.2) INTERNATIONA APPLICATION PU.LISHED UNDER THE PATENT COOPE TION TREATY
`IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII
`
`(19) World Intellectual Property Organization
`International Bureau
`
`(43) International Publication Date
`16 September 2010 (16.09.2010)
`
`PUT
`
`(10) International Publication Number
`WO 2010/105052 A1
`
`(51) lnternational PatentClassification:
`A61K8/02 (2006.01)
`
`(21) InternationalApplication Number:
`PCT/US2010/026976
`
`(22) International Filing Date:
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`11 March 2010 (11.03.2010)
`
`English
`
`English
`
`(30) Priority Data:
`61/159,284
`61/170,278
`
`11 March 2009 (11.03.2009)
`17 April 2009 (17.04.2009)
`
`US
`US
`
`(74) Agent: DAVIS, William, J.; International Specialty
`Products, 1361 Alps Road, Wayne, NJ 07470 (US).
`
`(81) Designated States (unless otherwise indicated, for every
`kind of national protection 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, 1D, 1L, 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.
`
`(71) Applicant (for all designated States except US): ISP IN-
`VESTMENTS INC. [US/US]; 1011 Centre Road, Suite
`315, Wilmington, DE 19805 (US).
`
`(84) Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
`ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, T J,
`(72) Inventors; and TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE,
`(75) Inventors/Applicants (for US only): HANI, Fares ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV,
`[US/US]; 1 Rue Matisse, Somerset, NJ 08873 (US).
`MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, SM,
`CHRIS, Barrett [US/US]; 30 Powdennill Lane, Oak-
`TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW,
`land, NJ 07436 (US). TRACEY, Ross [US/US]; 11
`ME, MR, NE, SN, TD, TG).
`Awosting Road, Hewitt, NJ 07421 (US). ANTHONY,
`Luschen [US/US]; 16 Oak Street, Wayne, NJ 07470 Published:
`(US). -- with international search report (Art. 21(3))
`
`1
`1
`1
`1
`
`1
`
`1
`
`1 (54) Title: TOPICAL PERSONAL CARE AND PHARMACEUTICAL COMPOSITIONS AND USES THEREOF
`
`35,000
`
`(57) Abstract: Topical compositions are provid-
`ed that have 0.5% or more of at least one person-
`al care or pharmaceutical acid, and lightly- to
`moderately-crosslinked PVP, which is an ef~Ec-
`32,500 --A-45C tive thickener in the low pH systems. In pre-
`
`fbrred embodiments, the acid is a hydroxy acid
`and the composition used fbr personal care, or
`prescriptive or non-prescriptive medication indi-
`cations fbr use on the skin, hair, scalp, foot, or
`lips. Also provided is the use of the topical com-
`positions to deliver the acid(s) to the skin, hair,
`scalp, fbot, or lips. Especially prefbrred is a use
`to reduce irritation and stinging compared to an
`equivalent compositions not having lightly- to
`moderately-cro sslinked PVP.
`
`~, 30,000
`~
`.,i~ 27,500
`
`’~
`
`25,000
`
`22,500
`
`20,000
`
`1
`
`<
`¢q
`
`tt~
`
`eq
`
`0
`
`2
`
`4
`
`6
`
`8
`
`10
`
`12
`
`time (weeks)
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`Fig: 1
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`Almirall EXHIBIT 2007
`Amneal v. Almirall
`IPR2018-00608
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`WO 2010/105052
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`PCT/US2010/026976
`
`TOPICAL PERSONAL CARE AND PHARMACEUTICAL COMPOSITIONS AND
`
`USES THEREOF
`
`FIELD OF THE INVENTION
`
`[0001] The present invention relates to topical compositions comprising at least one personal care
`
`acid or one pharmaceutical acid, and lightly- to moderately crosslinked poly(N-vinyi-2-pyrrolidone)
`
`("PVP"). The lightly- to moderately crosslinked PVP has been found to provide unique thickening
`
`effects in acidic systems that are essentially stable (e.g., do not phase separate and maintain
`
`rheological properties) even with prolonged storage.
