(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`(43) International Publication Date
`16 September 2010 (16.09.2010)
`
`(10) International Publication Number
`WO 2010/105052 Al
`
`(51) International Patent Classification:
`A61K 8/02 (2006.01)
`
`(74) Agent: DAVIS, William,
`J.;
`International Specialty
`Products, 1361 Alps Road, Wayne, NJ 07470 (US).
`
`(21) International Application Number:
`PCT/US20 10/026976
`
`(22) International Filing Date:
`
`11 March 2010 ( 11.03.2010)
`
`(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, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP,
`KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD,
`ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI,
`NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD,
`(30) Priority Data:
`SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR,
`61/159,284
`US
`11 March 2009 ( 11.03.2009)
`TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.
`61/170,278
`US
`17 April 2009 (17.04.2009)
`(71) Applicant (for all designated States except US): ISP IN¬ (84) Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`VESTMENTS INC. [US/US]; 101 1 Centre Road, Suite
`GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
`3 15, Wilmington, DE 19805 (US).
`ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ,
`(72) Inventors; and
`TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE,
`(for US only): HANI, Fares
`(75) Inventors/Applicants
`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 Powdermill Lane, Oak
`TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW,
`land, NJ 07436 (US). TRACEY, Ross [US/US]; 11
`ML, MR, NE, SN, TD, TG).
`Awosting Road, Hewitt, NJ 07421 (US). ANTHONY,
`16 Oak Street, Wayne, NJ 07470 Published:
`Luschen [US/US];
`(US).
`— with international search report (Art. 21(3))
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(54) Title: TOPICAL PERSONAL CARE AND PHARMACEUTICAL COMPOSITIONS AND USES THEREOF
`
`(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 effec
`tive thickener
`in the low pH systems. In pre
`ferred embodiments,
`the acid is a hydroxy acid
`and the composition used for personal care, or
`prescriptive or non-prescriptive medication in di
`cations for 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, foot, or lips. Especially preferred is a use
`to reduce irritation and stinging compared to an
`equivalent compositions not having lightly- to
`moderately-crosslinked PVP.
`
`4
`
`6
`
`10
`
`12
`
`time (weeks)
`
`Fig: 1
`
`Almirall, LLC
`Exhibit 2002
`Page 1
`
`

`

`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 poIy( V-vinyl-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
`
`rlieological properties) even with prolonged storage.
`
`[0002] Particularly, 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.
`
`[0003]
`
`Surprisingly, the topical compositions described herein deliver the personal care and/or
`
`pharmaceutical acid with reduced skin irritation, a significant breakthrough in this field where
`
`discomfort issues are well known.
`
`DESCRIPTION OF RELATED ART
`
`[0004] Topical personal care and pharmaceutical compositions are products consumers around 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 waits), or fall somewhere between the cosmetic and
`
`medical indications. Across all these uses, many different product forms are employed, and vary
`
`Almirall, LLC
`Exhibit 2002
`Page 2
`
`

`

`DN 3168 P3
`
`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 modem 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 low 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," Climes 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 of photoaging," Clinics in Dermal, 1996;
`
`14: 217-226, which also is incorporated in its entirety by reference. This article recognizes pHs in
`
`the range from 0.6 to 4.0.
`
`[0006] While low pH topical compositions can provide useful benefits to the consumer, they can
`
`pose real 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 formulary 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.
`
`Almirall, LLC
`Exhibit 2002
`Page 3
`
`

`

`DN 3168 P3
`
`[0008] Other thickeners are known. For example, Carbopol® Aqua SF-I, 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 veiy 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 12, which discloses a thickener system including a
`
`combination of xanthan 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 lowpH systems.
`
`[OQlO]
`
`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(
`
`-vinyl-2-pyi*rolidone) 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 2003/01 18620 teaches a thickening system for cosmetic
`
`composition of low pH, comprising a polysaccharide and taurate copolymer.
`
`[0014]
`
`Polymeric thickeners for acidic surfactant 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.
`
`Almirall, LLC
`Exhibit 2002
`Page 4
`
`

`

`DN 3168 P3
`
`[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, EJ., "Alpha hydroxy acids:
`
`procedures for use in clinical practice, Cutis, 1989; 43: 222-228), a non-prescriptive market demand
`
`did not exist until 1992, when Avon launched Anew Perfecting Complex For Face (Avon Products,
`
`Inc. website: www.avoncompany. com/brand s/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 forty-two such product registrations were received by the
`
`FDA.
`
`[0017] With the growth of this new market segment, consumers began to experience potentially
`
`harmful 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/fda/gov/guidance.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-
`crosslmked poly(iV-vinyl-2-pyit olidone).
`In that patent it is taught to be the precipitation polymerization product of JV-vinyl^-
`5,073,614.
`
`introduced in U.S. patent
`
`This polymer was first
`
`Almirall, LLC
`Exhibit 2002
`Page 5
`
`

