% of the standardized topical corticosteroid Another embodiment provides the method wherein the dura concentration. Another embodiment provides the chemical tion of treatment is three weeks. Another embodiment pro matrix wherein the corticosteroid is presentina concentration vides the method wherein the duration of treatment is four between about 1% and about 85% of the standardized topical weeks. Another embodiment provides the method wherein corticosteroid concentration. Another embodiment provides the topical administration is once a day. Another embodiment 40 the chemical matrix wherein the corticosteroid is present in a provides the method wherein the topical administration is concentration between about 1% and about 75% of the stan twice a day. Another embodiment provides the method dardized topical corticosteroid concentration. Another wherein the topical administration is three times a day. embodiment provides the chemical matrix wherein the corti Another embodiment provides the method wherein the topi costeroid is present in a concentration between about 1% and cal administration is four times a day. Another embodiment 45 about 65% of the standardized topical corticosteroid concen provides the method of treating a skin disease or disorder in tration. Another embodiment provides the chemical matrix an individual comprising topical application of a pharmaceu wherein the corticosteroid is present in a concentration tical composition Suitable for topical administration as between about 1% and about 55% of the standardized topical directed by a physician during the duration of treatment. corticosteroid concentration. Another embodiment provides Another embodiment provides the method wherein the 50 the chemical matrix wherein the corticosteroid is present in a percentage of ethanol is increased every 2 days during the concentration between about 1% and about 45% of the stan duration of treatment. Another embodiment provides the dardized topical corticosteroid concentration. Another method wherein the percentage of ethanol is increased every embodiment provides the chemical matrix wherein the corti 3 days during the duration of treatment. Another embodiment costeroid is present in a concentration between about 1% and provides the method wherein the percentage of ethanol is 55 about 35% of the standardized topical corticosteroid concen increased when there is visible improvement of the skin con tration. Another embodiment provides the chemical matrix dition during the duration of treatment. Another embodiment wherein the corticosteroid is present in a concentration provides the method of treating a skin disease or disorder in between about 1% and about 25% of the standardized topical an individual comprising topical application of a non-homo corticosteroid concentration. Another embodiment provides geneous pharmaceutical composition Suitable for topical 60 the chemical matrix wherein the corticosteroid is present in a administration from one to four times a day as part of a concentration between about 1% and about 15% of the stan progressive ratio therapy in which the percentage of ethanol dardized topical corticosteroid concentration. Another was increased as directed by a physician during the duration embodiment provides the chemical matrix wherein the corti of treatment. costeroid is present in a concentration between about 10% Another embodiment provides the method wherein the 65 and about 91% of the standardized topical corticosteroid con initial percentage of ethanol is 5% and the final percentage of centration. Another embodiment provides the chemical ethanol is 31% during the duration of treatment. Another matrix wherein the corticosteroid is presentina concentration US 8,647,671 B2 33 34 between about 10% and about 85% of the standardized topi topical corticosteroid concentration is 0.05%. Another cal corticosteroid concentration. Another embodiment pro embodiment provides the chemical matrix wherein the des vides the chemical matrix wherein the corticosteroid is onide is present in an amount of about 0.0005%, about present in a concentration between about 10% and about 75% 0.0025%, about 0.005%, about 0.009%, about 0.02%, or of the standardized topical corticosteroid concentration. about 0.045%. Another embodiment provides the chemical Another embodiment provides the chemical matrix wherein matrix wherein the desonide is present in an amount of about the corticosteroid is present in a concentration between about 0.0025%, about 0.005%, about 0.01%, about 0.02%, about 10% and about 65% of the standardized topical corticosteroid 0.03%, or about 0.04%. Another embodiment provides the concentration. Another embodiment provides the chemical chemical matrix wherein the desonide is present in an amount matrix wherein the corticosteroid is presentina concentration 10 of about 0.005%, about 0.01%, about 0.015%, or about between about 10% and about 55% of the standardized topi O.O2%. cal corticosteroid concentration. Another embodiment pro Another embodiment provides the chemical matrix vides the chemical matrix wherein the corticosteroid is wherein the corticosteroid is mometasone and the standard present in a concentration between about 10% and about 45% ized topical corticosteroid concentration is 0.1%. Another of the standardized topical corticosteroid concentration. 15 embodiment provides the chemical matrix wherein the Another embodiment provides the chemical matrix wherein mometasone is present in an amount of about 0.001%, about the corticosteroid is present in a concentration between about 0.005%, about 0.01%, about 0.02%, about 0.04%, or about 10% and about 35% of the standardized topical corticosteroid 0.09%. Another embodiment provides the chemical matrix concentration. Another embodiment provides the chemical wherein the mometaSone is present in an amount of about matrix wherein the corticosteroid is presentina concentration 0.005%, about 0.01%, about 0.02%, about 0.03%, about between about 10% and about 25% of the standardized topi 0.04%, or about 0.05%. Another embodiment provides the cal corticosteroid concentration. Another embodiment pro chemical matrix wherein the mometasone is present in an vides the chemical matrix wherein the corticosteroid is amount of about 0.01%, about 0.02%, about 0.03%, or about present in a concentration between about 10% and about 15% O.04%. of the standardized topical corticosteroid concentration. 25 Another embodiment provides the chemical matrix Another embodiment provides the chemical matrix wherein wherein the alcohol is ethanol. Another embodiment provides the corticosteroid is present in a concentration between about the chemical matrix wherein the alcohol is isopropanol. 20% and about 91% of the standardized topical corticosteroid Another embodiment provides the chemical matrix wherein concentration. Another embodiment provides the chemical the alcohol is n-propanol. matrix wherein the corticosteroid is presentina concentration 30 Another embodiment provides the chemical matrix between about 20% and about 85% of the standardized topi wherein the ointment is selected from AQUAPHORR), white cal corticosteroid concentration. Another embodiment pro petrolatum USP, white ointment USP hydrophilic petrolatum vides the chemical matrix wherein the corticosteroid is USP or hydrophilic ointment USP present in a concentration between about 20% and about 75% Another embodiment provides the chemical matrix of the standardized topical corticosteroid concentration. 35 wherein the chemical matrix comprises from about 2% to Another embodiment provides the chemical matrix wherein about 10% ethanol by volume. Another embodiment provides the corticosteroid is present in a concentration between about the chemical matrix wherein the chemical matrix comprises 20% and about 65% of the standardized topical corticosteroid from about 10% to about 20% ethanol by volume. Another concentration. Another embodiment provides the chemical embodiment provides the chemical matrix wherein the matrix wherein the corticosteroid is presentina concentration 40 chemical matrix comprises from about 20% to about 30% between about 20% and about 55% of the standardized topi ethanol by volume. cal corticosteroid concentration. Another embodiment pro One embodiment provides a chemical matrix comprising vides the chemical matrix wherein the corticosteroid is from about 2% to about 30% of an alcohol by volume, a present in a concentration between about 20% and about 45% therapeutically effective amount of a corticosteroid and at of the standardized topical corticosteroid concentration. 45 least one excipient, wherein the chemical matrix is an oint Another embodiment provides the chemical matrix wherein ment Suitable for topical administration, the alcohol is prima the corticosteroid is present in a concentration between about rily dispersed into the chemical matrix in the form of 20% and about 35% of the standardized topical corticosteroid microbubbles, the alcohol is selected from ethanol, isopro concentration. Another embodiment provides the chemical panol, or n-propanol, or combinations thereof, and the thera matrix wherein the corticosteroid is presentina concentration 50 peutically effective amount of a corticosteroid is between between about 20% and about 25% of the standardized topi about 1% and about 91% of the standardized topical corticos cal corticosteroid concentration. teroid concentration. Another embodiment provides the Another embodiment provides the chemical matrix chemical matrix wherein the corticosteroid is present in a wherein the corticosteroid is present in a concentration of concentration between about 1% and about 85% of the stan about 1%, about 5%, about 10%, about 15%, about 25%, 55 dardized topical corticosteroid concentration. Another about 35%, about 50%, about 65%, about 75%, about 85%, or embodiment provides the chemical matrix wherein the corti about 91% of the standardized topical corticosteroid concen costeroid is present in a concentration between about 1% and tration. Another embodiment provides the chemical matrix about 75% of the standardized topical corticosteroid concen wherein the corticosteroid is present in a concentration of tration. Another embodiment provides the chemical matrix about 1%, about 5%, about 10%, about 15%, or about 25% of 60 wherein the corticosteroid is present in a concentration the standardized topical corticosteroid concentration. between about 1% and about 65% of the standardized topical Another embodiment provides the chemical matrix wherein corticosteroid concentration. Another embodiment provides the corticosteroid is present in a concentration of about 10%, the chemical matrix wherein the corticosteroid is present in a about 15%, about 25%, or about 35% of the standardized concentration between about 1% and about 55% of the stan topical corticosteroid concentration. 65 dardized topical corticosteroid concentration. Another Another embodiment provides the chemical matrix embodiment provides the chemical matrix wherein the corti wherein the corticosteroid is desonide and the standardized costeroid is present in a concentration between about 1% and US 8,647,671 B2 35 36 about 45% of the standardized topical corticosteroid concen present in a concentration between about 20% and about 25% tration. Another embodiment provides the chemical matrix of the standardized topical corticosteroid concentration. wherein the corticosteroid is present in a concentration Another embodiment provides the chemical matrix between about 1% and about 35% of the standardized topical wherein the therapeutically effective amount of a corticoster corticosteroid concentration. Another embodiment provides oid is about 1%, about 5%, about 10%, about 15%, about the chemical matrix wherein the corticosteroid is present in a 25%, about 35%, about 50%, about 65%, about 75%, about concentration between about 1% and about 25% of the stan 85%, or about 91% of the standardized topical corticosteroid dardized topical corticosteroid concentration. Another concentration. Another embodiment provides the chemical embodiment provides the chemical matrix wherein the corti matrix wherein the therapeutically effective amount of a cor 10 ticosteroid is present in a concentration between about 1%, costeroid is present in a concentration between about 1% and about 5%, about 10%, about 15%, or about 25% of the stan about 15% of the standardized topical corticosteroid concen dardized topical corticosteroid concentration. Another tration. Another embodiment provides the chemical matrix embodiment provides the chemical matrix wherein the thera wherein the corticosteroid is present in a concentration peutically effective amount of a corticosteroid is present in a between about 10% and about 91% of the standardized topi 15 concentration between about 10%, about 15%, about 25%, or cal corticosteroid concentration. Another embodiment pro about 35% of the standardized topical corticosteroid concen vides the chemical matrix wherein the corticosteroid is tration. present in a concentration between about 10% and about 85% Another embodiment provides the chemical matrix of the standardized topical corticosteroid concentration. wherein the corticosteroid is desonide and the standardized Another embodiment provides the chemical matrix wherein topical corticosteroid concentration is 0.05%. Another the corticosteroid is present in a concentration between about embodiment provides the chemical matrix wherein the des 10% and about 75% of the standardized topical corticosteroid onide is present in an amount of about 0.0005%, about concentration. Another embodiment provides the chemical 0.0025%, about 0.005%, about 0.009%, about 0.02%, or matrix wherein the corticosteroid is presentina concentration about 0.045%. Another embodiment provides the chemical between about 10% and about 65% of the standardized topi 25 matrix wherein the desonide is present in an amount of about cal corticosteroid concentration. Another embodiment pro 0.0025%, about 0.005%, about 0.01%, about 0.02%, about vides the chemical matrix wherein the corticosteroid is 0.03%, or about 0.04%. Another embodiment provides the present in a concentration between about 10% and about 55% chemical matrix wherein the desonide is present in an amount of the standardized topical corticosteroid concentration. of about 0.005%, about 0.01%, about 0.015%, or about Another embodiment provides the chemical matrix wherein 30 O.O2%. the corticosteroid is present in a concentration between about Another embodiment provides the chemical matrix 10% and about 45% of the standardized topical corticosteroid wherein the corticosteroid is mometasone and the standard concentration. Another embodiment provides the chemical ized topical corticosteroid concentration is 0.1%. Another matrix wherein the corticosteroid is presentina concentration embodiment provides the chemical matrix wherein the between about 10% and about 35% of the standardized topi 35 mometasone is present in an amount of about 0.001%, about cal corticosteroid concentration. Another embodiment pro 0.005%, about 0.01%, about 0.02%, about 0.04%, or about vides the chemical matrix wherein the corticosteroid is 0.09%. Another embodiment provides the chemical matrix present in a concentration between about 10% and about 25% wherein the mometaSone is present in an amount of about of the standardized topical corticosteroid concentration. 0.005%, about 0.01%, about 0.02%, about 0.03%, about Another embodiment provides the chemical matrix wherein 40 0.04%, or about 0.05%. Another embodiment provides the the corticosteroid is present in a concentration between about chemical matrix wherein the mometasone is present in an 10% and about 15% of the standardized topical corticosteroid amount of about 0.01%, about 0.02%, about 0.03%, or about concentration. Another embodiment provides the chemical O.04%. matrix wherein the corticosteroid is presentina concentration Another embodiment provides the chemical matrix between about 20% and about 91% of the standardized topi 45 wherein the alcohol is ethanol. Another embodiment provides cal corticosteroid concentration. Another embodiment pro the chemical matrix wherein the alcohol is isopropanol. vides the chemical matrix wherein the corticosteroid is Another embodiment provides the chemical matrix wherein present in a concentration between about 20% and about 85% the alcohol is n-propanol. Another embodiment provides the of the standardized topical corticosteroid concentration. chemical matrix wherein the ointment is selected from Another embodiment provides the chemical matrix wherein 50 AQUAPHORR), white petrolatum USP, white ointment USP the corticosteroid is present in a concentration between about hydrophilic petrolatum USP or hydrophilic ointment USP 20% and about 75% of the standardized topical corticosteroid Another embodiment provides the chemical matrix concentration. Another embodiment provides the chemical wherein the chemical matrix comprises from about 2% to matrix wherein the corticosteroid is presentina concentration about 10% ethanol by volume. Another embodiment provides between about 20% and about 65% of the standardized topi 55 the chemical matrix wherein the chemical matrix comprises cal corticosteroid concentration. Another embodiment pro from about 10% to about 20% ethanol by volume. Another vides the chemical matrix wherein the corticosteroid is embodiment provides the chemical matrix wherein the present in a concentration between about 20% and about 55% chemical matrix comprises from about 20% to about 30% of the standardized topical corticosteroid concentration. ethanol by volume. Another embodiment provides the chemical matrix wherein 60 One embodiment provides a chemical matrix comprising the corticosteroid is present in a concentration between about from about 2% to about 30% of an alcohol by volume, a 20% and about 45% of the standardized topical corticosteroid corticosteroid and at least one excipient, wherein the chemi concentration. Another embodiment provides the chemical cal matrix is a cream Suitable for topical administration, the matrix wherein the corticosteroid is presentina concentration alcohol is primarily dispersed into the chemical matrix in the between about 20% and about 35% of the standardized topi 65 form of microbubbles, the alcohol is selected from ethanol, cal corticosteroid concentration. Another embodiment pro isopropanol, or n-propanol, or combinations thereof, and the vides the chemical matrix wherein the corticosteroid is corticosteroid is present in a concentration between about 1% US 8,647,671 B2 37 38 and about 91% of the standardized topical corticosteroid con of the standardized topical corticosteroid concentration. centration. Another embodiment provides the chemical Another embodiment provides the chemical matrix wherein matrix wherein the corticosteroid is presentina concentration the corticosteroid is present in a concentration between about between about 1% and about 85% of the standardized topical 20% and about 65% of the standardized topical corticosteroid corticosteroid concentration. Another embodiment provides concentration. Another embodiment provides the chemical the chemical matrix wherein the corticosteroid is present in a matrix wherein the corticosteroid is presentina concentration concentration between about 1% and about 75% of the stan between about 20% and about 55% of the standardized topi dardized topical corticosteroid concentration. Another cal corticosteroid concentration. Another embodiment pro embodiment provides the chemical matrix wherein the corti vides the chemical matrix wherein the corticosteroid is costeroid is present in a concentration between about 1% and 10 present in a concentration between about 20% and about 45% about 65% of the standardized topical corticosteroid concen of the standardized topical corticosteroid concentration. tration. Another embodiment provides the chemical matrix Another embodiment provides the chemical matrix wherein wherein the corticosteroid is present in a concentration the corticosteroid is present in a concentration between about between about 1% and about 55% of the standardized topical 20% and about 35% of the standardized topical corticosteroid corticosteroid concentration. Another embodiment provides 15 concentration. Another embodiment provides the chemical the chemical matrix wherein the corticosteroid is present in a matrix wherein the corticosteroid is presentina concentration concentration between about 1% and about 45% of the stan between about 20% and about 25% of the standardized topi dardized topical corticosteroid concentration. Another cal corticosteroid concentration. embodiment provides the chemical matrix wherein the corti Another embodiment provides the chemical matrix costeroid is present in a concentration between about 1% and wherein the corticosteroid is present in a concentration of about 35% of the standardized topical corticosteroid concen about 1%, about 5%, about 10%, about 15%, about 25%, tration. Another embodiment provides the chemical matrix about 35%, about 50%, about 65%, about 75%, about 85%, or wherein the corticosteroid is present in a concentration about 91% of the standardized topical corticosteroid concen between about 1% and about 25% of the standardized topical tration. Another embodiment provides the chemical matrix corticosteroid concentration. Another embodiment provides 25 wherein the corticosteroid is present in a concentration of the chemical matrix wherein the corticosteroid is present in a about 1%, about 5%, about 10%, about 15%, or about 25% of concentration between about 1% and about 15% of the stan the standardized topical corticosteroid concentration. dardized topical corticosteroid concentration. Another Another embodiment provides the chemical matrix wherein embodiment provides the chemical matrix wherein the corti the corticosteroid is present in a concentration of about 10%, costeroid is present in a concentration between about 10% 30 about 15%, about 25%, or about 35% of the standardized and about 91% of the standardized topical corticosteroid con topical corticosteroid concentration. centration. Another embodiment provides the chemical Another embodiment provides the chemical matrix matrix wherein the corticosteroid is presentina concentration wherein the corticosteroid is desonide and the standardized between about 10% and about 85% of the standardized topi topical corticosteroid concentration is 0.05%. Another cal corticosteroid concentration. Another embodiment pro 35 embodiment provides the chemical matrix wherein the des vides the chemical matrix wherein the corticosteroid is onide is present in an amount of about 0.0005%, about present in a concentration between about 10% and about 75% 0.0025%, about 0.005%, about 0.009%, about 0.02%, or of the standardized topical corticosteroid concentration. about 0.045%. Another embodiment provides the chemical Another embodiment provides the chemical matrix wherein matrix wherein the desonide is present in an amount of about the corticosteroid is present in a concentration between about 40 0.0025%, about 0.005%, about 0.01%, about 0.02%, about 10% and about 65% of the standardized topical corticosteroid 0.03%, or about 0.04%. Another embodiment provides the concentration. Another embodiment provides the chemical chemical matrix wherein the desonide is present in an amount matrix wherein the corticosteroid is presentina concentration of about 0.005%, about 0.01%, about 0.015%, or about between about 10% and about 55% of the standardized topi O.O2%. cal corticosteroid concentration. Another embodiment pro 45 Another embodiment provides the chemical matrix vides the chemical matrix wherein the corticosteroid is wherein the corticosteroid is mometasone and the standard present in a concentration between about 10% and about 45% ized topical corticosteroid concentration is 0.1%. Another of the standardized topical corticosteroid concentration. embodiment provides the chemical matrix wherein the Another embodiment provides the chemical matrix wherein mometasone is present in an amount of about 0.001%, about the corticosteroid is present in a concentration between about 50 0.005%, about 0.01%, about 0.02%, about 0.04%, or about 10% and about 35% of the standardized topical corticosteroid 0.09%. Another embodiment provides the chemical matrix concentration. Another embodiment provides the chemical wherein the mometaSone is present in an amount of about matrix wherein the corticosteroid is presentina concentration 0.005%, about 0.01%, about 0.02%, about 0.03%, about between about 10% and about 25% of the standardized topi 0.04%, or about 0.05%. Another embodiment provides the cal corticosteroid concentration. Another embodiment pro 55 chemical matrix wherein the mometasone is present in an vides the chemical matrix wherein the corticosteroid is amount of about 0.01%, about 0.02%, about 0.03%, or about present in a concentration between about 10% and about 15% O.04%. of the standardized topical corticosteroid concentration. Another embodiment provides the chemical matrix Another embodiment provides the chemical matrix wherein wherein the alcohol is ethanol. Another embodiment provides the corticosteroid is present in a concentration between about 60 the chemical matrix wherein the alcohol is isopropanol. 20% and about 91% of the standardized topical corticosteroid Another embodiment provides the chemical matrix wherein concentration. Another embodiment provides the chemical the alcohol is n-propanol. matrix wherein the corticosteroid is presentina concentration Another embodiment provides the chemical matrix between about 20% and about 85% of the standardized topi wherein the chemical matrix comprises from about 2% to cal corticosteroid concentration. Another embodiment pro 65 about 10% ethanol by volume. Another embodiment provides vides the chemical matrix wherein the corticosteroid is the chemical matrix wherein the chemical matrix comprises present in a concentration between about 20% and about 75% from about 10% to about 20% ethanol by volume. Another US 8,647,671 B2 39 40 embodiment provides the chemical matrix wherein the Another embodiment provides the chemical matrix wherein chemical matrix comprises from about 20% to about 30% the corticosteroid is present in a concentration between about ethanol by volume. 10% and about 15% of the standardized topical corticosteroid One embodiment provides a chemical matrix comprising concentration. Another embodiment provides the chemical from about 2% to about 30% of an alcohol by volume, a matrix wherein the corticosteroid is presentina concentration therapeutically effective amount of a corticosteroid and at between about 20% and about 91% of the standardized topi least one excipient, wherein the chemical matrix is a cream cal corticosteroid concentration. Another embodiment pro Suitable for topical administration, the alcohol is primarily vides the chemical matrix wherein the corticosteroid is dispersed into the chemical matrix in the form of present in a concentration between about 20% and about 85% microbubbles, the alcohol is selected from ethanol, isopro 10 of the standardized topical corticosteroid concentration. panol, or n-propanol, or combinations thereof, and the thera Another embodiment provides the chemical matrix wherein peutically effective amount of a corticosteroid is between the corticosteroid is present in a concentration between about about 1% and about 91% of the standardized topical corticos 20% and about 75% of the standardized topical corticosteroid teroid concentration. Another embodiment provides the concentration. Another embodiment provides the chemical chemical matrix wherein the corticosteroid is present in a 15 matrix wherein the corticosteroid is presentina concentration concentration between about 1% and about 85% of the stan between about 20% and about 65% of the standardized topi dardized topical corticosteroid concentration. Another cal corticosteroid concentration. Another embodiment pro embodiment provides the chemical matrix wherein the corti vides the chemical matrix wherein the corticosteroid is costeroid is present in a concentration between about 1% and present in a concentration between about 20% and about 55% about 75% of the standardized topical corticosteroid concen of the standardized topical corticosteroid concentration. tration. Another embodiment provides the chemical matrix Another embodiment provides the chemical matrix wherein wherein the corticosteroid is present in a concentration the corticosteroid is present in a concentration between about between about 1% and about 65% of the standardized topical 20% and about 45% of the standardized topical corticosteroid corticosteroid concentration. Another embodiment provides concentration. Another embodiment provides the chemical the chemical matrix wherein the corticosteroid is present in a 25 matrix wherein the corticosteroid is presentina concentration concentration between about 1% and about 55% of the stan between about 20% and about 35% of the standardized topi dardized topical corticosteroid concentration. Another cal corticosteroid concentration. Another embodiment pro embodiment provides the chemical matrix wherein the corti vides the chemical matrix wherein the corticosteroid is costeroid is present in a concentration between about 1% and present in a concentration between about 20% and about 25% about 45% of the standardized topical corticosteroid concen 30 of the standardized topical corticosteroid concentration. tration. Another embodiment provides the chemical matrix Another embodiment provides the chemical matrix wherein the corticosteroid is present in a concentration wherein the therapeutically effective amount of a corticoster between about 1% and about 35% of the standardized topical oid is about 1%, about 5%, about 10%, about 15%, about corticosteroid concentration. Another embodiment provides 25%, about 35%, about 50%, about 65%, about 75%, about the chemical matrix wherein the corticosteroid is present in a 35 85%, or about 91% of the standardized topical corticosteroid concentration between about 1% and about 25% of the stan concentration. Another embodiment provides the chemical dardized topical corticosteroid concentration. Another matrix wherein the therapeutically effective amount of a cor embodiment provides the chemical matrix wherein the corti ticosteroid is present in a concentration between about 1%, costeroid is present in a concentration between about 1% and about 5%, about 10%, about 15%, or about 25% of the stan about 15% of the standardized topical corticosteroid concen 40 dardized topical corticosteroid concentration. Another tration. Another embodiment provides the chemical matrix embodiment provides the chemical matrix wherein the thera wherein the corticosteroid is present in a concentration peutically effective amount of a corticosteroid is present in a between about 10% and about 91% of the standardized topi concentration between about 10%, about 15%, about 25%, or cal corticosteroid concentration. Another embodiment pro about 35% of the standardized topical corticosteroid concen vides the chemical matrix wherein the corticosteroid is 45 tration. present in a concentration between about 10% and about 85% Another embodiment provides the chemical matrix of the standardized topical corticosteroid concentration. wherein the corticosteroid is desonide and the standardized Another embodiment provides the chemical matrix wherein topical corticosteroid concentration is 0.05%. Another the corticosteroid is present in a concentration between about embodiment provides the chemical matrix wherein the des 10% and about 75% of the standardized topical corticosteroid 50 onide is present in an amount of about 0.0005%, about concentration. Another embodiment provides the chemical 0.0025%, about 0.005%, about 0.009%, about 0.02%, or matrix wherein the corticosteroid is presentina concentration about 0.045%. Another embodiment provides the chemical between about 10% and about 65% of the standardized topi matrix wherein the desonide is present in an amount of about cal corticosteroid concentration. Another embodiment pro 0.0025%, about 0.005%, about 0.01%, about 0.02%, about vides the chemical matrix wherein the corticosteroid is 55 0.03%, or about 0.04%. Another embodiment provides the present in a concentration between about 10% and about 55% chemical matrix wherein the desonide is present in an amount of the standardized topical corticosteroid concentration. of about 0.005%, about 0.01%, about 0.015%, or about Another embodiment provides the chemical matrix wherein O.O2%. the corticosteroid is present in a concentration between about Another embodiment provides the chemical matrix 10% and about 45% of the standardized topical corticosteroid 60 wherein the corticosteroid is mometasone and the standard concentration. Another embodiment provides the chemical ized topical corticosteroid concentration is 0.1%. Another matrix wherein the corticosteroid is presentina concentration embodiment provides the chemical matrix wherein the between about 10% and about 35% of the standardized topi mometasone is present in an amount of about 0.001%, about cal corticosteroid concentration. Another embodiment pro 0.005%, about 0.01%, about 0.02%, about 0.04%, or about vides the chemical matrix wherein the corticosteroid is 65 0.09%. Another embodiment provides the chemical matrix present in a concentration between about 10% and about 25% wherein the mometaSone is present in an amount of about of the standardized topical corticosteroid concentration. 0.005%, about 0.01%, about 0.02%, about 0.03%, about US 8,647,671 B2 41 42 0.04%, or about 0.05%. Another embodiment provides the and the corticosteroid is selected from desonide or mometa chemical matrix wherein the mometasone is present in an Sone. Another embodiment provides the chemical matrix amount of about 0.01%, about 0.02%, about 0.03%, or about wherein the chemical matrix comprises from about 20% to O.04%. about 30% ethanol by volume and the corticosteroid is Another embodiment provides the chemical matrix selected from desonide or mometasone. wherein the alcohol is ethanol. Another embodiment provides Another embodiment provides the chemical matrix the chemical matrix wherein the alcohol is isopropanol. wherein the chemical matrix comprises from about 2% to Another embodiment provides the chemical matrix wherein about 10% ethanol by volume, the corticosteroid is selected the alcohol is n-propanol. from desonide or mometasone, and the corticosteroid com Another embodiment provides the chemical matrix 10 prises from about 0.1% (w/w) to about 0.0001% (w/w) of the wherein the chemical matrix comprises from about 2% to chemical matrix. Another embodiment provides the chemical about 10% ethanol by volume. Another embodiment provides matrix wherein the chemical matrix comprises from about the chemical matrix wherein the chemical matrix comprises 10% to about 20% ethanol by volume, the corticosteroid is from about 10% to about 20% ethanol by volume. Another selected from desonide or mometaSone, and the corticoster embodiment provides the chemical matrix wherein the 15 oid comprises from about 0.1% (w/w) to about 0.0001% chemical matrix comprises from about 20% to about 30% (w/w) of the chemical matrix. Another embodiment provides ethanol by volume. the chemical matrix wherein the chemical matrix comprises In some embodiments, the microbubbles are dispersed into from about 20% to about 30% ethanol by volume, the corti a chemical matrix which is an ointment. In other embodi costeroid is selected from desonide or mometaSone, and the ments, the microbubbles are dispersed into a chemical matrix corticosteroid comprises from about 0.1% (w/w) to about which is a semi-solid. In other embodiments, the 0.0001% (w/w) of the chemical matrix. microbubbles are dispersed into a chemical matrix which is a Another embodiment provides the chemical matrix CCa. wherein the alcohol is 1-propanol. Another embodiment pro One embodiment provides a chemical matrix comprising vides the chemical matrix wherein the corticosteroid is from about 2% to about 30% of an alcohol by volume, a 25 selected from desonide or mometasone. Another embodiment corticosteroid and at least one excipient, wherein the chemi provides the chemical matrix wherein the chemical matrix cal matrix is an ointment Suitable for topical administration, comprises from about 2% to about 10% 1-propanol by vol the alcohol is primarily dispersed into the chemical matrix in ume. Another embodiment provides the chemical matrix the form of microbubbles, and the alcohol is selected from wherein the chemical matrix comprises from about 10% to ethanol, isopropanol, or n-propanol. 30 about 20% 1-propanol by volume. Another embodiment pro Another embodiment provides the chemical matrix vides the chemical matrix wherein the chemical matrix com wherein the alcohol is ethanol. Another embodiment provides prises from about 20% to about 30% 1-propanol by volume. the chemical matrix wherein the chemical matrix comprises Another embodiment provides the chemical matrix wherein from about 2% to about 10% ethanol by volume. Another the corticosteroid is selected from desonide or mometasone. embodiment provides the chemical matrix wherein the 35 Another embodiment provides the chemical matrix chemical matrix comprises from about 10% to about 20% wherein the alcohol is 2-propanol. Another embodiment pro ethanol by volume. Another embodiment provides the chemi vides the chemical matrix wherein the corticosteroid is cal matrix wherein the chemical matrix comprises from about selected from desonide or mometasone. Another embodiment 20% to about 30% ethanol by volume. provides the chemical matrix wherein the chemical matrix Another embodiment provides the chemical matrix 40 comprises from about 2% to about 10% 2-propanol by vol wherein the ointment is selected from AQUAPHORR), white ume. Another embodiment provides the chemical matrix petrolatum USP, white ointment USP hydrophilic petrolatum wherein the chemical matrix comprises from about 10% to USP or hydrophilic ointment USP about 20% 2-propanol by volume. Another embodiment pro Another embodiment provides the chemical matrix vides the chemical matrix wherein the chemical matrix com wherein the corticosteroid is selected from desonide or 45 prises from about 20% to about 30% 2-propanol by volume. mometasone. Another embodiment provides the chemical Another embodiment provides the chemical matrix wherein matrix wherein the corticosteroid comprises from about 0.1% the corticosteroid is selected from desonide or mometasone. (w/w) to about 0.0001% (w/w) of the chemical matrix. Another embodiment provides the chemical matrix wherein Another embodiment provides the chemical matrix wherein the corticosteroid is selected from desonide or mometasone. the corticosteroid comprises from about 0.1% (w/w) to about 50 Another embodiment provides the chemical matrix wherein 0.001% (w/w) of the chemical matrix. Another embodiment the corticosteroid is selected from desonide or mometasone. provides the chemical matrix wherein the corticosteroid com One embodiment provides a pharmaceutical composition prises from about 0.1% (w/w) to about 0.01% (w/w) of the Suitable for topical administration comprising from about 2% chemical matrix. Another embodiment provides the chemical to no more than 59.9% of an alcohol by volume, a second matrix wherein the corticosteroid comprises from about 0.1% 55 active ingredient and at least one excipient wherein said com (w/w) to about 0.005% (w/w) of the chemical matrix. Another position is a non-homogeneous semisolid and the alcohol is embodiment provides the chemical matrix wherein the corti selected from ethanol, isopropanol, or n-propanol. One costeroid comprises from about 0.1% (w/w) to about 0.05% embodiment provides a pharmaceutical composition Suitable (w/w) of the chemical matrix. Another embodiment provides for topical administration comprising from about 2% to no the chemical matrix wherein the corticosteroid comprises 60 more than 59.9% ethanol by volume, a second active ingre from about 0.05% (w/w) to about 0.005% (w/w) of the chemi dient and at least one excipient wherein said composition is a cal matrix. Another embodiment provides the chemical non-homogeneous semisolid. Another embodiment provides matrix wherein the chemical matrix comprises from about the pharmaceutical composition as a semisolid dispersion. 2% to about 10% ethanol by volume and the corticosteroid is Another embodiment provides the pharmaceutical composi selected from desonide or mometasone. Another embodiment 65 tion as a semisolid emulsion. Another embodiment provides provides the chemical matrix wherein the chemical matrix the pharmaceutical composition as a non-homogenous cream comprises from about 10% to about 20% ethanol by volume or a non-homogenous ointment. Another embodiment pro US 8,647,671 B2 43 44 vides the pharmaceutical composition as a non-homogenous selected from hydrocortisone, desonide, mometaSone, ointment. Another embodiment provides the pharmaceutical betamethasone, fluticaSone, fluocinolone, triamcinolone, tri composition as a non-homogenous cream. amcinolone acetonide, triamcinolone diacetonide, or clobe One embodiment provides a pharmaceutical composition tasol, and a pharmaceutically acceptable salt thereof, orphos Suitable for topical administration comprising from about 2% phate prodrug thereof, or ester prodrug thereof. Another to no more than 59.9% of an alcohol by volume, a second embodiment provides the pharmaceutical composition active ingredient and at least one excipient wherein said com wherein the second active ingredient is a corticosteroid position is a non-homogeneous emulsion and the alcohol is selected from hydrocortisone, desonide, mometaSone, triam selected from ethanol, isopropanol, or n-propanol. One cinolone, triamcinolone acetonide, triamcinolone diac embodiment provides a pharmaceutical composition Suitable 10 for topical administration comprising from about 2% to no etonide, fluocinolone or fluticasone; and a pharmaceutically more than 59.9% ethanol by volume, a second active ingre acceptable salt thereof, or phosphate prodrug thereof, or ester dient and at least one excipient wherein said composition is a prodrug thereof. Another embodiment provides the pharma non-homogenous emulsion. Another embodiment provides ceutical composition wherein the second active ingredient is the pharmaceutical composition as a dispersion. Another 15 hydrocortisone or a pharmaceutically acceptable salt thereof, embodiment provides the pharmaceutical composition as a or phosphate prodrug thereof, or ester prodrug thereof. non-homogenous cream or a non-homogenous lotion. Another embodiment provides the pharmaceutical composi Another embodiment provides the pharmaceutical composi tion wherein the second active ingredient is desonide, or a tion as a non-homogenous lotion. Another embodiment pro pharmaceutically acceptable Salt thereof, or phosphate pro vides the pharmaceutical composition as a non-homogenous drug thereof, or ester prodrug thereof. Another embodiment CCa. provides the pharmaceutical composition wherein the second Another embodiment provides the pharmaceutical compo active ingredient is mometasone. Another embodiment pro sition wherein the second active ingredient is selected from vides the pharmaceutical composition wherein the second salicylic acid, glycolic acid, benzoyl peroxide, Sulfur, resor active ingredient is fluticasone, or a pharmaceutically accept cinol, tretinoin, adapalene, tazarotene, clindamycin or eryth 25 able salt thereof, or phosphate prodrug thereof, or ester pro romycin. Another embodiment provides the pharmaceutical drug thereof. Another embodiment provides the pharmaceu composition wherein the second active ingredient is selected tical composition wherein the second active ingredient is from Salicylic acid, glycolic acid, benzoyl peroxide, Sulfur, fluocinolone. Another embodiment provides the pharmaceu resorcinol, tretinoin, adapalene, tazarotene, clindamycin, tical composition wherein the second active ingredient is erythromycin, metronidazole, or azelaic acid. Another 30 triamcinolone. embodiment provides the pharmaceutical composition The numerous corticosteroids have been classified by sev wherein the second active ingredient is selected from salicylic eral protocols. Classification by chemical structure is known acid, terbenafine, econazole, miconazole, clotrimazole, as the Coopman classification and is indicated below. butenafine, or tolnaftate. Another embodiment provides the Group A Hydrocortisone Type pharmaceutical composition wherein the second active is not 35 menthol. hydrocortisone, hydrocortisone acetate, cortisone acetate, Another embodiment provides the pharmaceutical compo tiXocortol pivalate, prednisolone, methylprednisolone, sition wherein the second active ingredient is a corticosteroid. and prednisone (short- to medium-acting glucocorti Another embodiment provides the pharmaceutical composi coids) tion wherein the second active ingredient is selected from a 40 Group B—Acetonides (and Related Substances) corticosteroid, tar derivatives, Salicylic acid, calcipotriene, or triamcinolone acetonide, triamcinolone alcohol, mometa anthralin. Sone, amcinonide, budesonide, desonide, fluocinonide, Another embodiment provides the pharmaceutical compo fluocinolone acetonide, and halcinonide sition wherein the second active ingredient is a corticosteroid Group C. Betamethasone Type selected from 21-acetoxypregnenolone, alclometasone, alge 45 betamethasone, betamethasone sodium phosphate, dexam stone, amcinonide, beclomethasone, betamethasone, budes ethasone, dexamethasone sodium phosphate, and fluo onide, chloroprednisone, clobetasol, clobetaSone, clocor cortolone tolone, cloprednol, corticosterone, cortisone, cortivaZol. Group D Esters deflazacort, desonide, desoximetaSone, dexamethasone, Group D1—Halogenated (Less Labile) diflorasone, diflucortolone, difluprednate, enoXolone, fluaza 50 hydrocortisone-17-Valerate, aclometaSone dipropionate, cort, flucloronide, flumethasone, flunisolide, fluocinolone betamethasone Valerate, betamethasone dipropionate, acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluo rometholone, fluperolone acetate, fluprednidene acetate, flu prednicarbate, clobetasone-17-butyrate, clobetasol-17 prednisolone, flurandrenolide, fluticasone propionate, for propionate, fluocortolone caproate, fluocortolone piv mocortal, halcinonide, halobetasol propionate, 55 alate, and fluprednidene acetate halometaSone, halopredone acetate, hydrocortamate, hydro Group D2—Labile Prodrug Esters cortisone, loteprednol etabonate, maZipredone, medrysone, hydrocortisone-17-butyrate, 17-aceponate, 17-buteprate, meprednisone, methylprednisolone, mometaSone furoate, and prednicarbate paramethasone, prednicarbate, prednisolone, prednisolone The Coopman classification is particularly useful in cases 25-diethylamino-acetate, prednisolone sodium phosphate, 60 where a certain corticosteroid serves an allergen. In this situ prednisone, prednival, prednylidene, rimexolone, tiXocortol, ation allergic reactions to one member of a class typically triamcinolone, triamcinolone acetonide, triamcinolone bene indicate an intolerance of all members of the class. tonide, triamcinolone diacetonide, and triamcinolone hexac An alternative classification protocol involves grouping by etonide; and a pharmaceutically acceptable salt thereof, or strength in an standard vasoconstriction assay (Ference and phosphate prodrug thereof, or ester prodrug thereof. 65 Last, Am Fam Physician. 2009, Jan. 15: 79(2):135-140). In Another embodiment provides the pharmaceutical compo this protocol, seven potency groups have been established sition wherein the second active ingredient is a corticosteroid ranging from high potency to low potency. US 8,647,671 B2 45 46 TABLE 1

