(is 1NTERNAT ONA PLICAT ON PU.LlSHED UNDER THE PATENT COOPERATION TREATY (PC
`lllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllll
`
`(19) World Intellectual Property Organization
`International Bureau
`
`(43) International Publication Date
`3 February 2011 (03.02.2011)
`
`PUT
`
`(10) International Publication Number
`WO 2011/014627 A1
`
`(51) International Patent Classification:
`A 61K 9/06 (2006.01)
`A 61K 9/00 (2006.01)
`A61K 31/136 (2006.01)
`AMP 17/10 (2006.01)
`A61K 31/192 (2006.01)
`
`(21) International Application Number:
`PCTiUS2010i043671
`
`(22) International Filing Date:
`
`29 July 2010 (29.07.2010)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) Priority Data:
`61/229,903
`
`30 July 2009 (30.07.2009)
`
`US
`
`(71) Applicant (for all designated States except US’): AL-
`LERGAN, INC. [US/US]; 2525 Dupont Drive, T2-7H,
`Irvine, Calitbrnia 92612 (US).
`
`(74) Agents: WURST, John et al.; Allergan, Inc., 2525
`Dupont Drive, Irvine, Cali~bmia 92612 (US).
`
`(81) Designated States (unless otherwise indicated, for every
`kind ofnationalprotection available): AE, AG, AL, AM,
`AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ,
`CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO,
`DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT,
`HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP,
`KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD,
`ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI,
`NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD,
`SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR,
`TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.
`
`(84) Designated States (unless otherwise indicated,/’or every
`kind ofregionalprotection available): ARIPO(BW, GH,
`GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG,
`ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ,
`TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK,
`EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU,
`LV, MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK,
`SM, TR), OAPI (BF, B J, CF, CG, CI, CM, GA, GN, GQ,
`GW, ML, MR, NE, SN, TD, TG).
`
`(72) Inventors; and
`(75) Illvelltors/Applicants (for US only): AHLUWALIA,
`Gurpreet [US/US]; 3131 Michelson Drive, #303, h’vine,
`Califbrnia 92612 (US). WARNER, Kevin, S. [US/US];
`1281 N. Walden Lane, Anaheim, Calitbmia 92807 (US).
`CHEN, Haigang [CNiUS]; 1962 Lansdowne Way, Published:
`Petaluma, Cali~bmia 94954 (US). YANG, Meidong [CNi
`with international search report (Art. 21 (3))
`US]; 1400 Pimlacle Court, #204, Richmond, Calitbrnia
`94801 (US).
`
`1
`
`1
`
`1
`1
`1
`1
`-.z__.._
`
`1
`
`l
`
`l
`l
`
`----
`
`1
`
`1
`
`1
`
`1
`
`(54) Title: COMBINATION OF DAPSONE WITH ADAPALENE
`
`l~ig. I
`
`Ingredient
`
`Dapsonc
`
`Adapalene
`
`Transcutol~ P
`
`Benzyl Alcohol
`
`PEG 400
`
`I I
`
`2 2.I-a
`
`Composition (% w/w~
`3
`
`I
`
`.
`
`5.0
`
`5.0
`
`5.0
`
`5:0
`
`*
`
`5.0
`
`I
`
`4.1 a
`
`5.0
`
`, S --
`5.0
`
`0.1 ~nd 0.3
`
`0.1 and 0.3
`
`0.1 and 03
`
`0.1 ~0.3
`
`0.1 ~0.3
`
`0A and 0.3
`
`0.1 ~0.3
`
`25.0
`
`1.5
`
`25.0
`
`25 0
`
`1.5
`
`5-15
`
`t
`" ~5
`
`25.0
`
`]
`1.5 ....