`
`100021 Pal~icularly, the invention relates to the compositions having 0.5% (% w/w) or more of at
`
`least one personal care acid or pharmaceutical acid. These compositions ideally have an acidic pH,
`
`especially a pH less than 6, and more preferably a pH less than 4, and especially preferably less than
`
`2. These formulations find application on the skin, hair, scalp, foot, or lip of an mammal, preferably
`
`man, as a smoothing composition, a moisturizing composition, a skin firming composition, a skin
`
`lightening composition, an age-spot composition, a shampoo, or a cream for use around the eyes or
`
`mouth.
`
`[00031 Suq~risingly, the topical compositions described herein deliver the personal care and/or
`
`pharmaceutical acid with reduced skin irritation, a significant breaktlu’ough in this field where
`
`discomfol~t issues are well known.
`
`DESCRIPTION OF RELATED ART
`
`[0004] Topical personal care and pharmaceutical compositions are products consumers m’ound the
`
`globe have come to depend and rely on for the innumerable benefits they impart. Sold both by
`
`prescription and over-the-counter (non-prescriptive), they are applied to the exterior of the body to
`
`the skin, scalp, hair, feet, and lips. They may be cosmetic in effect, meaning they impart primarily
`
`aesthetically beneficial results (like minimizing fine lines and wrinkles), or they may relieve or cure
`
`clinical conditions (like acne vulgaris or wm’ts), or fall somewhere between the cosmetic and
`
`medical indications. Across all these uses, many different product forms are employed, and vary
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`from thickened "semi-solids" like foundations, concealers, lipsticks, and lip balms, to creamy
`
`emulsions, gels, ointments, and lotions, or may be lighter "bodied" compositions such as liquid
`
`soaps, washes, and rinses. In short, topical personal care and pharmaceutical compositions are
`
`ubiquitous in today’s modern world.
`
`[0005] It has been known for some time that acidic personal and pharmaceutical compositions
`
`elicit special responses when applied topically. In this broad concept, the term tow pH means
`
`having a pH of 6 or less. More particularly, low pH compositions can cause an increase in
`
`epidermis exfoliation to alleviate skin conditions (e.g., hyperkeratosis, dry/flaky/itchy skin),
`
`enhance moisturization to help minimize the appearance of lines and wrinkles, increase dermal
`
`thickness, and increase dermal perfusion (vascular effects). A review of these actions as related to a
`
`particular type of acids, hydroxy acids and retinoids, is provided in Ramos-e-Silva, et aL, "Hydroxy
`
`acids and retinoids in cosmetics," Clinics in Dermatog., 2001; 19:460-466, which is hereby
`
`incorporated in its entirety by reference. Also, an instructive review of alpha hydroxy acids,
`
`including the types, mechanisms of action, formulations, and treatment results, is provided by Van
`
`Scott, E.J., "Alpha-hydroxyacids in the treatment of signs ofphotoaging," Clinics in Dermat., 1996;
`
`14: 217-226, which also is incorporated in its entirety by reference. This article recognizes pHs in
`
`the range fi’om 0.6 to 4.0.
`
`[0006] While low pH topical compositions can provide usefill benefits to the consumer, they can
`
`pose leal challenges to the formulation scientist, production staff, and even the consumer. It is well
`
`appreciated by one skilled in the art that low pH fluids can be difficult to thicken, or to maintain a
`
`stable viscosity and/or pH. Thickeners commonly used in low pH systems include xanthan gum
`
`and magnesium aluminum silicate combinations. At addition levels to create "thick" or "stiff"
`
`consistencies, these thickeners may cause pilling (localized fol~ulary incompatibility that leads to
`
`coagulation) or impart an unpleasant, stringy texture to the end product.
