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

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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 in an indi matrix polymers, such fluid compositions, may, although vidual in need thereof, the method comprising the steps of may not, include cross linked matrix polymers, which, by its administering a fluid composition disclosed in the present nature, is a gel or other Solid Substance. As such, certain fluid specification into a dermal region of the individual, wherein compositions disclosed in the present specification exhibit the administration improves the condition. Skin conditions Viscoelastic properties. treated by the disclosed fluid compositions include, without 0012 Aspects of the present specification provide, in part, limitation, skin dehydration, a lack of skin elasticity, skin a fluid composition comprising a matrix polymer. As used roughness, a lack of skin tautness, a skin stretch line or mark, herein, the term “matrix polymer refers to a polymer that can skin paleness, and/or skin wrinkles. become part of or function as an extracellular matrix polymer and pharmaceutically acceptable salts thereof. Non-limiting BRIEF DESCRIPTION OF THE DRAWINGS examples of a matrix polymer include a glycosaminoglycan 0009 FIG. 1 is a graph showing the results of hyaluronan like chondroitin Sulfate, dermatan Sulfate, keratan Sulfate, polymer degradation with and without mannitol. FIG. 1A hyaluronan, lubricants; and collagens. Non-limiting shows a graph plotting G"G" overtime. FIG.1B shows a graph examples of a pharmaceutically acceptable salt of a matrix plotting dynamic viscosity over time. SGM181a is a fluid polymer includes sodium salts, potassium salts, magnesium composition comprising 13.5 mg/mL hyaluronan polymer salts, calcium salts, and combinations thereof. without mannitol (control) and SGM181b is a fluid compo 0013 Aspects of the present specification provide, in part, sition comprising 13.5 mg/mL hyaluronan polymer and 5% a fluid composition comprising a glycosaminoglycan. As mannitol. used herein, the term 'glycosaminoglycan' is synonymous 0010 FIG. 2 is a graph showing the effects of increasing with “GAG” and “mucopolysaccharide' and refers to long stabilizing concentration on the dynamic viscosity of a fluid unbranched polysaccharides consisting of a repeating disac composition comprising a matrix polymer. The graph plots charide units. The repeating unit consists of a hexose (six carbon Sugar) or a hexuronic acid, linked to a hexosamine dynamic viscosity (Pas) over time (s). SGM173a is a fluid (six-carbon Sugar containing nitrogen) and pharmaceutically composition comprising 13.5 mg/mL hyaluronan polymer acceptable salts thereof. Members of the GAG family vary in without mannitol (control), SGM173c is a fluid composition the type of hexosamine, hexose or hexuronic acid unit they comprising 13.5 mg/mL hyaluronan polymer and 5% man contain, such as, e.g., glucuronic acid, iduronic acid, galac nitol and SGM173d is a fluid composition comprising 13.5 tose, galactosamine, glucosamine) and may also vary in the mg/mL hyaluronan polymer and 9% mannitol. geometry of the glycosidic linkage. Any glycosaminoglycan is useful in the compositions disclosed in the present specifi DETAILED DESCRIPTION cation with the proviso that the glycosaminoglycan improves 0011 Aspects of the present specification provide, in part, a condition of the skin, Such as, e.g., hydration or elasticity. a fluid composition comprising a matrix polymer and a sta Table 1 lists representative GAGs.

TABLE 1. Examples of GAGs Glycosidic Hexuronic linkage Name acid Hexose Hexosamine geometry Unique features

Chondroitin GlcUA or GalNAc or -4GlcUAB1- Most prevalent GAG sulfate GlcUA(2S) GalNAc(4S) or 3GalNAcf.1- GalNAc(6S) or GalNAc(4S,6S) Dermaitan GlcUA or GalNAc or -4Idol JAB1- Distinguished from chondroitin sulfate Idol JA or GalNAc(4S) or 3GalNAcf.1- Sulfate by the presence of Idol JA(2S) GalNAc(6S) or iduronic acid, although some GalNAc(4S,6S) hexuronic acid monosaccharides may be glucuronic acid. Keratan Gal or GlcNAc or -3Gal(6S)B1- Keratan sulfate type II may be sulfate Gal(6S) GlcNAc(6S) 4GlcNAc(6S)B1- flucosylated. Heparin GlcUA or GlcNAc or -4Idol JA(2S)C1- Highest negative charge Idol JA(2S) GlcNS or 4GlcNS(6S)C1- density of any known GlcNAc(6S) or biological molecule GlcNS(6S) US 2011/0224164 A1 Sep. 15, 2011

TABLE 1-continued Examples of GAGs Glycosidic Hexuronic linkage Name acid.Hexose Hexosamine geometry Unique features Heparan GlcUA or GlcNAc or -4GlcUAB1 Highly similar in structure to sulfate Idol JA or GlcNS or 4GlcNAco.1- heparin, however heparan Idol JA(2S) GlcNAc(6S) or Sulfates disaccharide units are GlcNS(6S) organised into distinct Sulfated and non-sulfated domains. Hyaluronan GlcUA GlcNAc -4GlcUAB1- The only GAG that is 3GlcNAcf.1- exclusively non-sulfated GlcUA = B-D-glucuronic acid GlcuA(2S) = 2-O-sulfo-f-D-glucuronic acid Idol JA = O-L-iduronic acid Idol JA(2S) = 2-O-sulfo-O-L-iduronic acid Gal = B-D-galactose Gal(6S) = 6-O-sulfo-f-D-galactose GalNAc = B-D-N-acetylgalactosamine GalNAc-4S) = B-D-N-acetylgalactosamine-4-O-sulfate GalNAccGS) = B-D-N-acetylgalactosamine-6-O-sulfate GalNAc?4S,6S) = B-D-N-acetylgalactosamine-4-O, 6-O-sulfate GlcNAc = C-D-N-acetylglucosamine GlcNS = C-D-N-sulfoglucosamine GlcNS(6S) = C-D-N-sulfoglucosamine-6-O-sulfate

0014 Aspects of the present specification provide, in part, 0016 Aspects of the present specification provide, in part, a fluid composition comprising a chondroitin Sulfate. As used a fluid composition comprising a hyaluronan. As used herein, herein, the term “chondroitin sulfate” refers to an the term "hyaluronic acid is synonymous with “HA'. unbranched, sulfated GAG of variable length comprising dis “hyaluronic acid', and "hyaluronate” refers to an anionic, accharides of two alternating monosaccharides of D-glucu non-sulfated glycosaminoglycan polymer comprising disac ronic acid (GlcA) and N-acetyl-D-galactosamine (GalNAc) charide units, which themselves include D-glucuronic acid and pharmaceutically acceptable salts thereof. A chondroitin and D-N-acetylglucosamine monomers, linked together via Sulfate may also include D-glucuronic acid residues that are alternating B-1.4 and B-1.3 glycosidic bonds and pharmaceu epimerized into L-iduronic acid (IdoA), in which case the tically acceptable salts thereof. Hyaluronan can be purified resulting disaccharide is referred to as dermatan Sulfate. A from animal and non-animal sources. Polymers of hyaluro chondroitin sulfate polymer can have a chain of over 100 nan can range in size from about 5,000 Da to about 20,000, individual sugars, each of which can be sulfated in variable 000 Da. Any hyaluronan is useful in the compositions dis positions and quantities. Chondroitin Sulfate is an important closed in the present specification with the proviso that the structural component of cartilage and provides much of its hyaluronan improves a condition of the skin, Such as, e.g., resistance to compression. Any chondroitin Sulfate is useful hydration or elasticity. Non-limiting examples of pharmaceu in the compositions disclosed in the present specification with tically acceptable salts of hyaluronan include Sodium hyalu the proviso that the chondroitin sulfate improves a condition roman, potassium hyaluronan, magnesium hyaluronan, cal of the skin, such as, e.g., hydration or elasticity. Non-limiting cium hyaluronan, and combinations thereof. examples of pharmaceutically acceptable salts of chondroitin 0017 Aspects of the present specification provide, in part, Sulfate include Sodium chondroitin Sulfate, potassium chon a fluid composition comprising a lubricin. As used herein, the droitin Sulfate, magnesium chondroitin Sulfate, calcium term “lubricin’ refers to a large, water soluble glycoprotein chondroitin Sulfate, and combinations thereof. encoded by the PRG4 gene and pharmaceutically acceptable 00.15 Aspects of the present specification provide, in part, salts thereof. It has a molecular weight of 206,000 Da and a fluid composition comprising a keratan Sulfate. As used comprises approximately equal proportions of protein and herein, the term "keratan sulfate' refers to a GAG of variable glycosaminoglycans. The structure of lubricin molecule is length comprising disaccharide units, which themselves that of a partially extended flexible rod and, in solution, include B-D-galactose and N-acetyl-D-galactosamine (Gal occupies a smaller spatial domain than would be expected NAc) and pharmaceutically acceptable salts thereof. Disac from structural predictions. This characteristic may aid in the charides within the repeating region of keratan Sulfate may be molecule's boundary lubricating ability. Lubricin is present fucosylated and N-Acetylneuraminic acid caps the end of the in synovial fluid and on the surface (superficial layer) of chains. Any keratan Sulfate is useful in the compositions articular cartilage and therefore plays an important role in disclosed in the present specification with the proviso that the joint lubrication and synovial homeostasis. Any lubricin is keratan Sulfate improves a condition of the skin, such as, e.g., useful in the compositions disclosed in the present specifica hydration or elasticity. Non-limiting examples of pharmaceu tion with the proviso that the lubricin improves a condition of tically acceptable salts of keratan Sulfate include sodium the skin, such as, e.g., hydration or elasticity. Non-limiting keratan Sulfate, potassium keratan Sulfate, magnesium kera examples of pharmaceutically acceptable salts of lubricin tan Sulfate, calcium keratan Sulfate, and combinations include Sodium lubricin, potassium lubricin, magnesium thereof. lubricin, calcium lubricin, and combinations thereof. US 2011/0224164 A1 Sep. 15, 2011

0018 Aspects of the present specification provide, in part, polymer and uncrosslinked polymer. This ratio of crosslinked a fluid composition comprising a crosslinked matrix polymer. and uncrosslinked matrix polymer is also known as the gel: As sued herein, the term “crosslinked’ refers to the intermo fluid ratio. Any gel: fluid ratio is useful in making the fluid lecular bonds joining the individual polymer molecules, or compositions disclosed in the present specification with the monomer chains, into a more stable structure like a gel. As proviso that Such ratio produces a fluid composition disclosed Such, a crosslinked matrix polymer has at least one intermo in the present specification that improves a skin condition as lecular bondjoining at least one individual polymer molecule disclosed in the present specification. Non-limiting examples to another one. Matrix polymers disclosed in the present of gel:fluid ratios include 100:0, 98:2, 90:10, 75:25, 70:30, specification may be crosslinked using dialdehydes and disu 60:40, 50:50, 40:60, 30:70, 25:75, 10:90: 2:98, and 0:100. fides crosslinking agents including, without limitation, divi 0025 Aspects of the present specification provide, in part, nyl Sulfones, diglycidyl ethers, and bis-epoxides. Non-limit a fluid composition comprising a matrix polymer having a ing examples of hyaluronan crosslinking agents include mean molecular weight. As used herein, the term "molecular divinyl sulfone (DVS), 1,4-butanediol diglycidyl ether weight” refers to the sum of the atomic weights of the atoms (BDDE), 1.2-bis(2,3-epoxypropoxy)ethylene (EGDGE), in a molecule. For example, that of methane (CH) is 16.043 1,2,7,8-diepoxyoctane (DEO), biscarbodiimide (BCDI), adi g/mol, the atomic weights being carbon-12.011 g/mol. pic dihydrazide (ADH), bis(sulfosuccinimidyl)suberate hydrogen-1.008 g/mol. (BS), hexamethylenediamine (HMDA), 1-(2,3-epoxypro 0026. Thus, in an embodiment, a fluid composition com pyl)-2,3-epoxycyclohexane, or combinations thereof. prises a Substantially uncrosslinked matrix polymer. In other 0019 Aspects of the present specification provide, in part, aspects of this embodiment, a fluid composition comprises an a fluid composition comprising a crosslinked matrix polymer uncrosslinked matrix polymer where the uncrosslinked having a degree of crosslinking. As used herein, the term matrix polymer represents, e.g., about 90% by weight, about “degree of crosslinking refers to the percentage of matrix 91% by weight, about 92% by weight, about 93% by weight, polymer monomeric units that are bound to a cross-linking about 94% by weight, about 95% by weight, about 96% by agent, such as, e.g., the disaccharide monomer units of hyalu weight, about 97% by weight, about 98% by weight, or about roman. Thus, a fluid composition that that has a crosslinked 99%, or about 100% by weight, of the total matrix polymer matrix polymer with a 4% degree of crosslinking means that present in the composition. In yet other aspects of this on average there are four crosslinking molecules for every embodiment, a fluid composition comprises an uncrosslinked 100 monomeric units. Every other parameter being equal, the matrix polymer where the uncrosslinked matrix polymer rep greater the degree of crosslinking, the harder the gel becomes. resents, e.g., at least 90% by weight, at least 91% by weight, Non-limiting examples of a degree of crosslinking include at least 92% by weight, at least 93% by weight, at least 94% about 1% to about 15%. by weight, at least 95% by weight, at least 96% by weight, at 0020 Aspects of the present specification provide, in part, least 97% by weight, at least 98% by weight, or at least 99% a fluid composition comprising a uncrosslinked matrix poly by weight, of the total matrix polymer present in the compo mer. As used herein, the term "uncrosslinked’ refers to a lack sition. In still other aspects of this embodiment, a fluid com of intermolecular bonds joining the individual matrix poly position comprises an uncrosslinked matrix polymer where mer molecules, or monomer chains. As such, an the uncrosslinked matrix polymer represents, e.g., about 90% uncrosslinked matrix polymer is not linked to any other to about 100% by weight, about 93% to about 100% by matrix polymer by an intermolecular bond. weight, about 95% to about 100% by weight, or about 97% to 0021 Aspects of the present specification provide, in part, about 100% by weight, of the total matrix polymer present in a fluid composition comprising a Substantially uncrosslinked the composition. matrix polymer. As sued herein, the term “substantially 0027. In another embodiment, a fluid composition com uncrosslinked’ refers to the presence of uncrosslinked matrix prises a substantially uncrosslinked glycosaminoglycan. In polymers in a fluid composition disclosed in the present aspects of this embodiment, a fluid composition comprises a specification at a level of at least 90% by weight of the Substantially uncrosslinked chondroitin Sulfate polymer, a composition, with the remaining at most 10% by weight of Substantially uncrosslinked chondroitin Sulfate polymer, or a the composition being comprised of other components Substantially uncrosslinked hyaluronan polymer. In other including crosslinked matrix polymers. The matrix polymer aspects of this embodiment, a fluid composition comprises an included in a fluid composition disclosed in the present speci uncrosslinked glycosaminoglycan where the uncrosslinked fication exhibit a low degree of cross-linking in order to glycosaminoglycan represents, e.g., about 90% by weight, remain water soluble. about 91% by weight, about 92% by weight, about 93% by 0022 Aspects of the present specification provide, in part, weight, about 94% by weight, about 95% by weight, about a fluid composition that is essentially free of a crosslinked 96% by weight, about 97% by weight, about 98% by weight, matrix polymer. As used herein, the term “essentially free” or about 99%, or about 100% by weight, of the total gly (or “consisting essentially of) refers to a fluid composition cosaminoglycan present in the composition. In yet other where only trace amounts of cross-linked matrix polymers aspects of this embodiment, a fluid composition comprises an can be detected. uncrosslinked glycosaminoglycan where the uncrosslinked 0023 Aspects of the present specification provide, in part, glycosaminoglycan represents, e.g., at least 90% by weight, a fluid composition that is entirely free of a crosslinked matrix at least 91% by weight, at least 92% by weight, at least 93% polymer. As used herein, the term “entirely free” refers to a by weight, at least 94% by weight, at least 95% by weight, at fluid composition that within the detection range of the instru least 96% by weight, at least 97% by weight, at least 98% by ment or process being used, crosslinked matrix polymers weight, or at least 99% by weight, of the total glycosami cannot be detected or its presence cannot be confirmed. noglycan present in the composition. In still other aspects of 0024 Aspects of the present specification provide, in part, this embodiment, a fluid composition comprises an a fluid composition comprising a ratio of crosslinked matrix uncrosslinked glycosaminoglycan where the uncrosslinked US 2011/0224164 A1 Sep. 15, 2011

glycosaminoglycan represents, e.g., about 90% to about 0035. In another embodiment, a fluid composition com 100% by weight, about 93% to about 100% by weight, about prises a crosslinked matrix polymer. In other aspects of this 95% to about 100% by weight, or about 97% to about 100% embodiment, a fluid composition comprises a crosslinked by weight, of the total glycosaminoglycan present in the matrix polymer where the partially crosslinked matrix poly composition. mer represents, e.g., about 1% by weight, about 2% by 0028. In yet another embodiment, a fluid composition weight, about 3% by weight, about 4% by weight, about 5% comprises a Substantially uncrosslinked lubricin. In aspects by weight, about 6% by weight, about 7% by weight, about of this embodiment, a fluid composition comprises an 8% by weight, or about 9%, or about 10% by weight, of the uncrosslinked lubricin where the uncrosslinked lubricin rep total matrix polymer present in the composition. In yet other resents, e.g., about 90% by weight, about 91% by weight, aspects of this embodiment, a fluid composition comprises a about 92% by weight, about 93% by weight, about 94% by crosslinked matrix polymer where the partially crosslinked weight, about 95% by weight, about 96% by weight, about matrix polymer represents, e.g., at most 1% by weight, at 97% by weight, about 98% by weight, or about 99%, or about most 2% by weight, at most 3% by weight, at most 4% by 100% by weight, of the total lubricin present in the compo weight, at most 5% by weight, at most 6% by weight, at most sition. In other aspects of this embodiment, a fluid composi 7% by weight, at most 8% by weight, at most 9% by weight, tion comprises an uncrosslinked lubricin where the or at most 10% by weight, of the total matrix polymer present uncrosslinked lubricin represents, e.g., at least 90% by in the composition. In still other aspects of this embodiment, weight, at least 91% by weight, at least 92% by weight, at a fluid composition comprises a crosslinked matrix polymer least 93% by weight, at least 94% by weight, at least 95% by where the partially crosslinked matrix polymer represents, weight, at least 96% by weight, at least 97% by weight, at e.g., about 0% to about 10% by weight, about 1% to about least 98% by weight, or at least 99% by weight, of the total 10% by weight, about 3% to about 10% by weight, or about lubricin present in the composition. In yet other aspects of this 5% to about 10% by weight, of the total matrix polymer embodiment, a fluid composition comprises an uncrosslinked present in the composition. lubricin where the uncrosslinked lubricin represents, e.g., 0036. In other aspects of this embodiment, a fluid compo about 90% to about 100% by weight, about 93% to about sition comprises a crosslinked matrix polymer where the 100% by weight, about 95% to about 100% by weight, or degree of crosslinking is about 1%, about 2%, about 3%, about 97% to about 100% by weight, of the total lubricin about 4%, about 5%, about 6%, about 7%, about 8%, about present in the composition. 9%, about 10%, about 11%, about 12%, about 13%, about 0029. In another embodiment, a fluid composition com 14%, or about 15%. In yet other aspects of this embodiment, prises an uncrosslinked matrix polymer that is entirely free of a fluid composition comprises a crosslinked matrix polymer a crosslinked matrix polymer. where the degree of crosslinking is at most 1%, at most 2%, at 0030. In yet another embodiment, a fluid composition most 3%, at most 4%, at most 5%, at most 6%, at most 7%, at comprises an uncrosslinked glycosaminoglycan that is most 8%, at most 9%, at most 10%, at most 11%, at most 12%, entirely free of a crosslinked glycosaminoglycan. In an aspect at most 13%, at most 14%, or at most 15%. In still other of this embodiment, a fluid composition comprises an aspects of this embodiment, a fluid composition comprises a uncrosslinked chondroitin sulfate polymer that is entirely free crosslinked matrix polymer where the degree of crosslinking of a crosslinked chondroitin Sulfate polymer. In another is about 1% to about 15%, about 2% to about 11%, about 3% aspect of this embodiment, a fluid composition comprises an to about 10%, about 1% to about 5%, about 10% to about uncrosslinked keratan sulfate polymer that is entirely free of 15%, about 11% to about 15%, about 6% to about 10%, or a crosslinked keratan Sulfate polymer. In yet another aspect of about 6% to about 8%. this embodiment, a fluid composition comprises an 0037. In yet another embodiment, a fluid composition uncrosslinked hyaluronan polymer that is entirely free of a comprises a crosslinked glycosaminoglycan. In aspect of this crosslinked hyaluronan polymer. embodiment, a fluid composition comprises a crosslinked 0031. In still another embodiment, a fluid composition chondroitin Sulfate polymer, a crosslinked keratan Sulfate comprises an uncrosslinked lubricin that is entirely free of a polymer, or a crosslinked hyaluronan polymer. In other crosslinked lubricin. aspects of this embodiment, a fluid composition comprises a 0032. In another embodiment, a fluid composition com crosslinked glycosaminoglycan where the crosslinked gly prises an uncrosslinked matrix polymer that is essentially free cosaminoglycan represents, e.g., about 1% by weight, about of a crosslinked matrix polymer. 2% by weight, about 3% by weight, about 4% by weight, 0033. In yet another embodiment, a fluid composition about 5% by weight, about 6% by weight, about 7% by comprises an uncrosslinked glycosaminoglycan that is essen weight, about 8% by weight, or about 9%, or about 10% by tially free of a crosslinked glycosaminoglycan. In an aspect of weight, of the total glycosaminoglycan present in the com this embodiment, a fluid composition comprises an position. In yet other aspects of this embodiment, a fluid uncrosslinked chondroitin Sulfate polymer that is essentially composition comprises a crosslinked glycosaminoglycan free of a crosslinked chondroitin sulfate polymer. In another where the crosslinked glycosaminoglycan represents, e.g., at aspect of this embodiment, a fluid composition comprises an most 1% by weight, at most 2% by weight, at most 3% by uncrosslinked keratan Sulfate polymer that is essentially free weight, at most 4% by weight, at most 5% by weight, at most of a crosslinked keratan Sulfate polymer. In yet another aspect 6% by weight, at most 7% by weight, at most 8% by weight, of this embodiment, a fluid composition comprises an at most 9% by weight, or at most 10% by weight, of the total uncrosslinked hyaluronan polymer that is essentially free of a glycosaminoglycan present in the composition. In still other crosslinked hyaluronan polymer. aspects of this embodiment, a fluid composition comprises a 0034. In still another embodiment, a fluid composition crosslinked glycosaminoglycan where the crosslinked gly comprises an uncrosslinked lubricin that is essentially free of cosaminoglycan represents, e.g., about 0% to about 10% by a crosslinked lubricin. weight, about 1% to about 10% by weight, about 3% to about US 2011/0224164 A1 Sep. 15, 2011