`

`DN 3168 P3
`
`pyiTolidone 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 m L of polymer, and a Brookfield viscosity hi 5%
`
`aqueous solution of at least about 10,000 cP.
`
`[0019] This lightly- to moderately-crosslinked poly(/V-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 formulations is small, much less than 0.5% (% w/w). As such, formulation scientists
`
`regard these acids at these levels not as functional acids {e.g., for the treatment of skin or hair
`
`conditions), but, instead as pH adjusters, necessaiy to protonate the quaternary polymer(s) to make
`
`them more substantive to hair.
`
`[0020] U.S. patent 5,716,634 teaches a lightly-crosslinked iV-vinyl lactam polymer in form of
`
`stable, clear, flowable, homogenized hydrogel, may be used as a earner for cosmetic/pharma active
`
`for hair or skin use. A controlled release drug-delivery composition comprising a lightly-
`
`crosslinked poly(7V-vinyl-2-pyrrolidone) polymer is the subject of U.S. patent 5,252,61 1. Also, the
`
`production of lightly-crosslinked polyt
`
`-vinyW-pyrrolidone) 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 moderately-crosslinked poly(7V-vinyl-2-
`
`pyrrolidone)
`
`is
`
`given
`
`in
`
`SMh,
`
`J.S.,
`
`"Characteristics
`
`of
`
`lightly
`
`crosslinked
`
`po
`
`vinylpyrrolidone)," Polymer Materials: Science & Engineering Preprint, 72, 374, 1995.
`
`[0022]
`
`Still more information on this lightly crosslinked pory(/V-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 6,582,71 1.
`
`Almirall, LLC
`Exhibit 2002
`Page 6
`
`

`

`DN 3168 P3
`
`[0023] These nine U.S. patents ('770,
`
`'634, '61 1, '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/pharmaceutical 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 appeal.
`
`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 smprising, it has been discovered that the use of these topical
`
`compositions thickened with lightly- to moderately-crosslinked PVP reduce irritation and sting
`
`discomfort 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.
`
`Almirall, LLC
`Exhibit 2002
`Page 7
`
`

`

`DN 3168 P3
`
`[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 graph of viscosity as a function of time for an acne gel produced in
`
`accordance with Example 8.
`
`[0031] Figure 2 is a graph of pH 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 personal care or
`
`pharmaceutical acid, and lightly- to moderately-crosslinked PoIy(
`
`-vinyl-2-pyrrolidone) ("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 performance 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.
`
`Almirall, LLC
`Exhibit 2002
`Page 8
`
`

`

`DN 3168 P3
`
`[0034] Due to the inherent complexity in these compositions, their ingredients, product forms, and
`
`uses, it will be appreciated that definitions of terms will help describe preferred embodiments of the
`
`invention.
`
`[0035] The term personal care compositions (ot formulations) refer to compositions intended for
`
`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 from 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 lightly- to moderately-crosslinked PVP, unless otherwise noted, specifically
`
`refers to
`
`polymer essentially consisting of lightly- to moderately-crosslinked poly(JV-vinyl-2-
`
`pyrrolidone) having at least one of the following characteristics:
`
`(1) an aqueous swelling parameter
`
`defined by its gel volume from 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 mL/g to about 150 mL/g, or (2) a
`
`Brookfield viscosity of 5% lightly- to moderately-crosslinked PVP in a liquid carrier 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 art 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
`
`Almirall, LLC
`Exhibit 2002
`Page 9
`
`

`

`DN 3168 P3
`
`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 vary for compositions containing lightly- to
`
`moderately-crossl inked PVP made by these different methods. Nonetheless, these variations are
`
`within the scope of the invention, as the lightly- to moderately-crossl inked PVPs thicken low pH
`
`compositions.
`
`[0039] Unless otherwise specified, "lightly- to moderately-crosslinked PVP" does not refer to
`
`swellable but water-insoluble cross]inked 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 proportionality 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 from low shear rate, rotational flow, especially the viscosity measured by the
`
`Brookfield LVT and Brookfield RVT viscometers operating at 10 revolutions per minute (rpm) at
`
`250C. References describing the Brookfield measurement of viscosities include the following, each
`
`of which is hereby incorporated in its entirety by reference: Thibodeau, L., "Measuring viscosity of
`
`pastes," American Laboratory News, June 2004; McGregor, R.G., "Shelf life: does viscosity
`
`matter?" Pharmaceutical Online, October 31, 2007; and McGregor, R.G., "When ointments
`
`disappoint, the viscosity story," Brookfield Engineering brochure.
`
`[0041] The term sub-formulation refers to a composition having two or more ingredients that is
`
`first prepared and then later blended with other ingredients as necessary. For example, sub-
`
`formulations may be made containing thickening agent(s) and liquid carrier(s) [which may or may
`
`not be solvents for the thickening agent(s)] with or without additional ingredients, and then divided
`
`into specific lots for use in specific formulation(s) at a later time.
`
`Almirall, LLC
`Exhibit 2002
`Page 10
`
`