`
`[0007] Alternatively, acrylic acid polymers, and polyacrylamides may be used. Their
`
`manufacturers usually recommend dispersing them in water and then neutralizing to attain a desired
`
`viscosity target, which simply is not possible when the product inherently remains strongly acidic.
`
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`[0008] Other thickeners are known. For example, Carbopol® Aqua SF-1, a lightly crosslinked
`
`acrylate copolymer is sold by The Lubrizol Corporation. Product information indicates it is
`
`effective at a pH of 3.5 and higher. Also sold by The Lubrizol Corporate is Carbopol® Aqua CC
`
`Polymer, a polyacrylate-1 crosspolymer. The product white paper recommends neutralizing the
`
`polymer between a pH of 3.5 to 4.0, and, optionally, the pH can be adjusted (higher) by the addition
`
`of base. However, there still remains a need for a thickening agent that is effective at pHs of 6 or
`
`less, more preferably at very low pHs of 4 or less, and especially at extremely low pH of 2 or less.
`
`[0009] Also known is U.S. patent 5,422,1 i2, which discloses a thickener system including a
`
`combination ofxanthan gum, magnesium aluminum silicate and polyacrylamide. The compositions
`
`are the to be particularly effective at low pH used especially for thickening alpha-hydroxy
`
`carboxylic acids and salts thereof. Typically, magnesium aluminum silicates have a recommended
`
`pH range of about 4.2 to 5.2, and typically are not the choice thickener for very low pH systems.
`
`[0010] Similarly, U.S. patent 5,874,095 claims an enhanced skin penetration system comprising a
`
`nonionic polyacrylamide of high molecular weight, for improved topical delivery of drugs at low
`
`pH.
`
`[0011] Further descriptions of acrylic acid thickeners are given in U.S. patents 2,883,351;
`
`2,956,046; 3,035,004; and 3,436,378.
`
`[0012] Poly(N-vinyl-2-pyrrolidone) and its salts and esters are described in U.S. patents
`
`6,436,380; 6,197,281; 6,333,039; 6,685,952; and 7,108,860 as rheology modifiers or thickeners in
`
`personal care products.
`
`[0013] U.S patent application 2003/0118620 teaches a thickening system for cosmetic
`
`composition of low pH, comprising a polysaccharide and taurate copolymer.
`
`[0014] Polymeric thickeners for acidic suffactant compositions are described by U.S. patent
`
`4,552,685, and by U.S. patent 4,529,773. However, these acidic-thickened solutions require high
`
`levels of surfactant in order to solubilize the copolymers and they have higher viscosities at pH 7
`
`than when the pH is lowered into the acidic region.
`
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`[0015] As shown in this summary, there remains a strong demand and need for a thickening
`
`material for low pH, very low pH, and extremely low pH systems, particularly one that maintains
`
`stable viscosity, pH, and preferably viscosity and pH. Preferably, this thickener is easy to handle,
`
`readily dispersible, and provides smooth, thickened consistencies, without being stringy or creating
`
`pilling.
`
`[0016] Interest in thickening acidic compositions stems, in part, from the growth of acid products
`
`that consumers are demanding and using. Although the use of alpha hydroxy acids as therapy for
`
`photoaged skin was known to medical doctors by 1989 (Van Scott, E.J., "Alpha hydroxy acids:
`
`procedures for use in clinical practice, Curls, 1989; 43: 222-228), a non-prescriptive market demand
`
`did not exist until 1992, when Avon launched Anew Pelfecting Complex For Face (Avon Products,
`
`Inc. website: wv~w.avoncompanv.com/brands/skincare.html). Indeed, the U.S. Food and Drug
`
`Administration (FDA) confirms that it was not until 1992 that they received the first four
`
`registrations for new consumer products containing glycolic acid as an active ingredient (Barrows,
`
`J.N., Memorandum to the Administrative File, "Guidance for Industry: Labeling for Topically
`
`Applied Cosmetic Products Containing Alpha Hydroxy Acids as Ingredients," Office of Cosmetics
`
`and Colors, CFSAN, FDA, September 12, 2002.) Market demand for these low pH, topically
`
`applied products grew such that by 1997 folly-two such product registrations were received by the
`
`FDA.