10% by weight, or about 5% to about 10% by weight, of the about 8 mg/mL, about 9 mg/mL, about 10 mg/mL, about 11 total glycosaminoglycan present in the composition. mg/mL, about 12 mg/mL, about 13 mg/mL, about 13.5 0038. In other aspects of this embodiment, a fluid compo mg/mL, about 14 mg/mL, about 15 mg/mL, about 16 mg/mL, sition comprises a crosslinked glycosaminoglycan where the about 17 mg/mL, about 18 mg/mL, about 19 mg/mL, or about degree of crosslinking is about 1%, about 2%, about 3%, 20 mg/mL. In other aspects of this embodiment, a fluid com about 4%, about 5%, about 6%, about 7%, about 8%, about position comprises an uncrosslinked matrix polymer where 9%, about 10%, about 11%, about 12%, about 13%, about the uncrosslinked matrix polymer is present at a concentra 14%, or about 15%. In yet other aspects of this embodiment, tion of, e.g., at least 1 mg/mL, at least 5 mg/mL, at least 10 a fluid composition comprises a crosslinked glycosaminogly mg/mL, at least 15 mg/mL, at least 20 mg/mL, or at least 25 can where the degree of crosslinking is at most 1%, at most mg/mL. In yet other aspects of this embodiment, a fluid 2%, at most 3%, at most 4%, at most 5%, at most 6%, at most composition comprises an uncrosslinked matrix polymer 7%, at most 8%, at most 9%, at most 10%, at most 11%, at where the uncrosslinked matrix polymer is present at a con most 12%, at most 13%, at most 14%, or at most 15%. In still centration of, e.g., at most 1 mg/mL, at most 5 mg/mL, at most other aspects of this embodiment, a fluid composition com 10 mg/mL, at most 15 mg/mL, at most 20 mg/mL, or at most prises a crosslinked glycosaminoglycan where the degree of 25 mg/mL. In still other aspects of this embodiment, a fluid crosslinking is about 1% to about 15%, about 2% to about composition comprises an uncrosslinked matrix polymer 11%, about 3% to about 10%, about 1% to about 5%, about where the uncrosslinked matrix polymer is present at a con 10% to about 15%, about 11% to about 15%, about 6% to centration of, e.g., about 7.5 mg/mL to about 19.5 mg/mL, about 10%, or about 6% to about 8%. about 8.5 mg/mL to about 18.5 mg/mL, about 9.5 mg/mL to 0039. In still another embodiment, a fluid composition about 17.5 mg/mL, about 10.5 mg/mL to about 16.5 mg/mL, comprises a crosslinked lubricin. In aspects of this embodi about 11.5 mg/mL to about 15.5 mg/mL, or about 12.5 ment, a fluid composition comprises a crosslinked lubricin mg/mL to about 14.5 mg/mL. where the crosslinked lubricin represents, e.g., about 1% by 0042. In yet another embodiment, a fluid composition weight, about 2% by weight, about 3% by weight, about 4% comprises an uncrosslinked glycosaminoglycan where the by weight, about 5% by weight, about 6% by weight, about uncrosslinked glycosaminoglycan is present in an amount 7% by weight, about 8% by weight, or about 9%, or about Sufficient to improve a condition of the skin, such as, e.g., 10% by weight, of the total lubricin present in the composi hydration or elasticity. In aspects of this embodiment, a fluid tion. In other aspects of this embodiment, a fluid composition composition comprises an uncrosslinked glycosaminoglycan comprises a crosslinked lubricin where the crosslinked lubri where the uncrosslinked glycosaminoglycan is present at a cin represents, e.g., at most 1% by weight, at most 2% by concentration of, e.g., about 2 mg/mL, about 3 mg/mL, about weight, at most 3% by weight, at most 4% by weight, at most 4 mg/mL, about 5 mg/mL, about 6 mg/mL, about 7 mg/mL, 5% by weight, at most 6% by weight, at most 7% by weight, about 8 mg/mL, about 9 mg/mL, about 10 mg/mL, about 11 at most 8% by weight, at most 9% by weight, or at most 10% mg/mL, about 12 mg/mL, about 13 mg/mL, about 13.5 by weight, of the total lubricin present in the composition. In mg/mL, about 14 mg/mL, about 15 mg/mL, about 16 mg/mL, yet other aspects of this embodiment, a fluid composition about 17 mg/mL, about 18 mg/mL, about 19 mg/mL, or about comprises a crosslinked lubricin where the crosslinked lubri 20 mg/mL. In other aspects of this embodiment, a fluid com cin represents, e.g., about 0% to about 10% by weight, about position comprises an uncrosslinked glycosaminoglycan 1% to about 10% by weight, about 3% to about 10% by where the uncrosslinked glycosaminoglycan is present at a weight, or about 5% to about 10% by weight, of the total concentration of e.g., at least 1 mg/mL, at least 2 mg/mL, at lubricin present in the composition. least 3 mg/mL, at least 4 mg/mL, at least 5 mg/mL, at least 10 0040. In other aspects of this embodiment, a fluid compo mg/mL, at least 15 mg/mL, at least 20 mg/mL, or at least 25 sition comprises a crosslinked lubricin where the degree of mg/mL. In yet other aspects of this embodiment, a fluid crosslinking is about 1%, about 2%, about 3%, about 4%, composition comprises an uncrosslinked glycosaminoglycan about 5%, about 6%, about 7%, about 8%, about 9%, about where the uncrosslinked glycosaminoglycan is present at a 10%, about 11%, about 12%, about 13%, about 14%, or about concentration of, e.g., at most 1 mg/mL, at most 2 mg/mL, at 15%. In yet other aspects of this embodiment, a fluid compo most 3 mg/mL, at most 4 mg/mL, at most 5 mg/mL, at most sition comprises a crosslinked lubricin where the degree of 10 mg/mL, at most 15 mg/mL, at most 20 mg/mL, or at most crosslinking is at most 1%, at most 2%, at most 3%, at most 25 mg/mL. In still other aspects of this embodiment, a fluid 4%, at most 5%, at most 6%, at most 7%, at most 8%, at most composition comprises an uncrosslinked glycosaminoglycan 9%, at most 10%, at most 11%, at most 12%, at most 13%, at where the uncrosslinked glycosaminoglycan is present at a most 14%, or at most 15%. In still other aspects of this concentration of, e.g., about 7.5 mg/mL to about 19.5 mg/mL, embodiment, a fluid composition comprises a crosslinked about 8.5 mg/mL to about 18.5 mg/mL, about 9.5 mg/mL to lubricin where the degree of crosslinking is about 1% to about about 17.5 mg/mL, about 10.5 mg/mL to about 16.5 mg/mL, 15%, about 2% to about 11%, about 3% to about 10%, about about 11.5 mg/mL to about 15.5 mg/mL, or about 12.5 1% to about 5%, about 10% to about 15%, about 11% to about mg/mL to about 14.5 mg/mL. 15%, about 6% to about 10%, or about 6% to about 8%. 0043. In still another embodiment, a fluid composition 0041. In another embodiment, a fluid composition com comprises an uncrosslinked lubricin where the uncrosslinked prises an uncrosslinked matrix polymer where the lubricin is present in an amount Sufficient to improve a con uncrosslinked matrix polymer is present in an amount Suffi dition of the skin, Such as, e.g., hydration or elasticity. In cient to improve a condition of the skin, such as, e.g., hydra aspects of this embodiment, a fluid composition comprises an tion or elasticity. In aspects of this embodiment, a fluid com uncrosslinked lubricin where the uncrosslinked lubricin is position comprises an uncrosslinked matrix polymer where present at a concentration of, e.g., about 5 mg/mL, about 6 the uncrosslinked matrix polymer is present at a concentra mg/mL, about 7 mg/mL, about 8 mg/mL, about 9 mg/mL, tion of e.g., about 5 mg/mL, about 6 mg/mL, about 7 mg/mL, about 10 mg/mL, about 11 mg/mL, about 12 mg/mL, about 13 US 2011/0224164 A1 Sep. 15, 2011 mg/mL, about 13.5 mg/mL, about 14 mg/mL, about 15 uncrosslinked hyaluronan where the uncrosslinked hyaluro mg/mL, about 16 mg/mL, about 17 mg/mL, about 18 mg/mL, nan represents, e.g., about 90% by weight, about 91% by about 19 mg/mL, or about 20 mg/mL. In other aspects of this weight, about 92% by weight, about 93% by weight, about embodiment, a fluid composition comprises an uncrosslinked 94% by weight, about 95% by weight, about 96% by weight, lubricin where the uncrosslinked lubricin is present at a con about 97% by weight, about 98% by weight, or about 99%, or centration of, e.g., at least 1 mg/mL, at least 5 mg/mL, at least about 100% by weight, of the total hyaluronan present in the 10 mg/mL, at least 15 mg/mL, at least 20 mg/mL, or at least composition. In other aspects of this embodiment, a fluid 25 mg/mL. In yet other aspects of this embodiment, a fluid composition comprises an uncrosslinked hyaluronan where composition comprises an uncrosslinked lubricin where the the uncrosslinked hyaluronan represents, e.g., at least 90% by uncrosslinked lubricin is presentata concentration of, e.g., at weight, at least 91% by weight, at least 92% by weight, at most 1 mg/mL, at most 5 mg/mL, at most 10 mg/mL, at most least 93% by weight, at least 94% by weight, at least 95% by 15 mg/mL, at most 20 mg/mL, or at most 25 mg/mL. In still weight, at least 96% by weight, at least 97% by weight, at other aspects of this embodiment, a fluid composition com least 98% by weight, or at least 99% by weight, of the total prises an uncrosslinked lubricin where the uncrosslinked hyaluronan present in the composition. In yet other aspects of lubricin is presentata concentration of, e.g., about 7.5 mg/mL this embodiment, a fluid composition comprises an to about 19.5 mg/mL, about 8.5 mg/mL to about 18.5 mg/mL, uncrosslinked hyaluronan where the uncrosslinked hyaluro about 9.5 mg/mL to about 17.5 mg/mL, about 10.5 mg/mL to nan represents, e.g., about 90% to about 100% by weight, about 16.5 mg/mL, about 11.5 mg/mL to about 15.5 mg/mL, about 93% to about 100% by weight, about 95% to about or about 12.5 mg/mL to about 14.5 mg/mL. 100% by weight, or about 97% to about 100% by weight, of 0044. In a further embodiment, a fluid composition com the total hyaluronan present in the composition. prises a crosslinked matrix polymer and an uncrosslinked 0047. In yet another embodiment, a fluid composition matrix polymer. In another aspect of this embodiment, a fluid comprises an uncrosslinked hyaluronan where the composition comprises a crosslinked matrix polymer and an uncrosslinked hyaluronan is presentinanamount Sufficient to uncrosslinked matrix polymer where the gel:fluid ratio is improve a condition of the skin, Such as, e.g., hydration or sufficient to form a fluid. In other aspects of this embodiment, elasticity. In aspects of this embodiment, a fluid composition a fluid composition comprises a crosslinked matrix polymer comprises an uncrosslinked hyaluronan where the and an uncrosslinked matrix polymer where the gel: fluid ratio uncrosslinked hyaluronan is present at a concentration of is, e.g., about 0:100, about 1:99, about 2:98, about 3:97, about e.g., about 5 mg/mL, about 6 mg/mL, about 7 mg/mL, about 4:96, about 5:95, about 6:94, about 7:93, about 8:92, about 8 mg/mL, about 9 mg/mL, about 10 mg/mL, about 11 mg/mL, 9:91, or about 10:90. In yet other aspects of this embodiment, about 12 mg/mL, about 13 mg/mL, about 13.5 mg/mL, about a fluid composition comprises a crosslinked matrix polymer 14 mg/mL, about 15 mg/mL, about 16 mg/mL, about 17 and an uncrosslinked matrix polymer where the gel: fluid ratio mg/mL, about 18 mg/mL, about 19 mg/mL, or about 20 is, e.g., at most 1:99, at most 2:98, at most 3:97, at most 4:96, mg/mL. In other aspects of this embodiment, a fluid compo at most 5:95, at most 6:94, at most 7:93, at most 8:92, at most sition comprises an uncrosslinked hyaluronan where the 9:91, or at most 10:90. In still other aspects of this embodi uncrosslinked hyaluronan is present at a concentration of ment, a fluid composition comprises a crosslinked matrix e.g., at least 1 mg/mL, at least 5 mg/mL, at least 10 mg/mL, at polymer and an uncrosslinked matrix polymer where the least 15 mg/mL, at least 20 mg/mL, or at least 25 mg/mL. In gel: fluid ratio is, e.g., about 0:100 to about 3:97, about 0:100 yet other aspects of this embodiment, a fluid composition to about 5:95, or about 0:100 to about 10:90. comprises an uncrosslinked hyaluronan where the 0045. In other aspects of this embodiment, a fluid compo uncrosslinked hyaluronan is present at a concentration of sition comprises a crosslinked matrix polymer and an e.g., at most 1 mg/mL, at most 5 mg/mL, at most 10 mg/mL, uncrosslinked matrix polymer where the gel: fluid ratio is, at most 15 mg/mL, at most 20 mg/mL, or at most 25 mg/mL. e.g., about 15:85, about 20:80, about 25:75, about 30:70, In still other aspects of this embodiment, a fluid composition about 35:65, about 40:60, about 45:55, about 50:50, about comprises an uncrosslinked hyaluronan where the 55:45, about 60:40, about 65:35, about 70:30, about 75:25, uncrosslinked hyaluronan is present at a concentration of about 80:20, about 85:15, about 90:10, about 95:5, about e.g., about 7.5 mg/mL to about 19.5 mg/mL, about 8.5 mg/mL 98:2, or about 100:0. In yet other aspects of this embodiment, to about 18.5 mg/mL, about 9.5 mg/mL to about 17.5 mg/mL, a fluid composition comprises a crosslinked matrix polymer about 10.5 mg/mL to about 16.5 mg/mL, about 11.5 mg/mL and an uncrosslinked matrix polymer where the gel: fluid ratio to about 15.5 mg/mL, or about 12.5 mg/mL to about 14.5 is, e.g., at most 15:85, at most 20:80, at most 25:75, at most mg/mL. 30:70, at most 35:65, at most 40:60, at most 45:55, at most 0048. In other aspects of this embodiment, a fluid compo 50:50, at most 55:45, at most 60:40, at most 65:35, at most sition comprises an uncrosslinked hyaluronan where the 70:30, at most 75:25, at most 80:20, at most 85:15, at most uncrosslinked hyaluronan has a mean molecular weight of 90:10, at most 95:5, at most 98:2, or at most 100:0. In still e.g., about 1,000,000 Da, about 1,500,000 Da, about 2,000, other aspects of this embodiment, a fluid composition com 000 Da, about 2,500,000 Da, about 3,000,000 Da, about prises a crosslinked matrix polymer and an uncrosslinked 3,500,000 Da, about 4,000,000 Da, about 4,500,000 Da, or matrix polymer where the gel:fluid ratio is, e.g., about 10:90 about 5,000,000 Da. In yet other aspects of this embodiment, to about 70:30, about 15:85 to about 70:30, about 10:90 to a fluid composition comprises an uncrosslinked hyaluronan about 55:45, about 80:20 to about 95:5, about 90:10 to about where the uncrosslinked hyaluronan has a mean molecular 100:0, about 75:25 to about 100:0, or about 60:40 to about weight of, e.g., at least 1,000,000 Da, at least 1,500,000 Da, at 100:O. least 2,000,000 Da, at least 2,500,000 Da, at least 3,000,000 0046. In another embodiment, a fluid composition com Da, at least 3,500,000 Da, at least 4,000,000 Da, at least prises a Substantially uncrosslinked hyaluronan. In aspects of 4,500,000 Da, or at least 5,000,000 Da. In still other aspects of this embodiment, a fluid composition comprises an this embodiment, a fluid composition comprises an US 2011/0224164 A1 Sep. 15, 2011 uncrosslinked hyaluronan where the uncrosslinked hyaluro 10% by weight, about 3% to about 10% by weight, or about nan has a mean molecular weight of, e.g., about 1,000,000 Da 5% to about 10% by weight, of the total hyaluronan present in to about 5,000,000 Da, about 1,500,000 Da to about 5,000, the composition. 000 Da, about 2,000,000 Da to about 5,000,000 Da, about 0052. In other aspects of this embodiment, a fluid compo 2,500,000 Da to about 5,000,000 Da, about 2,000,000 Da to sition comprises a crosslinked hyaluronan where the degree about 3,000,000 Da, about 2,500,000 Da to about 3,500,000 of crosslinking is about 1%, about 2%, about 3%, about 4%, Da, or about 2,000,000 Da to about 4,000,000 Da. In further about 5%, about 6%, about 7%, about 8%, about 9%, about aspects, a fluid composition comprises an uncrosslinked 10%, about 11%, about 12%, about 13%, about 14%, or about hyaluronan where the uncrosslinked hyaluronan has a mean 15%. In yet other aspects of this embodiment, a fluid compo molecular weight of, e.g., greater than 2,000,000 Da and less sition comprises a crosslinked hyaluronan where the degree than about 3,000,000 Da, greater than 2,000,000 Da and less of crosslinking is at most 1%, at most 2%, at most 3%, at most 4%, at most 5%, at most 6%, at most 7%, at most 8%, at most than about 3,500,000 Da, greater than 2,000,000 Da and less 9%, at most 10%, at most 11%, at most 12%, at most 13%, at than about 4,000,000 Da, greater than 2,000,000 Da and less most 14%, or at most 15%. In still other aspects of this than about 4,500,000 Da, greater than 2,000,000 Da and less embodiment, a fluid composition comprises a crosslinked than about 5,000,000 Da. hyaluronan where the degree of crosslinking is about 1% to 0049. In another embodiment, a fluid composition com about 15%, about 2% to about 11%, about 3% to about 10%, prises an uncrosslinked hyaluronan where the uncrosslinked about 1% to about 5%, about 10% to about 15%, about 11% hyaluronan comprises a combination of both high molecular to about 15%, about 6% to about 10%, or about 6% to about weight hyaluronan and low molecular weight hyaluronan, in 8%. various ratios. As used herein, the term “high molecular 0053. In other aspects of this embodiment, a fluid compo weighthyaluronan’ refers to a hyaluronan polymer that has a sition comprises a crosslinked hyaluronan where the molecular weight of 1,000,000 Da or greater. Non-limiting crosslinked hyaluronan has a mean molecular weight of, e.g., examples of a high molecular weight hyaluronan include a about 1,000,000 Da, about 1,500,000 Da, about 2,000,000 hyaluronan of about 1,500,000 Da, a hyaluronan of about Da, about 2,500,000 Da, about 3,000,000 Da, about 3,500, 2,000,000 Da, a hyaluronan of about 2,500,000 Da, a hyalu 000 Da, about 4,000,000 Da, about 4,500,000 Da, or about roman of about 3,000,000 Da, a hyaluronan of about 3,500, 5,000,000 Da. In yet other aspects of this embodiment, a fluid 000 Da, a hyaluronan of about 4,000,000 Da, a hyaluronan of composition comprises a crosslinked hyaluronan where the about 4,500,000 Da, and a hyaluronan of about 5,000,000 Da. crosslinked hyaluronan has a mean molecular Weight of, e.g., As used herein, the term “low molecular weight hyaluronan' at least 1,000,000 Da, at least 1,500,000 Da, at least 2,000,000 refers to a hyaluronan polymer that has a molecular weight of Da, at least 2,500,000 Da, at least 3,000,000 Da, at least less than 1,000,000 Da. Non-limiting examples of a low 3,500,000 Da, at least 4,000,000 Da, at least 4,500,000 Da, or at least 5,000,000 Da. In still other aspects of this embodi molecular weight hyaluronan include a hyaluronan of about ment, a fluid composition comprises a crosslinked hyaluro 200,000 Da, a hyaluronan of about 300,000 Da, a hyaluronan nan where the crosslinked hyaluronan has a mean molecular of about 400,000 Da, a hyaluronan of about 500,000 Da, a weight of, e.g., about 1,000,000 Da to about 5,000,000 Da. hyaluronan of about 600,000 Da, a hyaluronan of about 700, about 1,500,000 Da to about 5,000,000 Da, about 2,000,000 000 Da, a hyaluronan of about 800,000 Da, and a hyaluronan Da to about 5,000,000 Da, about 2,500,000 Da to about of about 900,000 Da. 5,000,000 Da, about 2,000,000 Da to about 3,000,000 Da, 0050 Thus, in an embodiment, a fluid composition com about 2,500,000 Da to about 3,500,000 Da, or about 2,000, prises an uncrosslinked hyaluronan where the uncrosslinked 000 Da to about 4,000,000 Da. hyaluronan comprises a combination of both high molecular 0054. In a further embodiment, a fluid composition com weighthyaluronan and low molecular weighthyaluronan in a prises a crosslinked hyaluronan and an uncrosslinked hyalu ratio of about 20:1, about 15:1, about 10:1, about 5:1, about roman. In an aspect of this embodiment, a fluid composition 1:1, about 1:5 about 1:10, about 1:15, or about 1:20. comprises a crosslinked hyaluronan and an uncrosslinked 0051. In still another embodiment, a fluid composition hyaluronan where the gel: fluid ratio is sufficient to form a comprises a crosslinked hyaluronan. In aspects of this fluid. In other aspects of this embodiment, a fluid composition embodiment, a fluid composition comprises a crosslinked comprises a crosslinked hyaluronan and an uncrosslinked hyaluronan where the crosslinked hyaluronan represents, hyaluronan where the gel: fluid ratio is, e.g., about 0:100, e.g., about 1% by weight, about 2% by weight, about 3% by about 1:99, about 2:98, about 3:97, about 4:96, about 5:95, weight, about 4% by weight, about 5% by weight, about 6% about 6:94, about 7:93, about 8:92, about 9:91, or about by weight, about 7% by weight, about 8% by weight, or about 10:90. In yet other aspects of this embodiment, a fluid com 9%, or about 10% by weight, of the total hyaluronan present position comprises a crosslinked hyaluronan and an in the composition. In other aspects of this embodiment, a uncrosslinked hyaluronan where the gel: fluid ratio is, e.g., at fluid composition comprises a crosslinked hyaluronan where most 1:99, at most 2:98, at most 3:97, at most 4:96, at most the crosslinked hyaluronan represents, e.g., at most 1% by 5:95, at most 6:94, at most 7:93, at most 8:92, at most 9:91, or weight, at most 2% by weight, at most 3% by weight, at most at most 10:90. In still other aspects of this embodiment, a fluid 4% by weight, at most 5% by weight, at most 6% by weight, composition comprises a crosslinked hyaluronan and an at most 7% by weight, at most 8% by weight, at most 9% by uncrosslinked hyaluronan where the gel: fluid ratio is, e.g., weight, or at most 10% by weight, of the total hyaluronan about 0:100 to about 3:97, about 0:100 to about 5:95, or about present in the composition. In yet other aspects of this O:100 to about 10:90. embodiment, a fluid composition comprises a crosslinked 0055. In other aspects of this embodiment, a fluid compo hyaluronan where the crosslinked hyaluronan represents, sition comprises a crosslinked hyaluronan and an e.g., about 0% to about 10% by weight, about 1% to about uncrosslinked hyaluronan where the gel: fluid ratio is, e.g., US 2011/0224164 A1 Sep. 15, 2011

