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`(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
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`(19) World Intellectual Property Organization
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`I IIIII IIIIIIII II IIIIII IIIII IIIII IIIII IIII I II Ill lllll lllll lllll lllll lllll llll 1111111111111111111
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`International Bureau
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`(10) International Publication Number
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`(43) International Publication Date
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`3 February 2011 (03.02.2011)
`PCT
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`WO 2011/014627 Al
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`(51) International
`(74) Agents: WURST, John et al.; Allergan, Inc., 2525
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`Patent Classification:
`A61K 9/06 (2006.01) A61K 9/00 (2006.01)
`
`
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`Dupont Drive, Irvine, California 92612 (US).
`A61K 31/136 (2006.01)
`A61P 17/10 (2006.01)
`(81) Designated
`States (unless otherwise indicated, for every
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`
`
`
`A61K 31/192 (2006.01)
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`kind of national protection available): AE, AG, AL, AM,
`AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ,
`(21) International Application Number:
`
`
`CA,CH,CL,CN,CO,CR,CU,CZ,DE,DK,DM,DO,
`DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT,
`(22) International Filing Date:
`
`
`HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP,
`29 July2010 (29.07.2010)
`KR,KZ,LA,LC,LK,LR,LS,LT,LU,LY,MA,MD,
`ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI,
`English
`NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD,
`English
`SE, SG, SK, SL, SM, ST, SY, SY, TH, TJ, TM, TN, TR,
`TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.
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`PCT/US2010/04367 l
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`
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`(25) Filing Language:
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`
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`(26) Publication Language:
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`(30) Priority Data:
`
`61/229,903 30 July 2009 (30.07.2009)
`us (84) Designated
`States (unless otherwise indicated, for every
`
`
`
`
`
`
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`kind of regional protection available): ARIPO (BW, GH,
`(71) Applicant (for all designated States except US): AL
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`
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`GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG,
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`LERGAN, INC. [US/US]; 2525 Dupont Drive, T2-7H,
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`ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ,
`Irvine,
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`California 92612 (US).
`TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK,
`(72)
`Inventors; and
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`EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU,
`
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`Inventors/ Applicants (for US only): AHLUWALIA,
`(75)
`LV, MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK,
`
`Gurpreet [US/US]; 3131 Michelson Drive, #303, Irvine,
`
`
`
`SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ,
`California 92612 (US). WARNER, Kevin, S. [US/US];
`
`GW, ML, MR, NE, SN, TD, TG).
`=
`1281 N. Walden Lane, Anaheim, California 92807 (US).
`
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`Published:
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`CHEN, Haigang [CN/US]; 1962 Lansdowne Way,
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`Petalmna, California 94954 (US). YANG, Meidong [CN/
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`US]; 1400 Pimiacle Court, #204, Richmond, California
`94801 (US).
`=
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`with international search report (Art. 21 (3))
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`(54) Title: COMBINATION OF DAPSONE WITH ADAP ALENE
`=
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`Hg. I
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`Ingredient
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`Comuosition
`(% w/w)
`4.1-a
`2.1-a
`Dapsonc 5.0 5.0 5.0 5.0 5.0 5.0 5.0
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`Ada pal enc 0.1 and 0.3 0.1 and 0.3 0.1 and 0.3 0.1 and 0.3 0.1 and 0.3 0.1 and 0.3 0.1 and 0.3
`Transcutof
`R' P 25.0 25.0 25.0 25.0 25.0 25.0 25.0
`Benzyl Alcohol 1.5 1.5 1.5 1.5 1.5 1.5
`PEG400 25.0 5-15 5-15 13.0
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`Lactic Acid
`2.0
`Dimethyl lso.sorbidc 5-15 5-15
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`Propylene Glycol
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`5-13 5-13
`10.0 10.0 10.0
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`- =
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`;;;;;;;;;;;;;;
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`=
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`-
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`-;;;;;;;;;;;;;;
`;;;;;;;;;;;;;;
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`2.0
`2.0 2.U
`Glycerin
`EDTA Disodium 0.01 0.01 0.QJ 0.01 0.01 0.01
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`Citric Acid 0.03 0.03 0.03 0.03 0.03 0.03
`HEC
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`1-4 1-4
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`1-2
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`C:arbopol 980
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`0.5-2 0.75
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`0.5-2 0.85
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`q.s. pH 5.5 q.s. pH 5.5 q.s. pH 5.5 q.s. pH 5.5 q.s. pH 5.5 q.s. pH 5.5 0.2 (NaOH)
`NaOH or Trolamine
`Diluted Hydrochloric
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`q.s. pH 5.5 q.s. pH 5.5 q.s. pH 5.5 q.s. pH 5.5 q.s. pH 5.5 q.s. pH 5.5
`Acid
`Methylparabcn
`0.2
`q.s.a.d. q.s.a.d. q.s.a.d q.s.a.d. q.s.a.d. q.s.a.d
`q.s.a.d.