`
`[0017] With the growth of this new market segment, consumers began to experience potentially
`
`hal~nful side effects like stinging, redness, and burning. Between 1992 and 2004 the FDA received
`
`114 side-effect complaints (U.S. Food and Drug Administration, Guidance. Labeling for cosmetics
`
`containing alpha hydroxy acids, http://www.cfsan/fdalgov/~uidance.html, January 10, 2005).
`
`Hence, there remains a real need for products and methods for reducing the irritation of these
`
`products while maintaining their efficacy in treating various skin and hair conditions.
`
`[0018] As it will be explained later, the present invention is also related to lightly- to moderately-
`
`crosslinked poly(N-vinyl-2-pyn’olidone). This polymer was first introduced in U.S. patent
`
`5,073,614. In that patent it is taught to be the precipitation polymerization product of N-vinyl-2-
`
`4
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`pyrmlidone monomer in an organic solvent, such as an aliphatic hydrocarbon solvent (preferably
`
`cyclohexane or heptane) or an aromatic hydrocarbon (such as toluene) in the presence of about
`
`0.2% to 1% by weight of a crosslinking agent. The fine, white powders thus produced have an
`
`aqueous gel volume of about 15 mL to 150 mL of polymer, and a Brookfield viscosity in 5%
`
`aqueous solution of at least about 10,000 cP.
`
`[0019] This lightly- to moderately-crosslinked poly(N-vinyl-2-pyrrolidone) polymer also was the
`
`subject of U.S. patent 5,139,770, filed December 17, 1990 and issued August 18, 1992, In this
`
`patent examples are provided for a cream rise (pH of 4), a hair conditioner (pH of 4), and a blow
`
`dry styling lotion (pH of 6), which have been pH-adjusted by the addition of citric acid or
`
`phosphoric acid. Although not specified, one skilled in the art recognizes that the acid addition
`
`level in these fbrmulations is small, much less than 0.5% (% w/w). As such, formulation scientists
`
`regard these acids at these levels not as fimctional acids (e.g., for the treatment of skin or hair
`
`conditions), but, instead as pH adjustors, necessat3, to protonate the quaternary polymer(s) to make
`
`them more substantive to hair.
`
`[0020] U.S. patent 5,716,634 teaches a lightly-crosslinked N-vinyl lactam polymer in form of
`
`stable, clear, flowable, homogenized hydrogel, may be used as a carrier for cosmetic/phanna active
`
`for hair or skin use. A controlled release drug-delivery composition comprising a lightly-
`
`crosslinked poly(N-vinyl-2-pyrrolidone) polymer is the subject of U.S. patent 5,252,611. Also, the
`
`production of lightly-crosslinked poly(N-vinyl-2-pyn’olidone) polymer in an oil-in-water or water-
`
`in-oil emulsion is taught in U.S. patent 6,177,068.
`
`[0021] A summary of some properties of light- to modemtely-crosstinked poly(N-vinyl-2-
`
`pyn’olidone) is given in Shih, J.S., "Characteristics of lightly crosslinked poly(N-
`
`vinylpylTolidone)," Polymer Materials: Seience & Engineering Preprint, 72, 374, 1995.
`
`[0022] Still more infbnnation on this lightly crosslinked poly(N-vinyl-2-pyrrolidone) polymer is
`
`given in the following U.S. patents: 5,162,417; 5,312,619; 5,622,168; 5,564,385; and 6,582,711.
`
`5
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`[0023] These nine U.S. patents (’770, ’634, ’611, ’068, ’417, ’619, ’168, ’385, and ’711) and the
`
`Shih article mentioned in the above paragraphs are hereby incorporated in their entirety by
`
`reference.