about 15:85, about 20:80, about 25:75, about 30:70, about 0.058 A fluid composition disclosed in the present speci 35:65, about 40:60, about 45:55, about 50:50, about 55:45, fication comprises a polyol that is pharmaceutically accept about 60:40, about 65:35, about 70:30, about 75:25, about able. As used herein, the term “pharmaceutically acceptable' 80:20, about 85:15, about 90:10, about 95:5, about 98:2, or means any molecular entity or composition that does not about 100:0. In yet other aspects of this embodiment, a fluid produce an adverse, allergic or other untoward or unwanted composition comprises a crosslinked hyaluronan and an reaction when administered to a mammal. It is known in the uncrosslinked hyaluronan where the gel: fluid ratio is, e.g., at art that the two-carbon polyol, glycol, is not pharmaceutically most 15:85, at most 20:80, at most 25:75, at most 30:70, at most 35:65, at most 40:60, at most 45:55, at most 50:50, at acceptable because this polyol is toxic to mammals. It is also most 55:45, at most 60:40, at most 65:35, at most 70:30, at known in the art that polyols comprising three or more carbon most 75:25, at most 80:20, at most 85:15, at most 90:10, at atoms are typically pharmaceutically acceptable. As such, most 95:5, at most 98:2, or at most 100:0. In still other aspects polyols comprising three or more carbon atoms are generally of this embodiment, a fluid composition comprises a useful in making the compositions disclosed in the present crosslinked hyaluronan and an uncrosslinked hyaluronan specification. where the gel: fluid ratio is, e.g., about 10:90 to about 70:30, 0059 A fluid composition disclosed in the present speci about 15:85 to about 70:30, about 10:90 to about 55:45, about fication comprises a polyol in an amount Sufficient to protect 80:20 to about 95:5, about 90:10 to about 100:0, about 75:25 uncrosslinked glycosaminoglycans, like hyaluronan, from to about 100:0, or about 60:40 to about 100:0. degradation, such as enzymatic degradation and chemical 0056 Aspects of the present specification provide, in part, degradation. One primary means of Such glycosaminoglycan a fluid composition comprising a stabilizing component. As degradation is chemical breakdown from exposure to free used herein, the term “stabilizing component” refers to a radicals, such as, e.g., OH. radicals. Free radicals are atoms, molecule that reduces or prevents the degradation of a matrix molecules, or ions with unpaired electrons on an open shell polymer disclosed in the present specification. The stabilizing configuration. The unpaired electrons cause them to be highly component can reduce or prevent enzymatic degradation and/ chemically reactive. or reduce or prevent chemical degradation. Non-limiting 0060 Free radicals play an important role in a number of examples of Stabilizing components include a polyol and a biological processes, some of which are necessary for life, flavinoid. Such as the intracellular killing of bacteria by phagocytic cells 0057 Aspects of the present specification provide, in part, Such as granulocytes and macrophages. Free radicals have a fluid composition comprising a polyol. As used herein, the also been implicated in certain cell signaling processes, called term “polyol is synonymous with "sugar alcohol.” “polyhy redox signaling. The two most important oxygen-centered dric alcohol.” and “polyalcohol and refers to a hydrogenated free radicals are superoxide and hydroxyl radical. They are form of carbohydrate, whose carbonyl group (aldehyde or derived from molecular oxygen under reducing conditions. ketone, reducing Sugar) has been reduced to a primary or For example, the Superoxide anion (O ) can capture secondary hydroxyl group (hence the alcohol). Such as, e.g., another electron to form the peroxide ion (O, ), which in mannitol from mannose, Xylitol from Xylose, and lactitol turn may react with two H" protons to form hydrogen perox from lactulose. Polyols have the general formula H(HCHO) ide (H2O). The degradation of hydrogen peroxide in the +1 H. Both monosaccharides and disaccharides can form presence of transition metals in their reduced form (Fenton's polyols; however, polyols derived from disaccharides are not reaction) leads to the formation of the hydroxyl radical (OH.). entirely hydrogenated because only one aldehyde group is A free radical formed in this way can give rise to a series of available for reduction. A fluid composition disclosed in the reactions leading to the formation of different species of present specification may comprise a single polyol, or a plu active oxygen. Table 2 describes the principal active species rality of polyols. of oxygen.

TABLE 2 Principal species of active oxygen

Chemical Name Symbol Comments Superoxide O Superoxide anions are formed by reduction of molecular anion oxygen. They are minimally reactive in aqueous media, which enables them to migrate quite a long way from their site of production. Superoxide anions have a weak oxidative action but are capable of generating more reactive radicals. Hydrogen H2O2 Hydrogen peroxides are formed either by bivalent reduction peroxide of molecular oxygen, or by dismutation of the Superoxide anion. The absence of electric charges on their Surface makes them very lipophilic and minimally reactive in aqueous media. The degradation of hydrogen peroxides (Fenton's reaction) produces very reactive radicals called hydroxyl radicals. Hydroxyl radical OH Hydroxyl radicals are formed by degradation of hydrogen peroxide in the presence of transition metals in their reduced form (Fenton's reaction). Hydroxyl radicals are very reactive. Their half-life is on the order of 10's. US 2011/0224164 A1 Sep. 15, 2011

TABLE 2-continued Principal Species of active oxygen Chemical Name Symbol Comments Peroxyl radical ROO Peroxyl radicals are formed by addition of molecular oxygen to free carbon radicals. They are minimally reactive. Organic ROOH Organic hydroperoxides are the protonated form of peroxyl hydroperoxide radicals. They are very reactive and decompose anew into peroxyl radicals and alcoxyl radicals. Alcoxyl radical RO Alcoxyl radicals are formed during the degradation of organic peroxides. They are very reactive. Their half-life is on the order of 10s. Nitric oxide NO Nitric oxides are synthesized from arginine (an amino acid) via the action of nitric oxide synthetase. They interact with hydroxyl radicals to form peroxynitrites. Nitric oxide is a neuromediator and can also be used by immune cells to destroy microbes or dangerous cells. Peroxynitrite ONOO Peroxynitrites are capable of oxidizing certain Substances Such as methionine (an amino acid serving as a constituent of proteins and enzymes) or of reacting with SOD (Cf. S 1.3.2.a) thereby “nitrating tyrosine (another very important amino acid) Nitrosyl radical ONOOH Degradation of nitrosyl radicals leads to the formation of hydroxyl radicals. Oxidizing power: OH >RO >ROO > NO

0061. However, because of their reactivity, these same free 0063 Thus, any polyol is useful in making the composi radicals can participate in unwanted side reactions resulting tions disclosed in the present specification, with the proviso in cell damage. For purposes of the present specification, OH. that the polyol is non-toxic to a mammal and the polyol radicals interact with the hydrogen located on the carbon protects uncrosslinked matrix polymers like hyaluronan from adjacent to the carboxyl group in the glucuronic ring of hyalu degradation. Non-limiting examples of polyols include, glyc roman and other glycosaminoglycans, thereby removing it. erol, erythritol, threitol, arabitol, erythritol, ribitol, xylitol, This removal causes splitting of the glycoside bond and hence galactitol (or dulcitol), gluctiol (or Sorbitol), iditol, inositol, depolymerization of the polymer. mannitol, isomalt, lactitol, maltitol, and polyglycitol. Other non-limiting examples of polyols can be found in, e.g., Phar maceutical Dosage Forms and Drug Delivery Systems Site of OH attach (Howard C. Ansel et al., eds., Lippincott Williams & Wilkins Publishers, 7" ed. 1999); Remington: The Science and Prac OH / tice of Pharmacy (Alfonso R. Gennaro ed., Lippincott, Will H HOC iams & Wilkins, 20' ed. 2000); Goodman & Gilman's The O 4 O Pharmacological Basis of Therapeutics (Joel G. Hardman et HO O O al., eds., McGraw-Hill Professional, 10" ed. 2001); and O HO OH Handbook of Pharmaceutical Excipients (Raymond C. Rowe NH et al., APhA Publications, 4" edition 2003), each of which is O hereby incorporated by reference in its entirety. ={ pi 0064. Thus in an embodiment, a fluid composition com CH prises a pharmaceutically acceptable polyol that can reduce or prevent degradation of a matrix polymer. In aspects of this 0062. In general, the crosslinking observed in the hyalu embodiment, a fluid composition comprises a pharmaceuti roman and other matrix polymers used in dermal fillers protect cally acceptable three-carbon polyol, a pharmaceutically these polymers against the chemical breakdown of free radi acceptable four-carbon polyol, a pharmaceutically accept cal species of oxygen. This is because the bonds formed able five-carbon polyol, a pharmaceutically acceptable six during crosslinking mask the hydrogen attached by the free carbon polyol, a pharmaceutically acceptable seven-carbon radicals. However, the uncrosslinked glycosaminoglycans polyol, a pharmaceutically acceptable eight-carbon polyol, a disclosed in the present specification is afforded no Such pharmaceutically acceptable nine-carbon polyol, a pharma protection. The present specification discloses an alternative ceutically acceptable ten-carbon polyol, a pharmaceutically means of protecting matrix polymers from oxidative degra acceptable eleven-carbon polyol, or a pharmaceutically dation of free radicals. It has been determined that polyols acceptable twelve-carbon polyol. In other aspects of this disclosed in the present specification act as stabilizing agents embodiment, a fluid composition comprises glycerol, eryth that can neutralize free radicals of active oxygen. As a stabi ritol, threitol, arabitol, erythritol, ribitol, xylitol, galactitol (or lizing, a polyol is stabilizing component that protects matrix dulcitol), gluctiol (or Sorbitol), iditol, inositol, mannitol, iso polymers like hyaluronan against the effects of oxidative malt, lactitol, maltitol, or polyglycitol. stress and limiting the degradation of the fluid compositions 0065. In another embodiment, a fluid composition com disclosed in the present specification. prises a single polyol that can reduce or prevent degradation US 2011/0224164 A1 Sep. 15, 2011

of a matrix polymer. In yet another embodiment, a fluid composition, about 0.5% (w/v) to about 1.0% (w/v) of the composition comprises a plurality of polyols, each of which composition, or about 0.5% (w/v) to about 2.0% (w/v) of the can reduce or prevent the degradation of a matrix polymer. In composition. aspects of this embodiment, a fluid composition comprises 0067. In other aspects of this embodiment, a fluid compo one or more polyols, two or more polyols, three or more sition comprises a polyol is presentata concentration of, e.g., polyols, four or more polyols, or five or more polyols. In other about 0.01 mg/mL, about 0.02 mg/mL, about 0.03 mg/mL, aspects of this embodiment, a fluid composition comprises about 0.04 mg/mL, about 0.05 mg/mL, about 0.06 mg/mL, one to five polyols, two to five polyols, three to five polyols, about 0.07 mg/mL, about 0.08 mg/mL, about 0.09 mg/mL, two to four polyols, two to five polyols, or three to five about 0.1 mg/mL, about 0.2 mg/mL, about 0.3 mg/mL, about polyols. 0.4 mg/mL, about 0.5 mg/mL, about 0.6 mg/mL, about 0.7 0066. In yet another embodiment, a fluid composition mg/mL, about 0.8 mg/mL, about 0.9 mg/mL, about 1.0 comprises a polyol in an amount Sufficient to reduce or pre mg/mL, about 2.0 mg/mL, about 3.0 mg/mL, about 4.0 vent degradation of a matrix polymer. In aspects of this mg/mL, about 5.0 mg/mL, about 6.0 mg/mL, about 7.0 embodiment, a fluid composition comprises a polyol in an mg/mL, about 8.0 mg/mL, about 9.0 mg/mL, or about 10 amount of, e.g., about 0.1% (w/v) of the composition, about mg/mL. In yet other aspects of this embodiment, a fluid 0.2% (w/v) of the composition, about 0.3% (w/v) of the composition comprises a polyol presentata concentration of composition, about 0.4% (w/v) of the composition, about e.g., at least 0.01 mg/mL, at least 0.02 mg/mL, at least 0.03 0.5% (w/v) of the composition, about 0.6% (w/v) of the mg/mL, at least 0.04 mg/mL, at least 0.05 mg/mL, at least composition, about 0.7% (w/v) of the composition, about 0.06 mg/mL, at least 0.07 mg/mL, at least 0.08 mg/mL, at 0.8% (w/v) of the composition, about 0.9% (w/v) of the least 0.09 mg/mL, at least 0.1 mg/mL, at least 0.2 mg/mL, at composition, about 1.0% (w/v) of the composition, about least 0.3 mg/mL, at least 0.4 mg/mL, at least 0.5 mg/mL, at 2.0% (w/v) of the composition, about 3.0% (w/v) of the least 0.6 mg/mL, at least 0.7 mg/mL, at least 0.8 mg/mL, at composition, about 4.0% (w/v) of the composition, about least 0.9 mg/mL, at least 1.0 mg/mL, at least 2.0 mg/mL, at 5.0% (w/v) of the composition, about 6.0% (w/v) of the least 3.0 mg/mL, at least 4.0 mg/mL, at least 5.0 mg/mL, at composition, about 7.0% (w/v) of the composition, about least 6.0 mg/mL, at least 7.0 mg/mL, at least 8.0 mg/mL, at 8.0% (w/v) of the composition, about 9.0% (w/v) of the least 9.0 mg/mL, or at least 10 mg/mL. In still other aspects of composition, or about 10% (w/v) of the composition. In other this embodiment, a fluid composition comprises a polyol aspects, a fluid composition comprises a polyol in an amount present at a concentration of, e.g., at most 0.01 mg/mL, at of, e.g., at least 0.1% (w/v) of the composition, at least 0.2% most 0.02 mg/mL, at most 0.03 mg/mL, at most 0.04 mg/mL, (w/v) of the composition, at least 0.3% (w/v) of the compo at most 0.05 mg/mL, at most 0.06 mg/mL, at most 0.07 sition, at least 0.4% (w/v) of the composition, at least 0.5% mg/mL, at most 0.08 mg/mL, at most 0.09 mg/mL, at most 0.1 (w/v) of the composition, at least 0.6% (w/v) of the compo mg/mL, at most 0.2 mg/mL, at most 0.3 mg/mL, at most 0.4 sition, at least 0.7% (w/v) of the composition, at least 0.8% mg/mL, at most 0.5 mg/mL, at most 0.6 mg/mL, at most 0.7 (w/v) of the composition, at least 0.9% (w/v) of the compo mg/mL, at most 0.8 mg/mL, at most 0.9 mg/mL, at most 1.0 sition, at least 1.0% (w/v) of the composition, at least 2.0% mg/mL, at most 2.0 mg/mL, at most 3.0 mg/mL, at most 4.0 (w/v) of the composition, at least 3.0% (w/v) of the compo mg/mL, at most 5.0 mg/mL, at most 6.0 mg/mL, at most 7.0 sition, at least 4.0% (w/v) of the composition, at least 5.0% mg/mL, at most 8.0 mg/mL, at most 9.0 mg/mL, or at most 10 (w/v) of the composition, at least 6.0% (w/v) of the compo mg/mL. In further aspects, a fluid composition comprises a sition, at least 7.0% (w/v) of the composition, at least 8.0% polyol present at a concentration of e.g., about 0.01 mg/mL (w/v) of the composition, at least 9.0% (w/v) of the compo to about 0.7 mg/mL, about 0.06 mg/mL to about 0.7 mg/mL, sition, or at least 10% (w/v) of the composition. In yet other about 0.01 mg/mL to about 1.0 mg/mL, about 0.05 mg/mL to aspects, a fluid composition comprises a polyol in an amount about 1.0 mg/mL, about 0.06 mg/mL to about 1.0 mg/mL, of, e.g., at most 0.1% (w/v) of the composition, at most 0.2% about 0.1 mg/mL to about 1.0 mg/mL, about 0.1 mg/mL to (w/v) of the composition, at most 0.3% (w/v) of the compo about 2.0 mg/mL, about 0.1 mg/mL to about 3.0 mg/mL, sition, at most 0.4% (w/v) of the composition, at most 0.5% about 0.1 mg/mL to about 4.0 mg/mL, about 0.1 mg/mL to (w/v) of the composition, at most 0.6% (w/v) of the compo about 5.0 mg/mL, about 0.2 mg/mL to about 0.9 mg/mL, sition, at most 0.7% (w/v) of the composition, at most 0.8% about 0.2 mg/mL to about 1.0 mg/mL, about 0.2 mg/mL to (w/v) of the composition, at most 0.9% (w/v) of the compo about 2.0 mg/mL, about 0.5 mg/mL to about 1.0 mg/mL, or sition, at most 1.0% (w/v) of the composition, at most 2.0% about 0.5 mg/mL to about 2.0 mg/mL. (w/v) of the composition, at most 3.0% (w/v) of the compo 0068 Aspects of the present specification provide, in part, sition, at most 4.0% (w/v) of the composition, at most 5.0% a fluid composition that can optionally comprise or not com (w/v) of the composition, at most 6.0% (w/v) of the compo prise a flavonoid (Table 3). A flavonoid (or bioflavonoid) sition, at most 7.0% (w/v) of the composition, at most 8.0% refers to the class of polyphenolic ketone-containing and (w/v) of the composition, at most 9.0% (w/v) of the compo non-ketone-containing secondary metabolites found in plants sition, or at most 10% (w/v) of the composition. In still other that are well known to have diverse beneficial biochemical aspects, a fluid composition comprises a polyol in an amount and antioxidant effects. Non-limiting examples of flavonoids of, e.g., about 0.1% (w/v) to about 1.0% (w/v) of the compo include C-methylated flavonoids, O-methylated flavonoids, sition, about 0.1% (w/v) to about 2.0% (w/v) of the compo isoflavonoids, neoflavonoids, flavonolignans, furanofla sition, about 0.1% (w/v) to about 3.0% (w/v) of the compo vonoids, pyranoflavonoids, methylenedioxyflavonoids, pre sition, about 0.1% (w/v) to about 4.0% (w/v) of the nylated flavonoids, aurones, flavones, flavonols, flavanones, composition, about 0.1% (w/v) to about 5.0% (w/v) of the flavanonols, flavan-3-ols, flavan-4-ols, leucoanthocyanidin composition, about 0.2% (w/v) to about 0.9% (w/v) of the (flavan-3,4-diols), anthocyanidins, and tannins. It is under composition, about 0.2% (w/v) to about 1.0% (w/v) of the stood that these and other substances known in the art of composition, about 0.2% (w/v) to about 2.0% (w/v) of the pharmacology can be included in a fluid composition dis US 2011/0224164 A1 Sep. 15, 2011 closed in the present specification. See for example, Reming C-ring) with an hydroxyl group on carbon 3. The A ring is ton's Pharmaceutical Sciences Mac Publishing Company, similar to a resorcinol moiety while the Bring is similar to a Easton, Pa. 16" Edition 1980. catechol moiety. There are two chiral centers on the molecule 0069. Aurones are compounds derived from 2-ben on carbons 2 and 3. It has therefore four diastereoisomers. Zylidene-1-benzofuran-3-one. Non-limiting examples of Two of the isomers are in trans configuration and are called aurones include 4.5,6-trihydroxy-aurone, aureusidin, hispi catechin and the other two are in cis configuration and are dol, leptosidin, maritimetin, and Sulfuretin. called epicatechin. Non-limiting examples of non-ketone 0070 Three major classes of ketone-containing fla containing flavonoids include afzelechin, arthromerin A, vonoids are flavones, compounds derived from 2-phenyl arthromerin B, catechin, epicatechin, epigallocatechin, epi chromen-4-one (2-phenyl-1,4-benzopyrone); isoflavones, catechin gallate, epigallocatechin gallate, epigallocatechin compounds derived from 3-phenylchromen-4-one (3-phenyl gallate, epiafzelechin, fisetinidol, gallocatechin, gallocat 1,4-benzopyrone); and neoflavones, compounds derived echin gallate, guibourtinidol, meciadanol (3-O-methylcat from 4-phenylcoumarine (4-phenyl-1,2-benzopyrone) (Table echin), mesquitol, robinetinidol, and thearubigin. 3). Flavones are themselves divided into four groups based on 0075 Flavan-4-ols (3-deoxyflavonoids) are flavone-de the presence or absence of 3-hydroxyl 2,3-dihydro functional rived alcohols derived from 2-phenylchroman-4-ol. Non-lim groups: flavones, compounds derived from 2-phenyl iting examples of flavan-4-ols include apiforoland luteoforol. chromen-4-one lack both functional groups; flavonols (3-hy 0076 Leucoanthocyanidin (flavan-3,4-diols) are com droxyflavone), compounds derived from 3-hydroxy-2-phe pounds derived from 2-phenyl-3,4-dihydro-2H-chromene-3, nylchromen-4-one have the 3-hydroxyl group, but lack the 4-diol. Non-limiting examples of flavan-3,4-diols include 2,3-dihydro group; flavanones, compounds derived from 2,3- leucocyanidin, leucodelphinidin, leucomalvidin, leucopelar dihydro-2-phenylchromen-4-one have the 2,3-dihydro gonidin, leucopeonidin, leucorobinetinidin, and melacacidin. group, but lack the 3-hydroxyl group; and flavanonols (3-hy 0077 Anthocyanidins are compounds derived from droxyflavanone or 2,3-dihydroflavonol), compounds derived 2-phenylchromenylium. Non-limiting examples of anthocya from 3-hydroxy-2,3-dihydro-2-phenylchromen-4-one have nidins include antirrhinin, apigeninidin, aurantinidin, cap both functional groups. ensinidin, chrysanthenin, columnidin, commelinin, cyanidin, 0071 Non-limiting examples of flavones include acacetin, 6-hydroxycyanidin, cyanidin-3-(di-p-coumarylglucoside)-5- apiin, apigenin, apigetirin, artoindonesianin P. baicalein, glucoside, cyanoSalvianin, delphinidin, dioSmetinidin, euro baicalin, chrysin, cynaroside, dioSmetin, dioSmin, eupatilin, pinidin, fisetinidin, gesneridin, guibourtinidin, hirsutidin, flavoxate, 6-hydroxyflavone, genkwanin, hidrosmin, luteo luteolinidin, malvidin, 5-desoxy-malvidin, malvin, myrtillin, lin, nepetin, nepitrin (nepetin 7-glucoside), nobiletin, orientin oenin, peonidin, 5-desoxy-peonidin, pelargonidin, petunidin, (isoorientin), oroXindin, oroxylin A. rhoifolin, Scutellarein, primulin, protocyanin, protodelphin, pulchellidin, pulchelli Scutellarin, tangeritin, techtochrysin, tetuin, tricin, Veronicas din 3-glucoside, pulchellidin 3-rhamnoside, robinetinidin, troside, Vitexin (isoVitexin), and wogonin. Non-limiting rosinidin, tricetinidin, tulipanin, and violdelphin. examples of flavonols include 3-hydroxyflavone, azaleatin, 0078 Tannins are compounds derived from 2-phenyl fisetin, galangin, gossypetin, kaempferide, kaempferol, chromenylium. There are three major classes of tannins: isorhamnetin, morin, myricetin, natsudaidain, pachypodol. hydrolyzable tannins; non-hydrolyzable tannins (condensed quercetin, rhamnazin, rhamnetin, and Sophorin. Non-limiting tannins; proanthocyanidins); and pseudotannins. examples of flavanones includebutin, eriodictyol. hesperetin, 0079 Hydrolyzable tannins are themselves divided into hesperidin, homoeriodictyol, isosakuranetin, naringenin, four groups: oliomer tannins including aglycone tannins and naringin, pinocembrin, poncirin, Sakuranetin, Sakuranin, and glycoside tannins; ellagitannins; gallotannins, and unclassi Sterubin. Non-limiting examples of flavanonols include taxi fied tannins. Non-limiting examples of aglycone tannins folin (dihydroquercetin), and aromadedrin (dihydro include elagic acid, gallagic acid, and gallic acid. Non-lim kaempferol). iting examples of glycoside tannins include glucose, quinic 0072 Isoflavonoids include isoflavones and isoflavanes acid, and shikimic acid. Non-limiting examples of ellagitan (Table 3). Non-limiting examples of isoflavonoids include nins include castalagin (vescalagin), castalin, casuarictin, alpinumisoflavone, anagyroidisoflavone A and B, calycosin, casuarin, casuarinin, cornusin E. grandinin, pedunculagin, daidzein, daidzin, derrubone, di-O-methylalpinumisofla punicacortein C, punigluconin, punicalagin, punicalagin vone, formononetin, genistein, genistin, glycitein, iprifla alpha, punicalin, 2-O-galloyl-punicalin, stachyurin, stricti vone, irigenin, iridin, irilone, 4'-methyl-alpinumisoflavone, nin, and tellimagrandin II. Non-limiting examples of gallo tannins include corilagin, galloyl glucose, digalloyl glucose, 5-O-methylgenistein, luteone, ononin, orobol, pratensein, trigalloyl glucose, tetragalloylglucose, pentagalloyl glucose, prunetin, pseudobaptigenin, psi-tectorigenin, puerarin, hexagalloyl glucose, heptagalloyl glucose, octagalloyl glu retusin, tectoridin, tectorigenin, and wighteone. cose, and tannic acid. Non-limiting examples of unclassified 0073 Neoflavonoids include 4-arylcoumarins (neofla tannins include acutissimin A, acutissimin B, chebulagic Vones), 4-arylchromanes, dalbergiones and dalbergiquinols acid, chebulinic acid, cinnamtannin B1, combreglutinin, (Table 3). Neoflavones are compounds derived from 4-phe geraniin, granatin B, roburin A, roburin B, roburin C. roburin nylcoumarin (or 4-Aryl-coumarin); neoflavenes compounds D, roburin E, stachyurin, tercatin, terflavins A, terflavins B, derived from 4-phenylchromen. Non-limiting examples of tergallagin, Vescalin, 1.3,4-tri-O-galloylquinic acid, 3,5-di neoflavonoids include calophyllolide, coutareagenin, dalber O-galloyl-shikimic acid, and 3,4,5-tri-O-galloylshikimic gichromene, dalbergin, and nivetin. acid. 0074 Non-ketone-containing flavonoids, include flavan 0080 Condensed tannins (proanthocyanidins) are essen 3-ols and catechins. Flavan-3-ols (flavanols) are a class of tially polymer chains of flavonoids such as catechins. Non flavonoids derived from 2-phenyl-3,4-dihydro-2H-chromen limiting examples of condensed tannins include proanthocya 3-ol skeleton. Catechin possesses two benzene rings (called nidin, prodelphinidin, profisetinidin, proguibourtinidin, and the A- and B-rings) and a dihydropyran heterocycle (the prorobinetidin. US 2011/0224164 A1 Sep. 15, 2011 13