Ultra high (I) Augmented betamethasone dipropionate 0.05% Standardized Clobetasol propionate 0.05% Topical Corticosteroid Concentration Diflorasone diacetate 0.05% Fluocinonide 0.1% AlclometaSone dipropionate Ung (Aclovate (R) O.OSO% Furandrenolide 0.05% Amcinonide Cr (Cyclocort (R) O. 100% High (II) Amcinonide 0.1% Amcinonide Ung (Cyclocort (R) O. 100% Augmented betamethasone dipropionate 0.05% Betamethasone dipropionate Aug Ung O.OSO% Betamethasone dipropionate 0.05% (Diprolene (R) Desoximetasone 0.25% Betamethasone dipropionate Ung (Diprolene (R) O.OSO% Diflorasone diacetate 0.05% 10 Betamethasone valerate Ung (Valisone (R) O. 100% Fluocinonide 0.05% Clobetasol propionate Cr (Temovate (R) O.OSO% Halcinonide 0.1% Clobetasol propionate Ung (Temovate (R) O.OSO% Halobetasol propionate 0.05% Clocortolone pivalate Cr (Cloderm (R) O. 100% Medium to high (III) Amcinonide 0.1% Desonide Cr O.OSO% Betamethasone dipropionate 0.05% Desonide Ung O.OSO% FluticasOne propionate 0.005% 15 Desoximetasone Ung (Topicort (R) O.250% Triamcinolone acetonide 0.5% Diflorasone diacetate Ung (Psorcon (R) O.OSO% Halobetasol propionate 0.05% Fluocinolone acetonide Ung (Synalar (R) O.025% Medium (IV and V) Betamethasone valerate 0.1% Fluocinonide Cr (Lidex (R) O.OSO% Desoximetasone 0.05% Fluocinonide Ung (Lidex (R) O.OSO% Fluocinolone acetonide 0.025% Flurandrenolide Cr (Cordran SP (R) O.OSO% FluticasOne propionate 0.05% FluticaSone propionate Ung (Cutivate (R) O.005% Hydrocortisone butyrate 0.1% Halobetasol propionate Cr (Ultravate (R) O.OSO% Hydrocortisone probutate 0.1% Halocinonide Cr (Halog (R) O. 100% Hydrocortisone valerate 0.2% Hydrocortisone Cr OTC 1.OOO% Mometasome furoate 0.1% Hydrocortisone Ung 2.5% Triamcinolone acetonide 0.025% Hydrocortisone butyrate Cr (Locoid (R) O. 100% Triamcinolone acetonide 0.1% Hydrocortisone butyrate Ung (Locoid (R) O. 100% Low (VI) Alclometasone dipropionate 0.05% 25 Hydrocortisone valerate Ung (Westcort (R) O.200% DeSonide 0.05% Mometasone Cr (Elocon (R) O. 100% Fluocinolone 0.01% Mometasone Ung (Elocon (R) O. 100% Hydrocortisone butyrate 0.1% Prednicarbate Ung (Dermatop (R) O. 100% Least potent (VII) Hydrocortisone 1%, 2.5% Triamcinolone acetonide Cr (Kenalog (R) O. 100% Triamcinolone acetonide Ung (Kenalog (R) O. 100% 30 Triamcinolone diacetate Ung (Aristocort (R) O. 100% Ultra-high-potency topical steroids should not be used continuously for longer than three weeks. Low- to high-po In some embodiments, the amount of corticosteroid tency topical steroids should not be used continuously for present in the formulation is equivalent to the FDA approved longer than three months to avoid side effects. Prolonged use wt %. In other embodiments, the amount of corticosteroid of topical corticosteroids may cause side effects. To reduce 35 the risk, the least potent steroid should be used for the shortest present in the formulation is about 100% of the FDA time, while still maintaining effectiveness. approved wt %. In other embodiments, the amount of corti In addition to allowing for the use of an antiseptic alcohol, costeroid present in the formulation is about 90% of the FDA Such as ethanol. 1-propanol, or 2-propanol, in a manner which approved wt %. In other embodiments, the amount of corti avoids stinging when applied to cracked or damaged skin, the 40 costeroid present in the formulation is about 80% of the FDA compositions and methods described herein allow for the use approved wt %. In other embodiments, the amount of corti of corticosteroids at lower concentrations than previously costeroid present in the formulation is about 70% of the FDA employed while maintaining efficacy. The benefits derived approved wt %. In other embodiments, the amount of corti from this treatment regimen at lower doses of corticosteroid costeroid present in the formulation is about 60% of the FDA 45 approved wt %. In other embodiments, the amount of corti are several. First, a lower dose or exposure level of corticos costeroid present in the formulation is about 50% of the FDA teroid will result infewer side effects from corticosteroid use. approved wt %. In other embodiments, the amount of corti Second, if lower doses or exposure levels are possible, the costeroid present in the formulation is about 40% of the FDA attending physician optionally elects to use a more potent approved wt %. In other embodiments, the amount of corti corticosteroid for difficult to treat cases. Also, the use of the 50 costeroid present in the formulation is about 30% of the FDA more potent corticosteroid allows for faster resolution of der approved wt %. In other embodiments, the amount of corti matological condition and an overall shortening of the period costeroid present in the formulation is about 20% of the FDA of time during which the patient is undergoing therapy. Thus, approved wt %. In other embodiments, the amount of corti one advantage of the compositions and methods described costeroid present in the formulation is about 10% of the FDA herein is that the compositions described herein provide equal 55 approved wt %. In other embodiments, the amount of corti or greater efficacy than currently accepted treatments but at a costeroid present in the formulation is about 5% of the FDA lower exposure level of corticosteroid to the patient. approved wt %. In other embodiments, the amount of corti Corticosteroids are provided in formulations suitable for costeroid present in the formulation is about 4% of the FDA topical administration. The standardized topical corticoster approved wt %. In other embodiments, the amount of corti oid concentrations are provided in the United States Pharma 60 costeroid present in the formulation is about 3% of the FDA copeia, which is hereby incorporated by reference in its approved wt %. In other embodiments, the amount of corti entirety. As used herein, the term standardized topical corti costeroid present in the formulation is about 2% of the FDA costeroid concentration is the same as United States Food and approved wt %. In other embodiments, the amount of corti Drug Administration (US FDA) approved concentration for costeroid present in the formulation is about 1% of the FDA topical use. Table 1 provides a Summary of Standardized 65 approved wt %. topical corticosteroid concentrations for many corticoster A feature of the non-homogenous chemical matrices and oids. compositions described herein is the compartmentalized or US 8,647,671 B2 47 48 segregated nature of the matrices and compositions. As wherein the composition comprises from about 10% to about described herein the alcohol, selected from ethanol, 1-pro 15% ethanol by volume. Another embodiment provides the panol or 2-propanol, is located primarily within the pharmaceutical composition wherein the composition com microbubbles and the microbubbles are dispersed into the prises from about 10% to about 16% ethanol by volume. chemical matrix. The corticosteroid or other second active Another embodiment provides the pharmaceutical composi ingredient, however, is dispersed primarily in the chemical tion wherein the composition comprises from about 10% to matrix and is not found substantially within the about 21% ethanol by volume. microbubbles. In some embodiments, at least 95% of the Another embodiment provides the pharmaceutical compo alcohol is located within the microbubble. In some embodi sition wherein the composition comprises from about 20% to ments, at least 90% of the alcohol is located within the 10 microbubble. In some embodiments, at least 85% of the alco about 30% ethanol by volume. Another embodiment provides hol is located within the microbubble. In some embodiments, the method wherein the composition comprises from about at least 80% of the alcohol is located within the microbubble. 21% to about 31% ethanol by volume. Another embodiment In some embodiments, at least 75% of the alcohol is located provides the pharmaceutical composition wherein the com within the microbubble. In some embodiments, at least 70% 15 position comprises about 25% ethanol by volume. Another of the alcohol is located within the microbubble. In some embodiment provides the pharmaceutical composition embodiments, at least 65% of the alcohol is located within the wherein the composition comprises about 30% ethanol by microbubble. In some embodiments, at least 60% of the alco Volume. Another embodiment provides the pharmaceutical hol is located within the microbubble. In some embodiments, composition wherein the composition comprises about 31% at least 55% of the alcohol is located within the microbubble. ethanol by volume. Another embodiment provides the phar In some embodiments, at least 50% of the alcohol is located maceutical composition wherein the composition comprises within the microbubble. about 32% ethanol by volume. Another embodiment provides Another embodiment provides the pharmaceutical compo the pharmaceutical composition wherein the composition sition wherein the composition comprises about 2% ethanol comprises from about 25% to about 30% ethanol by volume. by volume. Another embodiment provides the pharmaceuti 25 Another embodiment provides the pharmaceutical composi cal composition wherein the composition comprises about tion wherein the composition comprises from about 30% to 3% ethanol by volume. Another embodiment provides the about 35% ethanol by volume. Another embodiment provides pharmaceutical composition wherein the composition com the pharmaceutical composition wherein the composition prises about 4% ethanol by volume. Another embodiment comprises from about 30% to about 40% ethanol by volume. provides the pharmaceutical composition wherein the com 30 Another embodiment provides the pharmaceutical composi position comprises about 5% ethanol by volume. Another tion wherein the composition comprises from about 40% to embodiment provides the pharmaceutical composition about 50% ethanol by volume. Another embodiment provides wherein the composition comprises about 6% ethanol by the pharmaceutical composition wherein the composition Volume. Another embodiment provides the pharmaceutical comprises from about 50% to about 55% ethanol by volume. composition wherein the composition comprises about 7% 35 All non-homogeneous pharmaceutical compositions com ethanol by volume. Another embodiment provides the phar prising ethanol disclosed herein do not contain greater than maceutical composition wherein the composition comprises 59.9% ethanol. about 8% ethanol by volume. Another embodiment provides Another embodiment provides the pharmaceutical compo the pharmaceutical composition wherein the composition sition wherein the composition is non-comedogenic. comprises about 9% ethanol by volume. Another embodi 40 Another embodiment provides the pharmaceutical compo ment provides the pharmaceutical composition wherein the sition wherein topical application of the pharmaceutical com composition comprises about 10% ethanol by volume. position does not irritate the skin. Another embodiment pro Another embodiment provides the pharmaceutical composi vides the pharmaceutical composition wherein topical tion wherein the composition comprises from about 6% to application of the pharmaceutical composition does not cause about 10% ethanol by volume. Another embodiment provides 45 subjective irritation of the skin. Another embodiment pro the pharmaceutical composition wherein the composition vides the pharmaceutical composition wherein topical appli comprises from about 2% to about 10% ethanol by volume. cation of the pharmaceutical composition does not cause a Another embodiment provides the pharmaceutical composi Stinging sensation. tion wherein the composition comprises from about 5% to The compositions described herein contain alcohols which about 10% ethanol by volume. 50 provide an antiseptic effect when applied to the skin in high Another embodiment provides the pharmaceutical compo concentrations. By virtue of the non-homogeneous nature of sition wherein the composition comprises from about 10% to the compositions described herein, topical application of about 20% ethanol by volume. Another embodiment provides these compositions does not produce a stinging sensation the pharmaceutical composition wherein the composition when applied to the skin. These alcohols are selected from comprises about 11% ethanol by volume. Another embodi 55 ethanol, isopropanol (2-propanol), or n-propanol (1-pro ment provides the pharmaceutical composition wherein the panol), (Kampf et al., Clin. Microbiol. Rev. (2004), 17(4), composition comprises about 12% ethanol by Volume. 863-93; Federal Register Vol. 47, No. 99, Friday, May 21, Another embodiment provides the pharmaceutical composi 1982, pages 22324-22333). Based on the disclosure provided tion wherein the composition comprises about 13% ethanol herein a skilled practitioner can prepare and use the compo by volume. Another embodiment provides the pharmaceuti 60 sitions described herein comprising ethanol, isopropanol or cal composition wherein the composition comprises about n-propanol. For the compositions containing isopropanol the 14% ethanol by volume. Another embodiment provides the approximate effective concentration in the bubble-like pharmaceutical composition wherein the composition com regions of locally high concentration is about 60% to about prises about 15% ethanol by volume. Another embodiment 80%. For the compositions containing n-propanol the provides the pharmaceutical composition wherein the com 65 approximate effective concentration in the bubble-like position comprises about 16% ethanol by volume. Another regions of locally high concentration is about 60% to about embodiment provides the pharmaceutical composition 80%. US 8,647,671 B2 49 50 One embodiment provides a pharmaceutical composition composition as a non-homogenous lotion. Another embodi Suitable for topical administration comprising from about 2% ment provides the pharmaceutical composition as a non-ho to no more than 59.9% isopropanol by volume, a second mogenous cream. active ingredient and at least one excipient wherein said com Another embodiment provides the composition wherein position is a non-homogeneous semisolid. Another embodi the composition comprises from about 2% to about 10% ment provides the pharmaceutical composition as a semisolid n-propanol by volume. Another embodiment provides the dispersion. Another embodiment provides the pharmaceuti composition wherein the composition comprises from about cal composition as a semisolid emulsion. Another embodi 10% to about 20% n-propanol by volume. Another embodi ment provides the pharmaceutical composition as a non-ho ment provides the composition wherein the composition 10 comprises from about 20% to about 30% n-propanol by vol mogenous cream or a non-homogenous ointment. Another ume. Another embodiment provides the composition wherein embodiment provides the pharmaceutical composition as a the composition comprises from about 30% to about 40% non-homogenous ointment. Another embodiment provides n-propanol by volume. Another embodiment provides the the pharmaceutical composition as a non-homogenous composition wherein the composition comprises from about CCa. 15 40% to about 50% n-propanol by volume. Another embodi One embodiment provides a pharmaceutical composition ment provides the composition wherein the composition Suitable for topical administration comprising from about 2% comprises from about 50% to about 59.9% n-propanol by to no more than 59.9% isopropanol by volume, a second Volume. All non-homogeneous pharmaceutical compositions active ingredient and at least one excipient wherein said com comprising n-propanol disclosed herein do not contain position is a non-homogenous emulsion. Another embodi greater than 59.9% n-propanol. ment provides the pharmaceutical composition as a disper In some embodiments, a pharmaceutical composition Suit Sion. Another embodiment provides the pharmaceutical able for topical administrations described herein exhibits a composition as a non-homogenous cream or a non-homog viscosity of between about 10,000 and about 1,000,000 cen enous lotion. Another embodiment provides the pharmaceu tipoise. In some embodiments, a pharmaceutical composition tical composition as a non-homogenous lotion. Another 25 suitable for topical administrations described herein exhibits embodiment provides the pharmaceutical composition as a a viscosity of between about 50,000 and about 1,000,000 non-homogenous cream. centipoise. In some embodiments, a pharmaceutical compo Another embodiment provides the composition wherein sition suitable for topical administrations described herein the composition comprises from about 2% to about 10% exhibits a viscosity of between about 150,000 and about isopropanol by volume. Another embodiment provides the 30 1,000,000 centipoise. In some embodiments, a pharmaceuti composition wherein the composition comprises from about cal composition Suitable for topical administrations 10% to about 20% isopropanol by volume. Another embodi described herein exhibits a viscosity ofbetween about 50,000 ment provides the composition wherein the composition and about 600,000 centipoise. In some embodiments, a phar comprises from about 20% to about 30% isopropanol by maceutical composition Suitable for topical administrations Volume. Another embodiment provides the composition 35 described herein exhibits a viscosity of between about 100, wherein the composition comprises from about 30% to about 000 and about 500,000 centipoise. The viscosity is measured 40% isopropanol by volume. Another embodiment provides at a shear rate of 0.31 s' using a cone/plate viscometer the composition wherein the composition comprises from (Brookfield DVII+Pro viscometer with a CP50 spindle at about 40% to about 50% isopropanol by volume. Another 0.08 rpm as a reference). embodiment provides the composition wherein the composi 40 The compositions described herein are prepared by meth tion comprises from about 50% to about 59.9% isopropanol ods well known in the art of pharmacy described in standard by Volume. All non-homogeneous pharmaceutical composi texts, such as Remington. The Science and Practice of Phar tions comprising isopropanol disclosed herein do not contain macy, Nineteenth Ed (Easton, Pa.; Mack Publishing Com greater than 59.9% isopropanol. pany, 1995). The processes for preparing the non-homog One embodiment provides a pharmaceutical composition 45 enous compositions described herein are performed with Suitable for topical administration comprising from about 2% agitators, mechanical mixers, colloid mills homogenizers, to no more than 59.9% n-propanol by volume, a second active ultrasonic devices, microfluidizers and the like. In some ingredient and at least one excipient wherein said composi embodiments the bubble-like regions of locally high ethanol tion is a non-homogeneous semisolid. Another embodiment concentration can be viewed with the unaided eye. In other provides the pharmaceutical composition as a semisolid dis 50 embodiments, the bubble-like regions of locally high ethanol persion. Another embodiment provides the pharmaceutical concentrations require the use of a microscope to visualize. composition as a semisolid emulsion. Another embodiment Pharmaceutically Acceptable Salts and Prodrugs provides the pharmaceutical composition as a non-homog "Pharmaceutically acceptable salt includes both acid and enous cream or a non-homogenous ointment. Another base addition salts. A pharmaceutically acceptable salt of any embodiment provides the pharmaceutical composition as a 55 one of the corticosteroids described herein is intended to non-homogenous ointment. Another embodiment provides encompass any and all pharmaceutically suitable salt forms. the pharmaceutical composition as a non-homogenous Preferred pharmaceutically acceptable salts of the com CCa. pounds described herein are pharmaceutically acceptable One embodiment provides a pharmaceutical composition acid addition salts and pharmaceutically acceptable base Suitable for topical administration comprising from about 2% 60 addition salts. to no more than 59.9% n-propanol by volume, a second active "Pharmaceutically acceptable acid addition salt” refers to ingredient and at least one excipient wherein said composi those salts which retain the biological effectiveness and prop tion is a non-homogenous emulsion. Another embodiment erties of the free bases, which are not biologically or other provides the pharmaceutical composition as a dispersion. wise undesirable, and which are formed with inorganic acids Another embodiment provides the pharmaceutical composi 65 Such as hydrochloric acid, hydrobromic acid, Sulfuric acid, tion as a non-homogenous cream or a non-homogenous nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric lotion. Another embodiment provides the pharmaceutical acid, phosphorous acid, and the like. Also included are salts US 8,647,671 B2 51 52 that are formed with organic acids such as aliphatic mono A discussion of prodrugs is provided in Higuchi, T., et al., and dicarboxylic acids, phenyl-substituted alkanoic acids, “Pro-drugs as Novel Delivery Systems.” A.C.S. Symposium hydroxy alkanoic acids, alkanedioic acids, aromatic acids, Series, Vol. 14, and in Bioreversible Carriers in Drug Design, aliphatic and aromatic Sulfonic acids, etc. and include, for ed. Edward B. Roche, American Pharmaceutical Association example, acetic acid, trifluoroacetic acid, propionic acid, gly 5 and Pergamon Press, 1987, both of which are incorporated in colic acid, pyruvic acid, oxalic acid, maleic acid, malonic full by reference herein. acid, Succinic acid, fumaric acid, tartaric acid, citric acid, The term “prodrug is also meant to include any covalently benzoic acid, cinnamic acid, mandelic acid, methanesulfonic bonded carriers, which release the active compound in vivo acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic when such prodrug is administered to a mammalian Subject. 10 Prodrugs of an active compound, as described herein, are acid, and the like. Exemplary salts thus include Sulfates, pyro optionally prepared by modifying functional groups present Sulfates, bisulfates, Sulfites, bisulfites, nitrates, phosphates, in the active compound in Such a way that the modifications monohydrogenphosphates, dihydrogenphosphates, meta are cleaved, either in routine manipulation or in vivo, to the phosphates, pyrophosphates, chlorides, bromides, iodides, parent active compound. Prodrugs include compounds acetates, trifluoroacetates, propionates, caprylates, isobu 15 wherein a hydroxy, amino or mercapto group is bonded to any tyrates, oxalates, malonates. Succinate Suberates, sebacates, group that, when the prodrug of the active compound is fumarates, maleates, mandelates, benzoates, chloroben administered to a mammalian Subject, cleaves to form a free Zoates, methylbenzoates, dinitrobenzoates, phthalates, ben hydroxy, free amino or free mercapto group, respectively. Zenesulfonates, toluenesulfonates, phenylacetates, citrates, Examples of prodrugs include, but are not limited to, acetate, lactates, malates, tartrates, methanesulfonates, and the like. formate and benzoate derivatives of alcohol or amine func Also contemplated are salts of amino acids, such as arginates, tional groups in the active compounds and the like. gluconates, and galacturonates (see, for example, Berge S. M. In some embodiments, the corticosteroids described herein et al., “Pharmaceutical Salts.” Journal of Pharmaceutical are administered as phosphate prodrugs. In some embodi Science, 66:1-19 (1997), which is hereby incorporated by ments, the corticosteroids described herein are administered reference in its entirety). Acid addition salts of basic com 25 as Sodium phosphate prodrugs. In some embodiments, the pounds are optionally prepared by contacting the free base corticosteroids described herein are administered as ester forms with a sufficient amount of the desired acid to produce prodrugs. In some embodiments, the corticosteroids the salt according to methods and techniques with which a described herein are administered as acetyl, diacetyl, pro skilled artisan is familiar. In some embodiments, the corti panoate, dipropionate, pivalate, Valerate, butyrate, butyl, costeroid salts are selected from acetate, diacetate, propi 30 furoate, or ethoxycarbonyl ester prodrugs. onate, dipropionate, Valerate, pivalate, diacetate, or butyrate Excipients salts. Disclosed herein, in some embodiments, is a composition “Pharmaceutically acceptable base addition salt” refers to formulated as a non-homogenous ointment. In some embodi those salts that retain the biological effectiveness and prop ments, the ointment is AQUAPHORR). In some embodi erties of the free acids, which are not biologically or other 35 ments, the ointment base is a hydrocarbon base selected from wise undesirable. These salts are prepared from addition of an white petrolatum, USP or white ointment, USP. In some inorganic base or an organic base to the free acid. Pharma embodiments, the ointment base is an absorption base ceutically acceptable base addition salts are optionally selected from hydrophilic petrolatum, USP or lanolin, USP. formed with metals or amines, such as alkali and alkaline In some embodiments, the ointment base is water-removable earth metals or organic amines. Salts derived from inorganic 40 base, such as hydrophilic ointment, USP. In some embodi bases include, but are not limited to, sodium, potassium, ments, the ointment base is a water-soluble base, such as lithium, ammonium, calcium, magnesium, iron, Zinc, copper, polyethylene glycol ointment, NF. manganese, aluminum salts and the like. Salts derived from Disclosed herein, in some embodiments, is a pharmaceu organic bases include, but are not limited to, salts of primary, tical composition wherein the composition is a non-homog secondary, and tertiary amines, Substituted amines including 45 enous lotion or a non-homogenous cream. The hydrophobic naturally occurring Substituted amines, cyclic amines and component of a lotion or cream is derived from an animal basic ion exchange resins, for example, isopropylamine, tri (e.g., lanolin, cod liver oil, and ambergris), plant (e.g., saf methylamine, diethylamine, triethylamine, tripropylamine, flower oil, castor oil, coconut oil, cottonseed oil, menhaden ethanolamine, diethanolamine, 2-dimethylaminoethanol, oil, palm kernel oil, palm oil, peanut oil, Soybean oil, rapeseed 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, 50 oil, linseed oil, rice bran oil, pine oil, sesame oil, or Sunflower histidine, caffeine, procaine, N,N-dibenzylethylenediamine, seed oil), or petroleum (e.g., mineral oil, or petroleum jelly). chloroprocaine, hydrabamine, choline, betaine, ethylenedi The compositions described herein are not foams. amine, ethylenedianiline, N-methylglucamine, glucosamine, Disclosed herein, in certain embodiments, is a pharmaceu methylglucamine, theobromine, purines, piperazine, piperi tical composition wherein the composition comprises a thick dine, N-ethylpiperidine, polyamine resins and the like. See 55 ening agent. In some embodiments, the composition dis Berge et al., Supra. closed herein further comprises from about 0.1% to about “Prodrug is meant to indicate a compound that is con 5%, more preferably from about 0.1% to about 3%, and most Verted under physiological conditions or by Solvolysis to a preferably from about 0.25% to about 2%, of a thickening biologically active compound described herein. Thus, the agent. term “prodrug” refers to a precursor of a biologically active 60 In some embodiments, the excipient is selected from cel compound that is pharmaceutically acceptable. A prodrug luloses, cellulose derivatives, cellulose ethers (e.g., car may be inactive when administered to a subject, but is con boxymethylcellulose, ethylcellulose, hydroxyethylcellulose, Verted in vivo to an active compound, for example, by hydroxymethylcellulose, hydroxypropylmethylcellulose, hydrolysis. The prodrug compound often offers advantages of hydroxypropylcellulose, methylcellulose), guar gum, Xan solubility, tissue compatibility or delayed release in a mam 65 than gum, locust bean gum, alginates (e.g., alginic acid), malian organism (see, e.g., Bundgard, H., Design of Prodrugs silicates, starch, tragacanth, carboxyvinyl polymers, carrag (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam). eenan, paraffin, petrolatum, acacia (gum arabic), agar, alumi US 8,647,671 B2 53 54 num magnesium silicate, Sodium alginate, Sodium Stearate, Reviews 59 (2007) 522-530, which are herein incorporated bladderwrack, bentonite, carbomer, carrageenan, carbopol, by reference for such disclosures. xanthan, cellulose, microcrystalline cellulose (MCC), cera Device for the Treatment of Skin Diseases and Disorders tonia, chondrus, dextrose, furcellaran, gelatin, ghatti gum, Another embodiment provides a device to be used by the guar gum, hectorite, lactose, Sucrose, maltodextrin, mannitol, patient prior to topical application of the therapeutic pharma Sorbitol, honey, maize starch, wheat starch, rice starch, potato ceutical composition disclosed herein wherein said device starch, gelatin, Sterculia gum, polyethylene glycol (e.g. PEG contains two reservoirs: a first reservoir containing a first 200-4500), gum tragacanth, ethyl cellulose, ethylhydroxy pharmaceutical composition comprising ethanol a second ethyl cellulose, ethylmethyl cellulose, methyl cellulose, reservoir containing a second pharmaceutical composition hydroxyethyl cellulose, hydroxyethylmethyl cellulose, 10 comprising a second active agent. Another embodiment pro hydroxypropyl cellulose, poly(hydroxyethyl methacrylate), vides the device in which said first and second pharmaceutical oxypolygelatin, pectin, polygeline, povidone, propylene car compositions from said reservoirs are mixed by said device bonate, methyl vinyl ether/maleic anhydride copolymer prior to topical application of the therapeutic pharmaceutical (PVM/MA), poly(methoxyethyl methacrylate), poly(meth composition. Another embodiment provides the device in oxyethoxyethyl methacrylate), hydroxypropyl cellulose, 15 which said first and second pharmaceutical compositions hydroxypropylmethyl-cellulose (HPMC), sodium car from said reservoirs are mixed by said device prior to topical boxymethyl-cellulose (CMC), silicon dioxide, polyvinylpyr application of the therapeutic pharmaceutical composition rolidone (PVP: povidone), or combinations thereof. In some Such that topical application of said therapeutic pharmaceu embodiments, the excipient is not a polysiloxane. tical composition does not irritate the skin. Another embodi In some embodiments, the excipient is selected from Aloe ment provides the device in which said first and second phar barbadensis leaf juice, diisopropyl sebacate, glycerin, isopro maceutical compositions from said reservoirs are mixed by pyl myristate, tocopheryl acetate, aminomethyl propanol, said device prior to topical application of the therapeutic carbomer, caprylyl glycol, or C10-C30 alkyl acrylate cross pharmaceutical composition Such that topical application of polymer. said therapeutic pharmaceutical composition does not cause Disclosed herein, in some embodiments, is a pharmaceu 25 subjective irritation of the skin. Another embodiment pro tical composition wherein the composition comprises an vides the device in which said first and second pharmaceutical emollient. Emollients include, but are not limited to, castor oil compositions from said reservoirs are mixed by said device esters, cocoa butteresters, safflower oil esters, cottonseed oil prior to topical application of the therapeutic pharmaceutical esters, corn oil esters, olive oil esters, cod liver oil esters, composition Such that topical application of said therapeutic almond oil esters, avocado oil esters, palm oil esters, Sesame 30 pharmaceutical composition does not cause a stinging sensa oil esters, squalene esters, kikui oil esters, soybean oil esters, tion. acetylated monoglycerides, ethoxylated glyceryl monostear Another embodiment provides the device wherein the ate, hexyl laurate, isohexyl laurate, isohexyl palmitate, iso therapeutic pharmaceutical composition is a non-homoge propyl palmitate, methyl palmitate, decyloleate, isodecylole neous semisolid pharmaceutical composition Suitable for ate, hexadecyl Stearate decyl Stearate, isopropyl isostearate, 35 topical administration comprising from about 2% to no more methyl isostearate, diisopropyl adipate, diisohexyl adipate, than 59.9% ethanol by volume, at least one excipient, and a dihexyldecyl adipate, diisopropyl sebacate, lauryl lactate, second active ingredient. Another embodiment provides the myristyl lactate, and cetyl lactate, oleyl myristate, oleyl Stear device wherein the therapeutic pharmaceutical composition ate, and oleyl oleate, pelargonic acid, lauric acid, myristic is a non-homogenous semisolid dispersion. Another embodi acid, palmitic acid, Stearic acid, isostearic acid, hydroxyS 40 ment provides the device wherein the therapeutic pharmaceu tearic acid, oleic acid, linoleic acid, ricinoleic acid, arachidic tical composition is a non-homogenous semisolid emulsion. acid, behenic acid, erucic acid, lauryl alcohol, myristyl alco Another embodiment provides the device wherein the thera hol, cetyl alcohol, hexadecyl alcohol, Stearyl alcohol, isos peutic pharmaceutical composition is a non-homogenous tearyl alcohol, hydroxy Stearyl alcohol, oleyl alcohol, ricino ointment or a non-homogenous cream. Another embodiment leyl alcohol, behenyl alcohol, erucyl alcohol, 2-octyl 45 provides the device wherein the therapeutic pharmaceutical dodecanyl alcohol, lanolin and lanolin derivatives, beeswax, composition is a non-homogenous ointment. Another spermaceti, myristyl myristate, Stearyl Stearate, carnauba embodiment provides the device wherein the therapeutic wax, candelilla wax, lecithin, and cholesterol. pharmaceutical composition is a non-homogenous cream. Disclosed herein, in some embodiments, is a pharmaceu Another embodiment provides the device wherein the tical composition wherein the composition comprises essen 50 therapeutic pharmaceutical composition is a non-homoge tial oils, fragrances, skin-conditioning agents, skin healing neous emulsion pharmaceutical composition Suitable for agents, skin protectants (e.g., Sunscreens, or ultraviolet light topical administration comprising from about 2% to no more absorbers or scattering agents), skin soothing agents, preser than 59.9% ethanol by volume, at least one excipient, and a vatives or combinations thereof. second active ingredient. Another embodiment provides the Pharmaceutical compositions disclosed herein are formu 55 device wherein the therapeutic pharmaceutical composition lated in any suitable manner. Any suitable technique, carrier, is a dispersion. Another embodiment provides the device and/or excipient is contemplated for use with the non-homog wherein the therapeutic pharmaceutical composition is a non enous compositions disclosed herein. For a Summary of phar homogenous lotion or a non-homogenous cream. Another maceutical topical formulations described herein see Rem embodiment provides the device wherein the therapeutic ington. The Science and Practice of Pharmacy, Nineteenth 60 pharmaceutical composition is a non-homogenous lotion. Ed (Easton, Pa.; Mack Publishing Company, 1995); Hoover, Another embodiment provides the device wherein the thera John E., Remington's Pharmaceutical Sciences, Mack Pub peutic pharmaceutical composition is a non-homogenous lishing Co., Easton, Pa. 1975; Liberman, H. A. and Lachman, CCa: L., Eds. Pharmaceutical Dosage Forms, Marcel Decker, Another embodiment provides the device wherein the sec New York, N.Y., 1980; and Pharmaceutical Dosage Forms 65 ond active ingredient is selected from Salicylic acid, glycolic and Drug Delivery Systems, Eighth Ed. (Lippincott Williams acid, benzoyl peroxide, Sulfur, resorcinol, tretinoin, ada & Wilkins 2004), Muller, R. H. etal. Advanced Drug Delivery palene, tazarotene, clindamycin or erythromycin. Another US 8,647,671 B2 55 56 embodiment provides the device wherein the second active clobetasone, clocortolone, cloprednol, corticosterone, corti ingredient is selected from Salicylic acid, glycolic acid, ben Sone, cortivaZol, deflazacort, desonide, desoximetaSone, dex Zoyl peroxide, Sulfur, resorcinol, tretinoin, adapalene, tazaro amethasone, diflorasone, diflucortolone, difluprednate, enox tene, clindamycin, erythromycin, metronidazole, or azelaic olone, fluazacort, flucloronide, flumethasone, flunisolide, acid. Another embodiment provides the device wherein the fluocinolone acetonide, fluocinonide, fluocortin butyl, fluo second active ingredient is selected from Salicylic acid, ter cortolone, fluorometholone, fluperolone acetate, flupred benafine, econazole, miconazole, clotrimazole, butenafine, or nidene acetate, fluprednisolone, flurandrenolide, fluticasone tolnaftate. propionate, formocortal, halcinonide, halobetasol propi Another embodiment provides the device wherein the sec onate, halometaSone, halopredone acetate, hydrocortamate, ond active ingredient is a corticosteroid selected from 21-ac 10 hydrocortisone, loteprednol etabonate, maZipredone, etoxypregnenolone, alclometasone, algestone, amcinonide, medrysone, meprednisone, methylprednisolone, mometa beclomethasone, betamethasone, budesonide, chloropred Sone furoate, paramethasone, prednicarbate, prednisolone, nisone, clobetasol, clobetaSone, clocortolone, cloprednol, prednisolone 25-diethylamino-acetate, prednisolone sodium corticosterone, cortisone, cortivaZol, deflazacort, desonide, phosphate, prednisone, prednival, prednylidene, rimexolone, desoximetasone, dexamethasone, diflorasone, diflucor 15 tiXocortol, triamcinolone, triamcinolone acetonide, triamci tolone, difluprednate, enoXolone, fluazacort, flucloronide, nolone benetonide, and triamcinolone hexacetonide, or a flumethasone, flunisolide, fluocinolone acetonide, fluocino phosphate or ester prodrug thereof. nide, fluocortin butyl, fluocortolone, fluorometholone, flu Another embodiment provides the device wherein the sec perolone acetate, fluprednidene acetate, fluprednisolone, flu ond active ingredient is selected from hydrocortisone, des randrenolide, fluticasone propionate, formocortal, onide, mometasone, betamethasone, fluticaSone, triamcino halcinonide, halobetasol propionate, halometasone, halopre lone, fluocinolone or clobetasol. Another embodiment done acetate, hydrocortamate, hydrocortisone, loteprednol provides the device wherein the second active ingredient is etabonate, maZipredone, medrysone, meprednisone, methyl hydrocortisone, desonide, mometaSone, fluocinolone, triam prednisolone, mometasone furoate, paramethasone, predni cinolone or fluticasone. Another embodiment provides the carbate, prednisolone, prednisolone 25-diethylamino-ac 25 device wherein the second active ingredient is hydrocorti etate, prednisolone sodium phosphate, prednisone, prednival, sone. Another embodiment provides the device wherein the prednylidene, rimexolone, tiXocortol, triamcinolone, triamci second active ingredient is desonide. Another embodiment nolone acetonide, triamcinolone benetonide, triamcinolone provides the device wherein the second active ingredient is diacetonide, and triamcinolone hexacetonide; and a pharma mometasone. Another embodiment provides the device ceutically acceptable Salt thereof, or phosphate prodrug 30 wherein the second active ingredient is fluticaSone. Another thereof, or ester prodrug thereof. embodiment provides the device wherein the second active Another embodiment provides the device wherein the sec ingredient is fluocinolone. Another embodiment provides the ond active ingredient is a corticosteroid selected from hydro device wherein the second active ingredient is triamcinolone. cortisone, desonide, mometasone, betamethasone, flutica Another embodiment provides a device for the preparation Sone, fluocinolone, triamcinolone, triamcinolone acetonide, 35 of a non-homogenous ethanol containing topical composition triamcinolone diacetonide, or clobetasol; and a pharmaceuti wherein the first pharmaceutical composition is a gel, an cally acceptable salt thereof, orphosphate prodrug thereof, or emulsion, a dispersion, a lotion, a cream, an ointment, or a ester prodrug thereof. Another embodiment provides the solution. Another embodiment provides the device wherein pharmaceutical composition wherein the second active ingre the first pharmaceutical composition containing ethanol com dient is a corticosteroid selected from hydrocortisone, des 40 prises from about 10% to about 20% ethanol. Another onide, mometaSone, triamcinolone, triamcinolone acetonide, embodiment provides the device wherein the first pharma triamcinolone diacetonide, fluocinolone or fluticaSone; and a ceutical composition containing ethanol comprises from pharmaceutically acceptable salt thereof, or phosphate pro about 20% to about 30% ethanol. Another embodiment pro drug thereof, or ester prodrug thereof. Another embodiment vides the device wherein the first pharmaceutical composi provides the pharmaceutical composition wherein the second 45 tion containing ethanol comprises from about 30% to about active ingredient is hydrocortisone or a pharmaceutically 40% ethanol. Another embodiment provides the device acceptable salt thereof, or phosphate prodrug thereof, or ester wherein the first pharmaceutical composition containing prodrug thereof. Another embodiment provides the pharma ethanol comprises from about 40% to about 50% ethanol. ceutical composition wherein the second active ingredient is Another embodiment provides the device wherein the first desonide, or a pharmaceutically acceptable salt thereof, or 50 pharmaceutical composition containing ethanol comprises phosphate prodrug thereof, or ester prodrug thereof. Another from about 50% to about 60% ethanol. Another embodiment embodiment provides the pharmaceutical composition provides the device wherein the first pharmaceutical compo wherein the second active ingredient is mometaSone. Another sition containing ethanol comprises from about 60% to about embodiment provides the pharmaceutical composition 70% ethanol. Another embodiment provides the device wherein the second active ingredient is fluticaSone, or a phar 55 wherein the first pharmaceutical composition containing maceutically acceptable salt thereof, or phosphate prodrug ethanol comprises from about 70% to about 80% ethanol. thereof, or ester prodrug thereof. Another embodiment pro Another embodiment provides the device wherein the first vides the pharmaceutical composition wherein the second pharmaceutical composition containing ethanol comprises active ingredient is fluocinolone. Another embodiment pro from about 80% to about 90% ethanol. Another embodiment vides the pharmaceutical composition wherein the second 60 provides the device wherein the first pharmaceutical compo active ingredient is triamcinolone. sition containing ethanol comprises from about 25% to about Another embodiment provides the device wherein the sec 35% ethanol. Another embodiment provides the device ond active ingredient is a corticosteroid. Another embodi wherein the first pharmaceutical composition containing ment provides the method wherein the second active ingre ethanol comprises from about 35% to about 45% ethanol. dient is selected from 21-acetoxypregnenolone, 65 Another embodiment provides the device wherein the first alclometasone, algestone, amcinonide, beclomethasone, pharmaceutical composition containing ethanol comprises betamethasone, budesonide, chloroprednisone, clobetasol, from about 45% to about 55% ethanol. Another embodiment US 8,647,671 B2 57 58 provides the device wherein the first pharmaceutical compo TABLE 1-1 sition containing ethanol comprises from about 55% to about 65% ethanol. Sample ratios of corticosteroid ointment to 62% ethanol gel and the corresponding composition percent ethanol by volume Another embodiment provides a device for the preparation 5 Ratio of of a non-homogenous ethanol containing topical composition corticosteroid Volume of Composition wherein said device comprises means for mixing, agitating, ointment to corticosteroid Volume of 62% percent ethanol shaking, stirring or blending a first pharmaceutical composi ethanolgel ointment (mL) ethanol gel (mL) by volume (%) tion with a second pharmaceutical composition. Another 1:1 1.25 1.25 31 embodiment provides a device for the preparation of a non 10 2:1 1.7 O.8 21 homogenous ethanol containing topical composition wherein 3:1 1.9 O6 16 4:1 2.0 O.S 12 said device comprises containing means for a first pharma 5:1 2.1 0.4 10 ceutical composition, containing means for a second pharma 8:1 2.2 O.3 7 ceutical composition, blending means to produce a non-ho 10:1 2.3 O.2 6 mogenous composition, and dispensing means. Another 15 embodiment provides the device wherein the blending means is an enclosed chamber. Another embodiment provides the Example 1-3 device wherein the blending means is an enclosed chamber and the dispensing means is a contoured opening in the blend Preparation of an Ethanol Containing ing chamber. Non-homogenous Composition with Desonide Another embodiment provides the device wherein the O.05% therapeutic pharmaceutical composition is non-come dogenic. For a 5:1 ratio of desonide 0.05% ointment to 62% ethanol gel: 0.4 mL of 62% ethanol gel and desonide 0.05% ointment 25 (2.1 mL) were thoroughly mixed together. The composition EXAMPLES was immediately topically applied. For a 10:1 ratio of desonide 0.05% ointment to 62% etha I. Preparation of Composition for Topical nol gel: 0.2 mL of 62% ethanol gel and desonide 0.05% Administration 30 ointment (2.3 mL) were thoroughly mixed together. The com position was immediately topically applied. Example 1-1 Example 1-4