`
`[0024] Hence, a first objective of the present invention is to provide a wide range of easy-to-use,
`
`topical compositions having at least one personal care or pharmaceutical acid that are effectively
`
`thickened. The invention also seeks a method to deliver the personal care/phannaceutical acid(s),
`
`and also the use of this method to reduce the perceived irritation and sting discomfort so these
`
`compositions find greater efficacy and consumer appeai.
`
`SUMMARY OF THE INVENTION
`
`[0025] Surprisingly, it has been discovered that lightly- to moderately-crosslinked PVP effectively
`
`and quite elegantly thickens topical compositions having a personal care or pharmaceutical acid,
`
`even at a low pH of 6 or less, or very low pHs of 4 or less, or even extremely low pHs of 2 or less.
`
`[0026] Additionally and even more surprising, it has been discovered that the use of these topical
`
`compositions thickened with lightly- to moderately-crosslinked PVP reduce in’itation and sting
`
`discomfm~ compared to formulas without the lightly- to moderately-crosslinked PVP.
`
`[0027] Hence, a first object of the present invention is to provide a thickener system particularly
`
`suited for use with acidic topical compositions, wherein the thickening agent comprises lightly- to
`
`moderately-crosslinked PVP. The topical compositions are those compositions for use on the
`
`exterior (i. e., skin, hair, feet, and!or lips) of an mammal, such as man, horses, cats, and dogs. These
`
`thickened compositions serve both prescriptive and non-prescriptive markets, such as
`
`pharmaceutical and personal care compositions for skin care, hair care, foot care, scalp care, and
`
`sun care.
`
`[0028] In these topical compositions the amount of lightly- to moderately-crosslinked PVP
`
`represents from about 0.5% to about 10% by weight of the total composition, and more preferably
`
`from about 1% to about 6% by weight. At these addition levels the low-shear ("Brookfield")
`
`viscosity typically is about 7000 cP or more, and more typically is about 10,000 cP or more.
`
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`[0029] A second objective of the present invention is the use of these thickened, acidic
`
`compositions to deliver the personal care and/or pharmaceutical acid to the exterior of a mammal,
`
`and to use this method to reduce irritation and sting compared to compositions not having the
`
`lightly- to moderately-crosslinked PVP,
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`[0030] Figure 1 is a ga’aph of viscosity as a fimction of time for an acne gel produced in
`
`accordance with Example 8.
`
`[0031] Figure 2 is a graph ofpH as a function of time for an acne gel produced in accordance with
`
`Example 8.
`
`DESCRIPTION OF PREFERRED EMBODIMENTS OF THE INVENTION
`
`[0032] The present invention relates to compositions comprising at least one pel~onal care or
`
`pharmaceutical acid, and lightly- to moderately-cmsslinked poly(N-vinyl-2-pyn’olidone) ("lightly-
`
`to moderately-crosslinked PVP") to thicken the composition. Surprisingly, it has been discovered
`
`that the lightly- to moderately-crosslinked PVP increases the viscosity of these compositions,
`
`stabilizing the viscosity and pH of these formulations that historically have proved difficult to
`
`thicken and stabilize. Lightly- to moderately-crosslinked PVP creates elegant, smooth, thickened
`
`compositions even at a pH as low as 1.3, a perfbrmance that is essentially unmatched by other
`
`thickeners.
`
`[0033] Additionally, the invention relates to the use of these thickened compositions to deliver the
`
`acid to the skin, scalp, feet, or lips of a mammal, preferably man. Even more surprising, it has been
`
`discovered that the use of such thickened acidic compositions reduce irritation and sting discomfort
`
`compared to an equivalent formulation not having the lightly- to moderately-crosslinked PVP.
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`[0034] Due to the inherent complexity ha these compositions, their ingredients, product forms, and
`
`uses, it will be appreciated that definitions of terms will help describe prefelxed embodiments of the
`
`invention.