TABLE 3

Flavonoids Flavonoids Base compound Examples Aurones 2-benzylidene-1-benzofuran-3-one 4,5,6-trihydroxy-aurone, aureusidin, hispidol, leptosidin, maritimetin, and Sulfuretin Flavones 2-phenylchromen-4-one acacetin, apilin, apigenin, apigetirin, artoindonesianin P. baicalein, baicalin, chrysin, cynaroside, dioSmetin, dioSmin, eupatilin, flavoxate, 6-hydroxyflavone, genkwanin, hidrosmin, luteolin, nepetin, nepitrin, nobiletin, orientin, orOXindin, oroxylin A, rhoifolin, scutellarein, Scutellarin, tangeritin, techtochrysin, tetuin, tricin, Veronicastroside, Vitexin, wogonin Flavonols 3-hydroxy-2-phenylchromen-4-one 3-hydroxyflavone, azaleatin, fisetin, galangin, gossypetin, kaempferide, kaempferol, isorhamnetin, morin, myricetin, natsudaidain, pachypodol, quercetin, rhamnazin, rhamnetin, Sophorin Flavanones 2,3-dihydro-2-phenylchromen-4-one butin, eriodictyol, hesperetin, hesperidin, homoeriodictyol, isosakuranetin, maringenin, naringin, pinocembrin, poncirin, Sakura.netin, Sakuranin, Sterubin Flavanonols 3-hydroxy-2,3-dihydro-2- aromadedrin, taxifolin phenylchromen-4-one Isoflavones 3-phenylchromen-4-one alpinumisoflavone, anagyroidisoflavone A and B, calycosin, daidzein, daidzin, derrubone, di-O- methylalpinumisoflavone, formononetin, genistein, genistin, glycitein, ipriflavone, irigenin, iridin, irilone, 4'-methyl alpinumisoflavone, 5-O- methylgenistein, luteone, Ononin, orobol, pratensein, prunetin, pseudobaptigenin, psi-tectorigenin, puerarin, retusin, tectoridin, tectorigenin, wighteone Isoflavenes 3-phenylchroman lonchocarpane, laxiflorane Neoflavones 4-phenylcoumarine calophyllolide Neoflavenes 4-phenylchromen dalbergichromene Flavan-3-ols 2-phenyl-3,4-dihydro-2H-chromen-3- arthromerin A, arthromerin B, fisetinidol, guibourtinidol, meciadanol (3-O-methylcatechin), mesquitol, robinetinidol, thearubigin. Catechins (2R,3S)-2-(3,4-dihydroxyphenyl)- (+)-catechin (2R-3S), (-)-catechin 3,4-dihydro-2H-chromene-3,5,7-triol (2S-3R), (-)-Epicatechin (2R-3R), (+)-epicatechin (2S-3S) Flavan-4-ols 2-phenylchroman-4-ol apiforol, luteoforol Flavan-3,4- 2-phenyl-3,4-dihydro-2H-chromene leucocyanidin, leucodelphinidin, diols 3,4-diol leucomalvidin, leucopelargonidin, leucopeonidin, leucorobinetinidin, melacacidin Anthocyanidins 2-phenylchromenylium antirrhinin, apigeninidin, aurantinidin, capensinidin, chrysanthenin, columnidin, commelinin, cyanidin, 6– hydroxycyanidin, cyanidin-3-(di-p- coumarylglucoside)-5-glucoside, cyanoSalvianin, delphinidin, dioSmetinidin, europinidin, fisetinidin, gesneridin, guibourtinidin, hirsutidin, luteolinidin, malvidin, 5-desoxy malvidin, malvin, myrtillin, oenin, peonidin, 5-desoxy-peonidin, pelargonidin, petunidin, primulin, protocyanin, protodelphin, US 2011/0224164 A1 Sep. 15, 2011

TABLE 3-continued

Flavonoids Flavonoids Base compound Examples pulchellidin, pulchellidin 3 glucoside, pulchellidin 3 rhamnoside, robinetinidin, rosinidin, tricetinidin, tulipanin, violdelphin Hydrolyzable gallic acid or elagic acid castalagin, castalin, casuarictin, tannins casuariin, casuarinin, corilagin, cornusiin E, grandinin, galloyl glucose, digalloyl glucose, trigalloyl glucose, tetragalloylglucose, pentagalloyl glucose, hexagalloyl glucose, heptagalloyl glucose, octagalloyl glucose, pedunculagin, punicacortein C, punigluconin, punicalagin, punicalagin alpha, punicalin, 2-O-galloyl-punicalin, stachyurin, strictinin, tannic acid, tellimagrandin II Condensed polymer chains of flavonoid units proanthocyanidin, prodelphinidin, tannins profisetinidin, proguibourtinidin, prorobinetidin

0081. The amount of a flavonoid included in a fluid com flavonoids, three to five flavonoids, two to four flavonoids, position disclosed in the present specification is an amount two to five flavonoids, or three to five flavonoids. effective to reduce or prevent degradation of a matrix polymer I0084. In yet another embodiment, a fluid composition disclosed in the present specification. As such, the amount of comprises a flavonoid in an amount Sufficient to reduce or a flavonoid included in a fluid composition disclosed in the prevent degradation of a matrix polymer. In aspects of this present specification is between about 0.1% to about 10% by embodiment, a fluid composition comprises a flavonoid in an weight of the total composition. In addition, a fluid compo amount of, e.g., about 0.1% (w/v) of the composition, about sition disclosed in the present specification may comprise a 0.2% (w/v) of the composition, about 0.3% (w/v) of the single flavonoid, or a plurality of flavonoid. Further, a fluid composition, about 0.4% (w/v) of the composition, about composition disclosed in the present specification comprises 0.5% (w/v) of the composition, about 0.6% (w/v) of the a flavonoid that is pharmaceutically acceptable. composition, about 0.7% (w/v) of the composition, about 0082. Thus in an embodiment, a fluid composition com 0.8% (w/v) of the composition, about 0.9% (w/v) of the prises a pharmaceutically acceptable flavonoid that can composition, about 1.0% (w/v) of the composition, about reduce or prevent degradation of a matrix polymer. In aspects 2.0% (w/v) of the composition, about 3.0% (w/v) of the of this embodiment, a fluid composition comprises a pharma composition, about 4.0% (w/v) of the composition, about ceutically acceptable C-methylated flavonoid, a pharmaceu 5.0% (w/v) of the composition, about 6.0% (w/v) of the tically acceptable O-methylated flavonoid, a pharmaceuti composition, about 7.0% (w/v) of the composition, about cally acceptable isoflavonoid, a pharmaceutically acceptable 8.0% (w/v) of the composition, about 9.0% (w/v) of the neoflavonoid, a pharmaceutically acceptable flavonolignan, a composition, or about 10% (w/v) of the composition. In other pharmaceutically acceptable furanoflavonoid, a pharmaceu aspects, a fluid composition comprises a flavonoid in an tically acceptable pyranoflavonoid, a pharmaceutically amount of, e.g., at least 0.1% (w/v) of the composition, at acceptable methylenedioxyflavonoid, a pharmaceutically least 0.2% (w/v) of the composition, at least 0.3% (w/v) of the acceptable prenylated flavonoid, a pharmaceutically accept composition, at least 0.4% (w/v) of the composition, at least able aurone, a pharmaceutically acceptable flavone, a phar 0.5% (w/v) of the composition, at least 0.6% (w/v) of the maceutically acceptable flavonol, a pharmaceutically accept composition, at least 0.7% (w/v) of the composition, at least able flavanone, a pharmaceutically acceptable flavanonol, a 0.8% (w/v) of the composition, at least 0.9% (w/v) of the pharmaceutically acceptable flavan-3-ol, a pharmaceutically composition, at least 1.0% (w/v) of the composition, at least acceptable flavan-4-ol, a pharmaceutically acceptable leu 2.0% (w/v) of the composition, at least 3.0% (w/v) of the coanthocyanidin, a pharmaceutically acceptable anthocyani composition, at least 4.0% (w/v) of the composition, at least din, and a pharmaceutically acceptable tannin. 5.0% (w/v) of the composition, at least 6.0% (w/v) of the 0083. In another embodiment, a fluid composition com composition, at least 7.0% (w/v) of the composition, at least prises a single flavonoid that can reduce or prevent degrada 8.0% (w/v) of the composition, at least 9.0% (w/v) of the tion of a matrix polymer. In yet another embodiment, a fluid composition, or at least 10% (w/v) of the composition. In yet composition comprises a plurality of flavonoids, each of other aspects, a fluid composition comprises a flavonoid in an which can reduce or prevent the degradation of a matrix amount of, e.g., at most 0.1% (w/v) of the composition, at polymer. In aspects of this embodiment, a fluid composition most 0.2% (w/v) of the composition, at most 0.3% (w/v) of comprises one or more flavonoids, two or more flavonoids, the composition, at most 0.4% (w/v) of the composition, at three or more flavonoids, four or more flavonoids, or five or most 0.5% (w/v) of the composition, at most 0.6% (w/v) of more flavonoids. In other aspects of this embodiment, a fluid the composition, at most 0.7% (w/v) of the composition, at composition comprises one to five flavonoids, two to five most 0.8% (w/v) of the composition, at most 0.9% (w/v) of US 2011/0224164 A1 Sep. 15, 2011 the composition, at most 1.0% (w/v) of the composition, at tion. In other aspects of this embodiment, a fluid composition most 2.0% (w/v) of the composition, at most 3.0% (w/v) of comprises a matrix polymer, a stabilizing component, and a the composition, at most 4.0% (w/v) of the composition, at methyl Sulphonyl methane, Sodium bicarbonate, calamine, most 5.0% (w/v) of the composition, at most 6.0% (w/v) of allantoin, kaolin, peppermint, tea tree oil, or combinations the composition, at most 7.0% (w/v) of the composition, at thereof where the amount of methyl sulphonyl methane, most 8.0% (w/v) of the composition, at most 9.0% (w/v) of Sodium bicarbonate, calamine, allantoin, kaolin, peppermint, the composition, or at most 10% (w/v) of the composition. In or tea tree oil present is about 0.3%. In another embodiment, still other aspects, a fluid composition comprises a flavonoid a fluid composition comprises a matrix polymer, a stabilizing in an amount of, e.g., about 0.1% (w/v) to about 1.0% (w/v) of component, but not an anti-itch agent. the composition, about 0.1% (w/v) to about 2.0% (w/v) of the I0088 Aspects of the present specification provide, in part, composition, about 0.1% (w/v) to about 3.0% (w/v) of the a fluid composition that can optionally comprise or not com composition, about 0.1% (w/v) to about 4.0% (w/v) of the prise an anti-cellulite agent. The amount of an anti-cellulite composition, about 0.1% (w/v) to about 5.0% (w/v) of the agent included in a fluid composition disclosed in the present composition, about 0.2% (w/v) to about 0.9% (w/v) of the specification is an amount effective to mitigate a fatty deposit composition, about 0.2% (w/v) to about 1.0% (w/v) of the experienced by an individual upon administration of the com composition, about 0.2% (w/v) to about 2.0% (w/v) of the position. As such, the amount of an anti-cellulite agent composition, about 0.5% (w/v) to about 1.0% (w/v) of the included in a fluid composition disclosed in the present speci composition, or about 0.5% (w/v) to about 2.0% (w/v) of the fication is between about 0.1% to about 5% by weight of the composition. total composition. Non-limiting examples of anti-cellulite 0085 Aspects of the present specification provide, in part, agents include forskolin, Xanthine compounds such as, but a fluid composition that can optionally comprise or not com not limited to, caffeine, theophylline, theobromine, and ami prise another active ingredient. As used herein, the term nophylline, and combinations thereof. “active ingredient includes but is not limited to a drug. A I0089. Thus in an embodiment, a fluid composition com drug can generally be defined as a chemical Substance used in prises a matrix polymer, a stabilizing component, and an the treatment, cure, prevention, or diagnosis of disease or anti-cellulite agent. In aspects of this embodiment, a fluid used to otherwise enhance physical or mental well-being. composition comprises a matrix polymer, a stabilizing com I0086 Aspects of the present specification provide, in part, ponent, and an anti-cellulite agent where the amount of anti a fluid composition that can optionally comprise or not com cellulite agent present is about 0.1% (w/v) to about 5% (w/v) prise an anti-itch agent. The amount of an anti-itch agent of the total composition, about 0.1% (w/v) to about 1% (w/v) included in a fluid composition disclosed in the present speci of the total composition, or about 0.1% (w/v) to about 0.5% fication is an amount effective to mitigate an itch response (w/v) of the total composition. In other aspects of this experienced by an individual upon administration of the com embodiment, a fluid composition comprises a matrix poly position. As such, the amount of an anti-itchagent included in mer, a stabilizing component, and an anti-cellulite agent a fluid composition disclosed in the present specification is where the amount of anti-cellulite agent present is about between about 0.1% to about 5% by weight of the total 0.3%. In another aspect of this embodiment, a fluid compo composition. Non-limiting examples of anti-itch agents sition comprises a matrix polymer, a stabilizing component, include methyl Sulphonyl methane, Sodium bicarbonate, and forskolin, a Xanthine compound, or combinations calamine, allantoin, kaolin, peppermint, tea tree oil and com thereof. In aspects of this embodiment, a fluid composition binations thereof. comprises a matrix polymer, a stabilizing component, and a 0087 Thus in an embodiment, a fluid composition com forskolin, a Xanthine compound, or combinations thereof prises a matrix polymer, a stabilizing component, and an where the amount of forskolin or a Xanthine compound anti-itch agent. In aspects of this embodiment, a fluid com present is about 0.1% (w/v) to about 5% (w/v) of the total position comprises a matrix polymer, a stabilizing compo composition, about 0.1% (w/v) to about 1% (w/v) of the total nent, and an anti-itch agent where the amount of anti-itch composition, or about 0.1% (w/v) to about 0.5% (w/v) of the agent present is about 0.1% (w/v) to about 5% (w/v) of the total composition. In other aspects of this embodiment, a fluid total composition, about 0.1% (w/v) to about 1% (w/v) of the composition comprises a matrix polymer, a stabilizing com total composition, or about 0.1% (w/v) to about 0.5% (w/v) of ponent, and a forskolin, a Xanthine compound, or combina the total composition. In other aspects of this embodiment, a tions thereof where the amount of forskolin or a xanthine fluid composition comprises a matrix polymer, a stabilizing compound present is about 0.3%. In another embodiment, a component, and an anti-itch agent where the amount of anti fluid composition comprises a matrix polymer, a stabilizing itch agent present is about 0.3%. In another aspect of this component, but not an anti-cellulite agent. embodiment, a fluid composition comprises a matrix poly 0090 Aspects of the present specification provide, in part, mer, a stabilizing component, and methyl Sulphonyl methane, a fluid composition that can optionally comprise or not com Sodium bicarbonate, calamine, allantoin, kaolin, peppermint, prise an anti-scarring agent. The amount of an anti-scarring tea tree oil, or combinations thereof. In aspects of this agent included in a fluid composition disclosed in the present embodiment, a fluid composition comprises a matrix poly specification is an amount effective to mitigate a scaring mer, a stabilizing component, and a methyl Sulphonyl meth response experienced by an individual upon administration of ane, sodium bicarbonate, calamine, allantoin, kaolin, pepper the composition. As such, the amount of an anti-scarring mint, tea tree oil, or combinations thereof where the amount agent included in a fluid composition disclosed in the present of methyl Sulphonyl methane, Sodium bicarbonate, calamine, specification is between about 0.1% to about 5% by weight of allantoin, kaolin, peppermint, or tea tree oil present is about the total composition. Non-limiting examples of anti-scarring 0.1% (w/v) to about 5% (w/v) of the total composition, about agents include IFN-Y, fluorouracil, poly(lactic-co-glycolic 0.1% (w/v) to about 1% (w/v) of the total composition, or acid), methylated polyethylene glycol, polylactic acid, poly about 0.1% (w/v) to about 0.5% (w/v) of the total composi ethylene glycol and combinations thereof. US 2011/0224164 A1 Sep. 15, 2011