Preparation of an Ethanol Containing Gel 35 Preparation of an Ethanol Containing Non-Homogenous Composition with Mometasone FurOate 0.1% Compositions were prepared using the general method Ingredient Quantity 40 presented in Example 1-2. ethanol 62.0 g Water about 35.0 g Example 1-5 Carbomer USP 0.5g NaOH (10%) about 2.5g Preparation of an Ethanol Containing Composition 45 with Triamcinolone 0.1% A 100-g batch of ethanol gel formulation is prepared by suspending 0.5g of carbomer USP in 62 g ethanol and about Compositions were prepared using the general method 30 g of water. The resulting mixture is agitated to ensure presented in Example 1-2. complete dissolution. The pH of the solution is adjusted to pH 50 Example 1-6 7 by the addition of about 2.5g of 10% NaOH solution and the resulting solution is brought to 100 g total mass by the addi tion of about 5g of water. The resulting material is packaged Preparation of an Ethanol Containing Composition in a tube, bottle, or pump dispenser. with Fluocinolone 0.1% 55 Compositions were prepared using the general method Example 1-2 presented in Example 1-2. Example 1-7 General Procedure for the Preparation of an Ethanol Containing Non-homogenous Composition with 60 Preparation of Maintenance Non-Homogenous Corticosteroid Lotion Containing Ethanol Corticosteroid ointment and 62% ethanol gel were thor Moisturizing lotion, cream or ointment and 62% ethanol oughly mixed together. Volumes of the 62% ethanol and gel were thoroughly mixed together. Volumes of the 62% corticosteroid ointment varied and were dependent on the 65 ethanolgeland moisturizing lotion, cream, or ointment varied desired ratio of the two components (see Table 1-1). The and were dependent on the desired ratio of the two compo composition was immediately topically applied. nents. The composition was immediately topically applied. US 8,647,671 B2 59 60 Example 1-8 For this study, each formulation was freshly prepared and divided into two portions, each of which was transferred into Comparative Stability of Desonide-Ethanol Topical a screw-top container. One container was maintained at room Formulations when Stored at Room Temperature or temperature (72 degrees Fahrenheit) and the other container at Refrigerator Temperature 5 was kept in a refrigerator (40 degrees Fahrenheit). At each time period, the container was visually inspected, and an The purpose of this study was (1) to determine if ethanol aliquot of the formulation was placedon a glass slide, covered gel is homogeneously dissolved in ointment and cream for with a glass slip, and examined in a light microscope. Results mulations or present as a Suspension of discretely visible of these studies are summarized in Tables 1-2 to 1-6. microbubbles; (2) to determine if these physical properties 10 were retained over time; and (3) to determine the role of TABLE 1-2 storage temperature on formulation stability. Four desonide-ethanol topical formulations were prepared Visual assessment of the 0.005% desonide formulations for this study. 1) Cream formulation: desonide (10% of the standardized 15 Time Cream, Ointment Ointment, topical corticosteroid concentration) and ethanol gel. period Cream at RT refrigerated at RT refrigerated This cream formulation was prepared by mixing 2.5 mL of desonide cream (0.05%), 4 mL of 70% ethanolgel, and 18 mL Start creamy white creamy white opaque opaque of AQUAPHORR). Components were mixed to form a sticky sticky smooth, homogeneously white creamy texture by visual 20 1h intact intact intact inspection with the naked eye. The final ingredient concen 2h intact intact intact tration was 0.005% desonide (corresponding to 10% of the 3h intact intact intact standardized topical corticosteroid concentration of 0.05% 4h Possible intact intact intact for desonide cream) and 12% ethanol. separation 2) Ointment formulation: desonide (10% of the standard- 25 Sh Slight intact intact intact ized topical corticosteroid concentration) and ethanol gel. separation This ointment formulation was prepared by mixing 2.5 mL. 6h Separated intact intact intact of desonide ointment (0.05%), 4 mL of 70% ethanol gel, and 7h Separated intact intact intact 18 mL of AQUAPHORR). Components were mixed to form a 24h Separated intact intact intact Smooth, homogeneously milky-white, opaque sticky texture 30 48 h. Separated intact intact intact by visual inspection with the naked eye. The final ingredient concentration was 0.005% desonide (corresponding to 10% TABLE 1-3 Microscopic assessment of the formulation components Number of microbubbles Time AQUAPHOR(R) period desonide ointment desonide cream ethanol gel AQUAPHOR (R) with ethanolgel