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`Water
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`(57) Abstract: A composition suitable for topical application that contains at least two active ingredients, one of these being dap
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`sone and one selected from the group consisting of adapalene, tazarotene and treinion for the effective treatment of acne and other
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`dermatological conditions.
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`1 of 34
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`Almirall EXHIBIT 2008
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`Amneal v. Almirall
`IPR2019-00207
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`WO 2011/014627
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`PCT/US2010/043671
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`COMBINATION OF DAPSONE WITH ADAPALENE
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`Cross Reference
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`This application claims the benefit of U.S. Provisional Patent Application Serial
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`Number 61/229,903 filed on July 30, 2009, the entire disclosure of which is incorporated
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`herein by this specific reference.
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`Field of the Invention
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`The present invention is directed to compositions and methods for the treatment of
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`10 acne vulgaris and other dermatological conditions.
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`Background of the Invention
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`Acne is the most common skin disease that affects a large number of adolescents
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`and young adults after they reach puberty. Though not a life threatening disease, it has
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`serious psychological impact on the patient. Chronic inflammatory acne can also result in
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`15 permanent scarring of the face.
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`There are multiple factors that contribute to the pathogenesis of acne, these include:
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`1. over activity of sebum production as a result of hormonal changes at puberty; 2.
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`colonization of Propionibacterium acnes (P.acnes) in the pilosebaceous unit; 3.
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`hyperkeratinization or abnormal desquamation of epithelium of the upper follicle ( above
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`canal; 4. formation of in blockage of the pilosebaceous 20 the sebaceous gland) that results
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`inflammatory molecules as a result of the action of P.acnes on sebaceous lipids.
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`The obstruction of the pilosebaceous canal and inflammation caused by P.acnes
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`created inflammatory metabolites results in the formation of comedones. Excess sebum
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`production as a result of hormonal changes at puberty, combined with increased epithelium
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`25 turnover of the upper follicle leads to formation of microcomedones which progresses to
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`inflammatory papules and pustules in acne. The combination of lipid rich sebum and
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`protein rich desquamated cells provides an ideal environment for the growth and activity
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`of P.acnes which converts the sebaceous lipids to the inflammatory free fatty acid
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`molecules resulting in inflammatory acne lesions. The patient can have either non-
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`inflammatory ( open and closed comedones ), inflammatory (pa pules and pustules) or a
`combination of both which most often is the case. Topical treatments are generally
`sufficient in most patients to control the acne lesions.
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`Because acne is a multifactorial condition, the marketed products work on one or
`5 more of the underlying factors contributing to acne for its treatment. There are number of
`prescription and over-the-counter (OTC) products available that treat acne; however, they
`all lack either desired efficacy or tolerability or both. Currently available products include
`antibiotics (topical and systemic), benzoyl peroxide, retinoids (topical and systemic),
`dapsone, and a number of other compounds.
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`The anti-acne molecule dapsone is marketed as a commercial product Aczone®.
`Aczone® is a 5% dapsone gel with a gritty texture due to insoluble particles of dapsone
`drugs. The insolubility of dapsone limits the bioavilability of dapsone upon application and
`its absorption through the skin and is therefore administered twice daily. At the
`biochemical and molecular level, dapsone exhibits an anti-inflammatory activity which
`provides a unique mechanism of action for this molecule in treatment of inflammatory
`acne lesions. However, its mechanism of action is not entirely understood. A complex
`combination of inflammatory pathways produce the clinical inflammation observed in
`acne. It is known that neutrophils significantly contribute to inflammatory acne. Dapsone
`is known to suppress neutrophil recruitment & local production of toxic products there by
`inhibiting neutrophil chemotaxis and reducing generation of oxygen free radicals. It further
`inhibits release of lysosomal enzymes and reduces release and bocks inflammatory effects
`of prostaglandins & leukotrienes. These effects results in reduction of inflammatory acne
`lesions. In addition to its anti-inflammatory activity, dapsone is also effective against P.
`acnes. MIC90 against P. acnes is 8µg/ml.