`
`~.0
`
`1.5
`
`25.0
`
`1:5
`
`13.0
`
`25.0
`
`__
`
`lm
`
`/
`1
`
`"~
`
`"I~
`
`Lactic Acid
`
`2.0
`
`t
`
`Dtmetllyl lso~,bide
`
`PropylcneGlycol
`
`Glycol m
`
`EDTA Disodiunl
`
`0.01
`
`]
`
`Citric Acid
`
`~03
`
`HEC
`c~,~,pol 9so
`
`1 4
`
`515
`
`0.01
`
`0.03
`
`14
`
`5 15
`25.0[
`
`5 15
`
`I
`
`I
`
`0.01
`
`0.03
`
`0.5-2
`
`10.0
`
`2.0
`
`0.01
`
`0.03
`
`0.75
`
`__
`
`I
`
`I
`
`5-13
`
`lo.o
`
`2.0
`
`0.01
`
`’ ~03
`
`[
`
`5-13
`
`loo
`
`2.0
`
`0.01
`
`0.03
`
`i 2
`
`I
`I 0.52
`q.s. pH5.5
`
`0.~5
`
`0.2(NaOFI)
`
`i 0.2
`
`I q.s a.d
`
`q.s.a.d.
`
`~aOHorTrolamine
`
`q.s. pHS.5
`
`[ q.s. pH55
`
`q.s. pFi5.5
`
`q.s. pHS.5
`
`q.s. pH5.5
`
`Diluted Iclydxochloric
`Acid
`
`Meflly/parabcn
`
`q.s. pH5.5
`
`I q.s.pH5.5
`
`q.s. pH5.5
`
`q.s. pH5.5
`
`q.s.pH5.5
`
`q.s.pH5.5
`
`Water
`
`q.s.a.d,
`
`q.s.a.d,
`
`qs.ad
`
`q.s.a.d,
`
`q.s.a.d.
`
`(57) Abstract: A composition suitable tbr topical application that contains at least two active ingredients, one of these being dap-
`sone and one selected from the group consisting of adapalene, tazarotene and treinion tbr the effective treatment of acne and other
`(cid:128)",1 dermatological conditions.
`
`1 of 34
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`Almirall EXHIBIT 2005
`Amneal v. Almirall
`IPR2018-00608
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`

`

`WO2011/014627 PCT/US2010/043671
`
`COMBINATION OF DAPSONE WITH ADAPALENE
`
`Cross Reference
`
`5
`
`This application claims the benefit of U.S. Provisional Patent Application Serial
`
`Number 61/229,903 filed on July 30, 2009, the entire disclosure of which is incorporated
`
`herein by this specific reference.
`
`Field of the Invention
`
`The present invention is directed to compositions and methods for the treatment of
`
`10
`
`acne vulgaris and other dermatological conditions.
`
`Background of the Invention
`
`Acne is the most common skin disease that affects a large number of adolescents
`
`and young adults after they reach puberty. Though not a life threatening disease, it has
`
`serious psychological impact on the patient. Chronic inflammatory acne can also result in
`
`15
`
`permanent scarring of the face.
`
`There are multiple factors that contribute to the pathogenesis of acne, these include:
`
`1. over activity of sebum production as a result of hormonal changes at puberty; 2.
`
`colonization of Propionibacterium aches (P.acnes) in the pilosebaceous unit; 3.
`
`hyperkeratinization or abnormal desquamation of epithelium of the upper follicle (above
`
`20
`
`the sebaceous gland) that results in blockage of the pilosebaceous canal; 4. formation of
`
`inflammatory molecules as a result of the action of P.acnes on sebaceous lipids.
`
`The obstruction of the pilosebaceous canal and inflammation caused by P.acnes
`
`created inflammatory metabolites results in the formation of comedones. Excess sebum
`
`production as a result of hormonal changes at puberty, combined with increased epithelium
`
`25
`
`turnover of the upper follicle leads to formation of microcomedones which progresses to
`
`inflammatory papules and pustules in acne. The combination of lipid rich sebum and
`
`protein rich desquamated cells provides an ideal environment for the growth and activity
`
`of P.acnes which converts the sebaceous lipids to the inflammatory free fatty acid
`
`molecules resulting in inflammatory acne lesions. The patient can have either non-
`
`2 of 34
`
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`WO 2011/014627
`
`PCT/US2010/043671
`
`inflammatory (open and closed comedones), inflammatory (papules 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.
`
`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.
`
`10
`
`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
`
`15
`
`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
`
`20
`
`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.
`
`aches. MIC90 against P. aches is %g/ml.