0091 Thus in an embodiment, a fluid composition com lone, corticosterone, budesonide, estrogen, Sulfasalazine, prises a matrix polymer, a stabilizing component, and an mesalamine, or combinations thereof. In aspects of this anti-scarring agent. In aspects of this embodiment, a fluid embodiment, a fluid composition comprises a matrix poly composition comprises a matrix polymer, a stabilizing com mer, a stabilizing component, and a dexamethasone, pred ponent, and an anti-scarring agent where the amount of anti nisolone, corticosterone, budesonide, estrogen, Sulfasalazine, scarring agent present is about 0.1% (w/v) to about 5% (w/v) mesalamine, or combinations thereof where the amount of of the total composition, about 0.1% (w/v) to about 1% (w/v) dexamethasone, prednisolone, corticosterone, budesonide, of the total composition, or about 0.1% (w/v) to about 0.5% estrogen, Sulfasalazine, or mesalamine present is about 0.1% (w/v) of the total composition. In other aspects of this (w/v) to about 5% (w/v) of the total composition, about 0.1% embodiment, a fluid composition comprises a matrix poly (w/v) to about 1% (w/v) of the total composition, or about mer, a stabilizing component, and an anti-scarring agent 0.1% (w/v) to about 0.5% (w/v) of the total composition. In where the amount of anti-scarring agent present is about other aspects of this embodiment, a fluid composition com 0.3%. In another aspect of this embodiment, a fluid compo prises a matrix polymer, a stabilizing component, and a dex sition comprises a matrix polymer, a stabilizing component, amethasone, prednisolone, corticosterone, budesonide, estro and IFN-y, fluorouracil, poly(lactic-co-glycolic acid), methy gen, SulfaSalazine, mesalamine, or combinations thereof lated polyethylene glycol, polylactic acid, polyethylene gly where the amount of dexamethasone, prednisolone, corticos col, or combinations thereof. In aspects of this embodiment, terone, budesonide, estrogen, SulfaSalazine, or mesalamine a fluid composition comprises a matrix polymer, a stabilizing present is about 0.3%. In another embodiment, a fluid com component, and a IFN-y, fluorouracil, poly(lactic-co-glycolic position comprises a matrix polymer, a stabilizing compo acid), methylated polyethylene glycol, polylactic acid, poly nent, but not an anesthetic agent. ethylene glycol, or combinations thereof where the amount of 0094 Aspects of the present specification provide, in part, IFN-y, fluorouracil, poly(lactic-co-glycolic acid), methylated a fluid composition that can optionally comprise or not com polyethylene glycol, polylactic acid, or polyethylene glycol prise an anesthetic agent. An anesthetic agent is preferably a present is about 0.1% (w/v) to about 5% (w/v) of the total local anesthetic agent, i.e., an anesthetic agent that causes a composition, about 0.1% (w/v) to about 1% (w/v) of the total reversible local anesthesia and a loss of nociception, such as, composition, or about 0.1% (w/v) to about 0.5% (w/v) of the e.g., aminoamide local anesthetics and aminoester local anes total composition. In other aspects of this embodiment, a fluid thetics. The amount of an anesthetic agent included in a fluid composition comprises a matrix polymer, a stabilizing com composition disclosed in the present specification is an ponent, and a IFN-y, fluorouracil, poly(lactic-co-glycolic amount effective to mitigate pain experienced by an indi acid), methylated polyethylene glycol, polylactic acid, poly vidual upon administration of the composition. As such, the ethylene glycol, or combinations thereof where the amount of amount of an anesthetic agent included in a fluid composition IFN-y, fluorouracil, poly(lactic-co-glycolic acid), methylated disclosed in the present specification is between about 0.1% polyethylene glycol, polylactic acid, or polyethylene glycol to about 5% by weight of the total composition. Non-limiting present is about 0.3%. In another embodiment, a fluid com examples of anesthetic agents include lidocaine, ambucaine, position comprises a matrix polymer, a stabilizing compo amolanone, amylocaine, benoximate, benzocaine, betox nent, but not an anti-scarring agent. ycaine, biphenamine, bupivacaine, butacaine, butamben, 0092 Aspects of the present specification provide, in part, butanilicaine, butethamine, butoxycaine, carticaine, chlorop a fluid composition that can optionally comprise or not com rocaine, cocaethylene, cocaine, cyclomethycaine, dibucaine, prise an anti-inflammatory agent. The amount of an anti dimethysoduin, dimethocaine, diperodon, dycyclonine, inflammatory agent included in a fluid composition disclosed ecgonidine, ecgonine, ethyl chloride, etidocaine, beta in the present specification is an amount effective to mitigate eucaine, euprocin, fenalcomine, formocaine, hexylcaine, an inflammatory response experienced by an individual upon hydroxytetracaine, isobutyl p-aminobenzoate, leucinocaine administration of the composition. As such, the amount of an mesylate, levoxadrol, lidocaine, mepivacaine, meprylcaine, anti-inflammatory agent included in a fluid composition dis metabutoxycaine, methyl chloride, myrtecaine, naepaine, closed in the present specification is between about 0.1% to octacaine, orthocaine, oxethazaine, parethoxycaine, phen about 5% by weight of the total composition. Non-limiting acaine, phenol, piperocaine, piridocaine, polidocanol, examples of anti-inflammatory agents include dexametha pramoxine, prilocaine, procaine, propanocaine, propara Sone, prednisolone, corticosterone, budesonide, estrogen, caine, propipocaine, propoxycaine, pSuedococaine, pyr Sulfasalazine, mesalamine and combinations thereof. rocaine, ropivacaine, Salicyl alcohol, tetracaine, tolycaine, 0093. Thus in an embodiment, a fluid composition com trimecaine, Zolamine, combinations thereof, and salts prises a matrix polymer, a stabilizing component, and an thereof. Non-limiting examples of aminoester local anesthet anti-inflammatory agent. In aspects of this embodiment, a ics include procaine, chloroprocaine, cocaine, cyclom fluid composition comprises a matrix polymer, a stabilizing ethycaine, cimethocaine (larocaine), propoxycaine, procaine component, and an anti-inflammatory agent where the (novocaine), proparacaine, tetracaine (amethocaine). Non amount of anti-inflammatory agent present is about 0.1% limiting examples of aminoamide local anesthetics include (w/v) to about 5% (w/v) of the total composition, about 0.1% articaine, bupivacaine, cinchocaine (dibucaine), etidocaine, (w/v) to about 1% (w/v) of the total composition, or about levobupivacaine, lidocaine (lignocaine), mepivacaine, piper 0.1% (w/v) to about 0.5% (w/v) of the total composition. In ocaine, prilocaine, ropivacaine, and trimecaine. A non-limit other aspects of this embodiment, a fluid composition com ing example of a combination local anesthetic is lidocaine/ prises a matrix polymer, a stabilizing component, and an prilocaine (EMLA). anti-inflammatory agent where the amount of anti-inflamma 0.095 Thus in an embodiment, a fluid composition com tory agent present is about 0.3%. In another aspect of this prises a matrix polymer, a stabilizing component, and an embodiment, a fluid composition comprises a matrix poly anesthetic agent and salts thereof. In aspects of this embodi mer, a stabilizing component, and dexamethasone, predniso ment, a fluid composition comprises a matrix polymer, a US 2011/0224164 A1 Sep. 15, 2011

stabilizing component, and an aminoamide local anesthetic (G') and the viscous modulus (G"). Falcone, et al., Temporary and salts thereof or an aminoester local anesthetic and salts Polysaccharide Dermal Fillers: A Model for Persistence thereof. In other aspects of this embodiment, a fluid compo Based on Physical Properties, Dermatol Surg. 35.(8): 1238 sition comprises a matrix polymer, a stabilizing component, 1243 (2009); Tezel, supra, 2008; Kablik, supra, 2009; Beas and procaine, chloroprocaine, cocaine, cyclomethycaine, ley, supra, 2009; each of which is hereby incorporated by cimethocaine, propoxycaine, procaine, proparacaine, tetra reference in its entirety. Elastic modulus characterizes the caine, or salts thereof. In yet other aspects of this embodi firmness of a composition and is also known as the storage ment, a fluid composition comprises a matrix polymer, a modulus because it describes the storage of energy from the stabilizing component, and articaine, bupivacaine, cin motion of the composition. The elastic modulus describes the chocaine, etidocaine, levobupivacaine, lidocaine, mepiv interaction between elasticity and strength (G'=stress/strain) acaine, piperocaine, prilocaine, ropivacaine, trimecaine, or and, as Such, provides a quantitative measurement of a com salts thereof. In still other aspects of this embodiment, a fluid position's hardness or softness. Although depending on the composition comprises a matrix polymer, a stabilizing com speed at which the force is applied, a stiffer composition will ponent, and lidocaine/prilocaine combination. have a higher elastic modulus and it will take a greater force 0096. In other aspects of this embodiment, a fluid compo to deform the material a given distance, Such as, e.g., an sition comprises a matrix polymer, a stabilizing component, injection. and an anesthetic agent where the amount of anesthetic agent 0.100 Viscous modulus is also known as the loss modulus present is about 0.1% (w/v) to about 5% (w/v) of the total because it describes the energy that is lost as Viscous dissipa composition, about 0.1% (w/v) to about 1% (w/v) of the total tion. Tan Ö is the ratio of the viscous modulus and the elastic composition, or about 0.1% (w/v) to about 0.5% (w/v) of the modulus, tan 8–G/G". Falcone, supra, 2009. Fortan 8 values total composition. In other aspects of this embodiment, a fluid disclosed in the present specification, a tan Ö is obtained from composition comprises a matrix polymer, a stabilizing com the dynamic modulus at a frequency of 0.628 rad/s. A lower ponent, and an anesthetic agent where the amount of anes tan Ö corresponds to a stiffer, harder, or more elastic compo thetic agent present is about 0.3%. In other aspects of this sition. embodiment, a fluid composition comprises a matrix poly 0101 Thus, in an embodiment, a fluid composition exhib mer, a stabilizing component, and an aminoamide local anes its a complex modulus. In aspects of this embodiment, a fluid thetic and salts thereof oran aminoester local anesthetic and composition exhibits a complex modulus of, e.g., about 25 Pa, salts thereof where the amount of the local anesthetic present about 50 Pa, about 75 Pa, about 100 Pa, about 125 Pa, about is about 0.1% (w/v) to about 5% (w/v) of the total composi 150 Pa, about 175 Pa, about 200 Pa, about 250 Pa, about 300 tion, about 0.1% (w/v) to about 1% (w/v) of the total compo Pa, about 350 Pa, about 400 Pa, about 450 Pa, about 500 Pa, sition, or about 0.1% (w/v) to about 0.5% (w/v) of the total about 550 Pa, about 600 Pa, about 650 Pa, about 700 Pa, about composition. In other aspects of this embodiment, a fluid 750 Pa, or about 800 Pa. In other aspects of this embodiment, composition comprises a matrix polymer, a stabilizing com a fluid composition exhibits a complex modulus of, e.g., at ponent, and an aminoamide local anesthetic and salts thereof most 25 Pa, at most 50 Pa, at most 75 Pa, at most 100 Pa, at or an aminoester local anesthetic and salts thereof where the most 125 Pa, at most 150 Pa, at most 175 Pa, at most 200 Pa, amount of the local anesthetic agent present is about 0.3%. at most 250 Pa, at most 300 Pa, at most 350 Pa, at most 400 Pa, 0097. In another aspect of this embodiment, a fluid com at most 450 Pa, at most 500 Pa, at most 550 Pa, at most 600 Pa, position comprises a matrix polymer, a stabilizing compo at most 650 Pa, at most 700 Pa, at most 750 Pa, or at most 800 nent, and lidocaine or a lidocaine salt. In aspects of this Pa. In yet other aspects of this embodiment, a fluid composi embodiment, a fluid composition comprises a matrix poly tion exhibits a complex modulus of, e.g., about 25 Pato about mer, a stabilizing component, and a lidocaine or a lidocaine 150 Pa, about 25 Pato about 300 Pa, about 25 Pato about 500 salt where the amount of lidocaine or a lidocaine salt present Pa, about 25 Pato about 800 Pa, about 125 Pato about 300 Pa, is about 0.1% (w/v) to about 5% (w/v) of the total composi about 125 Pato about 500 Pa, or about 125 Pato about 800 Pa. tion, about 0.1% (w/v) to about 1% (w/v) of the total compo 0102. In another embodiment, a fluid composition exhib sition, or about 0.1% (w/v) to about 0.5% (w/v) of the total its an elastic modulus. In aspects of this embodiment, a fluid composition. In other aspects of this embodiment, a fluid composition exhibits an elastic modulus of, e.g., about 25 Pa, composition comprises a matrix polymer, a stabilizing com about 50 Pa, about 75 Pa, about 100 Pa, about 125 Pa, about ponent, and a lidocaine or a lidocaine salt where the amount 150 Pa, about 175 Pa, about 200 Pa, about 250 Pa, about 300 of lidocaine or a lidocaine salt present is about 0.3%. Pa, about 350 Pa, about 400 Pa, about 450 Pa, about 500 Pa, 0098. In another embodiment, a fluid composition com about 550 Pa, about 600 Pa, about 650 Pa, about 700 Pa, about prises a matrix polymer, a stabilizing component, but not an 750 Pa, or about 800 Pa. In other aspects of this embodiment, anesthetic agent. a fluid composition exhibits an elastic modulus of, e.g., at 0099 Aspects of the present specification provide, in part, most 25 Pa, at most 50 Pa, at most 75 Pa, at most 100 Pa, at a fluid composition disclosed in the present specification most 125 Pa, at most 150 Pa, at most 175 Pa, at most 200 Pa, exhibiting a complex modulus, an elastic modulus, a viscous at most 250 Pa, at most 300 Pa, at most 350 Pa, at most 400 Pa, modulus and a tan Ö. Matrix polymers disclosed in the present at most 450 Pa, at most 500 Pa, at most 550 Pa, at most 600 Pa, specification are viscoelastic in that the composition has an at most 650 Pa, at most 700 Pa, at most 750 Pa, or at most 800 elastic component (Solid-like Such as, e.g., crosslinked matrix Pa. In yet other aspects of this embodiment, a fluid composi polymer) and a viscous component (liquid-like Such as, e.g., tion exhibits an elastic modulus of, e.g., about 25 Pa to about uncrosslinked matrix polymer) when a force is applied 150 Pa, about 25 Pato about 300 Pa, about 25 Pato about 500 (stress, deformation). The rheological attribute that described Pa, about 25 Pato about 800 Pa, about 125 Pato about 300 Pa, this property is the complex modulus (G), which defines a about 125 Pato about 500 Pa, or about 125 Pato about 800 Pa. fluid compositions total resistance to deformation. The com 0103) In another embodiment, a fluid composition exhib plex modulus can be defined as the sum of the elastic modulus its a viscous modulus. In aspects of this embodiment, a fluid US 2011/0224164 A1 Sep. 15, 2011 composition exhibits a viscous modulus of, e.g., about 10 Pa, geometry 2/40 cm and a temperature of 20° C. Examples of about 20 Pa, about 30 Pa, about 40 Pa, about 50 Pa, about 60 the dynamic viscosity of various fluids at 20°C. is as follows: Pa, about 70 Pa, about 80 Pa, about 90 Pa, about 100 Pa, about water is about 1.0x10 Pas, blood is about 3-4x10 Pa's, 110 Pa, about 120 Pa, about 130 Pa, about 140 Pa, or about vegetable oil is about 60-85x10 Pas, motor oil SE 30 is 150 Pa. In other aspects of this embodiment, a fluid compo about 0.2 Pas, glycerin is about 1.4 Pas, maple syrup is about sition exhibits a viscous modulus of, e.g., at most 10 Pa, at 2-3 Pas, honey is about 10 Pas, chocolate syrup is about most 20 Pa, at most 30 Pa, at most 40 Pa, at most 50 Pa, at most 10-25 Pa's, peanut butter is about 150-250 Pa's, lard is about 60 Pa, at most 70 Pa, at most 80 Pa, at most 90 Pa, at most 100 1,000 Pas, vegetable shortening is about 1,200 Pas, and taris Pa, at most 110 Pa, at most 120 Pa, at most 130 Pa, at most 140 about 30,000 Pas. Pa, or at most 150 Pa. In yet other aspects of this embodiment, 0109 Thus, in an embodiment, a fluid composition com a fluid composition exhibits a viscous modulus of, e.g., about prising a matrix polymer and a stabilizing component exhib 10 Pa to about 30 Pa, about 10 Pa to about 50 Pa, about 10 Pa its a dynamic viscosity. In aspects of this embodiment, a fluid to about 100 Pa, about 10 Pa to about 150 Pa, or about 70 Pa composition comprising a matrix polymer and a stabilizing to about 100 Pa. component exhibits a dynamic viscosity of e.g., about 10 0104. In another embodiment, a fluid composition dis Pa's, about 20 Pas, about 30 Pas, about 40 Pas, about 50 closed in the present specification exhibiting a tan Ö. In Pa's, about 60 Pas, about 70 Pas, about 80 Pas, about 90 aspects of this embodiment, a fluid composition exhibits a tan Pa's, about 100 Pas, about 125 Pas, about 150 Pas, about 8 of, e.g., about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, 175 Pas, about 200 Pas, about 225 Pas, about 250 Pas, about 0.6, about 0.7, about 0.8, about 0.9, or about 1.0. In about 275 Pas, about 300 Pas, about 400 Pas, about 500 other aspects of this embodiment, a fluid composition exhib Pa's, about 600 Pas, about 700 Pas, about 750 Pas, about its a tan 8 of e.g., at most 0.1, at most 0.2, at most 0.3, at most 800 Pas, about 900 Pas, about 1,000 Pas, about 1,100 Pas, 0.4, at most 0.5, at most 0.6, at most 0.7, at most 0.8, at most or about 1,200 Pas. In other aspects of this embodiment, a 0.9, or at most 1.0. In yet other aspects of this embodiment, a fluid composition comprising a matrix polymer and a stabi fluid composition exhibits a tan 8 of, e.g., about 0.1 to about lizing component exhibits a dynamic viscosity of, e.g., at 0.3, about 0.3 to about 0.5, about 0.3 to about 0.6, about 0.1 to most 10 Pas, at most 20 Pas, at most 30 Pas, at most 40 Pas, about 0.5, or about 0.1 to about 0.6. at most 50 Pas, at most 60 Pas, at most 70 Pas, at most 80 0105 Aspects of the present specification provide, in part, Pa's, at most 90 Pas, at most 100 Pas, at most 125 Pas, at a fluid composition disclosed in the present specification most 150 Pas, at most 175 Pas, at most 200 Pas, at most 225 exhibiting a dynamic viscosity. Viscosity is resistance of a Pas, at most 250 Pas, at most 275 Pas, at most 300 Pas, at fluid to shear or flow caused by either shear stress or tensile most 400 Pas, at most 500 Pas, at most 600 Pas, at most 700 stress. Viscosity describes a fluid's internal resistance to flow Pa's, at most 750 Pas, at most 800 Pas, at most 900 Pas, or caused by intermolecular friction exerted when layers of flu at most 1000 Pas. In yet other aspects of this embodiment, a ids attempt to slide by one another and may be thought of as fluid composition comprising a matrix polymer and a stabi a measure of fluid friction. The less viscous the fluid, the lizing component exhibits a dynamic viscosity of e.g., about greater its ease of movement (fluidity). 10 Pa's to about 100 Pas, about 10 Pars to about 150 Pas, 0106 Viscosity can be defined in two ways; dynamic vis about 10 Pa's to about 250 Pas, about 50 Pa's to about 100 cosity (LL, although m is sometimes used) or kinematic viscos Pa's, about 50 Pa's to about 150 Pas, about 50 Pa's to about ity (V). Dynamic viscosity, also known as absolute or complex 250 Pas, about 100 Pa's to about 500 Pas, about 100 Pars to Viscosity, is the tangential force per unit area required to move about 750 Pas, about 100 Pa's to about 1,000 Pas, about 100 one horizontal plane with respect to the other at unit velocity Pa's to about 1,200 Pas, about 300 Pa's to about 500 Pas, when maintained a unit distance apart by the fluid. The SI about 300 Pa's to about 750 Pas, about 300 Pa's to about physical unit of dynamic viscosity is the Pascal-second (Pas), 1,000 Pas, or about 300 Pa's to about 1,200 Pars. which is identical to N-m-2's. Dynamic viscosity can be 0110 Aspects of the present specification provide, in part, expressed as tudvX/dz, where t shearing stress, L dynamic a fluid composition disclosed in the present specification that viscosity, and dvX/dz is the velocity gradient over time. For is injectable. As used herein, the term “injectable' refers to a example, if a fluid with a viscosity of one Pa's is placed fluid composition disclosed in the present specification hav between two plates, and one plate is pushed sideways with a ing the properties necessary to administer the composition shear stress of one Pascal, it moves a distance equal to the into a dermal region of an individual using an injection device thickness of the layer between the plates in one second. with a fine needle. As used herein, the term “fine needle’ Dynamic viscosity symbolize by is also used, is measured refers to a needle that is 27 gauge or smaller. Injectability of with various types of rheometers, devices used to measure the a fluid composition disclosed in the present specification can way in which a liquid, Suspension or slurry flows in response be accomplished by sizing the fluid composition, as discussed to applied forces. below. 0107 Kinematic viscosity (v) is the ratio of dynamic vis 0111. Thus, in an embodiment, a fluid composition com cosity to density, a quantity in which no force is involved and prising a matrix polymer and a stabilizing component, is defined as follows: VL/p, where L is the dynamic viscosity wherein the composition is injectable. In aspect of this p is density with the SI unit of kg/m. Kinematic viscosity is embodiment, a fluid composition comprising a matrix poly usually measured by a glass capillary viscometer as has an SI mer and a stabilizing component is injectable through a fine unit of m/s. needle. In other aspects of this embodiment, a fluid compo 0108. The viscosity of a fluid is highly temperature depen sition comprising a matrix polymer and a stabilizing compo dent and for either dynamic or kinematic viscosity to be nent is injectable through a needle of, e.g., about 27 gauge, meaningful, the reference temperature must be quoted. For about 30 gauge, or about 32 gauge. In yet other aspects of this the Viscosity values disclosed in the present specification, a embodiment, a fluid composition comprising a matrix poly dynamic viscosity is measured at 1 Pa with a cone/plane mer and a stabilizing component is injectable through a US 2011/0224164 A1 Sep. 15, 2011

