sign in sign up
<<
Home , Albaconazole, Hachimycin, Pramiconazole

USOO8841351B2

(12) United States Patent (10) Patent No.: US 8,841,351 B2 SaWant (45) Date of Patent: *Sep. 23, 2014

(54) POLYMERICTOPICAL COMPOSITIONS 4,938,964 A 7, 1990 Sakai et al. 4,940,579 A 7, 1990 Randen 4.954,332 A 9, 1990 Bissett et al. (71) Applicant: Stiefel Research Australia Pty Ltd., 5,081,157 A 1/1992 Pomerantz Rowville (AU) 5,082,656 A 1/1992 Hui et al. 5,304,368 A 4, 1994 Sherinov et al. (72) Inventor: Prashant Sawant, Rowville (AU) 5,436,241 A 7, 1995 Shin et al. 5,573,759 A 11/1996 Blank (73) Assignee: Stiefel Research Australia Pty Ltd., 5,658,559 A 8, 1997 Smith 5,674,912 A 10, 1997 Martin Rowville, Victoria (AU) 6,010,716 A 1/2000 Saunal et al. 6,017,520 A 1/2000 Synodis et al. (*) Notice: Subject to any disclaimer, the term of this 6,123,924 A 9/2000 Mistry et al. patent is extended or adjusted under 35 6,211,250 B1 4/2001 Tomlinson et al. U.S.C. 154(b) by 0 days. 6,582,683 B2 6/2003 Jezior 7,678,366 B2 3/2010 Friedman et al. This patent is Subject to a terminal dis 2005/0175641 A1 8, 2005 Deo et al. claimer. 2007/0196323 A1 8/2007 Zhang et al. 2007/0196325 A1 8/2007 Zhang et al. (21) Appl. No.: 13/910,158 2007/0219.171 A1 9, 2007 Lulla et al. 2008. O152603 A1 6/2008 Rudolph et al. (22) Filed: Jun. 5, 2013 2008. O17581.0 A1 7/2008 Zhang (65) Prior Publication Data FOREIGN PATENT DOCUMENTS US 2013/0267,486A1 Oct. 10, 2013 CA 1300515 5, 1992 EP O 212959 B1 3, 1993 EP O 944 398 B1 4/2004 Related U.S. Application Data WO WO 88,09185 A1 12, 1988 WO WO93/24105 A1 12, 1993 (62) Division of application No. 12/916.692, filed on Nov. WO WO95/30409 A1 11, 1995 1, 2010, now Pat. No. 8,481,591. WO WO99.49835 A1 10, 1999 WO WO O2/43739 A2 6, 2002 (51) Int. Cl. WO WO 2008/094910 A2 8, 2008 A6 IK 47/30 (2006.01) A6 IK 47/34 (2006.01) OTHER PUBLICATIONS A6 IK3I/35 (2006.01) A6 IK3I/92 (2006.01) Dictionary definition of “alcohol', downloaded from the internet A6 IK 47/32 (2006.01) Nov. 2, 2012. A6 IK3I/474 (2006.01) “Dermacryl 79 for Skin Care Formulations'. Personal Care Poly A6 IK9/00 (2006.01) mers, Specialty Products from Natl. Starch & Chem. Company, 1994, A6 IK 45/06 (2006.01) pp. 1-7. A6 IK3I/728 (2006.01) P. Sawant, et al. International J. of Pharmaceutics, 396:45-52 (2010). A6 IK3I/4164 (2006.01) Sawant, et al. Effect of Polymer Chemistry and Lipophilicity of A 6LX3/573 (2006.01) Drugs on Drug Release, Presentation 11th Pacific Polymer Confer A6 IK3I/2O3 (2006.01) ence, Dec. 6-11, 2009. A6 IK3I/7056 (2006.01) Sawant, et al. Abstract for 11th Pacific Polymer Conference, Dec. (52) U.S. Cl. 6-11, 2009. CPC ...... A61K 47/32 (2013.01); A61 K3I/351 (2013.01); A61 K31/192 (2013.01); A61 K 31/4174 (2013.01); A61 K9/0014 (2013.01): Primary Examiner — Layla Bland A61K 45/06 (2013.01); A61 K3I/728 (74) Attorney, Agent, or Firm — Dara L. Dinner; Theodore (2013.01); A61K 31/4164 (2013.01); A61 K Furman 31/573 (2013.01); A61 K3I/203 (2013.01); A6 IK3I/7056 (2013.01); A61 K47/34 (2013.01) (57) ABSTRACT USPC ...... 514/772.7 (58) Field of Classification Search The present invention relates to topical antibacterial compo None sitions. The compositions comprise an antibacterial agent See application file for complete search history. Such as mupirocin, water, a polymer and a volatile solvent present in an amount of less than about 40%. The invention (56) References Cited also relates to methods of treatment by administering the compositions to a patient in need thereof, and to the use of U.S. PATENT DOCUMENTS Such compositions in the treatment of bacterial conditions. 4,393,076 A 7, 1983 Noda et al. 4.675,009 A 6/1987 Hymes et al. 4,935,241 A 6, 1990 Saitoh et al. 23 Claims, 4 Drawing Sheets U.S. Patent Sep. 23, 2014 Sheet 1 of 4 US 8,841,351 B2

IOC

3. | 6. O

O SO OC: 15 SC 3CO 3S 4:O Fine (min.)

Figure 1 U.S. Patent Sep. 23, 2014 Sheet 2 of 4 US 8,841,351 B2

3 O 6 O 90 12 O 15 O 18O 21 O 24 O 27 O 3 OC Time (min.)

Figure 2 U.S. Patent Sep. 23, 2014 Sheet 3 of 4 US 8,841,351 B2

0.5 In Nk (1/min.) 0.4

S 0.3 N a 0.2 E. 0. 1 Š O S Š 70:30 60:40 30.70 PVPIVA Ratio

Figure 3 U.S. Patent Sep. 23, 2014 Sheet 4 of 4 US 8,841,351 B2

:::: 388 Al-A 38 8: . : s: : : & 888 . & 388 8: : 88: 388 3. 8:8 (A)

: .* ----- ...it 8. y is 8.388x -- $3.388 82, as 888 s 88: 888 as : i: s

88: &; :::::::::: (B)

: o 8. : to

: (C)

