US 20110224164A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0224164 A1 Lebreton (43) Pub. Date: Sep. 15, 2011 (54) FLUID COMPOSITIONS FOR IMPROVING Publication Classification SKIN CONDITIONS (51) Int. Cl. (75) Inventor: Pierre F. Lebreton, Annecy (FR) 3G 0.O :08: (73) Assignee: Allergan Industrie, SAS, Pringy (FR) (52) U.S. Cl. .......................................................... 514/54 (21)21) Appl. NoNo.: 12/777,1069 (57) ABSTRACT (22) Filed: May 10, 2010 The present specification discloses fluid compositions com O O prising a matrix polymerand stabilizing component, methods Related U.S. Application Data of making Such fluid compositions, and methods of treating (60) Provisional application No. 61/313,664, filed on Mar. skin conditions in an individual using Such fluid composi 12, 2010. tions. Patent Application Publication Sep. 15, 2011 Sheet 1 of 3 US 2011/0224164 A1 girl is" . .... i E.- &;',EE 3 isre. fire;Sigis's Patent Application Publication Sep. 15, 2011 Sheet 2 of 3 US 2011/0224164 A1 Wiscosity"in a a set g : i?vs. iii.tige: ssp. r. E. site is Patent Application Publication Sep. 15, 2011 Sheet 3 of 3 US 2011/0224164 A1 Fi; ; ; ; , ; i 3 -i-...-- m M mommam mm M. M. MS ' ' s 6. ;:S - - - is : s s: s e 3. 83 8 is is a is É . ; i: ; ------es----- .- mm M. Ma Yum YM Mm - m - -W Mmm-m a 'm m - - - S. 'm - i. So m m 3 - - - - - - - - --- f ; : : ---- ' - - - - - - - - - - - - - - - . : 2. ----------- US 2011/0224164 A1 Sep. 15, 2011 FLUID COMPOSITIONS FOR IMPROVING 0004. The fluid compositions disclosed in the present SKIN CONDITIONS specification achieve this goal. Such fluid compositions com prise a matrix polymer and a stabilizing component that reduces or prevents in Vivo degradation of the matrix polymer. 0001. This patent application claims priority pursuant to Administration of the disclosed fluid compositions improves 35 U.S.C. S 119(e) to U.S. Provisional Patent Application Ser. skin conditions such as, e.g., hydration and the cutaneous No. 61/313,664 filed Mar. 12, 2010, which is hereby incor elasticity by compensating for the loss of the endogenous porated by reference in its entirety. polymer. 0002 Dermal fillers are useful in soft tissue and dermal 0005 Thus, aspects of the present specification provide a correction. One common polymer used in dermal filler com fluid composition comprising a matrix polymer and a stabi positions is hyaluronan, also known as hyaluronic acid (HA). lizing component. Matrix polymers useful to make Such fluid Although exhibiting excellent biocompatibility and affinity compositions include, without limitation, a glycosaminogly for water molecules, in its natural state, hyaluronan exhibits can (like chondroitin Sulfate, dermatan Sulfate, keratan Sul poor biomechanical properties as a dermal filler. Tezel and fate, hyaluronan) and lubricin. Stabilizing components useful Fredrickson, The Science of Hyaluronic Acid Dermal Fillers, J Cosmet Laser Ther. 10(1): 35-42 (2008); Kablik, et al., to make Such fluid compositions include, without limitation, Comparative Physical Properties of Hyaluronic Acid Dermal polyols and flavonoids. Fillers, Dermatol Surg. 35 Suppl 1:302-312 (2009); Beasley, 0006. Other aspects of the present specification provide a et al., Hyaluronic Acid Fillers: A Comprehensive Review, method of making a fluid composition disclosed in the Facial Plast Surg. 25(2): 86-94 (2009); each of which is present specification. In an aspect, a method for making a hereby incorporated by reference in its entirety. One primary fluid composition comprises the steps of: a) combining a reason is that this polymer is soluble and is cleared rapidly stabilizing component with a physiologically-acceptable when administered into a skin region. Tezel, supra, 2008: buffer to make a stabilizing component-buffered solution; Kablik, Supra, 2009; Beasley, supra, 2009. This in vivo clear and b) combining a matrix polymer with the stabilizing com ance is primarily achieved by degradation, principally enzy ponent-buffered solution to hydrate the matrix polymer. In matic degradation via hyaluronidase and chemical degrada another aspect, a method for making a fluid composition tion via free-radicals. To minimize the effect of these in vivo comprises the steps of: a) combining a stabilizing component degradation pathways, matrix polymers like hyaluronan are with a physiologically-acceptable buffer to make a stabilizing crosslinked to one another to form a hydrogel. Because component-buffered solution; b) combining a matrix poly hydrogels are more solid Substance that are readily soluble, mer with the stabilizing component-buffered solution to dermal fillers comprising such crosslinked matrix polymers hydrate the matrix polymer, and; c) sizing the fluid composi