needle of e.g., 27 gauge or Smaller, 30 gauge or Smaller, or 32 mammal. Osmolality refers to the concentration of osmoti gauge or Smaller. In still other aspects of this embodiment, a cally active solutes per kilo of water in the body and is fluid composition comprising a matrix polymer and a stabi expressed interms of osmoles of osmotically active solute per lizing component is injectable through a needle of e.g., about kilogram of solvent (osmol/kg or Osm/kg) and is equal to the 27 gauge to about 32 gauge. sum of the molalities of all the solutes present in that solution. 0112. In other aspects of this embodiment, a fluid compo The osmolality of a solution can be measured using an sition comprising a crosslinked matrix polymer where the oSmometer. The most commonly used instrument in modern mean particle size of the crosslinked matrix polymer is, e.g., laboratories is a freezing point depression osmometer. This about 200 um, about 250 um, about 300 um, about 350 um, instruments measure the change in freezing point that occurs about 400 um, about 450 um, about 500 um, about 550 um, in a solution with increasing osmolality (freezing point about 600 um, about 650 um, about 700 um, about 750 um, or depression osmometer) or the change in vapor pressure that about 800 um. In yet other aspects of this embodiment, a fluid occurs in a solution with increasing osmolality (vapor pres composition comprising a crosslinked matrix polymer where Sure depression osmometer). the mean particle size of the crosslinked matrix polymer is, 0115 Thus, in an embodiment, a fluid composition com e.g., at most 200 um, at most 250 um, at most 300 um, at most prising a matrix polymer and a stabilizing component exhibit 350 Lum, at most 400 um, at most 450 Lim, at most 500 um, at a physiologically-acceptable osmolarity. In aspects of this most 550 um, at most 600 um, at most 650 um, at most 700 embodiment, a fluid composition comprising a matrix poly um, at most 750 um, or at most 800 um. In still other aspects mer and a stabilizing component exhibit an osmolarity of of this embodiment, a fluid composition comprising a e.g., about 100 mOsm/L, about 150 mOsm/L, about 200 crosslinked matrix polymer where the mean particle size of mOsm/L, about 250 mOsm/L, about 300 mOsm/L, about 350 the crosslinked matrix polymeris, e.g., about 200um to about mOsm/L, about 400 mOsm/L, about 450 mOsm/L, or about 300 um, about 300 um to about 400 um, about 400 um to 500 mOsm/L. In other aspects of this embodiment, a fluid about 500 um, about 500 um to about 600 um, about 600 um composition comprising a matrix polymer and a stabilizing to about 700 um, about 700 um to about 800 um, about 200 component exhibit an osmolarity of e.g., at least 100 mOsm/ um to about 400 um, about 200 um to about 500 um, about L., at least 150 mOsm/L, at least 200 mOsm/L, at least 250 200 um to about 600 um, about 200 um to about 700 um, mOsm/L, at least 300 mOsm/L, at least 350 mOsm/L, at least about 200 um to about 800 um, about 300 um to about 500 400 mOsm/L, at least 450 mOsm/L, or at least 500 mOsm/L. um, about 300 um to about 600 um, about 300 um to about In yet other aspects of this embodiment, a fluid composition 700 um, or about 300 um to about 800 um. comprising a matrix polymer and a stabilizing component 0113 Aspects of the present specification provide, in part, exhibit an osmolarity of e.g., at most 100 mOsm/L. at most a fluid composition disclosed in the present specification 150 mOsm/L, at most 200 mOsm/L, at most 250 mOsm/L, at exhibiting a physiologically-acceptable osmolarity. As used most 300 mOsm/L. at most 350 mOsm/L, at most 400 mOsm/ herein, the term “a physiologically-acceptable osmolarity” L., at most 450 mOsm/L, or at most 500 mOsm/L. In still other refers to an osmolarity in accord with, or characteristic of the aspects of this embodiment, a fluid composition comprising a normal functioning of a living organism. As such, adminis matrix polymer and a stabilizing component exhibit an osmo tration of a fluid composition disclosed in the present com larity of, e.g., about 100 mOsm/L to about 500 mOsm/L. position exhibits an osmolarity that has substantially no long about 200 mOsm/L to about 500 mOsm/L, about 200 term or permanent detrimental effect when administered to mOsm/L to about 400 mOsm/L, about 300 mOsm/L to about mammal. Osmolarity refers to the concentration of osmoti 400 mOsm/L, about 270 mOsm/L to about 390 mOsm/L. cally active solutes in Solution. Osmolarity is expressed in about 225 mOsm/L to about 350 mOsm/L, about 250 terms of osmoles of osmotically active solute per liter of mOsm/L to about 325 mOsm/L, about 275 mOsm/L to about solvent (Osmol/L or Osm/L). Osmolarity is distinct from 300 mOsm/L, or about 285 mOsm/L to about 290 mOsm/L. molarity because it measures moles of osmotically active 0116. In another embodiment, a fluid composition com solute particles rather than moles of solute. The distinction prising a matrix polymer and a stabilizing component exhibit arises because Some compounds can dissociate in solution, a physiologically-acceptable osmolality. In aspects of this whereas others cannot. The osmolarity of a solution can be embodiment, a fluid composition comprising a matrix poly calculated from the following expression: Osmol/L X (p, m, mer and a stabilizing component exhibit an osmolality of C, where p is the osmotic coefficient, which accounts for the e.g., about 100 mOsm/kg, about 150 mOsm/kg, about 200 degree of non-ideality of the solution; m is the number of mOsm/kg, about 250 mOsm/kg, about 300 mOsm/kg, about particles (e.g. ions) into which a molecule dissociates; and C 350 mOsm/kg, about 400 mOsm/kg, about 450 mOsm/kg, or is the molar concentration of the solute; and i is the index about 500 mOsm/kg. In other aspects of this embodiment, a representing the identity of aparticular Solute. The osmolarity fluid composition comprising a matrix polymer and a stabi of a composition disclosed in the present specification can be lizing component exhibit an osmolality of, e.g., at least 100 measured using a conventional method that measures solu mOsm/kg, at least 150 mOsm/kg, at least 200 mOsm/kg, at tions. least 250 mOsm/kg, at least 300 mOsm/kg, at least 350 0114 Aspects of the present specification provide, in part, mOsm/kg, at least 400 mOsm/kg, at least 450 mOsm/kg, or at a fluid composition disclosed in the present specification least 500 mOsm/kg. In yet other aspects of this embodiment, exhibiting a physiologically-acceptable osmolality. As used a fluid composition comprising a matrix polymer and a sta herein, the term “a physiologically-acceptable osmolality” bilizing component exhibit an osmolality of e.g., at most 100 refers to an osmolality inaccord with, or characteristic of the mOsm/kg, at most 150 mOsm/kg, at most 200 mOsm/kg, at normal functioning of a living organism. As such, adminis most 250 mOsm/kg, at most 300 mOsm/kg, at most 350 tration of a fluid composition disclosed in the present com mOsm/kg, at most 400 mOsm/kg, at most 450 mOsm/kg, or at position exhibits an osmolality that has substantially no long most 500 mOsm/kg. In still other aspects of this embodiment, term or permanent detrimental effect when administered to a fluid composition comprising a matrix polymer and a sta US 2011/0224164 A1 Sep. 15, 2011 20 bilizing component exhibit an osmolality of e.g., about 100 disclosed in the present specification, provided that the result mOsm/kg to about 500 mOsm/kg, about 200 mOsm/kg to ing preparation is pharmaceutically acceptable. Non-limiting about 500 mOsm/kg, about 200 mOsm/kg to about 400 examples of pharmaceutically acceptable buffers include mOsm/kg, about 300 mOsm/kg to about 400 mOsm/kg, about acetate buffers, borate buffers, citrate buffers, neutral buff 270 mOsm/kg to about 390 mOsm/kg, about 225 mOsm/kg to ered salines, phosphate buffers, and phosphate buffered about 350 mOsm/kg, about 250 mOsm/kg to about 325 salines. Any concentration of a pharmaceutically acceptable mOsm/kg, about 275 mOsm/kg to about 300 mOsm/kg, or buffer can be useful in formulating a pharmaceutical compo about 285 mCsm/kg to about 290 mOsm/kg. sition disclosed in the present specification, with the proviso 0117. Aspects of the present specification provide, in part, that a therapeutically effective amount of the matrix polymer a fluid composition disclosed in the present specification that active ingredient is recovered using this effective concentra is a pharmaceutical composition. As used herein, the term tion of buffer. Non-limiting examples of concentrations of “pharmaceutical composition' is synonymous with “pharma physiologically-acceptable buffers occur within the range of ceutically-acceptable composition' and refers to a therapeu about 0.1 mM to about 900 mM. The pH of pharmaceutically tically effective concentration of an active ingredient, such as, acceptable buffers may be adjusted, provided that the result e.g., any of the matrix polymers disclosed in the present ing preparation is pharmaceutically acceptable. It is under specification. A pharmaceutical composition comprising a stood that acids or bases can be used to adjust the pH of a matrix polymer active ingredient is useful for medical and pharmaceutical composition as needed. Any buffered pH Veterinary applications. A pharmaceutical composition may level can be useful in formulating a pharmaceutical compo be administered to a patient alone, or in combination with sition, with the proviso that atherapeutically effective amount other Supplementary active ingredients, agents, drugs or hor of the matrix polymeractive ingredientis recovered using this OS. effective pH level. Non-limiting examples of physiologi 0118 Aspects of the present specification provide, in part, cally-acceptable pH occur within the range of about pH 5.5 to a fluid composition disclosed in the present specification that about pH 8.5. is a pharmaceutical composition comprising a pharmacologi I0121 Pharmaceutically acceptable antioxidants include, cally acceptable excipient. As used herein, the term “pharma without limitation, sodium metabisulfite, sodium thiosulfate, cologically acceptable excipient' is synonymous with “phar acetylcysteine, butylated hydroxyanisole and butylated macological excipient’ or “excipient' and refers to any hydroxytoluene. Pharmaceutically acceptable preservatives excipient that has substantially no long term or permanent include, without limitation, benzalkonium chloride, chlo detrimental effect when administered to mammal and encom robutanol, thimerosal, phenylmercuric acetate, phenylmercu passes compounds such as, e.g., stabilizing agent, a bulking ric nitrate, a stabilized oxychloro composition, such as, e.g., agent, a cryo-protectant, a lyo-protectant, an additive, a PURITE(R) (Allergan, Inc. Irvine, Calif.) and chelants, such vehicle, a carrier, a diluent, or an auxiliary. An excipient as, e.g., DTPA or DTPA-bisamide, calcium DTPA, and generally is mixed with an active ingredient, or permitted to CaNaDTPA-bisamide. dilute or enclose the active ingredient and can be a solid, 0.122 Tonicity adjustors useful in a pharmaceutical com semi-solid, or liquid agent. It is also envisioned that a phar position include, without limitation, salts such as, e.g., maceutical composition comprising a matrix polymer active Sodium chloride and potassium chloride; and glycerin. The ingredient can include one or more pharmaceutically accept pharmaceutical composition may be provided as a salt and able excipients that facilitate processing of an active ingredi can be formed with many acids, including but not limited to, ent into pharmaceutically acceptable compositions. Insofar hydrochloric, Sulfuric, acetic, lactic, tartaric, malic, succinic, as any pharmacologically acceptable excipient is not incom etc. Salts tend to be more soluble in aqueous or other protonic patible with the matrix polymer active ingredient, its use in Solvents than are the corresponding free base forms. It is pharmaceutically acceptable compositions is contemplated. understood that these and other substances known in theart of Non-limiting examples of pharmacologically acceptable pharmacology can be included in a pharmaceutical composi excipients can be found in, e.g., Pharmaceutical Dosage tion useful in the invention. Other non-limiting examples of Forms and Drug Delivery Systems (Howard C. Ansel et al., pharmacologically acceptable components can be found in, eds., Lippincott Williams & Wilkins Publishers, 7" ed. 1999); e.g., Ansel, supra, (1999); Gennaro, supra, (2000); Hardman, Remington: The Science and Practice of Pharmacy (Alfonso supra, (2001); and Rowe, supra, (2003), each of which is R. Gennaro ed., Lippincott, Williams & Wilkins, 20" ed. hereby incorporated by reference in its entirety. 2000); Goodman & Gilman's The Pharmacological Basis of I0123. A pharmaceutical compositions disclosed in the Therapeutics (Joel G. Hardman et al., eds., McGraw-Hill present specification generally is administered as a pharma Professional, 10" ed. 2001); and Handbook of Pharmaceuti ceutical acceptable composition comprising a matrix poly cal Excipients (Raymond C. Rowe et al., APhA Publications, meractive ingredient. As used herein, the term “pharmaceu 4" edition 2003), each of which is hereby incorporated by tically acceptable” means any molecular entity or reference in its entirety. composition that does not produce an adverse, allergic or 0119. It is further envisioned that a pharmaceutical com other untoward or unwanted reaction when administered to an position disclosed in the present specification may optionally individual. include or not include, without limitation, other pharmaceu 0.124 Aspects of the present specification provide, in part, tically acceptable components (or pharmaceutical compo a method of making a fluid composition disclosed in the nents), including, without limitation, buffers, preservatives, present specification. In an aspect, a method for making a tonicity adjusters, salts, antioxidants, osmolality adjusting fluid composition, the method comprising the steps of: a) agents, emulsifying agents, wetting agents, Sweetening or combining a stabilizing component with a physiologically flavoring agents, and the like. acceptable buffer to make a stabilizing component-buffered 0120 Pharmaceutically acceptable buffer is any buffer Solution; b) combining a matrix polymer with the stabilizing that can be used to prepare a pharmaceutical composition component-buffered solution to hydrate the matrix polymer, US 2011/0224164 A1 Sep. 15, 2011 and; c) sizing the fluid composition. This method may, or may long period of time and then by mixing the matrix polymer not, further comprise a step comprising titrating a stabilizing with the stabilizing component-buffered solution using a component-buffered solution to obtain a desired pH after step cycle of alternating periods of agitation for a relatively short (a); a step comprising filtering the stabilizing component period of time followed by periods of rest for a relatively long buffered solution after step (a); a step (b) where combining a period of time; a step (b) where combining a matrix polymer matrix polymer with the stabilizing component-buffered with the stabilizing component-buffered solution to hydrate Solution to hydrate the matrix polymer occurs by mixing the the matrix polymer occurs by mixing the matrix polymer with matrix polymer with the stabilizing component-buffered the stabilizing component-buffered solution at a low speed Solution at a low speed for a relatively long period of time; a for a relatively long period of time and then by mixing the step (b) where combining a matrix polymer with the stabiliz matrix polymer with the stabilizing component-buffered ing component-buffered solution to hydrate the matrix poly Solution using a cycle of alternating periods of agitation for a mer occurs by mixing the matrix polymer with the stabilizing relatively short period of time followed by periods of rest for component-buffered solution at a low speed for a relatively a relatively long period of time, and then followed by a rest for long period of time and then followed by a rest for a relative a relative long period of time; a step comprising degassing a long period of time; a step (b) where combining a matrix fluid composition after step (b) or step (c); a step comprising polymer with the stabilizing component-buffered solution to filling a syringe with a fluid composition after step (c); and/or hydrate the matrix polymer occurs by mixing the matrix a step comprising sterilizing a syringe filled with a fluid polymer with the stabilizing component-buffered solution at composition after step (c). a low speed for a relatively long period of time and then by 0.126 Aspects of the present specification provide, in part, mixing the matrix polymer with the stabilizing component a method having a step of combining a stabilizing component buffered solution using a cycle of alternating periods of agi with a physiologically-acceptable buffer to make a stabilizing tation for a relatively short period of time followed by periods component-buffered solution. A stabilizing component can of rest for a relatively long period of time; a step (b) where be any one of the stabilizing components disclosed in the combining a matrix polymer with the stabilizing component present specification. As used herein, the term “a physiologi buffered solution to hydrate the matrix polymer occurs by cally-acceptable buffer refers to a buffer in accord with, or mixing the matrix polymer with the stabilizing component characteristic of the normal functioning of a living organism. buffered solution at a low speed for a relatively long period of AS Such, a buffer used to make a fluid composition disclosed time and then by mixing the matrix polymer with the stabi in the present specification exhibits a buffering capacity that lizing component-buffered solution using a cycle of alternat has substantially no long term or permanent detrimental ing periods of agitation for a relatively short period of time effect when administered to mammal. Physiologically-ac followed by periods of rest for a relatively long period of time, ceptable buffers include, without limitation, acetate buffers, and then followed by a rest for a relative long period of time: borate buffers, citrate buffers, neutral buffered salines, phos a step comprising degassing a fluid composition after step (b) phate buffers, and phosphate buffered salines. In addition, the or step (c); a step comprising filling a syringe with a fluid physiologically-acceptable buffer is at a concentration to composition after step (c); and/or a step comprising steriliz achieve an effective buffering capacity. Non-limiting ing a syringe filled with a fluid composition after step (c). examples of a concentration to a physiologically-acceptable 0.125 Aspects of the present specification provide, in part, buffer to achieve an effective buffering capacity is from a fluid composition disclosed in the present specification between about 0.1 mM to about 900 mM. made by a method disclosed in the present specification. In an I0127 Thus, in an embodiment, a stabilizing component is aspect, a fluid composition comprises a matrix polymer and a combined with a physiologically-acceptable buffer to make a stabilizing component wherein the fluid composition is made stabilizing component-buffered solution. In aspects of this by a method comprising the steps of: a) combining a stabi embodiment, a stabilizing component is combined with an lizing component with a physiologically-acceptable buffer to acetate buffer, a borate buffers, a citrate buffer, a neutral make a stabilizing component-buffered solution; b) combin buffered saline, a phosphate buffer, or a phosphate buffered ing a matrix polymer with the stabilizing component-buffered saline to make a stabilizing-buffered solution. In other an Solution to hydrate the matrix polymer, and; c) sizing the fluid stabilizing component is combined with sodium chloride, composition. This method may, or may not, further comprise Sodium phosphate, or both. a step comprising titrating a stabilizing component-buffered I0128. In another embodiment, a physiologically-accept Solution to obtain a desired pH after step (a); a step compris able buffer is at a concentration necessary to achieve an ing filtering the stabilizing component-buffered solution after effective buffering capacity. In aspects of this embodiment, a step (a); a step (b) where combining a matrix polymer with the physiologically-acceptable buffer is at a concentration of stabilizing component-buffered solution to hydrate the e.g., at least 0.1 mM, at least 0.2 mM, at least 0.3 mM, at least matrix polymer occurs by mixing the matrix polymer with the 0.4 mM, at least 0.5 mM, at least 0.6 mM, at least 0.7 mM, at stabilizing component-buffered solution at a low speed for a least 0.8 mM, or at least 0.9 mM. In other aspects of this relatively long period of time; a step (b) where combining a embodiment, a physiologically-acceptable buffer is at a con matrix polymer with the stabilizing component-buffered centration of, e.g., at least 1.0 mM, at least 2.0 mM, at least 3.0 Solution to hydrate the matrix polymer occurs by mixing the mM, at least 4.0 mM, at least 5.0 mM, at least 6.0 mM, at least matrix polymer with the stabilizing component-buffered 7.0 mM, at least 8.0 mM, or at least 9.0 mM. In yet other Solution at a low speed for a relatively long period of time and aspects of this embodiment, a physiologically-acceptable then followed by a rest for a relative long period of time; a step buffer is at a concentration of, e.g., at least 10 mM, at least 20 (b) where combining a matrix polymer with the stabilizing mM, at least 30 mM, at least 40 mM, at least 50 mM, at least component-buffered solution to hydrate the matrix polymer 60 mM, at least 70 mM, at least 80 mM, or at least 90 mM. In occurs by mixing the matrix polymer with the stabilizing still other aspects of this embodiment, a physiologically component-buffered solution at a low speed for a relatively acceptable buffer is at a concentration of, e.g., at least 100 US 2011/0224164 A1 Sep. 15, 2011 22 mM, at least 200 mM, at least 300 mM, at least 400 mM, at Solution may, or may not, be filtered to remove particulates least 500 mM, at least 600 mM, at least 700 mM, at least 800 and impurities from the stabilizing component-buffered solu mM, or at least 900 mM. tion. The filters used should be of a pore size that sufficiently 0129. In further aspects of this embodiment, a physiologi removes the particulates and impurities desired to be removed cally-acceptable buffer is at a concentration of, e.g., at most from a stabilizing component-buffered solution. Non-limit 0.1 mM, at most 0.2 mM, at most 0.3 mM, at most 0.4 mM, at ing examples of pore sizes are of the range of 5.0 Lim or less. most 0.5 mM, at most 0.6 mM, at most 0.7 mM, at most 0.8 0.133 Thus, in an embodiment, a stabilizing component mM, or at most 0.9 mM. In still other aspects of this embodi buffered solution is filtered to remove particulates and impu ment, a physiologically-acceptable buffer is at a concentra rities. In an aspect of this embodiment, a stabilizing compo tion of, e.g., at most 1.0 mM, at most 2.0 mM, at most 3.0 mM, nent-buffered solution is filtered through a pore size sufficient at most 4.0 mM, at most 5.0 mM, at most 6.0 mM, at most 7.0 to remove particulates and impurities. In other aspects of this mM, at most 8.0 mM, or at most 9.0 mM. In yet other aspects embodiment, a stabilizing component-buffered solution is of this embodiment, a physiologically-acceptable buffer is at filtered through a pore size of, e.g., about 0.1 um or less, about a concentration of e.g., at most 10 mM, at most 20 mM, at 0.25 um or less, about 0.5um or less, about 0.75 um or less, most 30 mM, at most 40 mM, at most 50 mM, at most 60 mM, about 1 um or less, about 2 Lim or less, about 3 um or less, at most 70 mM, at most 80 mM, or at most 90 mM. In still about 4 um or less, or about 5um or less. other aspects of this embodiment, a physiologically-accept 0.134 Aspects of the present specification provide, in part, able buffer is at a concentration of, e.g., at most 100 mM, at a method having a step of combining a matrix polymer with a most 200 mM, at most 300 mM, at most 400 mM, at most 500 stabilizing component-buffered solution to hydrate the mM, at most 600 mM, at most 700 mM, at most 800 mM, or matrix polymer. A matrix polymer can be any one of the at most 900 mM. In still further aspects of this embodiment, matrix polymers disclosed in the present specification, its a physiologically-acceptable buffer is at a concentration of salts, and/or mixtures thereof. A matrix polymer can be a e.g., about 0.1 mM to about 900 mM, 0.1 mM to about 500 partially crosslinked matrix polymer, a Substantially mM, 0.1 mM to about 100 mM, 0.1 mM to about 90 mM, 0.1 uncrosslinked matrix polymer, a matrix polymer that is essen mM to about 50 mM, 1.0 mM to about 900 mM, 1.0 mM to tially free of a crosslinked matrix polymer, or a matrix poly about 500 mM, 1.0 mM to about 100 mM, 1.0 mM to about 90 mer that is entirely free of a crosslinked matrix polymer as mM, or 1.0 mM to about 50 mM. disclosed in the present specification. The source of the 0130. Aspects of the present specification provide, in part, matrix polymer can be from a bacterial source or an animal a method having an optional step of titrating a stabilizing SOUCC component-buffered solution to obtain a desired pH. A stabi 0.135 Combining a matrix polymer with a stabilizing lizing component-buffered solution can be titrated to any component-buffered solution can be accomplished by any physiologically-acceptable pH desired. As used herein, the method with the proviso that the method used is sufficient to term “a physiologically-acceptable pH refers to a pH in hydrate the matrix polymer in a manner that produces a fluid accord with, or characteristic of the normal functioning of a composition disclosed in the present specification. It is also living organism. As such, a pH used to make a fluid compo understood that any method employed does not result in sition disclosed in the present specification is a pH that has Substantial degradation of matrix polymeras this is inconsis Substantially no long term or permanent detrimental effect tent with a fluid composition disclosed in the present speci when administered to mammal. Non-limiting examples of fication. For example, the step of combining a matrix polymer physiologically-acceptable pH occur within the range of with a stabilizing component-buffered solution can com about pH 5.5 to about pH 8.5. It is understood that acids or prises mixing a matrix polymer with a stabilizing component bases can be used to adjust the pH of a stabilizing component buffered solution at a low speed for a relatively long period of buffered solution. time. Non-limiting examples of a speed used for mixing is 0131 Thus, in an embodiment, a stabilizing component from about 50 rpm to about 500 rpm. The relatively long time buffered solution is titrated to a physiologically-acceptable period for agitation is a time period sufficient to effectively pH. In an aspect of this embodiment, a stabilizing compo combine a matrix polymer with a stabilizing component nent-buffered solution is titrated to pH of, e.g., at least about buffered solution to allow the matrix polymer to hydrate. pH 5.0, at least about pH 5.5, at least about pH 6.0, at least Non-limiting examples of time periods for mixing at a rela about pH 6.5, at least about pH 7.0 or at about pH 7.5. In tive low speed include from about 4 hours to about 16 hours. another aspect of this embodiment, a stabilizing component This combining step is performed at cool ambient tempera buffered solution is titrated to pH of, e.g., at most about pH ture. Non-limiting examples of a cool ambient temperature 5.0, at most about pH 5.5, at most about pH 6.0, at most about include a temperature not exceeding about 25°C. Such as, a pH 6.5, at most about pH 7.0 or at most about pH 7.5. In yet temperature not exceeding about 20° C., a temperature not another aspect of this embodiment, a stabilizing component exceeding about 15°C., or a temperature not exceeding about buffered solution is titrated to pH of, e.g., about pH 5.0 to 10°C. As another non-limiting example, a cool ambient tem about pH 8.0, an effective pH level is about pH 5.0 to about pH perature is a temperature from about 2°C. and about 8°C. 7.0, an effective pH level is about pH 5.0 to about pH 6.0, is 0.136. As another non-limiting example, the step of com about pH 5.5 to about pH 8.0, an effective pH level is about pH bining a matrix polymer with a stabilizing component-buff 5.5 to about pH 7.0, an effective pH level is about pH 5.5 to ered solution may, or may not, involve a cycle of alternating about pH 5.0, is about pH 5.5 to about pH 7.5, an effective pH periods of agitation for a relatively short period of time fol level is about pH 5.5 to about pH 6.5. lowed by periods of rest for a relatively long period of time. 0132 Aspects of the present specification provide, in part, This agitation/rest step may be performed once in order to a method having an optional step of filtering a stabilizing combine a matrix polymer with a stabilizing component component-buffered solution to remove particulates and buffered solution composition, or may be performed for a impurities. For example, a stabilizing component-buffered plurality of times. For example, the agitation/rest step may be US 2011/0224164 A1 Sep. 15, 2011