Figure 4 US 8,841,351 B2 1. 2 POLYMERC TOPCAL COMPOSITIONS after topical application to leave a film on the surface of the skin. The present invention is believed to address these unmet FIELD OF THE INVENTION needs. The present invention relates to topical antibacterial com SUMMARY OF THE INVENTION positions. According to an embodiment, the present invention pro BACKGROUND OF THE INVENTION vides a topical pharmaceutical composition comprising an antibacterial agent, a polymer, water and less than about 40% Bactroban R. (2% mupirocin) ointment and Bactroban R. 10 volatile solvent. (2% calcium mupirocin) cream and ointment are marketed by According to another embodiment the present invention GlaxoSmithKline for the treatment of furuncle, impetigo and provides for a method of treating a disease, disorder or con wounds that have become infected. dition of the skin, in a mammal in need thereof, the method U.S. Pat. No. 5,082,656 (Hui et al.) describes an antibac comprises administering to said mammal, preferably a terial composition for topical administration comprising: 15 human Subject, a topical pharmaceutical composition com prising an antibacterial agent, a polymer, water and less than from about 0.5% to about 10% of an antibacterial compound, about 40% volatile solvent. from about 1% to about 30% of a non water soluble polymeric According to a further embodiment, the invention relates to composition, from about 0.5% to about 40% of a plasticizer, the use of a topical pharmaceutical composition comprising and from about 50% to about 95% of a solvent (such as an antibacterial agent, a polymer, water and less than about ethanol or isopropanol). Upon topical application of the anti 40% volatile solvent, in the preparation of a medicament for bacterial composition, the solvent will evaporate and leave a the treatment of a disease, disorder or condition of the skin. thin protective film of polymeric composition which retains In another embodiment, the invention relates to the use of the antibacterial compound against the skin. a topical pharmaceutical composition comprising an antibac U.S. Pat. No. 6,211,250 (Tomlinson et al.) describes topi 25 terial agent, a polymer, water and less than about 40% volatile cal compositions comprising at least one rate modulating Solvent, in the treatment of a disease, disorder or condition of polymer, a Volatile solvent and at least one physiologically the skin. active agent. Tomlinson discloses compositions comprising a hydrophilic polymer and a hydrophobic polymer selected to BRIEF DESCRIPTION OF THE DRAWINGS modulate the rate of release of the active agent. The compo 30 sitions comprise greater than 50% volatile solvent. A high FIG. 1 illustrates modulation of the rate of release of cal level of volatile solvent is desirable in as much as it will cium mupirocin where different variants of PVP/VA are used, solubilize the hydrophobic polymer and evaporate to leave a i.e. PVP/VA 60:40 (O), PVP/VA 70:30 (0) and PVP/VA polymeric film on the surface of the skin. However, a high 30:70 (). level of volatile solvent has the potential disadvantage of 35 FIG. 2 illustrates modulation of the rate of release of cal irritating the skin, particularly on open wounds or lesions. cium mupirocin (first order derivative) where different vari U.S. Pat. No. 6,582,683 (Jezior) describes a dermal barrier ants of PVP/VA are used, i.e. PVP/VA 60:40 (O), PVP/VA composition which comprises water, a hydrophilic polymer 70:30 (0) and PVP/VA 30:70 (). emulsion and a hydrophobic polymer emulsion. The dermal FIG.3 illustrates the rate constant (k) and release exponent barrier composition is moisture activated, and remains inert 40 (n) in connection with release of calcium mupirocin from until the hydrophobic and hydrophilic polymer emulsions compositions comprising different variants of PVP/VA, i.e. contact a Suitable Substrate Such as human skin. The dermal PVP/VA 60:40, PVP/VA 70:30 and PVP/VA 30:70. barrier composition is itself an emulsion, and may contain a FIGS. 4a-4c illustrates the rub and water resistance of the biocidal agent for treatment of a skin disorder or condition. compositions of the invention. The dermal barrier composition may also contain other active 45 agents such as Sunscreens, insect repellents and fungicides. DETAILED DESCRIPTION OF THE INVENTION The composition does not contain a volatile solvent. US Published Application No. 2005/0175641 (Deo, et al.) The present invention provides for a topical pharmaceuti describes topical compositions comprising at least one physi cal composition comprising an antibacterial agent, a polymer, ologically active agent, a Volatile solvent, and ethyl cellulose 50 water and less than about 40% volatile solvent, and optionally as a hydrophobic polymer, along with a hydrophilic polymer. additional dermatologically acceptable excipients. The Volatile solvent is present in an amount of greater than Exemplary antibacterial agents include, but are not limited 50% by weight. to, mupirocin, gentamicin, neomycin, Streptomycin, cefpo U.S. Pat. No. 7,678,366 (Friedman et al.) describes athera doXime proxetil, , lincomycin, erythromycin, peutic nail varnish comprising a pharmaceutically active 55 bacitracin, gramicidin(s), Vancomycin, doxycycline, minocy agent, a humectant, water, less than about 7.5% by weight of cline, , tetracycline, fosfomycin, fusidic acid, a polymeric film forming agent, at least one additional excipi Sulfacetamide, , benzoyl peroxide and dap ent, and a solvent system including at least one volatile sol Sone, pharmaceutically acceptable salts thereof, and mixtures vent. Friedman et al. discloses pharmaceutically active agents thereof. which are agents, such as or . 60 Suitably, the antibacterial agent is present in the composi The nail varnish may further comprise a second active ingre tion in a therapeutically effective amount. In an embodiment, dient, Such as clobetasol. the antibacterial agent is present in an amount from about There remains a need in the art for topical preparations that 0.1% to about 10% by weight. are able to deliver an active agent, particularly an antibacte In one embodiment, the antibacterial agent is selected from rial, to the Surface of the skin in a controlled manner and 65 the group consisting of mupirocin, clindamycin, metronida without irritation. Furthermore, it is desirable that such a Zole and pharmaceutically acceptable salts thereof. In a par preparation would be cosmetically elegant, and rapidly dry ticular embodiment, the antibacterial agent is mupirocin or a US 8,841,351 B2 3 4 salt thereof. In an embodiment, the mupirocin or a salt thereof (60:40)) has also been shown to reduce the drug release of a is calcium mupirocin. In one embodiment, the mupirocin or a lipophilic drug as compared to the hydrophilic drug. salt thereof is sodium mupirocin. In one embodiment, the In an embodiment, the polymer is present in the composi mupirocin or a salt thereof is calcium mupirocin. In another tion in an amount from about 1% to about 60% by weight. In embodiment, the calcium mupirocin is present either as an 5 one embodiment, the polymer is present in an amount from amorphous or crystalline form. In another embodiment, the about 5% to about 30% by weight, such as about 10% by mupirocin or a salt thereof is mupirocin (the free acid). In yet weight. In another embodiment, the polymer is present in an another embodiment, the mupirocin or a salt thereof is a amount from about 30% to about 60% by weight, such as mixture of calcium mupirocin and mupirocin (the free acid). from about 45% to about 55% by weight, or about 50% by Suitably, the calcium mupirocin and mupirocin in Such an 10 weight. embodiment are present in a ratio of about 1:3 to about 3:1, Water suitably about 1:1. In an embodiment, the composition comprises water in an The benefit of combining calcium mupirocin and mupiro amount from about 20% to about 85% by weight. In one cin (the free acid) in a single composition according to the embodiment, the composition comprises water in an amount present invention is that the respective forms of mupirocin 15 from about 40% to about 85% by weight. In another embodi will be released from the topical composition at different ment the composition comprises from about 50% to about rates, so as to facilitate a combination of rapid release and 70% by weight. In another embodiment, the composition more Sustained release of the active agent. These differing comprises water in an amount from about 20% to about 40% release rates arise from the different hydrophilicity/hydro by weight. phobicity of calcium mupirocin and mupirocin (the free acid). Volatile Solvent The same would be present for Sodium mupirocin and mupi In an embodiment, the Volatile solvent is an organic Sol rocin (free acid), as well potentially as other salt forms of vent. The organic solvent is suitably selected from ethanol, mupirocin with the free acid. propanol, iso-propanol, n-butyl alcohol, t-butyl alcohol, In an embodiment, the mupirocin or a salt thereof is present butoxy ethanol, acetone, ethyl acetate or butyl acetate, and in an amount from about 0.1% to about 10% by weight. 25 mixtures thereof. In one embodiment the at least one volatile Suitably, the mupirocin or a salt thereof is present in an Solvent present in the composition is ethanol. amount from about 1% to about 3% by weight, such as about In another embodiment, the volatile solvent is a mixture of 1%, 2% or 3% by weight, for example. In a particular embodi at least two volatile solvents. Suitably the combination con ment, the mupirocin or a salt thereof is present in an amount tains ethanol as the first solvent in combination with a second of about 2% by weight. 