Start Ole Ole Ole Ole many (white film) (grey film) (clear film) (uniform grey dots) Number of microbubbles was scored as (1) none = 0 bubbles per 100x microscopic field; (2) rare = 1-3 bubbles per 100x microscopic field; (3) few = 5-8 bubbles per 100x microscopic field; (4) mild = 30-50 bubbles per 100x microscopic field; (5) moderate = 50-100 bubbles per 100x microscopic field; (6) many = 500-1000 bubbles per 100x microscopic field. of the standardized topical corticosteroid concentration of TABLE 1-4 0.05% for desonide ointment) and 12% ethanol. 3) Cream formulation: desonide (80% of the standardized Microscopic assessment of the 0.005% desonide formulations topical corticosteroid concentration) and ethanol gel. 50 This cream formulation was prepared by mixing 4 mL of Number of microbubbles desonide cream (0.05%) and 1 mL of 70% ethanol gel. Com Ce3 Ce3 ointment ointment ponents were mixed to form a smooth, homogeneously white Time formulation formulation, formulation formulation, creamy texture by visual inspection with the naked eye. The period at RT refrigerated at RT refrigerated final ingredient concentration was 0.04% desonide (corre Start few NA many NA sponding to 80% of the standardized topical corticosteroid 55 1h few few many many concentration of 0.05% for desonide cream) and 14% etha 2h few few many many nol. 3h few few many many 4) Ointment formulation: desonide (80% of the standard 4h few few many many Sh few few many many ized topical corticosteroid concentration) and ethanol gel. 6h 8t few many many This ointment formulation was prepared by mixing 4 mL of 60 7h 8t few many many desonide ointment (0.05%) and 1 mL of 70% ethanol gel. 24h Ole Ole many many Components were mixed to form a smooth, homogeneously 48 h. Ole Ole many many homogeneously milky-white, opaque sticky texture by visual Number of microbubbles was scored as (1) none = 0 bubbles per 100x microscopic field; inspection with the naked eye. The final ingredient concen (2) rare = 1-3 bubbles per 100x microscopic field; (3) few = 5-8 bubbles per 100x micro scopic field; (4) mild = 30-50 bubbles per 100x microscopic field; (5) moderate = 50-100 tration was 0.04% desonide (corresponding to 80% of the 65 bubbles per 100x microscopic field; (6) many = 500-1000 bubbles per 100x microscopic standardized topical corticosteroid concentration of 0.05% field. for desonide ointment) and 14% ethanol. US 8,647,671 B2 61 62 TABLE 1-5 further oral antibiotics were administered. The patient showed significant improvement in 3 days. Visual assessment of the 0.04% desonide formulations b. Man with Extensive Dermatitis Over his Trunk and Observa Limbs with Culture Proven Staphylococcus aureus. tion Cream, Ointment Ointment, Treatment with a non-homogenous composition com period Cream at RT refrigerated at RT refrigerated prising ethanol (31%) and triamcinolone (0.05%) was Start creamy white creamy white opaque opaque far more effective than oral antibiotic therapy (cephal sticky sticky exin) combined with triamcinolone (0.1%) cream. 1 hour intact intact intact intact Within 2 days the patient showed significant improve 2 hour intact intact intact 10 ment. 3 hour intact intact intact 4 hour Possible intact intact intact c. Woman with 20 Years of Hand Dermatitis Complicating separation Scleroderma (a Form of Skin Tightening which Com 5 hour Slight intact intact intact promises Blood Flow). The patient reported 75% clear separation ing of her condition within 3 days of starting a treatment 6 hour Separated intact intact intact 15 7 hour Separated intact intact intact with a non-homogenous composition comprising etha 24 hours Separated intact intact intact nol (31%) and clobetasol (0.025%). The patient’s 48 hours Separated intact intact intact chronic condition had failed to respond to oral antibiot ics, topical antibiotics, topical cortisones including clo betasol cream. This treatment with a non-homogenous TABLE 1-6 composition comprising ethanol (31%) and clobetasol (0.025%) worked when clobetasol cream under plastic Microscopic assessment of the 0.04% desonide formulations (glove occlusion) and cortisone tape had failed. Number of microbubbles Example 2-2 25 C8 Ce3 ointment ointment Time formulation formulation, formulation formulation, Treatment of Atopic Dermatitis (Eczema) period at RT refrigerated at RT refrigerated Start moderate NA many NA An 11 year old girl presented with recurrent persistent 1h moderate moderate many many eczema only partly improved on the combined use of 2h mild moderate many many 30 mometasone ointment and oral antibiotics. Within a week of 3h mild moderate many many starting a treatment with a non-homogenous composition 4h mild mild-moderate many many Sh mild mild-moderate many many comprising ethanol (31%) and mometasone (0.05%) the 24h few few many many patient’s condition was 85% clear. 48 h. Ole Ole many many 35 Example 2-3 Number of microbubbles was scored as (1) none = 0 bubbles per 100x microscopic field; (2) rare = 1-3 bubbles per 100x microscopic field; (3) few = 5-8 bubbles per 100x micro scopic field; (4) mild = 30-50 bubbles per 100x microscopic field; (5) moderate = 50-100 Treatment of Facial Eczema bubbles per 100x microscopic field; (6) many = 500-1000 bubbles per 100x microscopic field. Twenty-six patients with facial eczema were treated for Microbubbles of ethanol gel were visible in both cream and 40 two weeks twice daily with a non-homogenous ointment ointment formulations. The microbubbles remained present consisting of desonide 0.05% ointment mixed with 62% etha in Suspension for longer periods of time and in larger numbers nol gel. The non-homogenous ointment was used in fixed in the ointment than in the cream formulations. Refrigeration ratios ranging from 10:1 to 1:1 (desonide ointment/ethanol maintained the microbubble frequency in the cream formu gel), or as part of a progressive ratio therapy in which the lations. Refrigeration was not required to maintain the 45 initial ratio was 5:1 (desonide ointment/ethanol gel) and the microbubble frequency of the ointment formulations. ratio was changed every 2 days to 3:1, then 2:1 and ending at 1:1. Each preparation was prepared immediately prior to II. Treatment of Skin Diseases and Disorders application. Results from all 26 patients are displayed in Table 2-1. Results from nine patients who used fixed ratios of Example 2-1 50 desonide ointment/ethanol gel are displayed in Table 2-2. Results from 17 patients who underwent progressive ratio Treatment of Secondarily Infected Dermatitis therapy are displayed in Table 2-3. Dermatitis is a common form of red, scaly, itchy patches TABLE 2-1 which frequently is infected due to the patients scratching 55 Outcome of treatment using desonide? ethanol non their itchy areas. Conventional treatment is based on use of homogenous composition BID for 2 weeks in 26 topical steroid creams, and oral or topical antibiotics. Treat patients with atopic dermatitis on the face: ment often is only partly helpful and patients often are reluc tant to use oral antibiotics due to potential side effects. Sev Number of patients eral patients have presented with secondarily infected 60 Outcome of Treatment with this outcome dermatitis and participated in the new course of treatment. WOSe a. Man with hand dermatitis. Treatment with topical S8ile 25-50% better mometasone cream and oral antibiotics and topical 51-74% better mupirocin provided partial response over 3 weeks treat 75-99% better ment. In an attempt to achieve complete response the 65 100% better patient was treated with a non-homogenous composition comprising mometasone (0.05%) and ethanol (31%); no US 8,647,671 B2 63 64 TABLE 2-2 TABLE 2-4 Outcome of treatment using mometasone/ethanol non Outcome of treatment using fixed ratios of desonide/ethanol homogenous composition BID for 2 weeks in 48 patients non-homogenous composition BID for 2 weeks in 9 patients with atopic dermatitis on the trunk and/or limbs: with atopic dermatitis on the face: 5 Number of patients Number of patients with this outcome Outcome of Treatment with this outcome WOSe 1:1 4:1 5:1 10:1 S8ile 10 25-50% better Outcome of desonide? desonide? desonide? desonide? 51-74% better Treatment EtOH EtOH EtOH EtOH 75-99% better 100% better WOSe O O O O S8ile O O O O 15 25-50% better O O O O TABLE 2-5 51-74% better O O O O 75-99% better 1 1 6 O Outcome of treatment using fixed ratios of mometaSone? ethanol non-homogenous composition BID for 2 weeks in 13 patients 100% better O O O 1 with atopic dermatitis on the trunk and/or limbs: Number of patients with this outcome TABLE 2-3 1:1 4:1 5:1 10:1 Outcome of mometaSonef mometaSone mometasone mometaSone? Outcome of treatment using progressive ratios of desonide? ethanol Treatment EtOH EtOH EtOH EtOH non-homogenous composition BID for 2 weeks in 17 patients 25 WOSe O O O O with atopic dermatitis on the face: S8ile O O O O Number of patients 25-50% better O O O O Outcome of Treatment with this outcome 51-74% better O O O O 75-99% better 1 2 4 1 WOSe 100% better O 1 4 O S8ile 30 25-50% better 51-74% better 75-99% better TABLE 2-6 100% better 1 Outcome of treatment using progressive ratios of mometaSone? ethanol 35 non-homogenous composition BID for 2 weeks in 35 patients Based on the results from Table 2-1, the median improve with atopic dermatitis on the trunk and/or limbs: ment score was 87%. The mean improvement score was 86%. Number of patients 88% of the patients achieved 75% or greater improvement Outcome of Treatment with this outcome compared to pretreatment. Treatment was well tolerated. 40 WOSe None of the patients had to stop treatment due to irritation. S8ile Patients using compositions of different ratios of the desonide 25-50% better 51-74% better ointment and ethanol gel, ranging from 10:1 (desonide oint 75-99% better ment/ethanol gel) to 1:1, achieved comparable results in this 100% better study. 45 Based on the data from Table 2-4, the median improvement Example 2-4 score was 87%. The mean improvement score was 90%.98% of the patients achieved 75% or greater improvement com Treatment of Atopic Dermatitis on the Trunk and/or 50 pared to pretreatment. Treatment was well tolerated. None of Limbs the patients had to stop treatment due to irritation. Patients using compositions of different ratios of the mometasone ointment and ethanol gel, ranging from 10:1 (mometaSone Forty-eight patients with trunk and/or limb eczema were ointment/ethanol gel) to 1:1, achieved comparable results in treated for two weeks twice daily with a non-homogenous this study. ointment consisting of mometasone furoate 0.1% ointment 55 mixed with 62% ethanol gel. The non-homogenous ointment was used in fixed ratios ranging from 10:1 (mometasone Example 2-5 furoate ointment/ethanol gel) to 1:1 or as part of a progressive ratio therapy in which the initial ratio was 5:1 mometasone 60 Summary of Corticosteroid-ethanol Formulations ointment/ethanol gel and the ratio was changed every 2 days Evaluated for the Treatment of Eczema to 3:1, then 2:1 and ending at 1:1. Each preparation was prepared immediately prior to application. Results from all 48 Table 2-7 provides a summary of the corticosteroid formula patients are displayed in Table 2-4. Results from 13 patients tions evaluated in the clinic for the treatment of eczema using who used fixed ratios of desonide ointment/ethanol gel are 65 the methods described herein. In all cases the eczema displayed in Table 2-5. Results from 35 patients who under improved at least 75% compared to pretreatment, and the went progressive ratio therapy are displayed in Table 2-6. treatment was well-tolerated. US 8,647,671 B2 65 66 TABLE 2-7 TABLE 2-7-continued