`
`25
`
`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
`
`30
`
`receptors and appears to be a modifier of cellular differentiation, keratinization and
`
`inflammatory processes which are involved in the pathology of ache vulgaris. Absorption
`
`of adapalene from either 0.1% or 0.3% gel or cream is low. In one pharmacokinetic study,
`
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`PCT/US2010/043671
`
`16 patients suffering from ache vulgaris received 0.3% adapalene gel applied to the Pace,
`
`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 of 0.553 -- 0.466
`
`ng/mL on Day 10 of treatment. Mean AUC0-24hr was 8.37 -- 8.46 ng.h/mL as determined
`
`5
`
`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.
`
`Summary of the Invention
`
`10
`
`There is an unmet consumer need for an efficacious product for the treatment of
`
`ache vulgaris as the currently available products for treatment of ache 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
`
`15
`
`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 ache vulgaris, rosacea, atopic dermatitis,
`
`20
`
`treatment of chronic wounds, bed sores, keratosis piralis, psoriasis, cosmetic improvement
`
`of surgical and acne scars, sebaceous cysts, inflammatory dermatoses, post inflammatory
`
`hyperpigrnentation, eczema, xerosis, pruritis, lichen planus, nodular prurigo, eczema, and
`
`miliaria and other dermatological conditions.
`
`Some embodiments of the present invention include:
`
`25
`
`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 ache 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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`WO 2011/014627
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`PCT/US2010/043671
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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
`
`5
`
`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
`
`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.
`
`15
`
`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.
`
`20
`
`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 ache vulgaris, rosacea, atopic
`
`25
`
`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 ache vulgarus by application of the compositions of
`
`30
`
`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:
`
`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
`
`5
`
`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 1;
`
`Fig. 3B is directed to variations of formulations for the treatment of dermatological
`
`conditions of Formula 2 of Figure 1;
`
`10
`
`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
`
`15
`
`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;
`
`20
`
`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
`
`25
`
`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
`
`30
`
`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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`WO 2011/014627
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`PCT/US2010/043671
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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);
`
`5
`
`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:
`
`10
`
`i. tretinoin or trans retinoic acid (0.02 - 0.1% w/w);
`
`ii. Tazarotene (0.05 - 0.1% w/w);
`
`iii. Adapalene (0.1 - 0.3% w/w); and,
`
`iv. additional retinoids.
`
`4. Topical antibiotics for directly killing P. aches:
`
`15
`
`a. erythromycin (1 - 3% w/w);
`
`b. clindamycin (1 - 2% w/w); and,
`
`c.
`
`tetracycline (1 - 3% w/w).
`
`Potential combinations that can be used:
`
`20
`
`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.
`
`25
`
`2. Dapsone + benzoyl peroxide:
`
`Examples:
`
`a. Dapsone 5% w/w + benzoyl peroxide 5% w/w;
`
`3. Dapsone + antibiotic:
`
`Examples:
`
`30 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
`
`5
`
`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
`
`15
`
`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 ache 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
`
`20
`
`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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`PCT/US2010/043671
`
`Table 1: Example Excipient Composition Ranges Utilized in Adapalene / Dapsone
`Topical Formulations:
`
`Ingredient
`
`Function
`Active
`Active
`
`Thickener
`
`Neutralizing Agent
`Neutralizing Agent
`
`Solubilizers
`
`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
`
`Dapsone
`Adapalene
`Carbomer 980
`Hydroxyethyl cellulose
`Hydroxypropyl cellulose
`NaOH
`Trolamine
`Ethanol
`Lactic acid
`diethylene glycol monoethyl
`ether
`propylene glycol
`1 - 60
`Dimethyl isosorbide
`1 -30
`1 - 50
`Polyethylene glycol 400
`Hexylene glycol
`1 - 50
`Isostearyl alcohol
`0.5 - 10
`Medium chain triglycerides
`0.5 - 10
`2 - 10
`Isopropyl myristate
`0.5-5
`Preservative
`Benzyl alcohol
`0.1-0.3
`Methyl Paraben
`Preservative
`0.01-1
`Preservative
`P ropyl Paraben
`0.1-0.2
`Preservative
`B enzalkonium Chloride
`0.1-2.7
`Preservative
`Sorbic Acid
`1 - 20
`Humectant
`Glycerol
`Polyvinyl alcohol
`1-30
`Film forming
`1 - 90
`Water
`Vehicle
`0.005 - 0.02
`EDTA Disodium
`Antioxidant
`0.015 - 0.06
`Antioxidant
`Citric Acid
`Butylated hydroxytoluene
`0.005 - 1
`Antioxidant
`Butylated hydroxyanisole
`0.01 -0.25
`Antioxidant
`Propyl gallate
`0.01 - 0.1
`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
`Silky wax 10
`Thickener
`Further specific compositions of the present invention of 5% w/w dapsone and 0.1%
`
`5
`
`w/w and 0.3% w/w adapalene formulations include but are not limited to:
`
`9 of 34
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`WO 2011/014627
`PCT/US2010/043671
`WO 2011/014627 PCT/US2010/043671
`
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`WO 2011/014627
`PCT/US2010/043671
`WO 2011/014627 PCT/US2010/043671
`
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`11 of 34
`11 of 34
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`

`

`WO 2011/014627
`
`PCT/US2010/043671
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`Table 2B, Adapalene / Dapsone Topical Formulations (cont.)