30 Solvent. Suitably, the second solvent is propanol, iso-pro In an alternative embodiment, the antibacterial agent is panol, n-butyl alcohol, t-butyl alcohol, butoxy ethanol, clindamycin or a salt thereof. Suitably, the clindamycin or a acetone, ethyl acetate or butyl acetate. In an embodiment, the salt thereof is clindamycin phosphate or clindamycin hydro Volatile solvent is a mixture of ethanol and iso-propanol. In chloride. In an embodiment, the clindamycin or a salt thereof another embodiment, the volatile solvent is a mixture of etha is clindamycin phosphate. In a further embodiment, the clin 35 nol and ethyl acetate. damycin or a salt thereof is present in an amount from about In an embodiment, the Volatile solvent is present in an 0.5% to about 2% by weight, such as about 1% by weight. amount of less than about 40% by weight. In one embodi In another embodiment, the antibacterial agent is metron ment, the Volatile solvent is present in an amount from about idazole. Suitably, the metronidazole is present in an amount 5% to about 30% by weight. In another embodiment, the from about 0.1% to about 2% by weight. In a particular 40 volatile solvent is present in an amount from about 10% to embodiment, the metronidazole is present in an amount of about 25% by weight. about 1% by weight. Suitably, the ratio of volatile solvent to water in the topical Polymer pharmaceutical composition is from about 1:1 to about 1:10. In an embodiment, the polymer present in the formulation In one embodiment, the ratio of volatile solvent to water in the is a copolymer. 45 topical pharmaceutical composition is from about 1:1 to Suitably, the copolymer is polyvinylpyrrolidone-vinyl about 1:3. In an embodiment, the ratio of volatile solvent to acetate copolymer, also known as PVP/VA. In one embodi water in the topical pharmaceutical composition is from ment, the ratio of PVP monomer to VA monomer in the about 1:1.25 to about 1:2. In another embodiment the ratio is PVP/VA copolymer is from about 30:70 to about 70:30. In about 1:1.65. another embodiment, the ratio of PVP monomerto VA mono 50 Second Pharmaceutically Active Agent mer is about 30:70. In another embodiment, the ratio of PVP According to an embodiment, the topical pharmaceutical monomer to VA monomer is about 60:40. In yet another composition may comprise a second pharmaceutically embodiment, the ratio of PVP monomer to VA monomer is acceptable active agent. about 70:30. While there are many suppliers of PVP/VA, In one embodiment, the second pharmaceutically active many ratios are available from 70:30 to 20:80 are available 55 agent is selected from the group consisting of a second anti under the tradename Luviskol, produced by BASF. bacterial agent, a retinoid, a corticosteroid, an antifungal Hydrophobic polymers are either insoluble in low ethan agent, a skin conditioning agent, a nutritional agent, and an olic formulations (s.20% ethanol) or precipitate out of the agent. formulation due to interactions with the hydrophilic drug. Suitably, the second pharmaceutically active agent is Hydrophilic homopolymers (such as hydroxypropylcellulose 60 present in an amount in the composition from about 0.001% (HPC)) form thermodynamically stable formulations, but to about 20% by weight, depending on the nature of the tend to give rise to a burst release of a hydrophilic drug. A second active agent. difference in drug release has been observed when the hydro Exemplary antibacterial agents Suitable for use as the sec phobicity of the copolymer PVP/VA is modified by changing ond antibacterial agent include, but are not limited to, gen the ratio of PVP (hydrophilic moiety) to VA (hydrophobic 65 tamicin, neomycin, Streptomycin, cefpodoxime proxetil, moiety) as will be further described herein in the Methods clindamycin, lincomycin, erythromycin, bacitracin, gramici Section. A hydrophilic polymer (e.g. a carbomer and PVP/VA din(s), Vancomycin, doxycycline, minocycline, oxytetracy US 8,841,351 B2 5 6 cline, tetracycline, fosfomycin, fusidic acid, Sulfacetamide, derivatives, cholesterol, di- and tri-glycerides, vegetable oils, metronidazole, benzoyl peroxide and , salts thereof, acetoglyceride esters, alkyl esters, alkenyl esters, lanolin, and mixtures thereof. Suitably, the second antibacterial agent milk tri-glycerides, wax esters, beeswax, sterols, phospholip is present in an amount from about 0.1% to about 10% by ids, hyaluronic acid, pharmaceutically acceptable salts weight. thereof, and mixtures thereof. In an embodiment, the skin Exemplary retinoids include, but are not limited to, tazaro conditioning agent is hyaluronic acid or a salt thereof. Such as tene, tretinoin, isotretinoin, acitretin, etretinate, adapalene, Sodium hyaluronate. Suitably, the skin conditioning agent is bexarotene, alitretinoin, retinol, retinal, retinyl palmitate, present in an amount from about 0.1% to about 20% by retinyl acetate, retinyl propionate, retinyl linoleate, ethyl weight. 5-(2-(4,4-dimethylthiochroman-6-yl)ethynyl)thiophene-2- 10 Exemplary nutritional agents include Vitamins such as carboxylate, 6-(2-4,4-dimethylthiochroman-6-yl)-ethynyl)- Vitamins A, B, C, D, E and K and prodrugs thereof, essential 3-pyridylmethanol, 6-(2-(4,4-dimethylthiochroman-6-yl)- amino acids, essential fats, antioxidants, pharmaceutically ethynyl)pyridine-3-carbaldehyde, pharmaceutically acceptable salts thereof, and mixtures thereof. Suitably, the acceptable salts thereof, and mixtures thereof. Suitably, the nutritional agent is present in an amount from about 0.01% to retinoid is present in an amount from about 0.01% to about 15 about 2% by weight. 1% by weight. Exemplary include, but are not limited to, In an embodiment, the retinoid is selected from the group hydrogen peroxide, chlorhexidine, cetrimide, povidone consisting of tretinoin, tazarotene and adapalene. In one iodine, silver Sulfadiazine, triclosan, pharmaceutically embodiment, the retinoid is tretinoin. In another embodi acceptable salts thereof, and mixtures thereof. ment, the retinoid is tazarotene. In yet another embodiment, In another embodiment, the first antibacterial agent is the retinoid is adapalene. mupirocin or a pharmaceutically acceptable salt thereof and Exemplary corticosteroids include, but are not limited to, the second pharmaceutically active agent is a second antibac alclometasone dipropionate, amcinonide, beclomethasone terial agent. Suitably, the first antibacterial agent is mupiro dipropionate, betamethasone benzoate, betamethasone cin, Sodium or calcium mupirocin or a mixture thereof. In one dipropionate, betamethasone Valerate, budesonide, clobeta 25 embodiment the first antibacterial agent is calcium mupiro Sol propionate, clobetaSone butyrate, cortisone acetate, des cin. In one embodiment, the second antibacterial agent is onide, desoximetasone, diflorasone diacetate, diflucortolone metronidazole. In another embodiment the first antibacterial Valerate, fluclorolone acetonide, flumethasone pivalate, fluo agent is calcium mupirocin and the second antibacterial agent cinolone acetonide, fluocinonide, fluocortin butyl, fluocor is metronidazole. tolone, fluprednidene acetate, flurandrenolide, flurandre 30 In another embodiment, the antibacterial agent is mupiro nolone, fluticaSone propionate, halcinonide, halobetasol cin or a pharmaceutically acceptable salt thereof and the propionate, hydrocortisone, hydrocortisone acetate, hydro second pharmaceutically active agent is a retinoid. Suitably, cortisone butyrate, hydrocortisone propionate, hydrocorti the antibacterial agentis mupirocin, Sodium or calcium mupi Sone Valerate, methylprednisolone acetate, mometaSone rocin or a mixture thereof. In one embodiment the antibacte furoate, pramoxine hydrochloride, prednisone acetate, pred 35 rial agent is calcium mupirocin. In one embodiment the ret nisone Valerate, triamcinolone acetonide, prednicarbate, salts inoid is tretinoin. In another embodiment, retinoid is thereof, and mixtures thereof. Suitably, the corticosteroid is adapalene. In one embodiment the antibacterial agent is cal present in an amount from about 0.01% to about 2% by cium mupirocin and the retinoid is tretinoin or adapalene. weight. In another embodiment, the antibacterial agent is mupiro Exemplary antifungal agents include, but are not limited to, 40 cin or a pharmaceutically acceptable salt thereof and the those selected from the group consisting of second pharmaceutically active agent is a corticosteroid. Such as anidulafunin, and ; polyenes Suitably, the antibacterial agent is mupirocin, Sodium or cal Such as , , filipin, fungichromin, cium mupirocin or a mixture thereof. In one embodiment the hachimycin, , lucensomycin, , natamy antibacterial agent is calcium mupirocin. In one embodiment, cin, , pecilocin, perimycin; such as buten 45 corticosteroid is clobetasol propionate. In another embodi afine, naftifine and terbinafine; Such as bifona ment, corticosteroid is hydrocortisone or an ester thereof. In Zole, , , cloconazole, one embodiment the antibacterial agent is calcium mupirocin , , enilconazole, , flutri and the antibacterial agent is clobetasol propionate or hydro mazole, , , lanoconazole, micona cortisone or an ester thereof. Zole, , , nitrate, Serta 50 In another embodiment, the antibacterial agent is mupiro conazole, and ; thiocarbamates Such cin or a pharmaceutically acceptable salt thereof and the as liranaftate, , tolindate and tolnafate; second pharmaceutically active agent is an antifungal agent. Such as , , , itracona Suitably, the antibacterial agent is mupirocin, Sodium or cal Zole, , , Saperconazole, tercona cium mupirocin or a mixture thereof. In one embodiment the Zole and ; and other antifungal agents such as 55 antibacterial agent is calcium mupirocin. In one embodiment, acrisorcin, , biphenamine, bromosalicylchloranil the antibacterial agent is calcium mupirocin and the antifun ide, buclosamide, calcium propionate, chlorphenesin, ciclo gal agent is clotrimazole. pirox, cloxyquin, coparaffinate, exalamide, , halo In another embodiment, the antibacterial agent is mupiro progin, hexetidine, loflucarban, , , cin or a pharmaceutically acceptable salt thereof and the propionic acid, pyrithione, Salicylanilide, sodium propionate, 60 second pharmaceutically active agent is a skin conditioning , tenonitrozole, triacetin, , Zinc agent. Suitably, the mupirocin or pharmaceutically accept propionate, , oligomycins, pyrrolnitrin, siccanin, able salt thereof is calcium mupirocin. viridian, pharmaceutically acceptable salts thereof, and mix In another embodiment, the antibacterial agent is mupiro tures thereof. Suitably, the antifungal agent is present in an cin or a pharmaceutically acceptable salt thereof and the amount from about 0.1% to about 5% by weight. 