`
`Adapalene is a third generation retinoid, which are compounds related to Vitamin
`A, and has been approved by the FDA for the treatment of acne. Adapalene is known to
`moderate inflammatory processes but its mechanism of action is also not entirely
`understood. Adapalene products are sold with the concentrations of 0.1 % and 0.3% w/v
`concentrations for gels and 0.1 % w/v concentration for cream. Adapalene acts on retinoid
`receptors and appears to be a modifier of cellular differentiation, keratinization and
`inflammatory processes which are involved in the pathology of acne vulgaris. Absorption
`of adapalene from either 0.1 % or 0.3% gel or cream is low. In one pharmacokinetic study,
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`16 patients suffering from acne vulgaris received 0.3% adapalene gel applied to the face,
`chest and back which is approximately a dosage of 2 mg/cm2. Fifteen patients resulted in
`quantifiable (LOQ = 0.1 ng/mL) adapalene levels with a mean Cmax of0.553 ± 0.466
`ng/mL on Day 10 of treatment. Mean AUC0-24hr was 8.37 ± 8.46 ng.h/mL as determined
`in 15 of the 16 patients on Day 10. Terminal apparent half-life, which was determined in
`15 of 16 patients, ranged from 7 to 51 hours, with a mean of 17.2 ± 10 .2 hours. Adapalene
`was rapidly cleared from plasma and was not detected 72 hours after the last application
`for all but one subject.
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`Summary of the Invention
`There is an unmet consumer need for an efficacious product for the treatment of
`acne vulgaris as the currently available products for treatment of acne vulgaris lack the
`desired efficacy and/or have side effects or tolerability issues that are undesired by the
`subjects.
`A combination acne product would provide the benefit of enhanced efficacy
`compared to the products containing single active agent by taking advantage of the
`synergistic mechanism of action of the active agents for treatment of acne. The present
`invention is directed to acne products with at least two active compounds and in particular
`are directed to dapsone and adapalene combination formulations for the use in the
`treatment of dermatological conditions such as acne vulgaris, rosacea, atopic dermatitis,
`treatment of chronic wounds, bed sores, keratosis piralis, psoriasis, cosmetic improvement
`of surgical and acne scars, sebaceous cysts, inflammatory dermatoses, post inflammatory
`hyperpigmentation, eczema, xerosis, pruritis, lichen planus, nodular prurigo, eczema, and
`miliaria and other dermatological conditions.
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`Some embodiments of the present invention include:
`1) A dermatological composition comprising dapsone, adapalene, and water.
`2) The dermatological composition of paragraph 1 wherein the composition
`comprises 5% w/w dapsone and 0.1 % or 0.3% w/w adapalene and is used for the
`treatment of acne vulgaris.
`3) The dermatological composition of paragraph 2 wherein the composition is 0.5%
`30 w/w dapsone and 0.3% w/w adapalene.
`4) The dermatological composition of paragraph 1 wherein the composition is a gel.
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`5) The compositions of paragraphs 1 and 4 wherein the composition is 0.5% w/w
`dapsone, 0.1 % w/w adapalene, 1.5% w/w benzyl alcohol, transcutol, 5 - 25% w/w PEG
`400, 0.01 % w/w EDTA, and 0.03% w/w citric acid . .
`6) The compositions of paragraphs 1 - 5 wherein the composition further comprises
`hydroxyl ethyl cellulose 1 - 4% w/w.
`7) The compositions of paragraphs 1 - 5 further comprising carbopol 980 at 0.5 - 2%
`w/w.
`8) The compositions of paragraphs 1 - 7 further comprising methyl paraben.
`9) The compositions of paragraphs 1 - 8 further comprising lactic acid.
`10) The compositions of paragraphs 1 - 9 further comprising glycerin.
`11) The composition of paragraph 5 further comprising dimethyl isosorbide in 5 - 15%
`w/w.
`12) The composition of paragraphs 1 - 5 wherein transcutol is present in the amount of
`25% w/w.
`13) The compositions of paragraphs 1 - 12 wherein a buffer selected from the group
`consisting ofNaOH, trolamine, and hycrochloric acid is added to adjust the pH.
`14) The compositions of paragraphs 1 - 13 wherein the pH of the composition is 5.5.
`15) The composition of paragraphs 1 - 5 further comprising 2 - 3 % hydroxyl ethyl
`cellulose.
`16) The compositions of paragraphs 1 - 15 wherein the composition is in the form of
`one selected from the group consisting of a gel, emulsion, cream, liquid, paste, lotion,
`nanoemulsion, microemulsion, reverse emulsion and liposomal cream.