`
`[0035] The term persona! care compositions (or formulations) refer to compositions intended fbr
`
`topical use on a mammal, including, man, horses, cats, and dogs. These compositions include skin,
`
`hair, scalp, foot, or lip compositions, including those compositions that can be purchased with and
`
`without a doctor’s prescription. These personal care compositions can provide any number of
`
`known benefits, such as: moisturize, prevent wrinkles, treat wrinkles, firm skin, treat blemishes,
`
`protect from ultraviolet radiation, protect fi’om thermal damage, lighten skin color, remove dirt / soil
`
`/ dead skin / blocked pores, and treat keratosis (e.g., corns, calluses, and warts). The personal care
`
`compositions also may comprise other active and non-active ingredients to assist in their benefit,
`
`delivery, spreadability, emolliency, film formation, stability, and/or thickening.
`
`[0036] The term tightly- to moderately-crosstinked PVP, unless otherwise noted, specifically
`
`refers to polymer essentially consisting of lightly- to moderately-crosslinked poly(N-vinyl-2-
`
`pyrrolidone) having at least one of the following characteristics: (1) an aqueous swelling parameter
`
`defined by its gel volume fi’om about 15 mL/g to about 300 mL/g, more preferably from about 15
`
`mL/g to about 250 mL/g, and most preferably from about 15 mug to about 150 mL/g, or (2) a
`
`Brookfield viscosity of 5% lightly- to moderately-crosslinked PVP in a liquid coaa’ier comprising
`
`water at 25°C of at least 2,000 cP, more preferably of at least about 5,000 cP, and most preferably
`
`of at least about 10,000 cP. Disclosure for these parameter ranges is provided in U.S. patent
`
`5,073,614 and in Shih, J.S., et at. (1995). Synthesis methods for the lightly- to moderately-
`
`crosslinked PVP are disclosed in a number of references, including U.S. patents 5,073,614;
`
`5,654,385; and 6,177,068. It is appreciated by a polymer scientist skilled in the m~ that the method
`
`of synthesis is immaterial, inasmuch as the produced polymer achieves at least one of the
`
`abovedefined parameters.
`
`[0037] For example, U.S. patent ’614 discloses different crosslinkers and crosslinker amounts that
`
`yield lightly- to moderately-crosslinked PVP suitable for the present invention. The effect of
`
`crosslinker amount on swell volume and viscosity is graphically presented in Shih, J.S., et al.
`
`(1995). Thus, the lightly- to moderately-crosslinked PVP may be produced by the precipitation
`
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`polymerization method of the ’614 patent, by the hydrogel method described in the ’385 patent, or
`
`by the non-aqueous, heterogeneous polymerization method of the ’068 patent. Certainly, other
`
`techniques are contemplated to synthesize this polymer, provided the product meets the aqueous
`
`swelling parameter and Brookfield viscosity requirements.
`
`[0038] Final product viscosities may slightly vaxy for compositions containing lightly- to
`
`moderately-crosslinked PVP made by these different methods. Nonetheless, these variations are
`
`within the scope of the invention, as the lightly- to moderately-crosslinked PVPs thicken low pH
`
`compositions.
`
`[0039] Unless otherwise specified, "lightly- to moderately-crosslinked PVP" does not refer to
`
`swellable but water-insoluble crosslinked PVP, such as the type sold into commercial trade under
`
`the trade name Polyclar® by International Specialty Products, which differs from the
`
`abovedescribed lightly- to moderately-crosslinked PVP.