65 second pharmaceutically active agent is an antiseptic agent. Exemplary skin-conditioning agents include, but are not Suitably, the mupirocin or pharmaceutically acceptable salt limited to, hydrocarbon oils and waxes, silicones, fatty acid thereof is calcium mupirocin. US 8,841,351 B2 7 8 Dermatologically Acceptable Excipients ing of citrate/citric acid, acetate/, phosphate/phos In an embodiment, the present topical pharmaceutical phoric acid, propionate/propionic acid, lactate/, compositions further comprise one or more dermatologically carbonate/carbonic acid, ammonium/ammonia and edetate/ acceptable excipients. edetic acid, or a combination or mixture thereof. In one Suitably, the excipient is selected from the group consist embodiment, the pH adjusting agent is citrate/citric acid. ing of a co-solvent, a pH adjusting agent, a humectant, a film In one embodiment, the pH adjusting agent is present in an extender, a chelating agent, an antioxidant, a preservative, a amount from about 0.01% to about 10% by weight. In another gelling agent, a fragrance, a colorant, a penetration enhancer, embodiment, the pH adjusting agent is present in an amount or a combination or mixture thereof. sufficient to adjust the pH of the composition to between In one embodiment, the present compositions are formu 10 about 4 to about 9. Suitably, the composition is adjusted to a lated as a Solution, gel, serum, aerosol spray or aerosol foam. pH between about 4 to about 6.5, or a pH between about 6.5 Suitably, the composition is formulated as a solution. In to about 9. another embodiment, the composition is formulated as a gel. Humectant Co-Solvent The topical pharmaceutical compositions may further The topical pharmaceutical compositions may further 15 comprise a humectant. comprise a co-solvent. The function of the co-solvent is to Exemplary humectants include, but are not limited to, glyc further solubilise (i.e. in conjunction with the volatile solvent) erol, Sorbitol, maltitol, polydextrose, triacetin, propylene gly the active agent and/or the polymer in the composition. col, polyethylene glycol (PEG) esters including PEG-20 Exemplary co-solvents include, but are not limited to, alco stearate, PEG-40 stearate, PEG-150 stearate, PEG-150 dis hols such as amyl alcohol, benzyl alcohol, cyclohex tearate and PEG-100 stearate, alkoxylated alcohols including anedimethanol, diacetone alcohol, hexyl alcohol, tetrahydro laureth-12, ceteareth-20, laureth-23, glycereth-7, glycereth furfuryl alcohol; carboxylic acids Such as acetic acid or multi 12, glycereth-26, PEG-4, PEG-6, PEG-8, PEG-12, PEG-32, carboxylic acid derivatives; diols such as 1.2-hexanediol. PEG-75, PEG-150, or a combination or mixture thereof. In an butylene glycol, diethylene glycol, dipropylene glycol, ethyl embodiment, the humectant is glycerol. hexanediol, ethylene glycol, hexylene glycol, pentylene gly 25 In one embodiment, the present compositions comprise col, propylene glycol, tetraethylene glycol, triethylene gly about 0.1% to about 10% by weight of a humectant. In col, tripropylene glycol; and polyols such as polyethylene another embodiment, the compositions comprise about 0.5% glycol, butanetriol, glycerol and 1.2.6-hexanetriol. to about 5% by weight of a humectant. In one embodiment, the co-solvent is propylene glycol. In Film Extenders another embodiment, the co-solventis hexylene glycol. In yet 30 The present topical pharmaceutical compositions may fur another embodiment, the co-solvent is a mixture of at least ther comprise a film extender. Exemplary film extenders two co-solvents. In an embodiment, the co-solvent is a mix include, but are not limited to, calcium carbonate, calcium ture of polyethylene glycol and propylene glycol. phosphate, calcium Stearate, magnesium Stearate, Zinc Stear In one embodiment, the co-solvent is present in the com ate, calcium Sulfate, colloidal silicon dioxide, kaolin, magne position in an amount of from about 1% to about 30% by 35 sium carbonate, magnesium silicate, sodium Stearyl fuma weight. In another embodiment, the co-solvent is present in rate, talc, titanium dioxide, Zinc oxide, or a combination or an amount of from about 1% to about 10% by weight. In yet mixture thereof. another embodiment, the co-solvent is present in an amount Suitably, the film extender is present in an amount from of from about 15% to about 25% by weight. about 0.1% to about 2% by weight. In an alternative embodiment, the topical pharmaceutical 40 Chelating Agents composition is devoid or substantially devoid of co-solvent. The present topical pharmaceutical compositions may fur In one embodiment, the topical pharmaceutical composition ther comprise a chelating agent. Exemplary chelating agents is devoid of co-solvent. In another embodiment, the topical include, but are not limited to, citric acid, isopropyl (mono) pharmaceutical composition is substantially devoid of co citrate, Stearyl citrate, lecithin citrate, gluconic acid, tartaric solvent. 45 acid, oxalic acid, phosphoric acid, Sodium tetrapyrophos In another embodiment, the topical pharmaceutical com phate, potassium monophosphate, Sodium hexametaphos position comprises a volatile solvent in an amount from about phate, calcium hexametaphosphate, Sorbitol, glycine (ami 10% to about 25% by weight and is substantially devoid of a noacetic acid), methyl glucamine, triethanolamine co-solvent. In yet another embodiment, the topical pharma (trolamine), ethylene diamine tetraacetic acid (EDTA), dihy ceutical composition comprises a volatile solvent in an 50 droxyethylglycine (DEG), diethylene triamine pentaacetic amount from about 10% to about 25% by weight, and is acid (DPTA), nitrilotriacetic acid (NTA), N-(hydroxyethyl)- devoid of co-solvent. ethylenetriaminetriacetic acid (HEDTA), aminocarboxy ph Adjusting Agent lates, dimercaperol (BAL), larixinic acid (maltol), unidentate The topical pharmaceutical compositions may further ligands (fluoride and cyanide ions), diphenylthiocarbazone, comprise a pH adjusting agent. In one embodiment, the pH 55 o-phenanthroline, barium diphenylamine Sulfonate, sodium adjusting agent is a base. Suitable bases include amines, glucoheptonate, 8-hydroxyquinoline, olefin complexes (such bicarbonates, carbonates, and hydroxides such as alkali or as dicyclopentadienyl iron), porphyrins, phosphonates, or a alkaline earth metal hydroxides, as well as transition metal combination or mixture thereof. hydroxides. In an embodiment, the base is sodium hydroxide In one embodiment, the chelating agent is EDTA. or potassium hydroxide. 60 Suitably, the chelating agent is present in an amount from In another embodiment, the pH adjusting agent is an acid, about 0.1% to about 1% by weight. an acid salt, or mixtures thereof. Suitably, the acid is selected Antioxidants from the group consisting of lactic acid, acetic acid, maleic The present topical pharmaceutical compositions may fur acid, Succinic acid, citric acid, phosphoric acid, nitric acid, ther comprise an antioxidant. Exemplary antioxidants Sulphuric acid and hydrochloric acid. 65 include, but are not limited to, butylated hydroxytoluene In yet another embodiment, the pH adjusting agent is a (BHT), butylated hydroxyanisole, tocopherol, propyl gallate, buffer. Suitably, the buffer is selected from the group consist vitamin ETPGS, or a combination or mixture thereof. US 8,841,351 B2 10 Suitably, the present compositions comprise an antioxidant (e) a gelling agent, and in an amount from about 0.001% to about 1% by weight. wherein the composition is devoid or substantially devoid Preservatives of co-solvent. The present topical pharmaceutical compositions may fur Suitably, the polymer in any of the above 4 formulations is ther comprise a preservative. Exemplary preservatives PVP/VA. In one embodiment, the ratio of PVP monomer to include, but are not limited to, benzyl alcohol, diazolidinyl VA monomer in the PVP/VA is from about 30:70 to about urea, methyl paraben, ethyl paraben, propyl paraben, butyl 70:30. In a particular embodiment, the ratio of PVP monomer paraben, phenoxyethanol, Sorbic acid, benzoic acid, salts to VA monomer is about 30:70. In another embodiment, the thereof, or a combination or mixture thereof. In one embodi ratio of PVP monomerto VA monomer is about 60:40. In yet ment, the preservative is benzyl alcohol. In another embodi 10 another embodiment, the ratio of PVP monomerto VA mono ment, the preservative is phenoxyethanol. mer is about 70:30. Suitably, the present compositions comprise a preservative Suitably, the calcium