`17) The compositions of paragraphs 1- 16 wherein the composition may be used for
`treatment of one selected from the group consisting of acne vulgaris, rosacea, atopic
`dermatitis, treatment of chronic wounds, bed sores, keratosis piralis, sebaceous cysts,
`inflammatory dermatoses, post inflammatory hyperpigmentation, eczema, xerosis, pruritis,
`lichen planus, nodular prurigo, dermatitis, eczema, and miliaria and other dermatological
`conditions.
`18) A method of treating acne vulgarus by application of the compositions of
`paragraphs 1 - 17.
`19) The method of treatment of paragraph 17, wherein the application is once a day.
`20) The method of treatment of paragraph 17, wherein the application is twice a day.
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`Brief Description of the Drawings:
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`Fig. 1 is directed to dapsone and adapalene formulations for the treatment of
`dermatological conditions;
`Fig. 2 is directed to variations of formulations for the treatment of dermatological
`conditions of Formula 1 of Figure 1;
`Fig. 3A is directed to variations of formulations for the treatment of dermatological
`conditions of Formula 2 of Figure l;
`Fig. 3B is directed to variations of formulations for the treatment of dermatological
`conditions of Formula 2 of Figure 1;
`Fig. 3C is directed to variations of formulations for the treatment of dermatological
`conditions of Formula 2.1 of Figure 1;
`Fig. 3D is directed to variations of formulations for the treatment of dermatological
`conditions of Formula 2.1 of Figure 1;
`Fig. 4A is directed to variations of formulations for the treatment of dermatological
`conditions of Formula 4 of Figure 1;
`Fig. 4B is directed to variations of formulations for the treatment of dermatological
`conditions of Formula 4 of Figure 1;
`Fig. 4C is directed to variations of formulations for the treatment of dermatological
`conditions of Formula 4 of Figure 1;
`Fig. 4D is directed to variations of formulations for the treatment of dermatological
`conditions of Formula 4 of Figure 1; and,
`Fig. 5 is directed to dapsone and adapalene formulations for the treatment of
`dermatological conditions.
`Detailed Description of the Invention
`The present invention is directed to topical compositions for treatment of
`dermatological conditions which contain at least two active ingredients, one of these being
`dapsone and the other(s) selected from the list below for an effective treatment of acne and
`other dermatological conditions such as rosacea.
`Some broad embodiments of the invention and possible combinations are found
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`below:
`Suitable compounds that can be combined with dapsone (2 - 10% w/w) include:
`1. Agents with bactericidal and/or comedolytic properties:
`a. Benzoyl peroxide (2.5 - 10% w/w); and,
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`b. other antimicrobial actives that are effective against P.acnes.
`2. Agents that inhibit comedogenesis by reducing pilosebaceous canal obstruction or
`have keratolytic properties such as:
`a. Salicylic acid (0.5 - 3% w/w);
`b. Azelaic acid (up to 20% w/w);
`c. Sulfacetamide-sulfur (5 - 10% w/w); and,
`d. other keratolytic agents.
`3. Agents that reduce sebaceous gland secretion and effect epithelial dysquamation:
`a. Retinoids:
`1. tretinoin or trans retinoic acid (0.02 - 0.1 % w/w);
`11. Tazarotene (0.05 - 0.1 % w/w);
`111. Adapalene (0.1 - 0.3% w/w); and,
`1v. additional retinoids.
`4. Topical antibiotics for directly killing P. acnes:
`a. erythromycin (1 - 3% w/w);
`b. clindamycin (1 - 2% w/w); and,
`tetracycline (1 - 3% w/w).
`c.
`
`Potential combinations that can be used:
`1. Dapsone (0.01 % - 10% w/w) + retinoid (0.001 % - 3% w/w)
`Examples:
`a. Dapsone 5% w/w + Adapalene 0.3% w/w;
`b. Dapsone 5% w/w + tazarotene 0.1 % w/w; and,
`c. Dapsone 5% w/w + tretinoin 0.1 % w/w.
`2. Dapsone + benzoyl peroxide:
`Examples:
`a. Dapsone 5% w/w + benzoyl peroxide 5% w/w;
`3. Dapsone + antibiotic:
`Examples:
`a. Dapsone 5% w/w + clindamycin 1 % w/w.
`4. Dapsone + keratolytic agent
`Examples:
`a. Dapsone 5% w/w + Azelaic acid 20% w/w.
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`The concentration values (w/w) in parenthesis represent preferred concentration;
`however, other concentrations values (w/v) can be used dependent on the formulation
`characteristics and the desired level of efficacy and tolerability.