performed two or more times, five or more times, or ten or or 14 hours or more. In yet other aspects of this embodiment, more times. Agitation of a matrix polymer with a stabilizing a matrix polymer is combined with a stabilizing component component-buffered solution can be accomplished by any buffered solution by mixing the matrix polymer with the method Sufficient to agitate the composition including, with stabilizing component-buffered solution at, e.g., at most 50 out limitation, mechanical shaking, manual shaking, ultra rpm, at most 100 rpm, at most 150 rpm, at most 200 rpm, at sound, vibration, and the like, and combinations thereof. The most 250 rpm, at most 300 rpm, at most 350 rpm, at most 400 relatively short time period for agitation is a time period rpm, at most 450 rpm, or at most 500 rpm for about 6 hours or sufficient to effectively combine a matrix polymer with a more, 7 hours or more, 8 hours or more, 9 hours or more, 10 stabilizing component-buffered solution to create a fluid hours or more, 11 hours or more, 12 hours or more, 13 hours composition disclosed in the present specification. Non-lim or more, or 14 hours or more. In still other aspects of this iting examples of time periods for agitation include from embodiment, a matrix polymer is combined with a stabilizing about 1 minute to about 15 minutes. Similarly, the relatively component-buffered solution by mixing the matrix polymer long time period for rest is a time period sufficient to effec with the stabilizing component-buffered solution at about 50 tively combine a matrix polymer with a stabilizing compo rpm to about 500 rpm for about 8 hours to about 12 hours. nent-buffered solution to create a fluid composition disclosed 0140. In another embodiment, a matrix polymer is com in the present specification. Non-limiting examples of time bined with a stabilizing component-buffered solution by mix periods for rest include from about 15 minute to about 180 ing the matrix polymer with the stabilizing component-buff minutes. For example, a matrix polymer with a stabilizing ered solution using a cycle of alternating periods of agitation component-buffered solution composition can be agitated for for a relatively short period oftime followed by periods of rest about 1 minute and then allowed to rest for about 30 minutes. for a relatively long period of time. In aspects of this embodi If such an agitation/rest step is used, it typically follows the ment, a matrix polymer and a stabilizing component-buffered combining step comprising a low speed for a relatively long Solution is agitated for about 1 minute, about 5 minutes, about period of time described above. 10 minutes, or about 15 minutes, and then allowed to rest for 0.137 After combining a matrix polymer with a stabilizing about 15 minutes, about 30 minutes, about 45 minutes, about component-buffered solution, this composition is allowed to 60 minutes, about 75 minutes, about 90 minutes, about 105 rest for a relative long period of time. A relatively long time minutes, about 120 minutes, about 135 minutes, about 150 period for rest is a time period sufficient to effectively com minutes, about 165 minutes, or about 180 minutes. In other bine a matrix polymer with a stabilizing component-buffered aspects of this embodiment, a matrix polymer and a stabiliz solution to create a fluid composition disclosed in the present ing component-buffered solution is agitated for about 1 specification. Non-limiting examples of time periods for rest minute or more, about 5 minutes or more, about 10 minutes or ing after the combining step include from about 4 hours to more, or about 15 minutes or more, and then allowed to rest about 16 hours. for about 15 minutes or more, about 30 minutes or more, 0.138. Thus, in an embodiment, a matrix polymer is com about 45 minutes or more, about 60 minutes or more, about 75 bined with a stabilizing component-buffered solution in order minutes or more, about 90 minutes or more, about 105 min to hydrate the matrix polymer. In an aspect of this embodi utes, about 120 minutes or more, about 135 minutes or more, ment, a matrix polymer is combined with a stabilizing com about 150 minutes or more, about 165 minutes or more, or ponent-buffered solution in order to hydrate the matrix poly about 180 minutes or more. In yet other aspects of this merand achieve a Smooth consistency of the composition. In embodiment, a matrix polymer and a stabilizing component other aspects of this embodiment, a stabilizing component buffered solution is agitated for at most 1 minute, at most 5 buffered solution is combined with a partially crosslinked minutes, at most 10 minutes, or at most 15 minutes, and then matrix polymer, a Substantially uncrosslinked matrix poly allowed to rest for at most 15 minutes, at most 30 minutes, at mer, a matrix polymer that is essentially free of a crosslinked most 45 minutes, at most 60 minutes, at most 75 minutes, at matrix polymer, or a matrix polymer that is entirely free of a most 90 minutes, at most 105 minutes, at most 120 minutes, crosslinked matrix polymer. at most 135 minutes, at most 150 minutes, at most 165 min 0.139. In another embodiment, a matrix polymer is com utes, or at most 180 minutes. In still other aspects of this bined with a stabilizing component-buffered solution by mix embodiment, a matrix polymer and a stabilizing component ing the matrix polymer with the stabilizing component-buff buffered solution is agitated for at most 1 minute, at most 5 ered solution at a low speed for a relatively long period of minutes, at most 10 minutes, or at most 15 minutes, and then time. In aspects of this embodiment, a matrix polymer is allowed to rest for about 15 minutes or more, about 30 min combined with a stabilizing component-buffered solution by utes or more, about 45 minutes or more, about 60 minutes or mixing the matrix polymer with the stabilizing component more, about 75 minutes or more, about 90 minutes or more, buffered solution at, e.g., about 50 rpm, about 100 rpm, about about 105 minutes, about 120 minutes or more, about 135 150 rpm, about 200 rpm, about 250 rpm, about 300 rpm, about minutes or more, about 150 minutes or more, about 165 350 rpm, about 400 rpm, about 450 rpm, or about 500 rpm for minutes or more, or about 180 minutes or more. In further about 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, aspects of this embodiment, a matrix polymer and a stabiliz 12 hours, 13 hours, or 14 hours. In other aspects of this ing component-buffered solution is agitated for about 1 embodiment, a matrix polymer is combined with a stabilizing minute to about 15 minutes, and then allowed to rest for about component-buffered solution by mixing the matrix polymer 30 minutes to about 60 minutes. with the stabilizing component-buffered solution at, e.g., 0141 Aspects of the present specification provide, in part, about 50 rpm, about 100 rpm, about 150 rpm, about 200 rpm, a method having a step of sizing the fluid composition. Sizing about 250 rpm, about 300 rpm, about 350 rpm, about 400 rpm, the fluid composition is particularly important if crosslinked about 450 rpm, or about 500 rpm for about 6 hours or more, 7 matrix polymers are present because this step 1) produces a hours or more, 8 hours or more, 9 hours or more, 10 hours or composition with a particular mean sized of gel particle, more, 11 hours or more, 12 hours or more, 13 hours or more, and/or 2) produces a composition with a smooth consistency US 2011/0224164 A1 Sep. 15, 2011 24 as opposed to a granular consistency. In fluid compositions wherein after sizing the mean particle size of the crosslinked comprising a crosslinked matrix polymer, the initial matrix polymer is, e.g., about 200 um to about 300 um, about crosslinking process produces a large gel mass that must be 300 um to about 400 um, about 400 um to about 500 um, sized down in order to produce a composition that can be about 500 um to about 600 um, about 600 um to about 700 properly administered to an individual. Such as, e.g., by injec um, about 700 um to about 800 um, about 200 um to about tion. Sizing of gel particles can be accomplished by any 400 um, about 200 um to about 500 um, about 200 um to method suitable to produce a fluid composition that can be about 600 um, about 200 um to about 700 um, about 200 um properly administered into an individual. Non-limiting to about 800 um, about 300 um to about 500 um, about 300 examples include sieving and homogenization. In a sieving um to about 600 um, about 300 um to about 700 um, or about method, a large gel mass included in a fluid composition is 300 um to about 800 um. broken down by passing through a series of sieves or screens 0144. In other aspects of this embodiment, a fluid compo in order to size the gel particles. This method produces gel sition is sized by recirculating between a first vessel and a particles that have a well-defined average size. In a homog second vessel through a narrow aperture wherein after recir enization method, a large gel mass included in a fluid com culation the mean particle size of the crosslinked matrix poly position is broken down by recirculating the fluid composi meris, e.g., about 200um, about 250 um, about 300 um, about tion between a first vessel and a second vessel through a 350 lum, about 400 um, about 450 um, about 500 um, about narrow aperture. The recirculation of a fluid composition may 550 um, about 600 um, about 650 um, about 700 um, about comprise passing the composition from a first vessel into a 750 um, or about 800 um. In yet other aspects of this embodi second vessel through an orifice having any diameter suffi ment, a fluid composition is sized by recirculating between a cient to achieve a Smooth fluid composition. Non-limiting first vessel and a second vessel through a narrow aperture examples of orifice diameters include about 2 mm to about 10 once wherein after recirculation the mean particle size of the mm. The recirculating step can be performed once or a plu crosslinked matrix polymer is, e.g., at most 200 um, at most rality of times, such as, e.g., from 2 to 10 times. 250 um, at most 300 um, at most 350 um, at most 400 um, at 0142. Thus, in an embodiment, a fluid composition is most 450 um, at most 500 um, at most 550 um, at most 600 sized. In other aspects of this embodiment, a fluid composi um, at most 650 um, at most 700 um, at most 750 um, or at tion is sized by sieving wherein after sizing the mean particle most 800 um. In still other aspects of this embodiment, a fluid size of the crosslinked matrix polymer is, e.g., about 200 um, composition is sized by recirculating between a first vessel about 250 um, about 300 um, about 350 um, about 400 um, and a second vessel through a narrow aperture wherein after about 450 um, about 500 um, about 550 um, about 600 um, recirculation the mean particle size of the crosslinked matrix about 650 um, about 700 um, about 750 um, or about 800 um. polymer is, e.g., about 200 um to about 300 um, about 300 um In yet other aspects of this embodiment, a fluid composition is to about 400 um, about 400 um to about 500 um, about 500 sized by sieving wherein after sizing the mean particle size of um to about 600 um, about 600 um to about 700 um, about the crosslinked matrix polymer is, e.g., at most 200 um, at 700 um to about 800 um, about 200 um to about 400 um, most 250 um, at most 300 um, at most 350 um, at most 400 about 200 um to about 500 um, about 200 um to about 600 um, at most 450 um, at most 500 um, at most 550 Lim, at most um, about 200 um to about 700 um, about 200 um to about 600 um, at most 650 um, at most 700 um, at most 750 um, or 800 um, about 300 um to about 500 um, about 300 um to at most 800 um. In still other aspects of this embodiment, a about 600 um, about 300 um to about 700 um, or about 300 fluid composition is sized by sieving wherein after sizing the um to about 800 um. mean particle size of the crosslinked matrix polymer is, e.g., 0145. In other aspects of this embodiment, a fluid compo about 200 um to about 300 um, about 300 um to about 400 sition comprising a crosslinked matrix polymer is sized by um, about 400 um to about 500 um, about 500 um to about recirculating between a first vessel and a second vessel 600 um, about 600 um to about 700 um, about 700 um to through a narrow aperture wherein after recirculation the about 800 um, about 200 um to about 400 um, about 200 um mean particle size of the crosslinked matrix polymer is, e.g., to about 500 um, about 200 um to about 600 um, about 200 about 200 um, about 250 um, about 300 um, about 350 um, um to about 700 um, about 200 um to about 800 um, about about 400 um, about 450 um, about 500 um, about 550 um, 300 um to about 500 um, about 300 um to about 600 um, about 600 um, about 650 um, about 700 um, about 750 um, or about 300 um to about 700 um, or about 300 um to about 800 about 800 um. In yet other aspects of this embodiment, a fluid lm. composition comprising a crosslinked matrix polymer is 0143. In other aspects of this embodiment, a fluid compo sized by recirculating between a first vessel and a second sition comprising a crosslinked matrix polymer is sized by vessel through a narrow aperture wherein after recirculation sieving wherein after sizing the mean particle size of the the mean particle size of the crosslinked matrix polymer is, crosslinked matrix polymer is, e.g., about 200 um, about 250 e.g., at most 200 um, at most 250 um, at most 300 um, at most um, about 300 um, about 350 um, about 400 um, about 450 350 Lum, at most 400 um, at most 450 um, at most 500 um, at um, about 500 um, about 550 um, about 600 um, about 650 most 550 um, at most 600 um, at most 650 um, at most 700 um, about 700 um, about 750 um, or about 800 um. In yet um, at most 750 um, or at most 800 um. In still other aspects other aspects of this embodiment, a fluid composition com of this embodiment, a fluid composition comprising a prising a crosslinked matrix polymer is sized by sieving crosslinked matrix polymer is sized by recirculating between wherein after sizing the mean particle size of the crosslinked a first vessel and a second vessel through a narrow aperture matrix polymer is, e.g., at most 200 um, at most 250 Lim, at wherein after recirculation the mean particle size of the most 300 um, at most 350 um, at most 400 um, at most 450 crosslinked matrix polymer is, e.g., about 200 um to about um, at most 500 um, at most 550 um, at most 600 um, at most 300 um, about 300 um to about 400 um, about 400 um to 650 um, at most 700 um, at most 750 um, or at most 800 um. about 500 um, about 500 um to about 600 um, about 600 um In still other aspects of this embodiment, a fluid composition to about 700 um, about 700 um to about 800 um, about 200 comprising a crosslinked matrix polymer is sized by sieving um to about 400 um, about 200 um to about 500 um, about US 2011/0224164 A1 Sep. 15, 2011