mupirocin is present in an amount in an amount from about 0.01% to about 2% by weight. from about 1% to about 3% by weight. In one embodiment, Gelling Agent the calcium mupirocin is present in an amount from about 2% The present topical pharmaceutical compositions may fur 15 by weight. ther comprise a gelling agent. Exemplary gelling agents In another embodiment, the topical pharmaceutical com include, but are not limited to, agar, alginate, arabinoxylan, position is devoid or substantially devoid of a lipid. In one carrageenan, carboxymethylcellulose, hydroxypropyl meth embodiment, the pharmaceutical composition is devoid of a ylcellulose, cellulose, curdlan, gelatin, gellan, B-glucan, lipid. In a further embodiment, the pharmaceutical composi tragacanth gum, guar gum, gum arabic, locust bean gum, tion is substantially devoid of a lipid. pectin, starch, a carbomer, acrylate copolymers, silica, Xan Methods of Treatment than gum, salts thereof, or a combination or mixture thereof. According to an embodiment, the invention provides a In one embodiment, the gelling agent is Xanthan gum. In method of treating a disease, disorder or condition of the skin, another embodiment, the gelling agent is a carbomer. In the method comprising administering to a Subject in need another embodiment, the gelling agent is a mixture of at least 25 thereof, a topical pharmaceutical composition comprising an two gelling agents. antibacterial agent, a polymer, water and less than about 40% Suitably, the gelling agent is present in the composition in volatile solvent. an amount from about 0.1% to about 2% by weight. In a particular embodiment, the disease, disorder or con In one embodiment, the invention provides a topical phar dition of the skin is caused by a bacterial . maceutical composition comprising: 30 Exemplary bacterial include, but are not limited (a) calcium mupirocin, to, infections caused by Gram-positive and Gram-negative (b) a polymer in an amount from about 30% to about 60% bacteria and mycoplasmas, including for example, Staphylo by weight, coccus aureus, Staphylococcus epidermidis, Staphylococcus (c) water in an amount from about 20% to about 40% by haemolyticus, Staphylococcus hominis, Staphylococcus weight, and 35 Sapropphyticus, Streptococcus pyogenes, Streptococcus aga (d) a volatile solvent in an amount from about 10% to about lactiae, Streptococcus pneumoniae, Streptococcus mutans, 25% by weight. Streptococcus sanguis, Streptococcus faecium, Streptococ In another embodiment, the invention provides a topical cus faecalis, Corynebacterium hofinannii, Bacillus subtilis, pharmaceutical composition comprising: Neisseria meningitides, Neisseria gonorrhoeae, Haemophi (a) calcium mupirocin, 40 lus influenzae, Pasteurella multocida, Branhamella catarrha (b) a polymer in an amount from about 30% to about 60% lis, Proteus vulgaris, Propionibacterium acnes, Enterobacter by weight, cloacae, Peptostreptococcus anaerobius, Clostridium sporo (c) water in an amount from about 20% to about 40% by genes, Clostridium difficile, Moraxella catarrhalis, Myco weight, plasma pneumoniae and Mycoplasma gallisepticum. (d) a volatile solvent in an amount from about 10% to about 45 Suitably, the bacterial infection is an infection caused by 25% by weight, and Staphylococcus aureus. (e) a gelling agent. In an embodiment, the disease, disorder or condition of the In yet another embodiment, the invention provides a topi skin caused by a bacterial infection is acne, impetigo, Super cal pharmaceutical composition comprising: ficially infected dermatoses, wounds which have become (a) calcium mupirocin, 50 infected, rosacea or folliculitis. (b) a polymer in an amount from about 30% to about 60% In one embodiment, the disease, disorder or condition of by weight, the skin is acne. In another embodiment, the disease, disorder (c) water in an amount from about 20% to about 40% by or condition of the skin is impetigo. weight, and In a further embodiment, the present compositions may be (d) a volatile solvent in an amount from about 10% to about 55 used as part of a regimen for the treatment or prevention of a 25% by weight, and disease, disorder or condition of the skin. In particular, the wherein the composition is devoid or substantially devoid present compositions may be used in combination with a of co-solvent. separate pharmaceutical dosage form. According to an In another embodiment, the invention provides a topical embodiment, the separate pharmaceutical dosage form is an pharmaceutical composition comprising: 60 oral preparation. In one embodiment, the oral preparation is a (a) calcium mupirocin, capsule or tablet comprising an antibacterial agent. (b) a polymer in an amount from about 30% to about 60% Definitions by weight, The phrases an “effective amount”, “an amount effective (c) water in an amount from about 20% to about 40% by to” or a “therapeutically effective amount are used herein to weight, 65 refer to an amount of the composition Sufficient to have a (d) a volatile solvent in an amount from about 10% to about therapeutic effect upon administration. Effective amounts 25% by weight, and will vary with the particular condition or conditions being US 8,841,351 B2 11 12 treated, the severity of the condition, the duration of the “Substantially devoid of a specified component refers to a treatment, and the specific components of the composition. composition with less than about 1% by weight of the speci The terms “administering and “administration' are used fied component. “Devoid of a specified component refers to herein to mean any method which in Sound medical practice a composition where the specified component is absent. delivers the composition to a subject in Such a manner as to Other terms used herein are intended to be defined by their provide the desired therapeutic effect. well known meanings in the art. The terms “treatment' or “treating of a skin disease, dis order or condition encompasses alleviation of at least one EXAMPLES symptom thereof, a reduction in the severity thereof, or the delay, prevention or inhibition of the progression thereof. 10 The invention will now be described by reference to the Treatment need not mean that the disorder is totally cured. A following examples which are merely illustrative and are not useful composition herein need only to reduce the severity of to be construed as a limitation of the scope of the present the disorder, reduce the severity of symptoms associated invention. therewith, provide improvement to a patient’s quality of life, The following compositions of Examples 1 and 2 may be or delay, prevent or inhibit the onset of the disorder. 15 The term “lipid' is a generic term to describe fats and oils, prepared by the methods of preparation as set forth below in Such as fatty acids, esters Example 4. offatty acids, esters of glycerin, fatty alcohols, waxes, unsa ponifiables, sterols, siloxanes, silanes, lanolin, hydrocarbons, Example 1 glyceryl esters, essential oils, vegetable oils, mineral oils, animal oils and edible oils. Calcium Mupirocin Polymeric Composition The term “salt thereof refers to salts that are pharmaceu tically acceptable. Such salts include: (1) acid addition salts, Item Ingredient % by weight formed with acids such as, for example, acetic acid, benzoic 1 PVPVA 30:70 10 acid, citric acid, gluconic acid, glutamic acid, glutaric acid, 25 2 Ethanol 10 3 Water 59.5 glycolic acid, hydrochloric acid, lactic acid, maleic acid, 4 Hexylene glycol 2O malic acid, malonic acid, mandelic acid, phosphoric acid, 5 Calcium mupirocin O.S propionic acid, Sorbic acid, Succinic acid, Sulfuric acid, tar taric acid, naturally and synthetically derived amino acids, Total 1OO and mixtures thereof or (2) salts formed when an acidic pro 30 ton present in the parent compound is either (i) replaced by a metal ion e.g. an alkali metalion, an alkaline earth metalion Example 2 or an aluminium ion; or (ii) protonates an organic base Such as, for example, ethanolamine, diethanolamine, triethanola Mupirocin Polymeric Composition mine, tromethamine and N-methylglucamine. 35 Any concentration range, percentage range or ratio range Item Ingredient % by weight recited herein is to be understood to include concentrations, 1 PVPVA 30:70 10 percentages or ratios of any integer within that range and 2 Ethanol 10 3 Water 55.7 fractions thereof. Such as one tenth and one hundredth of an 4 Hexylene glycol 23.8 integer, unless otherwise indicated. 40 5 Mupirocin O.S It should be understood that the terms “a” and “an as used herein refer to “one or more' of the enumerated components. Total 1OO It will be clear to one of ordinary skill in the art that the use of the singular includes the plural unless specifically stated oth erwise. Therefore, the terms 'a,” “an and “at least one' are 45 used interchangeably in this application. Example 3 Throughout the application, descriptions of various embodiments use “comprising language, however in some Additional Polymeric Compositions specific instances, an embodiment can alternatively be described using the language “consisting essentially of or 50 The following placebo compositions were also prepared. “consisting of. Each composition was a clear Solution. The mupirocin cal All numbers expressing quantities, percentages or propor cium or mupirocin may be added to the placebo composition tions, and other numerical values used in the specification and to form the final composition. A number of the compositions claims, are to be understood as being modified in all instances prepared were devoid of co-solvent (i.e. devoid of hexylene by the term “about.” glycol), but yet were still a clear Solution.