`In a recent clinical trial the safety and efficacy of dapsone gel co-administered with
`adapalene gel was assessed. The study design consisted of having patients apply the
`product Aczone® (5% w/w dapsone) twice a day, with morning and evening application.
`About 10 minutes after the evening application of Aczone®, patients applied a thin layer
`of 0.1 % w/w adapalene gel. The 10 minute separation between applications of the two
`products ensured complete absorption of the Aczone® formulation into the skin to
`10 minimize the potential negative impact on adapalene or dapsone skin penetration.
`Application of the 0.1 % w/w adapalene gel immediately after the Aczone® application
`may have resulted in a situation where the adapalene or dapsone would have a lower skin
`penetration because of the mixing of the two formulation vehicles. Further, the additional
`thickness of the combined formulation applications may increase the penetration distance
`of the two actives also resulting in reduced skin penetration of the actives.
`The results of the trial showed that dapsone gel administered concurrently (but not
`together) with adapalene gel is safe and well tolerated for the treatment of acne vulgaris.
`One aspect of the present invention is a combination adapalene/dapsone topical
`formulation combining the two actives into one formulation. The novelty of this invention
`is in part attributable to the use of additional excipients (solubilizers) in combination with
`diethylene glycol monoethyl ether ("DGME") in order to solubilize dapsone. Addition of
`cosolvents has enabled the complete dissolution of dapsone in the formulation and an
`increase in the solubility of adapalene (adapalene is not completely solubilized in these
`formulations). The increased concentration of dissolved dapsone and adapalene versus the
`25 marketed product comparators administered concurrently will increase the rate of skin
`penetration of both drugs into and through the skin
`Topical dosage forms of the present invention include, but are not limited to
`solutions, gels, creams, ointments, foams, emulsions, films, and facial/skin peels. The
`present invention is directed to topical dapsone and adapalene formulations which are
`30 formulated to optimize the dermal delivery profile of adapalene and dapsone to effectively
`treat acne and other dermatological conditions and improve the efficiency of
`pharmaceutical products applied to the skin.
`Examples of some formulations encompassed by the present invention excipients
`and concentration ranges are summarized in Table 1 below:
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`Table 1: Example Excipient Composition Ranges Utilized in Adapalene / Dapsone
`Topical Formulations:
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`Composition (% w/w)
`0.5 - 10
`0.1-0.3
`0.05 - 1.5
`1-8%
`1-6%
`0.01 - 2.0
`0.01 - 2.0
`1 - 90
`1- 10
`1 - 50
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`Function
`Active
`Active
`Thickener
`
`Neutralizing Agent
`Neutralizing Agent
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`Solubilizers
`
`Dapsone
`Adapalene
`Carbomer 980
`Hydroxyethyl cellulose
`Hydroxypropyl cellulose
`NaOH
`Trolamine
`Ethanol
`Lactic acid
`diethylene glycol monoethyl
`ether
`1 - 60
`propylene glycol
`1 -30
`Dimethyl isosorbide
`1 - 50
`Polyethylene glycol 400
`Hexylene glycol
`1 - 50
`0.5 - 10
`Isostearyl alcohol
`0.5 - 10
`Medium chain triglycerides
`2 - 10
`Isopropyl myristate
`0.5-5
`Preservative
`Benzyl alcohol
`0.1-0.3
`Preservative
`Methyl Paraben
`0.01-1
`Preservative
`Propyl Paraben
`0.1-0.2
`Preservative
`Benzalkonium Chloride
`0.1-2.7
`Preservative