`
`Ingredient
`Dapsone
`
`Adapalene
`
`diethylene
`glycol
`monoethyl
`ether
`
`Benzyl Alcohol
`
`PEG 400
`
`Dimethyl
`Isosorbide
`
`Propylene Glycol
`
`Glycerin
`
`EDTA Disodium
`
`Citric Acid
`
`Hydroxyethyl
`Cellulose
`Carbopol 980
`Hydroxypropyl
`Cellulose
`
`NaOH
`
`Dilmed
`Hydrochloric
`Acid
`Water
`
`Function
`Active
`Active
`
`Solubilizing
`Agent
`
`Composition (% w/w)
`5
`5
`5
`0.1%
`0.1%
`0.1%5
`or
`or
`or
`0.3%
`0.3%
`0.3%
`25
`25
`25
`
`10
`
`Preservative 1.5 1.5 1.5
`
`Solubilizing
`Agent
`
`Solubilizing
`Agent
`
`Solubilizing
`Agent
`Humectant
`Antioxidant
`Antioxidant
`Thickener
`
`Thickener
`Thickener
`
`13
`
`15
`
`2
`0.01
`0.03
`
`0.75
`
`13
`
`15
`
`2
`0.01
`0.03
`2
`
`15
`
`13
`
`1 ~0
`
`2
`0.01
`0.0~
`
`2
`
`Neutralizing
`Agent
`Neutralizing
`Agent
`
`q.s. 30
`q.s.
`q.s.
`pH5.5 pH5.5 pH5.5
`q.s.
`q.s.
`q.s.
`pH 5.5 pH 5.5 pH 5.5
`
`Vehicle
`
`q.s.a.d, q.s.a.d, q.s.a.d.
`
`The formulations of the present invention can be made as follows based on the
`
`35 excipients:
`
`Process fbr making lactic acid containing fbrmulations:
`
`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. ML,~
`
`40
`
`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;
`
`11
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`PCT/US2010/043671
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`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
`
`5
`
`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
`
`10
`
`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
`
`15
`
`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:
`
`20
`
`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;
`
`25 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:
`
`12
`
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`WO 2011/014627
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`PCT/US2010/043671
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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;
`
`5
`
`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
`
`10
`
`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
`
`15
`
`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, slowlyadd Carbopol 980 to mixture in step c avoid
`clumping. Mix vigorously at room temperature until a uniform lump-free
`
`20
`
`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:
`
`25
`
`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;
`
`30
`
`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,
`
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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
`
`5
`
`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 ache 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 ache lesion counts
`
`10
`
`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
`
`Ache 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,
`
`15
`
`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
`
`20
`
`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
`
`25
`
`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.
`
`30
`
`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.
`
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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
`
`5
`
`effect.
`
`Application of the formulations of the present invention:
`
`Example #1 -Application of 0.1% w/w adapalene of Formula 1 in FiR. 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
`
`10
`
`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 FiR. 5
`
`15
`
`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
`
`20
`
`inflammatory and non-inflammatory lesions.
`
`Example #3 - Application of 0.1% w/w adapalene of Formula 2 in FiR. 5
`
`A 23 year old African-American female 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 #2 in Fig. 5. The 23 year old female
`
`25
`
`patient applies the 0.1% w/w adapalene composition of Formula 2 once daily for 12
`
`weeks. After 12 weeks, the 23 year old female patient experiences a 24 % reduction in
`
`inflammatory and non-inflammatory lesions.
`
`Example #4 -Application o