Item Ingredient % % % % % % % % % % 1 PVPVA 11.9 12 4 10.2 10.3 3.2 10.7 20.9 49.1 49.8 30:70 2 Ethanol 23.4 24.5 23 21 20.7 23.8 4.7 S.S 17.9 18.9 3 Water 64.7 63S 73 66.2 66.9 73 65.6 S6.3 31.1 31.3 4 Hexylene O O O 2.6 2.1 O 19 17.3 1.9 O glycol

Total 1OO 100 1OO 100 100 100 100 100 100 100 US 8,841,351 B2 13 Example 4 -continued Methods of Preparation Item Ingredient % by weight 3 Water 31 Preparation of Calcium Mupirocin and Mupirocin Com- 5 4 Calcium mupirocin 2 positions Using PVP/VA (30:70) PVP/VA (30:70) is available as a 50% mixture in ethanol Total 1OO (Luviskol(R) VA 37E, BASF). PVP/VA (30:70) as an ethanol solution was added to water and a turbid solution formed. Hexylene glycol was subsequently added to form a transpar- 10 Example 5b ent Solution. Calcium mupirocin or mupirocin was added and Co-Solvent Free/Low Ethanol Calcium Mupirocin dissolved by vigorously shaking and rotating the preparation Polymeric Gel for 60 minutes (in accordance with Examples 1 and 2 respec tively). Item Ingredient % by weight Preparation of a Calcium Mupirocin Composition Using 15 PVPVA 30:70 47 PVP/VA (60:40 and 70:30) Ethanol 19 Calcium mupirocin was dissolved in water followed by Water 31 addition of an ethanolic solution of PVP/VA (70:30) (Lu Xanthan gum 1 viskol(R) VA 73E, BASF). A transparent solution resulted. Calcium mupirocin 2 Hexylene glycol was not required. Similarly, calcium mupirocin was dissolved in water, fol Total 1OO lowed by the addition of ethanol, and then PVP/VA (60:40) powder (Plasdon S630, ISP Corp.) was added. A transparent Solution resulted. Hexylene glycol was not required. Example 5c Preparation of Placebos Using PVP/VA (30:70) 25 An ethanolic solution of PVP/VA (30:70) was applied to a Co-Solvent Free/Low Ethanol Clindamycin polypropylene sheet and dried in an oven at 800° C. until the Phosphate Polymeric Gel ethanol had evaporated so as to afford a dried power. The dried PVP/VA powder was dissolved in ethanol to form a Item Ingredient % by weight transparent solution, followed by addition of water. Addition 30 PVPVA 30:70 25 of water was carefully monitored to observe the transforma Ethanol 10 tion from a transparent solution into a turbid mixture. Where Water 62.75 a turbid mixture resulted, hexylene glycol was added drop Xanthan gum 1 wise until a transparent Solution was obtained. The use of Clindamycin phosphate 1.25 PVP/VA (30:70) powder rather than an ethanolic solution of 35 Total 100 the polymer, afforded a number of compositions where the polymer could be solubilised in low levels of ethanol, yet be devoid of hexylene glycol. Example 5d Example 5 40 Co-Solvent Free/Low Ethanol Metronidazole Polymeric Compositions Polymeric Gel The following compositions (Examples 5a-5f) further Item Ingredient % by weight exemplify the present invention. 45 1 PVPVA 30:70 25 2 Ethanol 10 3 Water 63 Example 5a 4 Xanthan gum 1 5 Metronidazole 1 Co-Solvent Free/Low Ethanol Calcium Mupirocin Polymeric Solution 50 Total 1OO