`Sorbic Acid
`1 - 20
`Humectant
`Glycerol
`Polyvinyl alcohol
`1-30
`Film forming
`Water
`1 - 90
`Vehicle
`0.005 - 0.02
`EDT A Disodium
`Antioxidant
`Citric Acid
`0.015 - 0.06
`Antioxidant
`0.005 - 1
`Butylated hydroxytoluene
`Antioxidant
`0.01 -0.25
`Butylated hydroxyanisole
`Antioxidant
`0.01 - 0.1
`Propyl gallate
`Antioxidant
`0.1-90
`Thickener
`Elastomer 10
`0.1-50
`Thickener
`ST Wax 30
`0.1-50
`Thickener
`Dimethiconol blend 20
`0.1-50
`Emulsifier
`Emulsifier 10
`0.1-50
`Solvent
`cyclomethicone 5
`0.1-50
`Solvent
`Silicone fluid
`0.1-50
`Silkv wax 10
`Thickener
`Further specific compositions of the present invention of 5% w/w dapsone and 0.1 %
`w/w and 0.3% w/w adapalene formulations include but are not limited to:
`
`Ingredient
`
`5
`
`8
`
`9 of 34
`
`
`
`5
`
`-
`
`-
`
`-
`
`10 10 2 -
`
`20 20 10 -
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`15 -
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`0.01 -
`
`0.01 0.01 0.01 0.01 0.01 0.01 0.01
`
`Antioxidant
`
`Agent
`
`-
`
`-
`
`-
`
`-
`
`Solubilizing
`Humectant
`
`-
`
`-
`
`-
`
`-
`
`Agent
`
`Solubilizing
`
`-
`
`-
`
`Agent
`
`Solubilizing
`
`-
`
`-
`
`EDTA
`
`Myristate
`Isopropyl
`
`Glycerin
`
`Glycol
`Propylene
`
`Isosorbide
`Dimethyl
`
`5 4 -
`
`Solubilizing
`
`Agent
`
`Lactic Acid
`
`25 20 25 20 15 -
`
`Solubilizing
`
`Agent
`
`PEG 400
`
`0.3% 0.3%
`
`0.3% 0.3% 0.3%
`
`Active 0.1% 0.1% 0.1% 0.1% 0.1% 0.1% 0.1% 0.1% 0.1%
`Active 5 5
`Function
`
`5
`
`5 5 5 5 5 5
`
`Composition (% w/w)
`
`Dapsone
`In2redient
`
`Adapalene
`
`25 20 25 20 25 25 25 25 25
`0.3% 0.3% 0.3% 0.3%
`or or or or or or or or or
`
`Solubilizing
`
`Alcohol
`Benzyl
`ether
`monoethyl
`glycol Agent
`diethylene
`
`1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 -
`
`Preservative
`
`Formulations
`
`Topical
`
`/ Dapsone
`
`Table 2A: Adapalene
`
`10 of 34
`
`
`
`60
`
`-
`
`-
`
`3
`
`-
`
`-
`
`-
`
`-
`
`q.s.a.d. q.s.a.d. q.s.a.d. q.s.a.d. q.s.a.d.
`
`q.s.a.d. q.s.a.d. q.s.a.d.
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`pH5.5 pH 5.5 pH 5.5 pH5.5 pH 5.5
`q.s.
`pH5.5 pH 5.5 pH 5.5 pH5.5 pH 5.5
`q.s.
`
`q.s.
`
`q.s.
`
`q.s.
`
`q.s.
`
`q.s.
`
`q.s.
`
`q.s.
`
`q.s.
`
`pH 5.5
`q.s.
`pH5.5
`q.s.
`
`-
`
`-
`
`-
`
`-
`
`1.2
`
`1.5
`
`-
`
`-
`
`-
`
`0.75
`
`0.75
`
`0.75
`
`-
`
`-
`
`-
`
`0.03
`
`0.03
`
`0.03
`
`-
`
`-
`
`4
`0.03
`
`-
`
`0.75
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`-
`
`Thickener
`Thickener
`
`0.03
`
`0.03
`
`3
`0.03
`
`4
`0.03
`
`Thickener
`Antioxidant
`
`Vehicle
`Solubilizer
`
`Neutralizing
`
`Agent
`
`Neutralizing
`
`Agent
`
`Q
`"""
`
`Water
`
`Ethanol
`Acid
`Hydrochloric
`Diluted
`
`NaOH
`
`Cellulose
`Hydroxypropyl
`Carbopol 980
`Cellulose
`Hydroxyethyl
`Citric Acid
`
`Disodium
`
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`Table 2B, Adapalene / Dapsone Topical Formulations (cont.)
`
`In2redient
`Dapsone
`
`Adapalene
`
`diethylene
`glycol
`mono ethyl
`ether
`
`Benzyl Alcohol
`
`PEG 400
`
`Dimethyl
`Isosorbide
`
`Function
`Active
`Active
`
`Solubilizing
`Agent
`
`Preservative
`
`Solubilizing
`Agent
`
`Solubilizing
`Agent
`
`Propylene Glycol
`
`Solubilizing
`Agent
`Humectant
`Glycerin
`EDTA Disodium Antioxidant
`Antioxidant
`Citric Acid
`Thickener
`
`Hydroxyethyl
`Cellulose
`
`Carbopol 980
`
`Hydroxypropyl
`Cellulose
`
`NaOH
`
`Diluted
`Hydrochloric
`Acid
`
`Water
`
`Thickener
`Thickener
`
`Neutralizing
`Agent
`Neutralizing
`Agent
`Vehicle
`
`Composition (% w/w)
`5
`5
`5
`0.1%5
`0.1%
`0.1%
`or
`or
`or
`0.3%
`0.3%
`0.3%
`25
`25
`25
`
`10
`
`1.5
`
`1.5
`
`-
`
`13
`
`15
`
`2
`0.01
`0.03
`2
`
`-
`15
`
`13
`
`150
`
`2
`0.01
`O.o,1;
`-
`
`1.5
`
`13
`
`-
`
`15
`
`2
`0.01
`0.03
`-
`
`0.75
`-
`
`-
`
`-
`
`-
`2
`q.s. 30
`q.s.