Ratio Ratio Structural Corticosteroid Structural Corticosteroid Class of opical Concentra Class of Topical Concentra Cortico mixed with tion Ethanol 5 Cortico- mixed with tion Ethanol steroid Corticosteroid tested Ethanolgel gel steroid Corticosteroid tested Ethanolgel gel Class A Hydrocortisone 2.5% O:1 and 5: 70% FluticaSone propionate 10:1 and 5:1 62% Hydrocortisone ointment O.OO5% cream Type Hydrocortisone 1% O:1 and 5: 62% (Cutivate (R) OTC cream 10 FluticaSone propionate 10:1 and 5:1 62% Class B Amcinonide 0.1% O:1 and 5: 70% 0.005% ointment Triamcinalone cream (Cyclocort (R) (Cutivate (R) Acetonide Amcinonide 0.1% O:1 and 5: 70% MometaSone 0.1% 10:1, 5:1, 4:1, 62% Type ointment (Cyclocort (R) ointment 2:1, 1:1 Desonide 0.05% cream 4:1 and 1:1 62% Diflorasone diacetate 10:1 and 5:1 70% DeSonide 0.05% 0:1, 5:1, 4:1, 62% 15 0.05% ointment ointment 2:1, 1:1 (Psorcon (R) Fluocinolone acetonide O:1 and 1: 62% Clobetasol propionate 4:1 and 1:1 62% 0.025% ointment 0.05% ointment (Synalar (R) (Temovate (R) Fluocinonide 0.05% O:1 and 1: 62% Clobetasol propionate 5:1 62% cream (Lidex (R) O.05% cream Fluocinonide 0.05% O:1 and 1: 62% 2O (Temovate (R) ointment (Lidex (R) Class D2 Hydrocortisone Butyrate 10:1 and 5:1 62% Triamcinolone acetonide 1:1 62% Methyl- 0.1% ointment 0.1% cream prednisolone (Locoid (R) Triamcinolone acetonide 5:1 and 1:1 62% Aceponate Hydrocortisone Butyrate 10:1 62% 0.1% ointment Type 0.1% cream Triamcinalone diacetate O:1 and 5: 62% 25 (Locoid (R) 0.1% ointment Hydrocortisone valerate 10:1 and 5:1 70% Halocinonide 0.1% O:1 and 5: 62% 0.2% ointment ointment (Halog (R) Prednicarbate 0.1% 10:1 and 5:1 62% Halobetasol propionate O:1 and 5: 62% C8 0.05% ung (Ultravate (R) Uncertain fluradrenolide 0.05% 10:1 and 5:1 62% Class C Clocortolone pivalate :1 62% 30 structural cream (potency class 5) Betamethasone 0.1% cream (Cloderm (R) class Type Desoximetasone 0.25% O:1 and 5: 70% ointment Class D1 AlclometaSone O:1 and 5: 70% Betamethasone dipropionate 0.05% Example 2-6 Dipropionate (Aclovate (R) Ointment Type Betamethasone O:1 and 5: 70% 35 Summary of Outcomes of Various Combinations of dipropionate 0.05% Topical Corticosteroids and Ethanol for Treating ointment (Diprolene (R) Eczema (Arranged Alphabetically) Betamethasone O:1 and 5: 62% dipropionate augmented 0.05% ointment Table 2-8 provides a Summary of outcomes using the methods Betamethasone valerate O:1 and 5: 62% described herein of various combinations of topical corticos 0.1% ointment teroids and ethanol. In all cases the treatment was well-toler ated. TABLE 2-8 Ratio by volume of Amount of Net CS Initial CS topical CS reduction in concentration concentration and 62% CS in the non- % patients present in ethanol gel concentration homogenous Number achieving Topical CS topical in the in final mixture as of patients treatment tested preparation mixture * mixture administered treated success**