`

`DN 3168 P3
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`[0042] The term topical refers to any external parts 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 low pH refers to a pH of 6 or less.
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`[0044] The term veig
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`low pH refers to a pH of 4 or less.
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`[0045] The term extremely lowpHrefets to a pH of 2 or less.
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`First embodiment of the invention
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`[0046]
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`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.
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`In these compositions the lightly- to moderately-crosslinked PVP functions, in part, as a
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`thickener, especially to increase the low shear viscosity.
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`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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`[0047] By virtue of having at least one personal care or pharmaceutical acid,
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`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 veiy low pH, and in especially preferred 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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`irritation 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 according to the invention. Generally speaking, a most preferred family is
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`the hydroxy acid family, as their formulations most frequently 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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`Almirall, LLC
`Exhibit 2002
`Page 11
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`DN 3 168 P3
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`beta hydroxy acids, alpha and beta hydroxy acids, and polyhydroxy acids.
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`[0049] Alpha hydroxy acids are frequently 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,
`alpha hydroxycaprylic acid, ascorbic acid, adipic acid, caprylic acid, capiϊ c acid, glycolic acid,
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`lactic acid,
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`lauric acid, mandelic acid, myristic acid, palmitic acid, stearic acid, Hnoleic acid,
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`linolenic acid, ricinoleic acid, oleic acid, tartaric acid, elaidic acid, and erucic 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 then- 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:
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`beta hydroxybutanoic acid, tropic acid, trethocanic acid,
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`salicylic acid, and 5-(w-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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`Almirall, LLC
`Exhibit 2002
`Page 12
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`DN 3168 P3
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`hydroxyl group.
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`Polyhydroxy
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`acids also may be naturally occurring or
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`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:
`piperazine-L
`oxothiazoline-4-carboxylic acid (procysteine), pyruvic acid,
`trichloroacetic acid, etidronic acid,
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`'-2-ethanesulphonic
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`acid;
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`2-
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`aminosulphonic
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`compounds,
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`(JV-2-hydroxyethyl)
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`dioic acid, azelaic acid, their salts, esters and derivatives, and blends thereof.
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`[0055]
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`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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`[0056] 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,
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`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 treatment, a shampoo, or a cream for use around the eyes or mouth,
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`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 from about 1% to about 6% (w/w) of the total formulation. As
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`illustrated in Examples 2-6, thickened acid systems containing from 43% to 71% glycolic acid were
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`effectively thickened to viscosities ranging from 15,000 cP to 37,000 cP with the addition of 4.5%
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`lightly- to moderately-crosslinked PVP.
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`[0057] At these addition levels of lightly- to moderately-crosslinked PVP, the thickened low pH
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`Almirall, LLC
`Exhibit 2002
`Page 13
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`DN 3168 P3
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`compositions typically have a Brookfield viscosity, as measured at 10 ipm and 25°C using an
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`appropriate spindle (e.g., T-C or T-E), from about 1,000 cP to about 100,000 cP.
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`(Of course, the
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`product Brookfield viscosity depends on the panoply of factors outlined in the preceding
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`paragraph.) More preferably, based on the contemplated product forms, the compositions have a
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`Brookfield viscosity from about 10,000 cP to 50,000 cP.
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`[0058] Because of the stabilized viscosity and pH provided by lightly- to moderately-crosslinked
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`PVP in these low pH formulations, compositions comprising this thickener may be a sub-
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`formulation or a complete formulation. Considering the challenges facing production scheduling,
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`batch preparation, and formulation changes, for example, it may be advantageous to prepare a sub-
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`formulation batch having the lightly- to moderately-crosslinked PVP, and then use portions of it at
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`some later time to prepare one or more final formulations. Alternatively, a complete formulation
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`with the lightly- to moderately-crosslinked PVP may be made at essentially in one batch. The
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`compositions of Examples 2 6 may be viewed as examples of sub-formulations if they are not
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`desired as