`q.s.
`1JH 5.5 pH 5.5 pH 5.5
`q.s.
`q.s.
`q.s.
`pH 5.5 pH 5.5 pH 5.5
`q.s.a.d. q.s.a.d. q.s.a.d.
`
`35
`
`40
`
`The formulations of the present invention can be made as follows based on the
`excipients:
`Process for making lactic acid containing formulations:
`The combination adapalene/dapsone gels were prepared as follows:
`a. Weigh the Transcutol into a kettle. Add the dapsone, lactic acid, polyethylene
`glycol 400, benzyl alcohol. Stir with propeller mixer at room temperature. Mix
`until dissolved;
`b. Add water, EDTA, and citric acid to mixture in step a. Mix until dissolved;
`c. Add adapalene to mixture in step b;
`
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`5
`
`10
`
`15
`
`20
`
`25
`
`d. While continuing to mix, slowly add hydroxyethyl cellulose to mixture in step c
`avoid clumping. Mix vigorously at room temperature until a uniform lump-free
`dispersion is achieved; and,
`e. While mixing add sufficient sodium hydroxide to achieve a pH of 5 .3 to 5. 7. Mix
`until uniform.
`
`Process for making DMI / hydroxyethyl cellulose containing formulations:
`The combination adapalene/dapsone gels were prepared as follows:
`a. Weigh the Transcutol into a kettle. Add the dapsone, dimethyl isosorbide,
`polyethylene glycol 400, benzyl alcohol. Stir with propeller mixer at room
`temperature. Mix until dissolved;
`b. Add water, EDTA, and citric acid to mixture in step a. Mix until dissolved.
`c. Add adapalene to mixture in step b;
`d. While continuing to mix, slowly add hydroxyethyl cellulose to mixture in step c
`avoid clumping. Mix vigorously at room temperature until a uniform lump-free
`dispersion is achieved; and,
`e. While mixing add sufficient sodium hydroxide to achieve a pH of 5.3 to 5.7. Mix
`until uniform.
`
`Process for making DMI / Carbopol containing formulations:
`The combination adapalene/dapsone gels were prepared as follows:
`a. Weigh the Transcutol into a kettle. Add the dapsone, dimethyl isosorbide,
`polyethylene glycol 400, benzyl alcohol. Stir with propeller mixer at room
`temperature. Mix until dissolved;
`b. Add water, EDTA, and citric acid to mixture in step a. Mix until dissolved;
`c. Add adapalene to mixture in step b;
`d. While continuing to mix, slowly add Carbopol 980 to mixture in step c avoid
`clumping. Mix vigorously at room temperature until a uniform lump-free
`dispersion is achieved; and,
`e. While mixing add sufficient sodium hydroxide to achieve a pH of 5 .3 to 5. 7. Mix
`until uniform.
`
`30
`
`Process for making PG/PEG containing formulations:
`The combination adapalene/dapsone gels were prepared as follows:
`
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`a. Weigh the Transcutol into a kettle. Add the dapsone, propylene glycol,
`polyethylene glycol 400, benzyl alcohol. Stir with propeller mixer at room
`temperature. Mix until dissolved;
`b. Add water, EDTA, and citric acid to mixture in step a. Mix until dissolved;
`c. Add adapalene to mixture in step b;
`d. While continuing to mix, slowly add Carbopol 980 to mixture in step c avoid
`clumping. Mix vigorously at room temperature until a uniform lump-free
`dispersion is achieved; and,
`e. While mixing add sufficient sodium hydroxide to achieve a pH of 5 .3 to 5. 7. Mix
`until uniform.