AlclometaSone O.OSO% 5: f6 O.042% OO% dipropionate Ung (Aclovate (R) Amcinonide Cr O.100% 5: f6 O.O83% OO% (Cyclocort (R) Amcinonide Ung O.100% 5: f6 O.O83% OO% (Cyclocort (R) Betamethasone O.OSO% 5: f6 O.042% OO% propionate Aug Ung (Diprolene (R) Betamethasone O.OSO% 5: f6 O.042% OO% propionate Ung (Diprolene (R) Betamethasone O.100% 5: f6 O.O83% OO% Valerate Ung US 8,647,671 B2 67 TABLE 2-8-continued Ratio by volume of Amount of NetCS Initial CS topical CS reduction in concentration concentration and 62% CS in the non- % patients present in ethanolgel concentration homogenous Number achieving Topical CS topical in the in final mixture as of patients treatment ested preparation mixture * mixture administered treated success** (Valisone (R) Clobetasol O.OSO% 5: f6 O.O42% 1 OO% propionate Cr (Temovate (R) Clobetasol O.OSO% 1: f2 O.025% 2 OO% propionate Ung (Temovate (R) Clobetasol O.OSO% 4: 5 O.O40% 1 OO% propionate Ung (Temovate (R) Clocortolone O. 100% 1: f2 O.OSO% 1 OO% bivalate Cr (Cloderm (R) Desonide Cr O.OSO% 4: 5 O.O40% 1 OO% Desonide Cr O.OSO% 2: 3 O.O.33% 1 OO% Desonide Cr O.OSO% 1: f2 O.025% 2 OO% Desonide Ung O.OSO% 1: f2 O.025% 28 96% Desonide Ung O.OSO% 10: 11 O.O46% 6 OO% Desonide Ung O.OSO% 2: 3 O.O.33% 2 OO% Desonide Ung O.OSO% 4: 5 O.O40% 2 OO% Desonide Ung O.OSO% 5: f6 O.O42% 18 94% Desoximetasone 0.25.0% 5: f6 O.21% 3 OO% Ung (Topicort (R) Diflorasone O.OSO% 5: f6 O.O42% 1 OO% diacetate Ung (Psorcon (R) Fluocinolone O.025% 5: f6 O.O2.1% 2 OO% acetonide Ung (Synalar (R) Fluocinonide Cr 0.050% 1: f2 O.025% 4 OO% (Lidex (R) Fluocinonide O.OSO% 1: f2 O.025% 2 OO% Ung (Lidex (R) Flurand renolide 0.050% 5: f6 O.O42% 2 OO% Cr (Cordran SP (R) FluticaSone O.005% 5: f6 O.OO4% 3 OO% propionate Ung (Cultivate (R) alobetasol O.OSO% 5: f6 O.O42% 1 OO% propionate Cr (Ultravate (R) Halocinonide Cr 0.100% 1: f2 O.OSO% 1 OO% (Halog (R) Hydrocortisone 1.OOO% 5: f6 O.833% 1 OO% Cr OTC Hydrocortisone 2.5% 5: f6 2.083% 1 OO% Ung Hydrocortisone O. 100% 5: f6 O.O83% 1 OO% butyrate Cr (Locoid (R) Hydrocortisone O. 100% 5: f6 O.O83% 2 OO% butyrate Ung (Locoid (R) Hydrocortisone O.200% 5: f6 O.16.7% 1 OO% Valerate Ung (Westcort (R) MometaSone Cr 0.100% 1: f2 O.OSO% 2 OO% (Elocon (R) MometaSone Cr 0.100% 2: 3 O.O67% 1 OO% (Elocon (R) MometaSone Cr 0.100% 5: f6 O.O83% 1 OO% (Elocon (R) MometaSone O. 100% 5: f6 O.O83% 14 93% Ung (Elocon (R) MometaSone O. 100% 1: f2 O.OSO% 27 96% Ung (Elocon (R) MometaSone O. 100% 10: 11 O.O.91% 5 770, Ung (Elocon (R) MometaSone O. 100% 2: 3 O.O67% 5 100% Ung (Elocon (R) US 8,647,671 B2 69 70 TABLE 2-8-continued Ratio by volume of Amount of NetCS Initial CS topical CS reduction in concentration concentration and 62% CS in the non % patients present in ethanolgel concentration homogenous Number achieving Topical CS topical in the in final mixture as of patients treatment tested preparation mixture * mixture administered treated success** MometaSone O. 100% 4: 5 O.O80% Ung (Elocon (R) MometaSone O. 100% 3: f4 0.075% Ung (Elocon (R) Prednicarbate O. 100% 5: f6 O.O83% 1 OO% Ung (Dermatop (R) Triamcinolone O. 100% 1: f2 O.OSO% 1 OO% acetonide Cr (Kenalog (R) Triamcinolone O. 100% 1: f2 O.OSO% 1 OO% acetonide Ung (Kenalog (R) Triamcinolone O. 100% 5: f6 O.O83% acetonide Ung (Kenalog (R) Triamcinolone O. 100% 5: f6 O.O83% 1 OO% diacetate Ung (Aristocort (R)