Example 5e Item Ingredient % by weight 1 PVPVA 30:70 48 55 Calcium Mupirocin in Combination with (1) 2 Ethanol 19 Mupirocin, (2) Clotrimazole, (3) Hyaluronic Acid and (4) Clobetasol Propionate

(1) (2) (3) (4) Ingredient % by weight % by weight % by weight % by weight PVPVA 10 50 50 50 30:70 Ethanol 10 19 19 19 Water 58 28 27 28.9S Hexylene 2O O O O glycol US 8,841,351 B2 15 16 -continued

(1) (2) (3) (4) Ingredient % by weight % by weight % by weight % by weight Actives 1% mupirocin Ca 2% mupirocin Ca 2% mupirocin Ca 2% mupirocin 1% mupirocin 1% clotrimazole 2% hyaluronic CaO.05% acid clobetasol propionate

Total 100 100 1OO 100

Example 5f Calcium Mupirocin in Combination with (5) Tretinoin, (6) Hydrocortisone, (7) Adapalene and (8) Metronidazole

(5) (6) (7) (8) Ingredient % by weight % by weight % by weight % by weight PVPVA 50 50 50 SO 30:70 Ethanol 19 19 19 19 Water 28.975 28 28.9 28S Hexylene O O O O glycol Actives 2% mupirocin Ca 2% mupirocin Ca 2% mupirocin Ca 2% mupirocin 0.025% tretinoin 190 0.1% adapalene Ca hydrocortisone O.S90 metronidazole