`
`Process for making PG/DMI/Carbopol containing formulations:
`The combination adapalene/dapsone gels were prepared as follows:
`a. Weigh the Transcutol into a kettle. Add the dapsone, propylene glycol, dimethyl
`isosorbide, benzyl alcohol. Stir with propeller mixer at room temperature. Mix
`until dissolved;
`b. Add water, EDTA, and citric acid to mixture in step a. Mix until dissolved;
`c. Add adapalene to mixture in step b;
`d. While continuing to mix, slowly add Carbopol 980 to mixture in step c avoid
`clumping. Mix vigorously at room temperature until a uniform lump-free
`dispersion is achieved; and,
`e. While mixing add sufficient sodium hydroxide to achieve a pH of 5.3 to 5.7. Mix
`until uniform.
`
`Process for making PG/DMI/HEC containing formulations:
`The combination adapalene/dapsone gels were prepared as follows:
`a. Weigh the Transcutol into a kettle. Add the dapsone, propylene glycol, dimethyl
`isosorbide, benzyl alcohol. Stir with propeller mixer at room temperature. Mix
`until dissolved;
`b. Add water, EDTA, and citric acid to mixture in step a. Mix until dissolved;
`c. Add adapalene to mixture in step b;
`d. While continuing to mix, slowly add hydroxyethyl cellulose to mixture in step c
`avoid clumping. Mix vigorously at room temperature until a uniform lump-free
`dispersion is achieved; and,
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
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`e. While mixing add sufficient sodium hydroxide to achieve a pH of 5.3 to 5.7. Mix
`until uniform.
`
`The most effective dapsone and adapalene composition is selected based on
`clinical studies. For example, a clinical study is conducted by forming two treatment
`groups, one with daily application of a selected dapsone and adapalene formulation, and
`twice daily topical application of the same selected dapsone and adapalene formulation to
`the acne area of the skin for a period of 12 weeks. Two control groups are formed with
`application once and twice daily of a vehicle consisting of the same excipients but no
`active ingredients. The patient's inflammatory and non-inflammatory acne lesion counts
`should be recorded at baseline before initiation of treatment and then at select intervals
`throughout the study. The reduction in total, non-inflammatory or inflammatory lesions
`counts provides determination of the efficacy of the formulations. The established Global
`Acne Assessment Score (GAAS) should be used to assess efficacy of the product. The
`tolerability of the product can be determined by assessment of skin dryness, irritation,
`sensitivity and redness as a result of treatment. A product is considered to have better
`tolerability if there is less effect on these parameters.
`
`Application method:
`1. A suitable application method is topical cream, gel, lotion, ointment, foam, liquid
`or a semi solid preparation. A topical preparation may contain additional
`ingredients to provide aesthetic and moisturizing and anti-inflammatory benefits to
`the skin. Generally,
`a. A gel or liquid preparation can be alcohol or aqueous based or a
`combination of two;
`b. A nanoemulsion or microemulsion preparation can be used for enhanced
`delivery of actives;
`c. A liposomal cream or lotion preparation can be used for enhanced delivery
`of actives; and
`d. A foam preparation can be a quick breaking foam with additional emollient
`components.
`2. Topical preparations that result in slow release or controlled release of the active
`agent can also be used to provide an optimal efficacy and tolerability balance.
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
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`15 of 34
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`3. Active ingredients encapsulated in micro beads or adsorbed on microsponge can be
`used for control release and in addition solve any incompatibility issues between
`the formulation ingredients.
`4. The application is preferably once a day or more frequent depending on the desired
`effect.
`
`Application of the formulations of the present invention:
`Example #1 - Application of O. l % w/w adapalene of Formula 1 in Fig. 5
`A 17 year old Caucasian male patient suffers acne vulgaris with a combination of
`inflammatory and non-inflammatory lesions and applies a 0.1 % w/w adapalene
`formulation according to formulation #1 in Fig. 5. The 17 year old male patient applies
`the 0.1 % w/w adapalene composition of Formula 1 once daily for 12 weeks. After 12
`weeks, the 17 year old male patient experiences a 32% reduction in inflammatory and
`non-inflammatory lesions.
`
`Example #2 - Application of 0.3 % w/w adapalene of Formula 1 in Fig. 5
`A 16 year old Caucasian female patient suffers acne vulgaris with a combination of
`inflammatory and non-inflammatory lesions and applies a 0.3% w/w adapalene
`formulation according to formulation #1 in Fig. 5. The 16 year old female patient
`applies the 0.3% w/w adapalene composition of Formula 1 once daily for 12 weeks.
`After 12 weeks, the 16 year old female patient experiences a 41 % reduction in
`inflammatory and non-inflammatory lesions.
`
`Example #3 - Application of 0.1 % w/w adapalene of Formula 2 in Fig. 5
`A 23 year old African-American female patient suffers acne vulgaris with a
`combination of inflammatory and non-inflammatory