CS = corticosteroid * The ratio is the relative amount of the topica corticosteroid to be combined with the ethanolgel to form the mixture. For example: 5 to 1 ratio means 5 parts corticosteroid to 1 part ethanolgel. This results in a final corticosteroid concentration which is 5/6 of the initial concentration or a 17% drop in initial corticosteroid concentration. **Success is defined as 75% or greater reduction in amount of eczema rash compared to pretreatment,

Example 2-7 30 desonide 0.05% hydrogel and its hydrogel vehicle provided 19% and 3% success, respectively, after 2 weeks of therapy Comparison of the Results of Clinical Trials for and 39% and 11% success, respectively, after 3-6 weeks of Treating Eczema in Children with therapy (Hebert AA, Cook-Bolden FE. Basu S, Calvarese B. Corticosteroid/Ethanol Non-homogenous Trancik R.J. Safety and efficacy of desonide hydrogel 0.05% Composition Versus Published Results for Using 35 in pediatric Subjects with atopic dermatitis. J Drugs Derma Conventional Treatment tol. February 2007; 6(2):175-81). In these two studies, the desonide hydrogel contains propylene glycol in its vehicle 1) Topical Mometasone/Ethanol Prototype Compared to and the desonide ointment contains no alcohol. In sharp con “Bleach Baths” in Treating Children with Eczema. 40 trast, prototype non-homogenous ointment consisting of a A recent study (Huang JT, Abrams M, Tlougan B. Rade mixture of desonide/ethanol in fixed or progressive ratios led maker A, Paller A. S. Treatment of Staphylococcus aureus to 88% success after two weeks of twice daily treatment (data colonization in atopic dermatitis decreases disease severity. shown in Table 2-1). The prototype non-homogenous oint Pediatrics May 2009; 123(5): 808–814) evaluated a new ment provided better results in a shorter period of time. In all method for treating eczema employing "bleach baths’ to 45 studies, success was defined as the percentage of patients that topical corticosteroid treatment as a means to suppress the achieved 75% or better improvement compared to baseline. staphylococcal population on the skin. This bleach bath-topi 3) Topical Mometasone/Ethanol Non-homogenous Com cal corticosteroid treatment resulted in a mean improvement position Compared to Conventional Mometasone Cream in of 40% in 1 month of use. These results were inferior to twice Treating Children with Eczema. daily treatment of prototype non-homogenous ointment con 50 The use of commercially available mometaSone formula sisting of mometasone furoate 0.1% ointment mixed with tions for the treatment of children with eczema has been 62% ethanolgel in fixed or progressive ratios, which resulted reported in the literature. One study found that mometasone in a mean improvement of 90% in two weeks (data presented 0.1% cream provided 50% success after 3 weeks of therapy in Table 2-4). (Rafanelli A, Rafanelli S. Stanganelli I, et. al. Mometasone 2) Topical Desonide/Ethanol Non-homogenous Composi 55 furoate in the treatment of atopic dermatitis in children. J. Eur: tion Compared to Conventional Desonide Formulations in Acad. Dermatol. Venereol. 1993; 2(3):225-230). Another Treating Children with Eczema. study found that mometasone 0.1% cream led to 63% success The use of commercially available desonide formulations after 3 weeks of therapy (Vernon H J. Lane AT, Weston W. in treating children with eczema has been reported in the Comparison of mometasone furoate 0.1% cream and hydro literature. Desonide 0.05% hydrogel and desonide 0.05% 60 cortisone 1.0% cream in the treatment of childhood atopic ointment provided 25% and 34% success, respectively, after dermatitis.J. Am. Acad. Dermatol. April 1991; 24:603-7). A 2 weeks of therapy and 25% and 52% success, respectively, third study reported overall results similar to the other two after 3-6 weeks of therapy (Trookman NS, Rizer R L. Ran studies (Lebwohl M, Lane AT, Berman B, et. al. Efficacy and domized Controlled Trial of Desonide Hydrogel 0.05% ver safety of 0.1% mometasone furoate cream versus 0.2% sus Desonide Ointment 0.05% in the Treatment of Mild-to 65 hydrocortisone Valerate cream in pediatric patients with moderate Atopic Dermatitis. J Clin Aesthet Dermatol. atopic dermatitis un-responsive to topical hydrocortisone November 2011; 4(11): 34-38). Another study showed that treatment. Proceedings of the 55' Annual Meeting of the US 8,647,671 B2 71 72 American Academy of Dermatology Mar. 21-26, 1997: Example 2-10 abstract number P-43). In all cases, the mometasone 0.1% cream included propylene glycol Stearate (55% monoester) in Non-Stinging Test Using Superficial Skin Abrasion its vehicle. Use of the prototype non-homogenous ointment Model consisting of a mixture of mometasone/ethanol in fixed or 5 progressive ratios provided 98% success after only two weeks In a study with 20 subjects, this test is performed on a total of twice daily treatment (data in Table 2-4). In all studies, of 6 sites on each Subject: three test sites on each arm. Tape is Success was defined as percentage of patients achieving 75% used to sequentially strip the skin until the glistening layer is or better improvement compared to baseline. visible. The test materials include a positive stinging control 10 (70% ethanol solution), a negative stinging control (formula Example 2-8 tion vehicle without ethanol) and the novel formulation with ethanol (with or without a second active agent). Each material Clinical Trial of Moisturizer/Ethanol is applied to a single site on each forearm to allow for a Non-homogenous Composition in Preventing 15 separate determination of response consistency. Each mate Recurrence of Eczema rial is applied for 15 seconds to each site. Each subject reports the intensity of the stinging/burning sensation on a 0-4 point Demographics: 7 patients with chronic recurrent eczema scale. The outcome of the study is determined by comparing entered the trial. Prior to starting the trial all had cleared their the scores of all the sites. eczema rash using rash treatment prototype topical therapy. All had a past history of conventional moisturizers failing to Example 2-11 prevent recurrence of eczema within 10 days of stopping prior rash therapy. Treatment of Tinea Versicolor Protocol: All used maintenance non-homogenous lotion twice a day. 25 Tinea versicolor is a rash in humans known to be caused by Materials: The maintenance non-homogenous lotion was two species of malassezia: malassezia globosa and malasse CetaphiltM moisturizing lotion mixed in a ratio of 1:1 with Zia furfur. 62% ethanol gel immediately before application. The patient was a 39 year old man with a two-year history Duration of follow-up: of extensive tan moderately scaling patches symmetrically on a. 1 month: 2 patients 30 the chest and back. Condition failed to respond to a month of conventional treatment with Zinc pyrithione lotion. The diag b. 1.5 months: 1 patient nosis was confirmed by a KOH microscopic examination of a c. 2 months: 2 patients specimen from the back rash showing very large numbers of d. 6 months: 1 patient short fathyphae and round yeasts. e. 7 months: 1 patient 35 Treatment of once daily application of 70% ethanol gel to Outcome of Protocol Treatment: 6 of the 7 patients affected areas for two weeks was begun. The patient reported reported they stayed entirely clear while on consistent use that the treatment was well tolerated and comfortable to per maintenance therapy. One patient reported when the weather form. got very cold and dry, the rash recurred despite the mainte The course of treatment resulted in the back patches post nance therapy. 40 treatment showing 10% of the pretreatment scaling. KOH microscopic examination of the rash done post treatment Conclusion showed complete absence of hyphae and round yeast. The The maintenance prototype was strikingly effective in chest patches post treatment had 25% of pretreatment Scaling. maintaining patients rash-free. The KOH microscopic examination of the specimen post 45 treatment showed rare short fathyphae and no round yeasts. Example 2-9 Conclusions: Ethanol killed malassezia genus organisms in this in vivo therapeutic trial. The patient demonstrated Two Case Studies Demonstrating Killing or improvement in the rash both as measured by clinical exami Inhibition of S. Aureus Growth Using nation and microscopic assessment. Corticosteroid/Ethanol Non-homogenous 50 Compositions Example 2-12 Treatment of Seborrheic Dermatitis Case 1: A 26-year old man with eczema on the hand was treated twice daily for three days with a mixture of triamci 55 The patient was a 79-year old man with a prolonged, multi nolone 0.1% ointment in a 5:1 ratio with 62% ethanol gel. The year history of facial seborrheic dermatitis which failed to pre-treatment bacterial culture from the eczematous rash respond adequately to either a low potency prescription cor reported growth of S. aureus. The post-treatment bacterial ticosteroid cream (hydrocortisone valerate 0.2%), or to a mid culture performed after three days of treatment showed no S. potency corticosteroid cream (mometasone 0.1%) in combi aureus present. 60 nation with an anti-fungal cream (ketoconazole cream). In a Case 2: A 92-year old man with eczema on the hand was trial of the compositions described herein, he applied twice a treated twice daily for seven days with a mixture of fluocino day for 6 days a non-homogenous 10:1 mixture of hydrocor lone 0.1% ointment in a 1:1 ratio with 62% ethanol gel. The tisone butyrate cream 0.1% (10 parts) and 62% ethanol gel (1 pre-treatment bacterial culture from the eczematous rash part). This course of therapy resulted in 100% clearing of the reported growth of S. aureus. The post-treatment bacterial 65 facial areas treated and was well tolerated. The patient culture performed after seven days of treatment showed no S. reported he had never cleared this much, or this fast, from any aureus present. of the prior therapies. US 8,647,671 B2 73 74 Example 2-13 Treatment: A topical formulation was prepared containing 2.5 ml of Treatment of eczema 70% ethanol based hand sanitizer gel, 2.5 ml of mometasone ointment 0.1%, and 10 ml of AQUAPHORR). It was applied A chemical matrix for the treatment of eczema using tri twice daily for a week. amcinalone acetonide and ethanol was prepared as described in Example 1-3 using the following ingredients: Results: 2.5 ml of triamcinalone acetonide cream 0.1%; The patient reported that within two days of beginning the 2.5 ml of AQUAPHORR); and new treatment he saw marked improvement in his fingers 1 ml of 62% ethanol gel. 10 rash. For the first time ever he saw the tiny little blisters in the The final concentration of active ingredients in this new rash resolve without expanding, draining on the Surface and chemical matrix are: becoming painful. By the end of a week of treatment he triamcinalone acetonide 0.042%, and ethanol 10.3%. reported almost all the redness, Scaling, and itch was gone. He A 64-year-old woman presented with extensive, extremely reported that he had never seen such improvement with the itchy, crusted eczema on the trunk and legs and Such a con 15 prior treatment. dition had existed for over a year. The condition persisted despite treatment with triamcinalone acetonide cream 0.1% On examination at one week of treatment there was an 85% used daily for more than 9 months. No improvement was improvement in the rash on the fingers compared to pretreat observed when she covered the areas treated with the triam ment. cinalone cream for 8 hours with wet pajamas. Treatment was Conclusion: begun using the same triamcinalone acetonide 0.1% cream but now reformulated into the chemical matrix described This case demonstrates that this formulation containing a above. The triamcinalone acetonide and ethanol matrix was Suspension of ethanol microbubbles in a corticosteroid oint applied twice daily without any wet covering. The patient ment was Superior to the independent application of ethanol reported within 24 hours of treatment the itching was greatly 25 gel and corticosteroid topical cream. It is also noted that this reduced. When examined after 1 week of treatment, the improvement was achieved with a formulation containing former rash was 95% resolved. 17% of the standardized topical corticosteroid concentration of mometasone whereas the prior use of cream containing the Example 2-14 full 100% of the standardized topical corticosteroid concen 30 tration of triamcinalone had failed. Treatment of Persistent Pediatric Eczema A chemical matrix for the treatment of eczema using des Example 2-16 onide and ethanol was prepared as described in Example 1-3 using the following ingredients: 35 Treatment of Eczema with a Formulation Containing 2.5 ml of desonide ointment 0.05%; 5% of the Standardized Topical Corticosteroid 2.5 ml of AQUAPHORR); and Concentration of Desonide or Mometasone 1 ml of 62% ethanol gel. The final concentration of active ingredients in this new chemical matrix are: 40 Desonide formulation treated cases: 10 patients treated. 6 desonide 0.021%, and ethanol 10.3%. of the 10 patients demonstrated successful outcome. Aver An 18-month-old child presented with extensive, age improvement was 75% and the average number of days extremely itchy, crusted eczema on the face, trunk, arms, and on treatment was 16 days. legs persisting for several months, worsening in the preceding Mometasone formulation treated cases: 15 patients treated. 10 days. Treatment with moisturizing creams and 1% hydro 45 10 of the 15 patients demonstrated successful outcome. cortisone cream did not resolve the rash. Treatment was Average improvement was 67% and the average number of begun using the desonide and ethanol matrix described days on treatment was 10 days. above. The desonide and ethanol matrix was applied twice daily. The parents reported the rash was almost entirely * success defined as 75% or better improvement in their rash resolved at 4 days of treatment. 50 compared to pretreatment status. Example 2-15 Example 2-17 Treatment of Persistent Eczema with a Formulation Containing 17% of the Standardized Topical 55 Treatment of Eczema with a Formulation Containing Corticosteroid Concentration of Mometasone 1% of the Standardized Topical Corticosteroid Concentration of Desonide or Mometasone History: A 41 year old man presented with infected eczema on his Desonide formulation treated cases: 7 patients treated. All fingers for many years. His eczema had persisted despite 60 patients showed improvement, and 4 of the 7 patients dem daily use separately of both a topical corticosteroid and an onstrated successful outcome. ethanol gel. He had used triamcinalone 0.1% cream twice daily treatment for years without benefit. It also happens that Mometasone formulation treated cases: 3 patients treated. for years it has been his custom during the day to apply All patients showed improvement, and all 3 of the patients demonstrated Successful outcome. commercial hand sanitizer gel 5-6 times to his hands for 65 general health purposes. The rash persisted despite both these * success defined as 75% or better improvement in their rash separately applied topical agents. compared to pretreatment status. US 8,647,671 B2 75 76 Example 2-18 TABLE 2-9-continued Effect of Method of Preparation on Treatment Outcome 5 standardized % Average Clinical outcomes were compared using freshly prepared No. of concentration patients number of medication and using medication which had been prepared Therapeutic patients of cortico- achieving days on and then stored. Treatment outcome was determined at the end of 1 or 2 weeks of treatment. agent evaluated steroid success therapy Procedure: 10 A single use medication was a topical formulation that was mometaSone with 94 10%-84% 95% 11 days * prepared immediately before application and the excess was ethanol discarded after one application. A multi use medication was a topical formulation that was formulations prepared and then used for a week of twice daily applications. mometaSone with 15 59 67% 10 days It was stored in an open-top plastic container which was 15 ethanol further placed inside a Zip lock plastic bag in a refrigerator formulations between applications. Each week a new batch was prepared. desOnlide 0.05% 100% 39% 30 days Standardized topical corticosteroid concentrations of the cor ticosteroids studied: 8IOle Desonide Ung: 0.05% (published Mometasone Ung: 0.1% studies, Ref TAC Ung 0.1% 4 and 5) TAC Cr O.1% desonide with 74 10%-84% 96% 11 days * Procedure for the preparation of the medication: 1. The 2.5/2.5/1 medication was prepared by combining 25 ethanol 2.5 ml of the corticosteroid ointment, 2.5 ml of AQUA formulations PHOR(R) (moisturizer), and 1 ml of ethanol gel 70%. desonide with 10 59 60% 16 days 2. The 10/2.5/2.5 medication was prepared by combining ethanol 2.5 ml of the corticosteroid ointment, 10 ml of AQUA formulations PHOR(R) (moisturizer), and 2.5 ml of ethanol gel 70%. Successful clinical outcome is defined as greater or equal to 75% reduction in eczema rash compared to status pre *success defined as 75% or better improvement in rash during treatment treatment. **Outcome was assessed at either 7 or 14 days of treatment As shown in FIG. 1, successful outcomes were observed for References: both the single and multi use medications. Concentrations as 1. RafanelliA, RafanelliS, Stanganelli I, etal. Mometasome furoate in the treatmentofatopic low as 17% of the standardized topical corticosteroid concen dermatitis in children. J Eur Acad Dermatol Venereol 1993; 2 (3): 225-30. 2. Vernon HJ, Lane AT, Weston W. Comparison of mometasome furoate 0.1% cream and tration provided Successful outcomes. hydrocortisone 1.0% cream in the treatment of childhood atopic dermatitis, J Am Acad Dermatol 1991 April; 24: 603-7. Example 2-19 3. Lebwohl M, Lane AT, Berman B, et al. Efficacy and safety of 0.1% mometasome furoate 40 cream wersus 0.2%hydrocortisonewalerate creaminpediatric patients with atopic dermatitis un-responsive to topical hydrocortisone treatment abstract no. P-43). Proceedings of the 55th Annual Meeting of the American Academy of Dermatology: 1997 Mar, 21-26: San Summary of Outcomes for the Treatment of Eczema Francisco with Formulations Containing Less than the 4. Randomized Controlled Trial of Desonide Hydrogel 0.05% versus Desonide Ointment Standardized Topical Corticosteroid Concentration 0.05% in the Treatment of Mild-to-moderate Atopic Dermatitis Nathan S. Trookman, MD, of Corticosteroid FAAD and Ronald L. Rizer, J. Clin Aesthet Dermatol. 2011 November;4(11): 34-38. 45 5. Safety and efficacy of desonide hydrogel 0.05% in pediatric subjects with atopic derma titis, Hebert AA, Cook-Bolden FE, Basu S, Calvarese B, Trancik RJ; Desonide Hydrogel Table 2-9 provides a summary of outcomes for the treat Study Group, JDrugs Dermatol. 2007 February; 6(2): 175-81. ment of eczema with formulations as described herein con taining less than the standardized topical corticosteroid con centration of corticosteroid. From this data use of the Example 2-20 formulations described herein provides: 50 a) Markedly increased chance of Successful outcome; b) Reduced time of treatment up to 63%; and c) Reduced exposure to corticosteroid up to 90%. Treatment of Eczema with Various Formulations Containing Corticosteroids and Ethanol 55 TABLE 2-9 The purpose of this study was to compare the efficacy of % standardized % Average corticosteroid-ethanol topical formulations for the treatment No. of concentration patients number of 60 of eczema. All formulations were ointment dosage forms Therapeutic patients of cortico- achieving days on incorporating the same amount of ethanol but differed in the agent evaluated steroid success therapy identity of the corticosteroid component. The corticosteroid nonetaSone 100% 57% 21 days component was selected from desonide, mometasone, and 0.1% alone (published hydrocortisone. Concentrations of corticosteroid ranged studies, Ref 65 from 10-91% of the standardized topical corticosteroid con 1, 2, and 3) centration. Results from the study are described in Tables 2-10 to 2-12. US 8,647,671 B2 77 TABLE 2-10 Results using mometaSone-ethanol formulations to treat eczema on the trunk and limbs.