Total 1OO 100 100

Example 6 the receptor phase were drawn at certain time intervals and subjected to HPLC analysis for drug content. Each aliquot 35 Drug Release was replaced by an equivalent amount of PBS solution. HPLC Analysis The following formulations were also prepared and used to Methanol:HO (50:50) was used as the diluent for the assess drug release from the compositions of the present HPLC sample preparations. invention. 40 A reversed phase HPLC analytical method was used, with an Apollo C18 column (150x4.6 mm, 5 um), Photodiode array detector (210-300 nm range, detection at 223 nm), with Ingredient % by weight % by weight % by weight isocratic elution at 1.5 mL/min and a mobile phase containing 55% methanol and 45% 0.1 PVPVA (70:30) (60:40) (30:70) 10 10 10 45 Mammonium acetate buffer (pH 5.7). The retention time of Ethanol 10 10 10 calcium mupirocin was about 6 minutes and the total run time Water 79.5 78 59.5 Hexylene glycol O O 2O was 10 minutes. The error of analysis in the HPLC analyses Calcium mupirocin O.S 2 O.S was found to be 2-5%. Standard deviation (SD) and% relative standard deviation (% RSD) were found to be in the range of Total 100 1OO 1OO 50 1-7% and about 20%, respectively. Results and Discussion Methodology: In an attempt to prepare a homogeneous topical composi tion comprising calcium mupirocin where the rate of release Franz Cell Drug Release Studies of the active is modulated, a number of polymers (Eudragit In vitro drug release experiments were carried out using a 55 E100, Eudragit S100, Eudragit NE30D and Eudragit RLPO) Franz cell methodology (Fan et al. (2004) J. Contr. Rel. 98. were explored, but these polymers generally precipitated 355-365). from the composition. A Franz cell apparatus was used (Permegear, USA) with 12 Desirably, PVP/VA was shown to be able to modulate mL 0.01 M PBS solution, pH 7.4 (Aldrich) in the Franz cell release of the active agent, but remain solubilized in the receptor compartment and the donor compartment. Two 60 composition. In particular, PVP/VA with varying ratios of hydrophilic DuraporeTM polyvinylidene fluoride membranes PVP:VA monomers were explored, namely 70:30, 60:40 and (Millipore) were placed between the receptor and donor com 30:70. It was observed that PVP/VA 60:40 and 70:30 were partments (25 mm diameter, 0.1 um pore size with 70% soluble in compositions comprising 10% ethanol. However porosity, 125 um thickness). The temperature of the Franz PVP/VA 30:70 was not soluble and required the addition of cells was optimized and maintained at 30°C. 65 20% hexylene glycol to solubilize the copolymer. It was later About 30-50 mg of each formulation was placed on the demonstrated, however, that a composition comprising PVP/ membranes from the donor compartment. 200LL aliquots of VA30:70 but devoid of hexylene glycol could be prepared by US 8,841,351 B2 17 18 using PVP/VA 30.70 polymer powder, rather than as an etha The difference in the weight of each slide (i.e. before and nolic solution of the polymer. The PVP/VA30:70 as a powder, after being immersed in water) was calculated and repre rather than an ethanolic solution, afforded greater control sented the wash resistance of the polymeric films. over the relative concentrations of polymer, ethanol and water Results and Discussion present in the composition. FIG. 4(a) illustrates that the addition of hexylene glycol Modulation in the rate of release of calcium mupirocin is does not impact the rub resistance of the compositions. illustrated in FIG.1. This figure shows that for the composi FIG. 4(b) illustrates that good wash resistance may be tion comprising PVP:VA 30:70, calcium mupirocin release obtained with compositions comprising low amounts of etha reached equilibrium after 4 hours. This compares to only 2 nol e.g. about 20%. 10 FIG. 4(c) illustrates that the addition of hexylene glycol hours for the PVP:VA formulations having 60:40 and 70:30 negatively impacts the wash resistance of the compositions of ratios. This demonstrates a more gradual release of active the invention. agent where the ratio of the hydrophobic monomer (VA) is These data demonstrate that a composition with about 20% greater than the ratio of the hydrophilic monomer (PVP), i.e. ethanol, and free of hexylene glycol, will have both adequate as is the case for PCP/VA 30:70. 15 water and rub resistance. It was also observed that the com FIG. 2 illustrates the first order derivative of the release positions without hexylene glycol dried down more rapidly, data. These data show a clear difference in the release profile and result in a cosmetically elegant film (i.e. without the of PVP/VA 30:70 copolymer (on the one hand) and PVP:VA Stickiness or tackiness associated with hexylene glycol). 60:40 and PVP:VA 70:30. All publications, including but not limited to patents and FIG. 3 illustrates that as the PVP/VA ratio changes from patent applications, cited in this specification are herein 70:30 to 60:40 to 30:70 (increasing hydrophobicity), wherein incorporated by reference as if each individual publication the release exponent (n) increases from 0.17 for PVP:VA were specifically and individually indicated to be incorpo 70:30 to 0.47 for PVP:VA (60:40) and 0.41 for PVP:VA rated by reference herein as though fully set forth. (30:70). Furthermore, the rate constant (k) is reduced from The above description fully discloses the invention includ 0.3 min-1 (for PVP:VA 70:30) to 0.08 min-1 (for both PVP: 25 ing preferred embodiments thereof. Modifications and VA 60:40 and PVP:VA 30:70). improvements of the embodiments specifically disclosed Thus, the n and k values are affected by changes in the herein are within the scope of the following claims. Without hydrophobicity of the respective PVP/VA copolymers. further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention Example 7 30 to its fullest extent. Therefore, the Examples herein are to be construed as merely illustrative and not a limitation of the Rub Resistance and Water Resistance scope of the present invention in any way. The embodiments of the invention in which an exclusive property or privilege is The following placebo formulations were to assess the claimed are defined as follows. 35 What is claimed is: water- and rub-resistance of the compositions of the present 1. A topical pharmaceutical composition comprising: invention. (a) an antibacterial agent, (b) a polyvinylpyrrolidone-vinyl acetate (PVP/VA) % by co-polymer in an amount from about 30% to about 60% Ingredient % by weight % by weight % by weight weight 40 by weight, (c) water in an amount from about 20% to about 40% by Polymer (PVP/VA) 10 11.9 12 11 weight, and Ethanol 10 23.4 24.5 2O Water 60 64.7 63.5 69 (d) a volatile solvent in an amount from about 10% to about Hexylene glycol 2O O O O 25% by weight; 45 and optionally a gelling agent or other dermatologically Total 100 100 1OO 100 acceptable excipients thereof. 2. The composition according to claim 1 wherein the ratio Methodology of PVP monomerto VA monomer in the PVP/VA copolymer Rub Resistance Studies is from about 30:70 to about 70:30. Around 20 mg of each formulation was spread evenly on 50 3. The composition according to claim 2 wherein ratio of separate glass slides. The slides were dried at 45° C. for 3 PVP monomer to VA monomer in the PVP/VA copolymer is hours. Each film was subjected to abrasion with a 100 gm about 30:70 and wherein the composition is free of hexylene standard weight covered with a lint free tissue (KimwipesTM, glycol. Kimberley-Clark). In particular, the 100gm standard weight 4. The composition according to claim 1 wherein the Vola 55 tile solvent is a mixture of at least two volatile solvents, and covered with a lint free tissue was slowly oscillated 20 times wherein the first volatile solvent is ethanol. back and forth over each dried film. The weight of the glass 5. The composition according to claim 4 wherein the vola slides with the dried films before and after the abrasion was tile solvent is a mixture of ethanol and iso-propanol. measured to evaluate the rub-resistance of each film. 6. The composition according to claim 4 wherein the Vola Water Resistance Studies 60 tile solvent is a mixture of ethanol and ethyl acetate. TransporeTM medical tape (3M) was affixed to glass slides. 7. The composition according to claim 1 wherein the vola Around 200 mg of each formulation was spread evenly on the tile solvent is selected from ethanol, propanol, iso-propanol, medical tape. The slides were then dried at 45° C. for 3 hours. n-butyl alcohol, t-butyl alcohol, butoxy ethanol, acetone, The weight of each dried plate was noted. The dried plates ethyl acetate or butyl acetate. were subsequently immersed in water at 45° C. for 30 min 65 8. The composition according to claim 1 wherein the der utes. The plates were removed from the water and dried. matologically acceptable excipients are selected from the Again, the weight of each slide was noted. group consisting of a co-solvent, a pH adjusting agent, a US 8,841,351 B2 19 20 humectant, a film extender, a chelating agent, an antioxidant, 18. The composition according to claim 17 wherein the a preservative, afragrance, a colorant, a penetration enhancer, gelling agent is Xanthan gum. and a combination or mixture thereof. 19. The composition according to claim 1 wherein the 9. The composition according to claim 7 wherein the der topical pharmaceutical composition further comprises a sec matologically acceptable excipients are selected from the ond pharmaceutically acceptable active agent. group consisting of a co-solvent, a pH adjusting agent, a 20. The composition according to claim 19 wherein the humectant, a film extender, a chelating agent, an antioxidant, second pharmaceutically acceptable active agent is selected a preservative, afragrance, a colorant, a penetration enhancer, from the group consisting of a second antibacterial agent, a and a combination or mixture thereof. retinoid, a corticosteroid, an antifungal agent, a skin condi 10. The composition according to claim 1 wherein the 10 gelling agent is Xanthan gum. tioning agent, a nutritional agent, or an antiseptic agent. 11. The composition according to claim 8 wherein the 21. The composition according to claim 20 wherein the co-solvent is selected from an alcohol, a carboxylic acid, a second pharmaceutically acceptable active agent is mupiro diol, a polyol or a combination or mixture thereof, present in cin, clotrimazole, clobetasol propionate or hyaluronic acid. an amount from about 1% to about 30% by weight. 15 22. The composition according to claim 1 wherein the 12. The composition according to claim 11 wherein the antibacterial agent is gentamicin, neomycin, Streptomycin, alcohol is selected from amyl alcohol, benzyl alcohol, cyclo cefpodoxime proxetil, clindamycin, lincomycin, erythromy hexanedimethanol, diacetone alcohol, hexyl alcohol, or tet cin, bacitracin, gramicidin(s), Vancomycin, doxycycline, rahydrofurfuryl alcohol; and the diol is selected from 1,2- minocycline, Oxytetracycline, tetracycline, fosfomycin, hexanediol, butylene glycol, diethylene glycol, dipropylene fusidic acid, Sulfacetamide, metronidazole, benzoyl peroxide glycol, ethylhexanediol, ethylene glycol, hexylene glycol, and dapsone, a pharmaceutically acceptable salt of the afore pentylene glycol, propylene glycol, tetraethylene glycol, tri mentioned agents, and mixtures thereof. ethylene glycol, or tripropylene glycol; and the polyol is 23. A topical pharmaceutical composition comprising: selected from polyethylene glycol, butanetriol, glycerol or (a) an antibacterial agent, 12,6-hexanetriol. 25 (b) a polyvinylpyrrolidone-vinyl acetate (PVP/VA) 13. The composition according to claim 12 wherein the co-polymer in an amount from about 30% to about 60% co-solvent is propylene glycol. by weight, 14. The composition according to claim 1 which compo (c) water in an amount from about 20% to about 40% by sition is substantially devoid or devoid of a co-solvent. weight, and 15. The composition according to claim 12 wherein the 30 co-solvent is a mixture of polyethylene glycol and propylene (d) a volatile solvent in an amount from about 10% to about glycol. 25% by weight; 16. The composition according to claim 1 wherein the ratio (e) a co-solvent present in an amount of about 1% to about of PVP monomer to VA monomer in the PVP/VA is about 30% by weight; 60:40. 35 and optionally a gelling agent or other dermatologically 17. The composition according to claim 16 wherein the acceptable excipients thereof. PVP/VA copolymer is solubilized in the composition. k k k k k