`
`[0040] The term viscosity refers to the propol~ionality coefficient between shear stress and shear
`
`rate, and describes a composition’s resistance to flow. Because viscosity is dependent on shear rate,
`
`specific measurement information (such as viscometer, flow apparatus/spindle, and shear rate) is
`
`required to properly define viscosity. As used herein, viscosity refers to the proportionality
`
`coefficient determined fi’om low shear rate, rotational flow, especially the viscosity measured by the
`
`Brookfield LVT and Brookfield RVT viscometers operating at 10 revolutions per minute (lpm) at
`
`25°C. References describing the Brookfield measurement of viscosities include the following, each
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`of which is hereby incorporated in its entirety by reference: Thibodeau, L., "Measuring viscosity of
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`pastes," American Laboratory News, June 2004; McGregor, R.G., "Shelf life: does viscosity
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`matter?" Pharmaceutical Online, October 31, 2007; and McGregor, R.G., "When ointments
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`disappoint, the viscosity story," Brookfield Engineering brochure.
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`[0041] The term sub-formulation refers to a composition having two or more ingredients that is
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`first prepared and then later blended with other ingredients as necessary. For example, sub-
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`formuiations may be made containing thickening agent(s) and liquid can’ier(s) [which may or may
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`not be solvents for the thickening agent(s)] with or without additional ingredients, and then divided
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`into specific lots for use in specific formulation(s) at a later time.
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`[0042] The term topical refers to any external pal~s of a mammal, such as man, horses, cats, and
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`dogs, and especially man, and includes skin, hair, scalp, lips, and feet.
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`[0043] The term tow pH refers to a pH of 6 or less.
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`[0044] The telan vety low pH refers to a pH of 4 or less.
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`[0045] The term extremely lowpHrefers to a pH of 2 or less.
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`First embodiment of the invention
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`[0046] In a first embodiment of the invention, topical compositions are provided that have at least
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`one personal care acid or at least one pharmaceutical acid, and lightly- to moderately-crosslinked
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`PVP. In these compositions the lightly- to moderately-crosslinked PVP functions, in pal~, as a
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`thickener, especially to increase the low shear viscosity. It is surprising that lightly- to moderately-
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`crosslinked PVP effectively thickens low pH, very low pH, and extremely low pH personal care and
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`pharmaceutical compositions, with results that are essentially unmatched by existing thickeners.
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`[00471 By virtue of having at least one personal care or pharmaceutical acid, these topical
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`compositions have a pH of less than 7, and more preferably, are low pH compositions. Even more
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`preferable, these compositions have a velT low pH, and in especially prefe~l"ed embodiments, these
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`compositions have an extremely low pH. Generally speaking, very low pH and extremely low pH
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`are of greatest interest to the invention, as these compositions have proved most problematic to
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`thicken. As it will be discussed in greater detail separately, the use of acidic topical compositions
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`thickened with lightly- to moderately-crosslinked PVP has been discovered to produce less skin
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`ilTitation and sting than identical formulations without lightly- to moderately-crosslinked PVP.
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`[0048] A broad selection of personal care acid and pharmaceutical acid compositions may be
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`successfully thickened accolding to the invention. Generally speaking, a most prefen’ed family is
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`the hydroxy acid family, as their formulations most fi’equently exhibit acidic pHs that are difficult to
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`thicken and stabilize. Hydroxy acids can be divided into four subfamilies: alpha hydroxy acids,
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`beta hydroxy acids, alpha and beta hydroxy acids, and polyhydroxy acids.
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`[0049] Alpha hydroxy acids are fi:equently employed in skin lotions and the like, as they are
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`among the most useful exfoliation agents. By definition, alpha hydroxy acids possess a carboxylic
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`acid group with a hydroxyl group on the adjacent carbon atom. Both naturally occurring and
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`synthetic alpha hydroxy acids are known and suitable for use in the invention. Examples of alpha
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`hydroxy acids include, without limitation: alpha hydroxyethanoic acid, alpha hydroxyoctanoic acid,
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`alpha hydroxycaprylic acid, ascorbic acid, adipic acid, caprylic acid, capric acid, glycolic acid,
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`lactic acid, lauric acid, mandelic acid, myristic acid, palmitic acid, stearic acid, linoleic acid,
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`linolenic acid, ricinoleic acid, oleic acid, tartaric acid, elaidic acid, and emcic acid.