% standardized topical % evaluable corticosteroid i patients who % patients concentration of evaluable failed prior i with Successful average nonetaSone patients CS treatment successes treatment improvement

196 7 57.19% 6 85.7% 80.6% 59 17 58.8% 11 64.7% 68.3% 10% 10 40% 8 80% 83.4% 1796 15 40% 15 100% 92.7% 40% 1 100% 1 100% 90% 42% 3 33% 3 100% 93.3% SO% 2O 65% 19 95% 96.2% 67% 6 33% 6 100% 95% 75% 2 100% 2 100% 90% 80% 6 33% 6 100% 96.7% 83% 15 47% 14 93% 87.1% 83% to 50% 1 100% 1 100% 90% 91% 4 O% 3 75% 89.3% 91% to 50% 13 46% 11 85% 86.5%

Overall 120 49.2% 106 88.3% 90.8%

“Success” is defined as achieving 75% or better improvement with treatment compared to pretreatment baseline condition

TABLE 2-11 Results using desonide-ethanol formulations to treat eczema on the face and genital areas for adults and children, and trunk and limbs for children over the age of two. % standardized topical % evaluable corticosteroid i patients who % patients concentration of evaluable failed prior i with Successful average desonide patients CS treatment successes' treatment improvement 196 8 12.5% 4 SO% 68.5% 59 10 40% 7 70% 81.1% 10% 10 30% 9 90% 86.5% 1796 10 60% 10 100% 97% 42% 2 SO% 2 100% 90% SO% 10 60% 8 80% 85% 67% 3 O% 3 100% 100% 80% 3 33.3% 3 100% 93.3% 83% 13 46% 12 92.3% 90.6% 83% to 50% 3 33.3% 3 100% 90% 91% 6 O 6 100% 100% 91% to 50% 11 36.3% 11 100% 94.5%

Overall 89 37.1% 78 87.6% 88.7% “Success” is defined as achieving 75% or better improvement with treatment compared to pretreatment baseline condition

TABLE 2-12 Results using hydrocortisone-ethanol formulations to treat eczema. % evaluable % patients patients who with # evaluable failed prior CS Successful average location patients # children adults treatinent # successes treatment improvement face? 12 C: 3 A: 9 66.7% 10 83.3% 88.7% genital trunk? 16 C: S.A.: 11 56.3% 10 62.5% 73.5% limbs

Total 28 C: 8A: 20 60.7% 2O 71.4% 80% “Success” is defined as achieving 75% or better improvement with treatment compared to pretreatment baseline condition US 8,647,671 B2 79 80 Two of the eight patients in Table 2-12 who were unsuc 6. The chemical matrix of claim 1, wherein the desonide is cessful with treatment with 1% hydrocortisone ointment present in an amount of about 0.005%, about 0.01%, about treatment were switched to 10% standardized mometasone or 0.015%, or about 0.02%. 10% standardized desonide (depending on body area and age) 7. A chemical matrix comprising from about 2% to about and both Subsequently achieved treatment Success. 30% of an alcohol by volume, mometasone and at least one Summary for all Evaluable Patients Treated Using Ethanol excipient, wherein the chemical matrix is an ointment Suit Formulations Containing Desonide and Mometasone: able for topical administration, the alcohol is primarily dis Total # of patients using either desonide or mometasone: 168 persed into the chemical matrix in the form of microbubbles, Total it of patients achieving success: 157 the alcohol is selected from ethanol, isopropanol, or n-pro Overall treatment success rate: 93% 10 panol, or combinations thereof, and the mometasone is Overall treatment average improvement score: 92% present in a concentration between about 1% and about 91% * success is defined as achieving 75% or better clearing of rash of the standardized topical mometasone concentration that is after treatment O.1%. Summary for all Evaluable Patients Treated Using Ethanol 15 8. The chemical matrix of claim 7, wherein the mometa Formulations Containing Over-The-Counter Regulated sone is present in an amount of about 0.001%, about 0.005%, Hydrocortisone: about 0.01%, about 0.02%, about 0.04%, or about 0.09%. Total it of patients using hydrocortisone: 28 9. The chemical matrix of claim 7, wherein the mometa Total it of patients achieving success: 71% sone is present in an amount of about 0.01%, about 0.02%, Overall treatment success rate: about 0.03%, or about 0.04%. Overall treatment average improvement score: 80% 10. The chemical matrix of claim 1 or 7, wherein the * success is defined as achieving 75% or better clearing of rash alcohol is ethanol. after treatment 11. The chemical matrix of claim 1 or 7, wherein the The formulations with the desonide and mometaSone pro ointment is selected from white petrolatum USP, white oint duced significantly better success rate (93% versus 71%) and 25 ment USP hydrophilic petrolatum USP or hydrophilic oint average degree of improvement (92% versus 80%) than simi ment USP. lar ethanol formulations containing over-the-counter strength 12. The chemical matrix of claim 1 or 7, wherein the hydrocortisone. chemical matrix comprises from about 2% to about 10% While preferred embodiments of the present inventions ethanol by volume. have been shown and described herein, it will be obvious to 30 13. The chemical matrix of claim 1 or 7, wherein the those skilled in the art that such embodiments are provided by chemical matrix comprises from about 10% to about 20% way of example only. Numerous variations, changes, and ethanol by volume. substitutions will now occur to those skilled in the art without 14. The chemical matrix of claim 1 or 7, wherein the departing from the inventions. It should be understood that chemical matrix comprises from about 20% to about 30% various alternatives to the embodiments of the invention 35 ethanol by volume. described herein may be employed in practicing the inven 15. A chemical matrix suitable for the treatment of derma tion. It is intended that the following claims define the scope titis for a patient in need thereof comprising from about 2% to of the inventions and that methods and structures within the about 30% of an alcohol by volume, a therapeutically effec Scope of these claims and their equivalents be covered tive amount of desonide and at least one excipient, wherein thereby. 40 the chemical matrix is an ointment Suitable for topical admin istration, the alcohol is primarily dispersed into the chemical What is claimed is: matrix in the form of microbubbles, the alcohol is selected 1. A chemical matrix comprising from about 2% to about from ethanol, isopropanol, or n-propanol, or combinations 30% of an alcohol by volume, desonide and at least one thereof, and the therapeutically effective amount of desonide excipient, wherein the chemical matrix is an ointment Suit 45 is between about 1% and about 91% of the standardized able for topical administration, the alcohol is primarily dis topical desonide concentration that is 0.05%. persed into the chemical matrix in the form of microbubbles, 16. The chemical matrix of claim 15, wherein the thera the alcohol is selected from ethanol, isopropanol, or n-pro peutically effective amount of desonide is about 1%, about panol, or combinations thereof, and the desonide is present in 5%, about 10%, about 15%, about 25%, about 35%, about a concentration between about 1% and about 91% of the 50 50%, about 65%, about 75%, about 85%, or about 91% of the standardized topical desonide concentration that is 0.05%. standardized topical desonide concentration that is 0.05%. 2. The chemical matrix of claim 1, wherein the desonide is 17. The chemical matrix of claim 15, wherein the thera present in a concentration of about 1%, about 5%, about 10%, peutically effective amount of desonide is present in a con about 15%, about 25%, about 35%, about 50%, about 65%, centration between about 1%, about 5%, about 10%, about about 75%, about 85%, or about 91% of the standardized 55 15%, or about 25% of the standardized topical desonide con topical desonide concentration that is 0.05%. centration that is 0.05%. 3. The chemical matrix of claim 1, wherein the desonide is 18. The chemical matrix of claim 15, wherein the thera present in a concentration of about 1%, about 5%, about 10%, peutically effective amount of desonide is present in a con about 15%, or about 25% of the standardized topical desonide centration about 10%, about 15%, about 25%, or about 35% concentration that is 0.05%. 60 of the standardized topical desonide concentration that is 4. The chemical matrix of claim 1, wherein the desonide is O.05%. present in a concentration of about 10%, about 15%, about 19. The chemical matrix of claim 15, wherein the desonide 25%, or about 35% of the standardized topical desonide con is present in an amount of about 0.0005%, about 0.0025%, centration that is 0.05%. about 0.005%, about 0.009%, about 0.02%, or about 0.045%. 5. The chemical matrix of claim 1, wherein the desonide is 65 20. The chemical matrix of claim 15, wherein the desonide present in an amount of about 0.0005%, about 0.0025%, is present in an amount of about 0.005%, about 0.01%, about about 0.005%, about 0.009%, about 0.02%, or about 0.045%. 0.015%, or about 0.02%. US 8,647,671 B2 81 82 21. A chemical matrix suitable for the treatment of derma 27. The chemical matrix of claim 21, wherein the chemical titis for a patient in need thereof comprising from about 2% to matrix comprises from about 10% to about 20% ethanol by about 30% of an alcohol by volume, a therapeutically effec Volume. tive amount of mometasone and at least one excipient, 28. The chemical matrix of claim 21, wherein the chemical wherein the chemical matrix is an ointment suitable for topi cal administration, the alcohol is primarily dispersed into the matrix comprises from about 20% to about 30% ethanol by chemical matrix in the form of microbubbles, the alcohol is Volume. selected from ethanol, isopropanol, or n-propanol, or combi 29. The chemical matrix of claim 7 or 21, wherein the nations thereof, and the therapeutically effective amount of therapeutically effective amount of mometasone is present in mometasone is between about 1% and about 91% of the a concentration of about 1%, about 5%, about 10%, about standardized topical mometasone concentration that is 0.1%. 10 15%, about 25%, about 35%, about 50%, about 65%, about 22. The chemical matrix of claim 21, wherein the mometa 75%, about 85%, or about 91% of the standardized topical sone is present in an amount of about 0.001%, about 0.005%, mometasone concentration that is 0.1%. about 0.01%, about 0.02%, about 0.04%, or about 0.09%. 30. The chemical matrix of claim 7 or 21, wherein the 23. The chemical matrix of claim 21, wherein the mometa 15 therapeutically effective amount of mometasone is present in sone is present in an amount of about 0.01%, about 0.02%, a concentration of about 1%, about 5%, about 10%, about about 0.03%, or about 0.04%. 15%, or about 25% of the standardized topical mometasone 24. The chemical matrix of claim 21, wherein the alcohol is concentration that is 0.1%. ethanol. 25. The chemical matrix of claim 21, wherein the ointment 31. The chemical matrix of claim 7 or 21, wherein the is selected from white petrolatum USP, white ointment USP therapeutically effective amount of mometasone is present in hydrophilic petrolatum USP or hydrophilic ointment USP. a concentration of about 10%, about 15%, about 25%, or 26. The chemical matrix of claim 21, wherein the chemical about 35% of the standardized topical mometasone concen matrix comprises from about 2% to about 10% ethanol by tration that is 0.1%. Volume.