remain in place at the implant site. Tezel, supra, 2008; Kablik, tion. This method may, or may not, further comprise a step supra, 2009; Beasley, supra, 2009. A crosslinked matrix poly comprising titrating a stabilizing component-buffered solu mer like hyaluronan is also more Suitable as a component of tion to obtain a desired pH after step (a); a step comprising a dermal filler because it's more solid nature improves the filtering the stabilizing component-buffered solution after mechanical properties of the filler, allowing the filler to better step (a); a step (b) where combining a matrix polymer with the lift and fill a skin region. Tezel, supra, 2008; Kablik, supra, stabilizing component-buffered solution to hydrate the 2009; Beasley, supra, 2009. matrix polymer occurs by mixing the matrix polymer with the 0003 Hyaluronan is abundant in the different layers of the stabilizing component-buffered solution at a low speed for a skin, where it has multiple functions such as to ensure good relatively long period of time; a step (b) where combining a hydration, assist in the organization of the collagen matrix, matrix polymer with the stabilizing component-buffered and act as a filler material assisting the organization of the Solution to hydrate the matrix polymer occurs by mixing the extracellular matrix. However, with age, the quantity of matrix polymer with the stabilizing component-buffered hyaluronan present in the skin decreases. This lose of hyalu Solution at a low speed for a relatively long period of time and roman results in various skin conditions such as, e.g., skin then followed by a rest for a relative long period of time; a step dehydration, lack of skin elasticity, skin roughness, lack of (b) where combining a matrix polymer with the stabilizing skin tautness, skin stretch line and/or marks, skin paleness, component-buffered solution to hydrate the matrix polymer skin wrinkles, and the like. As such, it would be desirable to occurs by mixing the matrix polymer with the stabilizing have a skin therapy that can replace the endogenous matrix component-buffered solution at a low speed for a relatively polymers that are lost with age in order to treat these skin long period of time and then by mixing the matrix polymer conditions. However, current dermal fillers comprising with the stabilizing component-buffered solution using a hydrogels of crosslinked matrix polymers like crosslinked cycle of alternating periods of agitation for a relatively short hyaluronan cannot be used to replace the lost endogenous period of time followed by periods of rest for a relatively long polymers because the crosslinking prevents the ability of period of time; a step (b) where combining a matrix polymer these polymers to integrate into the extracellular matrix. with the stabilizing component-buffered solution to hydrate However, as discussed above, although uncrosslinked matrix the matrix polymer occurs by mixing the matrix polymer with polymers like hyaluronan are soluble, and as Such, could the stabilizing component-buffered solution at a low speed integrate into the extracellular matrix and replace lost endog for a relatively long period of time and then by mixing the enous hyaluronan, uncrosslinked matrix polymers are rapidly matrix polymer with the stabilizing component-buffered cleared from the body by in vivo degradation pathways. Thus, Solution using a cycle of alternating periods of agitation for a what is needed is a fluid composition comprising relatively short period of time followed by periods of rest for uncrosslinked matrix polymers that include an additional sta a relatively long period of time, and then followed by a rest for bilizing component that reduces or prevents matrix polymer a relative long period of time; a step comprising degassing a degradation. fluid composition after step (b) or step (c); a step comprising US 2011/0224164 A1 Sep. 15, 2011 filling a syringe with a fluid composition after step (c); and/or bilizing component. As used herein, the term “fluid refers to a step comprising sterilizing a syringe filled with a fluid a continuous, amorphous Substance whose molecules move composition after step (c). freely pastone another. A fluid cannot Sustain a shearing force 0007. Yet other aspects of the present specification pro when at rest and undergoes a continuous change in shape vide a fluid composition disclosed in the present specification when subjected to such a force. It should be noted, that made by a method disclosed in the present specification. although the compositions disclosed in the present specifica 0008 Still other aspects of the present specification pro tion are fluid in nature due to the presence of uncross linked vide a method of improving a condition of skin