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`[0050] Most preferred are alpha hydroxy acids that exhibit high epidermis penetration so that they
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`may exert a maximum effect on the underlying dermis layer. Thus, the most effective alpha
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`hydroxy acids are those of small molecular weight, such as glycolic acid and lactic acid. This
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`preference, however, is not to say that the invention does not work in thickening higher molecular
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`weight acids. Rather, this preference merely recognizes a special class of hydroxy acids that are
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`used in many personal care and pharmaceutical compositions.
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`[0051] Like their alpha counterparts, beta hydroxy acids also find utility in the invention and in
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`skin care products due to their ability to penetrate the epidermis and activity in the dermal layer.
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`Beta hydroxy acids are those molecules having a carboxylic acid group and a hydroxyl group
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`separated by two carbon atoms. Again, both naturally occurring and synthetic beta hydroxy acids
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`are known and may be used in the invention’s compositions. Specific examples of beta hydroxy
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`acids include, but are not limited to: beta hydroxybutanoic acid, tropic acid, trethocanic acid,
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`salicylic acid, and 5-(n-octanoyl) salicylic acid.
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`[0052] Also for use in the thickened topical compositions are alpha beta hydroxy acids. As the
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`same suggests, these acids contain at least one alpha hydroxy acid group and one beta hydroxy acid
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`group. Examples of alpha beta hydroxy acids include: malic acid, citric acid, and tartaric acid.
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`[0053] A final member of the hydroxy acid family is the polyhydroxy acid, which, as the name
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`suggests, are molecules having at least one carboxylic acid functional group and more than 1
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`hydroxyl group. Polyhydroxy acids also may be naturally occun’ing or synthetically
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`manufacturered, and have a higher molecular weight than glycolic acid or lactic acid. As a result,
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`polyhydroxy acids are less penetrating than these two alpha hydroxy acids, and, as a result, provide
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`gentler skin effects, typically with reduced irritation. Examples of suitable polyhydroxy acids
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`include lactobionic acid, galactose, and gluconic acid.
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`[0054] Other personal care acids and pharmaceutical acids are known and are contemplated for
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`use in the thickened compositions of the invention. Non-hydroxy acids that may be used are:
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`aminosulphonic compounds, (N-2-hydroxyethyl) piperazine-N’-2-ethanesulphonic acid; 2-
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`oxothiazoline-4-carboxylic acid (procysteine), pyruvic acid, trichlol~oacetic acid, etidronic acid,
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`dioic acid, azelaic acid, theft: salts, esters and derivatives, and blends thereof.
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`[0055] In order to achieve desired product performance, mixtures of different acids also may be
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`thickened, as well as combinations of acids and the corresponding salts. Suitable such salts include
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`the alkali metal salts of phosphoric and sulphuric acids, e.g. potassium biphosphate and sodium
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`bisulphate.
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`[00561 The thickened topical compositions of the invention may be used where ever acidic
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`personal care and acidic pharmaceutical preparations find utility. Accordingly, the amount of
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`lightly- to moderately-crosslinked PVP in the composition depends on a variety of parameters,
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`including the amount and type of acid(s), other ingredients, and the desired product form, delivery,
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`and consumer "thickness" acceptance. For example, the thickened compositions may be an anti-
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`aging cream, a lotion for skin blemishes, a smoothing lotion, a moisturizing composition, a skin
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`lightening la’eatment, a shampoo, or a cream for use around the eyes or mouth. In these
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`formulations the amount of lightly- to moderately-crosslinked PVP may vary from about 0.1% to
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`about 10% (w/w) of the total formulation. More typically, however, the amount of lightly- to
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`moderately-crosslinked PVP varies fi’om about 1% to about 6% (w/w) of the total folTnulation. As
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`illustrated in Examples 2-6, thickened acid systems containing f?om 43% to 71% glycolic acid were
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`effectively thickened to viscosities ranging from 15,000 cP to 37,000 cP with