200 um to about 600 um, about 200 um to about 700 um, 3.0 mL. In addition the type of needle used in conjunction about 200 um to about 800 um, about 300 um to about 500 with the syringe is a needle sufficient to effectively administer um, about 300 um to about 600 um, about 300 um to about a therapeutically effective amount of a fluid composition 700 um, or about 300 um to about 800 um. disclosed in the present specification into a dermal region, 0146 In aspects of this embodiment, a fluid composition is such as, e.g., a diameter of between about 18G and about 40G sized by recirculating between a first vessel and a second and a needle length of at about 2 mm or more in length. vessel through a narrow aperture once. In aspects of this 0151. Thus, in an embodiment, a fluid composition is embodiment, a fluid composition is sized recirculating filled into a syringe. In aspects of this embodiment, a fluid between a first vessel and a second vessel through a narrow composition is filled into a syringe having an internal Volume aperture, e.g., twice, three times, four times, five times, six of about 0.4 mL, about 0.5 mL, about 0.6 mL, about 0.7 mL, times, seven times, eight times, nine times, or ten times. In about 0.8 mL, about 0.9 mL, about 1 mL, about 1 mL, about aspects of this embodiment, a fluid composition is sized by 1.5 mL, about 2 mL, about 2.5 mL, or about 3 mL. In other recirculating between a first vessel and a second vessel aspects of this embodiment, a fluid composition is filled into through a narrow aperture, e.g., twice, three times, four times, a Syringe having an internal Volume of at least 0.4 mL, at least five times, six times, seven times, eight times, nine times, or 0.5 mL, at least 0.6 mL, at least 0.7 mL, at least 0.8 mL, at ten times. In other aspects of this embodiment, a fluid com least 0.9 mL, at least 1 mL, at least 1 mL, at least 1.5 mL, at position is sized by recirculating between a first vessel and a least 2 mL, at least 2.5 mL, or at least 3 mL. In yet other second vessel through a narrow aperture, e.g., twice to ten aspects of this embodiment, a fluid composition is filled into times, twice to eight times, twice to six times, twice to four a Syringe having an internal Volume of about 0.4 mL to about times, three times to five times, three times to six times, or 3 mL, about 0.5 mL to about 1.5 mL, or about 0.8 mL to about three times to seven times. 2.5 mL. In another aspect, a syringe filled with a fluid com 0147 In other aspects of this embodiment, a fluid compo position is combined with a needle. In aspects of this embodi sition is recirculated between a first vessel and a second vessel ment, a Syringe filled with a fluid composition is combined through a narrow aperture having a diameter of, e.g., about 2 with a needle having a diameter of about 18G, about 22G, mm, about 3 mm, about 4 mm, about 5 mm, about 6 mm, about 25G, about 28G, about 30G, about 33G, or about 40G. about 7 mm, about 8 mm, about 9 mm, or about 10 mm. In yet In other aspects of this embodiment, a syringe filled with a other aspects of this embodiment, a fluid composition is recir fluid composition is combined with a needle having a diam culated between a first vessel and a second vessel through a eter of about 18G or smaller, about 22G or smaller, about 25G narrow aperture having a diameter of, e.g., at least 2 mm, at or smaller, about 28G or smaller, about 30G or smaller, about least 3 mm, at least 4 mm, at least 5 mm, at least 6 mm, at least 33G or smaller, or about 40G or smaller. In yet other aspects 7 mm, at least 8 mm, at least 9 mm, or at least 10 mm. In still of this embodiment, a syringe filled with a fluid composition other aspects of this embodiment, a fluid composition is recir is combined with a needle having a diameter of about 18G to culated between a first vessel and a second vessel through a about 40G, about 22G to about 33G, or about 26G to about narrow aperture having a diameter of e.g., at most 2 mm, at 40G. most 3 mm, at most 4 mm, at most 5 mm, at most 6 mm, at 0152 Aspects of the present specification provide, in part, most 7 mm, at most 8 mm, at most 9 mm, or at most 10 mm. a method having an optional step of sterilizing a syringe filled In further aspects of this embodiment, a fluid composition is with a fluid composition disclosed in the present specifica recirculated between a first vessel and a second vessel tion. As used herein, the term “sterilizing refers to any through a narrow aperture having a diameter of, e.g., about 2 method known in the art to effectively kill or eliminate trans mm to about 4 mm, about 2 mm to about 6 mm, about 2 mm missible agents without Substantially altering of degrading a to about 8 mm, or about 2 mm to about 10 mm. fluid composition disclosed in the specification. A sterilized 0148. Additional method steps in accordance with making fluid composition can remain stable for about 3 months to a fluid composition disclosed in the present specification may, about 3 years. One method of sterilization of a filled syringe or may not, include degassing the composition, filling is by autoclave. Autoclaving can be accomplished by apply Syringes with the composition, and sterilizing the composi ing a mixture of heat, pressure and moisture to a sample in tion. need of sterilization. Many different sterilization tempera 0149 Aspects of the present specification provide, in part, tures, pressures and cycle times can be used for this step. For a method having an optional step of degassing a fluid com example, the filled Syringes may be sterilized at a temperature position disclosed in the present specification. Degassing a of at least about 120° C. to about 130° C. or greater. Moisture fluid composition disclosed in the present specification can be may or may not be utilized. The pressure applied is in some accomplished using a standard device based on conventional embodiments depending on the temperature used in the ster techniques and may be done under vacuum. Degassing is ilization process. The sterilization cycle may be at least about performed for a time period sufficient to remove the desired 1 minute to about 20 minutes or more. amount of gases from a fluid composition. Non-liming 0153. Another method of sterilization incorporates the use examples of Sufficient time period for degassing include of a gaseous species which is known to kill or eliminate about 2 hours to about 8 hours. transmissible agents. Preferably, ethylene oxide is used as the 0150. Aspects of the present specification provide, in part, sterilization gas and is known in the art to be useful in steril a method having an optional step of filling a syringe with a izing medical devices and products. fluid composition disclosed in the present specification. 0154) A further method of sterilization incorporates the Syringes useful according to the present description include use of an irradiation source which is known in the art to kill or any syringe known in the art for administering a therapeuti eliminate transmissible agents. A beam of irradiation is tar cally effective amount a fluid composition disclosed in the geted at the Syringe containing the HA composition, and the present specification into a dermal region, such as, e.g., a wavelength of energy kills or eliminates the unwanted trans Syringe having an internal Volume of about 0.4 mL to about missible agents. Preferable energy useful include, but is not US 2011/0224164 A1 Sep. 15, 2011 26 limited to ultraviolet (UV) light, gamma irradiation, visible vidual Suffering from skin roughness a fluid composition light, microwaves, or any other wavelength or band of wave comprising a matrix polymer and a stabilizing component, lengths which kills or eliminates the unwanted transmissible wherein the administration of the composition decreases skin agents, preferably without Substantially altering of degrading roughness, thereby treating skin roughness. In still another the HA composition. aspect of this embodiment, a method of treating a lack of skin 0155 Thus, in an embodiment, a syringe filled with a fluid tautness comprises the step of administering to an individual composition is sterilized. In aspects of this embodiment, a Suffering from a lack of skin tautness a fluid composition syringe filled with a fluid composition is sterilized by auto comprising a matrix polymer and a stabilizing component, claving, gas sterilization, or irradiation. In other aspects of wherein the administration of the composition makes the skin this embodiment, a syringe filled with a fluid composition can tauter, thereby treating a lack of skin tautness. remain stable after sterilization for about 3 months, about 6 0160. In a further aspect of this embodiment, a method of months, about 9 months, about 12 months, about 18 months, treating a skin stretch line or mark comprises the step of about 24 months, about 30 months, or about 36 months. In yet administering to an individual Suffering from a skin stretch other aspects of this embodiment, a syringe filled with a fluid line or marka fluid composition comprising a matrix polymer composition can remain stable after Sterilization for at least 3 and a stabilizing component, wherein the administration of months, at least 6 months, at least 9 months, at least 12 the composition reduces or eliminates the skin stretch line or months, at least 18 months, at least 24 months, at least 30 mark, thereby treating a skin stretch line or mark. In another months, or at least 36 months. In still other aspects of this aspect of this embodiment, a method of treating skin paleness embodiment, a Syringe filled with a fluid composition can comprises the step of administering to an individual Suffering remainstable after sterilization for about 3 months to about 12 from skin paleness a fluid composition comprising a matrix months, about 3 months to about 24 months, about 3 months polymer and a stabilizing component, wherein the adminis to about 36 months, about 6 months to about 12 months, about tration of the composition increases skin tone or radiance, 6 months to about 24 months, or about 6 months to about 36 thereby treating skin paleness. In another aspect of this months. embodiment, a method of treating skin wrinkles comprises 0156 Aspects of the present specification provide, in part, the step of administering to an individual Suffering from skin a method of improving a condition of skin in an individual in wrinkles a fluid composition comprising a matrix polymer need thereof, the method comprising the steps of administer and a stabilizing component, wherein the administration of ing a fluid composition disclosed in the present specification the composition reduces or eliminates skin wrinkles, thereby into a dermal region of the individual, wherein the adminis treating skin wrinkles. In yet another aspect of this embodi tration improves the condition. ment, a method of treating skin wrinkles comprises the step of 0157 Aspects of the present invention provide, in part, a administering to an individual a fluid composition compris condition of skin. Non-limiting examples of a skin condition ing a matrix polymer and a stabilizing component, wherein include dehydration, lack of skin elasticity, roughness, lack of the administration of the composition makes the skin resistant skin tautness, skin stretch line and/or marks, skin paleness, to skin wrinkles, thereby treating skin wrinkles. skin wrinkles, and the like. 0.161 Aspects of the present invention provide, in part, a 0158 Aspects of the present invention provide, in part, dermal region. As used herein, the term "dermal region' improving a skin condition. Non-limiting examples of refers to the region of skin comprising the epidermal-dermal improving a skin condition include rehydrating the skin, pro junction and the dermis including the Superficial dermis (pap viding increased elasticity to the skin, reducing skin rough illary region) and the deep dermis (reticular region). The skin ness, making the skin tauter, reducing or eliminating stretch is composed of three primary layers: the epidermis, which lines or marks, giving the skin better tone, shine, brightness provides waterproofing and serves as a barrier to infection; and/or radiance to reduce paleness, reducing or eliminating the dermis, which serves as a location for the appendages of wrinkles in the skin, providing wrinkle resistance to the skin, skin; and the hypodermis (Subcutaneous adipose layer). The and the like. epidermis contains no blood vessels, and is nourished by 0159. Thus, in an embodiment, a method of treating a skin diffusion from the dermis. The main type of cells which make condition comprises the step of administering to an individual up the epidermis are keratinocytes, melanocytes, Langerhans Suffering from a skin condition a fluid composition compris cells and Merkels cells. ing a matrix polymer and a stabilizing component, wherein 0162 The dermis is the layer of skin beneath the epidermis the administration of the composition improves the skin con that consists of connective tissue and cushions the body from dition, thereby treating the skin condition. In an aspect of this stress and strain. The dermis is tightly connected to the epi embodiment, a method of treating skin dehydration com dermis by a basement membrane. It also harbors many prises the step of administering to an individual Suffering Mechanoreceptor/nerve endings that provide the sense of from skin dehydration a fluid composition comprising a touch and heat. It contains the hair follicles, Sweat glands, matrix polymer and a stabilizing component, wherein the sebaceous glands, apocrine glands, lymphatic vessels and administration of the composition rehydrates the skin, blood vessels. The blood vessels in the dermis provide nour thereby treating skin dehydration. In another aspect of this ishment and waste removal from its own cells as well as from embodiment, a method of treating a lack of skin elasticity the Stratum basale of the epidermis. The dermis is structurally comprises the step of administering to an individual Suffering divided into two areas: a Superficial area adjacent to the from a lack of skin elasticity a fluid composition comprising epidermis, called the papillary region, and a deep thicker area a matrix polymer and a stabilizing component, wherein the known as the reticular region. administration of the composition increases the elasticity of 0163 The papillary region is composed of loose areolar the skin, thereby treating a lack of skin elasticity. In yet connective tissue. It is named for its fingerlike projections another aspect of this embodiment, a method of treating skin called papillae that extend toward the epidermis. The papillae roughness comprises the step of administering to an indi provide the dermis with a "bumpy” surface that interdigitates US 2011/0224164 A1 Sep. 15, 2011 27 with the epidermis, strengthening the connection between the Such fluid compositions, and methods of treating skin condi two layers of skin. The reticular region lies deep in the pap tions using Such fluid compositions. illary region and is usually much thicker. It is composed of dense irregular connective tissue, and receives its name from Example 1 the dense concentration of collagenous, elastic, and reticular A Method of Making a Fluid Composition fibers that weave throughout it. These protein fibers give the dermis its properties of strength, extensibility, and elasticity. 0169. This example illustrates how to make a fluid com Also located within the reticular region are the roots of the position disclosed in the present specification. hair, sebaceous glands, Sweat glands, receptors, nails, and 0170 To combine a stabilizing component with a physi blood vessels. Tattoo ink is held in the dermis. Stretch marks ologically-acceptable buffer to make a stabilizing compo from pregnancy are also located in the dermis. nent-buffered solution, 0.9 g of mannitol (Cooper Pharma ceutical, Inc.) was added to 1 L of a phosphate buffer solution 0164. The hypodermis is not part of the skin, and lies (comprising 8.5 g NaCl, 0.563 g NaH2PO, 0.045 g below the dermis. Its purpose is to attach the skin to under NaHPO, and water) in a 10 liter bottle, and mixed for 15 lying bone and muscle as well as Supplying it with blood minutes. This step produces a stabilizing component-buff vessels and nerves. It consists of loose connective tissue and ered solution comprising a phosphate buffer solution (pH 7.2) elastin. The main cell types are fibroblasts, macrophages and containing 0.9mg/mL of mannitol. adipocytes (the hypodermis contains 50% of body fat). Fat 0171 To filter the stabilizing component-buffered solu serves as padding and insulation for the body. tion, the mannitol-phosphate buffer solution made above was 0.165 Aspects of the present invention provide, in part, an filtered on line with a 0.2 Lum filter under pressure. individual. As used herein, the term “individual' refers to any 0172 To combining a matrix polymer with the stabilizing mammal including a human being. component-buffered solution to hydrate the matrix polymer, 0166 Aspects of the present invention provide, in part, about 60% of the mannitol-phosphate buffer solution was administering a fluid composition disclosed in the present poured in a new bottle and uncrosslinked sodium hyaluronan specification. As used herein, the term “administering means polymer having a molecular weight between about 2.5 MDa any delivery mechanism that provides a fluid composition and about 3.0 MDa was added to the mannitol-phosphate comprising a matrix polymer and a stabilizing component to buffer solution. This was completed with the remaining 40% an individual that potentially results in a clinically, therapeu of the mannitol-phosphate buffer Solution, giving a final con tically, or experimentally beneficial result. The actual deliv centration of uncrosslinked hyaluronan of about 13.5 mg/L. ery mechanism used to administer a fluid composition dis This composition was then gently, mechanically mixed at a closed in the present specification to an individual can be speed of about 100 rpm to about 200 rpm for about 8 hours to determined by a person of ordinary skill in the art by taking about 12 hours at a cool ambient temperature of about 2°C. to into account factors, including, without limitation, the type of about 8°C. The composition was then subjected to agitation skin condition, the location of the skin condition, the cause of by manually shaking the bottle containing the composition the skin condition, the severity of the skin condition, the for about 1 minute, followed by a period of rest for about 30 degree of relief desired, the duration of relief desired, the minutes. This mixing step was repeated three additional times particular fluid composition used, the rate of excretion of the before the composition was then allowed to rest about 8 to particular fluid composition used, the pharmacodynamics of about 12 hours. the particular fluid composition used, the nature of the other 0173 To size a fluid composition, the fluid composition compounds included in the particular fluid composition used, above was recirculated four times from one bottle into a the particular route of administration, the particular charac second bottle thorough a narrow orifice having a diameter of teristics, history and risk factors of the individual. Such as, about 3 mm and about 5 mm. e.g., age, weight, general health and the like, or any combi 0.174. To degas a fluid composition, the composition nation thereof. described above was degassed for about four hours using 0167 Thus, in an embodiment, a fluid composition com standard device based on conventional techniques. prising a matrix polymer and a stabilizing component is administered to a skin region of an individual. In an aspect of Example 2 this embodiment, a fluid composition comprising a matrix polymer and a stabilizing component is administered to a skin Stabilizing Component Reduces or Prevents Degra region of an individual by injection. In another aspect of this dation of Matrix Polymer embodiment, a fluid composition comprising a matrix poly 0.175. This example illustrates that the addition of a stabi mer and a stabilizing component is administered to a skin lizing component reduces or prevents degradation of a matrix region of an individual by injection into a dermal region. In polymer included in a fluid composition disclosed in the aspects of this embodiment, a fluid composition comprising a present specification. matrix polymer and a stabilizing component is administered 0176 Fluid compositions made for testing were prepared to a skin region of an individual by injection into, e.g., an as described in Example 1, except that 1) 1 mL of each fluid epidermal-dermal junction region, a papillary region, a composition was made and the amount of mannitol added to reticular region, or any combination thereof. the test fluid compositions was 0% (w/v) for control, 0.5% (w/v) and 5% (w/v). EXAMPLES 0177 Degradation of hyaluronan polymer included in the fluid compositions and rheological processing of the results 0168 The following examples illustrate representative were performed according to conventional methods. Resis embodiments now contemplated, but should not be construed tance of hyaluronan polymer to degradation was assessed in to limit the disclosed fluid compositions, methods of forming fluid composition with and without mannitol and these com US 2011/0224164 A1 Sep. 15, 2011 28 positions were compared by analyzing the time it took for the solubility in water is 1 g mannitol/5.5 ml water, i.e. mass composition to reach a dynamic viscosity of 5 Pa's T(m=5 solubility of 15.4%. Taken together, these results indicate that Pas). The degradation test was repeated twice and a mean fluid compositions comprising a matrix polymer can include dynamic viscosity T(m=5 Pas) 1 was calculated from the 2 about 15.4% mannitol before this polyol begins to precipitate tests (Table 4). In general, the shorter the time to reach a out of Solution. dynamic viscosity of 5 Pas T(m=5 Pas), the lower the 0182. The pH of the fluid compositions was measured resistance of hyaluronan polymer to degradation. Thus, to using a pH meter. Test compositions comprising 0% (w/v), show that addition of mannitol to a fluid composition had a 0.5% (w/v), 5% (w/v), and 9% (w/v) mannitol all had a pH of beneficial effect on resistance of hyaluronan polymer to 6.9, while the fluid composition comprising 17% (w/v) had a breakdown, it was shown that T(m5 Pas), , PT pH of 6.8 (Table 5). These results indicate that mannitol has (m-5 Pa's), it it. For each fluid composition the no effect on the pH of a fluid composition because all pH results of the rheological test (values of G', G", tan 8, m*=f values were within the measurement error range of the pH (time)+mathematical model of curve m=f(time)) were deter meter (+0.2). mined and the curves obtained (FIG. 1). 0183 Theosomolarity of the fluid compositions was mea Sured using an osmometer. Test compositions exhibited a TABLE 4 wide range of osmolarity that was correlated with the amount of mannitol added to the composition (Table 5). In general, Breakdown Test the osmolarity of a fluid composition increase as the amount Mean T ofmannitol increased. The results indicated that a fluid com Fluid T (m = Std. position comprising a matrix polymer and 0.5% mannitol Composition Test (m = 5 Pas) 5 Pas) deviation CV (%) preserved the required osmolarity for hyaluronan, namely an Hyaluronan 1 747 1099 498 45 osmolarity range of about 270 mOsm/L to about 390 mOsm/ (13.5 mg/L) 2 1452 L. It general, an osmolarity range of about 200 mOsm/L to Hyaluronan 1 3351 3127 317 10 about 400 mOsm/L is the range approved for viscoelastic (13.5 mg/L) 2 2903 5% mannitol ophthalmic devices. Hyaluronan 1 2933 2355 818 35 0.184 The data obtained from the osmolarity test were (13.5 mg/L) 2 1776 further analyzed by linear regression. This analysis revealed 0.5% mannitol that y=68.576x-17.118 and that R=0.9888. From this for mula, it was calculated that the addition of 1% mannitol to a 0.178 As shown in Table 4, hyaluronan polymer was more fluid composition comprising hyaluronan would increase the resistant to degradation when mannitol was included in the osmolarity of the composition by 52 mOsm/L to approxi fluid composition as compared to the resistance hyaluronan mately 351 mOsm/L. As such, a fluid composition compris polymer in composition without mannitol (Table 4, FIG. 1). ing a matrix polymer and 1% mannitol was an effective com In fact, the higher the mannitol concentration in a fluid com bination that balanced the opposite effects of improving a position, the longer the time required for the hyaluronan fluid composition's resistance to hyaluronan degradation and polymer to degrade. As such, incorporating a stabilizing com the increase in osmolarity upon addition of mannitol to the ponent like mannitol into a fluid composition allowed composition. uncrosslinked hyaluronan polymer remained intact longer because the stabilizing component increased the resistance of TABLE 5 hyaluronan polymer to degradation (FIG. 1). Thus, the addi tion of a stabilizing component to a fluid composition pro Mannitol Effects on Properties of Fluid Compositions vided protection to a matrix polymer to degradation. Appearance of Fluid Osmolarity Fluid Composition Composition pH (mCSm/L) Example 2 Hyaluronan (13.5 mg/L) Colorless and transparent 6.9 299 Hyaluronan (13.5 mg/L) Colorless and transparent 6.9 333 Effects of Stabilizing Component on Various Proper Mannitol (0.5%) ties of Fluid Composition Hyaluronan (13.5 mg/L) Colorless and transparent 6.9 589 Mannitol (5%) 0179 This example illustrates the effects of a stabilizing Hyaluronan (13.5 mg/L) Colorless and transparent 6.9 918 component on various properties of a fluid composition dis Mannitol (9%) closed in the present specification including fluid appearance, Hyaluronan (13.5 mg/L). White and cloudy 6.8 ND pH, osmolarity, and dynamic viscosity. Mannitol (17%) 0180 Fluid compositions made for testing were prepared as described in Example 1, except that 1) 1 mL of each fluid 0185. The dynamic viscosity of the fluid compositions composition was made and the amount of mannitol added to was measured using a rheometer. Test compositions compris the test fluid compositions was 0% (w/v) for control, 0.5% ing 0% (w/v), 5% (w/v), and 9% (w/v) mannitol exhibited a (w/v), 5% (w/v), 9%(w/v), and 17°/o(w/v). consistent dynamic viscosity over time and all within 20 Pa's 0181. The appearance of the fluid compositions was visu of each other at 1 Pa (FIG. 2). The mean dynamic viscosity of ally examined. Test compositions comprising 0% (w/v), 0.5% these three fluid compositions was as follows: compositions (w/v), 5% (w/v), and 9% (w/v) mannitol all appeared color comprising 0% (w/v) mannitol had a mean dynamic viscosity less and transparent, while the fluid composition comprising of 162 Pas; compositions comprising 5% (w/v) mannitol had 17% (w/v) mannitol appeared white and cloudy (Table 5). a mean dynamic viscosity of 152 Pars; compositions compris These results indicate that mannitol was soluble in all fluid ing 9% (w/v) mannitol had a mean dynamic viscosity of 148 compositions tested, except for the composition comprising Pas. These results indicate that the effect of a stabilizing 17% (w/v) mannitol. Furthermore, it is known that mannitol component was negligible because the addition of mannitol in US 2011/0224164 A1 Sep. 15, 2011 29 an amount less than or equal to about 9% only resulted in a test fluid compositions was about 1% (w/v). The degassed change in dynamic viscosity of about 20 Pa's at 1 Pa. fluid composition was then filled into a glass syringe and sterilized by autoclaving at 130° C. for 3 minutes. Example 3 0193 The resulting composition-filled syringes will be Effects of Sterilization on Fluid Compositions Com stored at about 2°C. to about 8°C. and at about 18°C. to about prising a Stabilizing Component 22°C. to determine shelf life of the fluid compositions. The stored compositions will be tested for various properties 0186 This example illustrates the effects of sterilization including dynamic viscosity, pH appearance and osmolarity on various properties of a fluid composition disclosed in the at 3 months, 6 months, 9 months, 12 months, 18 months, 24 present specification including pH, dynamic viscosity and months, 30 months, and 36 months. These tests will deter stability of Stabilizing component. mine the stability of fluid composition-filled Syringes and as 0187 Fluid compositions made for testing were prepared such the shelf life of such products. as described in Example 1, except that 1) 1 mL of each fluid composition was made and the amount of mannitol added to Example 5 the test fluid compositions was 0% (w/v) and 1.1%(w/v). Fluid compositions prepared above were filled in a glass Safety and Efficacy Study of Fluid Composition syringe and sterilized by autoclaving at 130°C. for 3 minutes. 0194 This example illustrates the safety and efficacy of a 0188 The pH of the fluid compositions was measured fluid composition disclosed in the present specification. using a pH meter. These results indicate that sterilization had 0.195 Fluid compositions were prepared as described in no effect on the pH of a fluid composition because all pH Example 1, except that the amount of mannitol added to the values were within the measurement error range of the pH test fluid compositions was about 1% (w/v). The degassed meter (+0.2) (Table 6). fluid composition was then filled into a glass syringe and 0189 The dynamic viscosity of the fluid compositions sterilized by autoclaving at 130° C. for 3 minutes. was measured before and after sterilization using a rheometer. 0196. The study included 39 individuals and comprised The difference in viscosity before and after sterilization was men and women between the ages of 30 and 45 years. All 54 Pa's for fluid compositions without mannitol and 61 Pa's baseline data including consent, demographics, adverse for fluid compositions comprising 1.1% (w/v) mannitol events and skin evidence was collected from each individual (Table 6). These results indicate that the addition of a stabi before the study began. After the baseline visit, each indi lizing component had a negligible effect on dynamic viscos vidual was subdermally injected with the fluid composition ity because the difference between the two compositions was described above and this was considered day 0 (DO). Follow within the measurement error range of the rheometer (10%). up visits took place at day 15 (D15 +7 days) for the second As such, there was no significant difference in dynamic vis injection, at day 30 (D30+7 days) for the third injection and cosity of the fluid compositions before and after sterilization. finally at day 60 (D60+7 days) for final assessment. Dermal 0190. The chemical and physical stability of mannitol administration was performed using either a depot injection after sterilization was determined by autoclaving 25% Man method or picotage injection method. At each study visit, nitol (Invenex Pharmaceuticals, Itasca, Ill.) five times at 121° individuals were examined for adverse events and skin evi C. for 15 minutes. The results indicate that mannitol was dence, and a questionnaire was given to assess physician and chemically and physically stable after this sterilization subject satisfaction. The total study duration was 60 days. regime. 0197) The study evaluated efficacy of the compositions on hydration and elasticity of the skin after 60 days of use of the TABLE 6 fluid composition on different skin areas including the region Effects of Sterilization on Properties of Fluid Compositions around the eye, the cheek region, the peri-oral region, and the neck region. Skin measurements were assessed at each of the Fluid Composition four visits from day 0 to day 60, on different areas, by Skin Hyaluronan Evidence for IOMATM (IntuiSkin, Research Triangle Park, Composition Hyaluronan (13.5 mg/L) N.C.). Skin Evidence for IOMA is a probe-based system that Sterilization Property (13.5 mg/L) Mannitol (1.1%) measures the physical and visual parameters of the skin. The Before Dynamic viscosity at 102 Pa. S 118 Pa. S Visio Probe uses its high-resolution sensor to capture with an sterilization 1 Pa extreme precision the skin images including wrinkles, sebum, pH 7.1 7.0 hairiness, dark spots, and clogged pores/bacterial infection. After Dynamic viscosity at 48 Pa. S S7 Pa. S The Physio Probe contains high-technology sensors and sterilization 1 Pa extracts in Vivo the key characteristics of the skin including pH 7.1 7.0 hydration, trans-epidermal water loss (TEWL), and the skin temperature. 0198 For each individual administered the fluid compo Example 4 sition using a depot injection method, the cheek, neck, peri Determining the Stability of Fluid Composition oral and eye regions were measured for hydration (%) at each Filled Syringe visit from D0 to D60 by Skin Evidence for IOMATM and a mean hydration was determined at each visit (Table 7). Coef 0191 This example illustrates how to determine the long ficient of anisotropy (%), arithmetical roughness (Ra), and term stability of a fluid composition disclosed in the present luminance (L) were also measured for each individual at each specification. visit from D0 to D60 by Skin Evidence for IOMATM and 0.192 Fluid compositions were prepared as described in mean values calculated. Statistical analyses were performed Example 1, except that the amount of mannitol added to the using SASR software version 9.1 (SAS Institute, Inc. Cary, US 2011/0224164 A1 Sep. 15, 2011 30

N.C.). The results indicate that overall skin hydration of the region. In particular, skin roughness of the neck region was cheek (p=0.0036), neck (p=0.0346) and peri-oral (p=0.0024) significantly decreased by D30 of treatment (median of regions was significantly increased by the treatment with the 16.7%) as compared to D0 (median of 13.9%, p=0.0001). No fluid composition. In particular, skin hydration of the cheek statistically significant difference was observed in skin region was significantly increased by D15 of treatment (mean roughness when the fluid compositions were administered of 55.8%) as compared to D0 (mean of 50.9%) and this using a picotage injection method. improvement in skin condition was maintain through D30 of 0202) No statistically significant differences in skin lumi treatment (mean of 56.4%) as compared to D0 (mean of nance were detected for any of the four regions examined 50.9%, p=0.0262) and D60 of treatment (mean of 59.3%) as using either the depot injection method or the picotage injec compared to D0 (mean of 50.9%, p=0.0021). In addition, skin tion method. hydration of the neck region was significantly increased by 0203 Treatment was well-tolerated with all adverse D15 of treatment (mean of 66.0%) as compared to D0 (mean events related to injection technique rather than to the prod of 59.0%) and this improvement in skin condition was main uct. All adverse events were transient, with a mean duration of tain through D30 of treatment (mean of 66.5%) of as com 4 days, with no sequels. pared to D0 (mean of 59.0%, p=0.0022), and D60 of treat 0204 Regarding questionnaires designed to evaluate phy ment (mean of 65.3%) as compared to D0 (mean of 59.0%, sicians assessment of treatment, physicians using the depot p=0.0448). Furthermore, skin hydration of the peri-oral injection method assessed skin texture (roughness) as region was significantly increased by D15 of treatment (mean “improved” or “very improved” in 88.9% of individuals of 58.9%) as compared to D0 (mean of 52.4%) and this administered the fluid composition at D15, in 100% of indi improvement in skin condition was maintain through D30 of viduals administered the fluid composition at D30, and in treatment (mean of 61.2%) as compared to D0 (mean of 95.7% of individuals administered the fluid composition at 52.4%, p=0.0041) and D60 of treatment (mean of 59.3%) as D60. Physicians using the depot injection method assessed compared to D0 (mean of 52.4%, p=0.0467). skin brightness as “improved' or “very improved in 74.1%

TABLE 7 Assessment of Fluid Composition on Hydration of Skin Regions (Depot Method Skin Visit

Region DO D15 D30 D60 C

Cheek N 23 2O 17 18 Mixed Mean SO.9% 11.0% 55.8% 10.5% 56.4% 13.9% 59.3% + 11.4% model Median 54.3% 57.70% SS.6% 58.5% P = 0.0036 MiniMax 29.1%. 68.2%. 36.5%f 72.7%. 28.0%83.1% 41.0%, 76.1% Neck N 2O 19 17 16 Mixed Mean 59.0% 9.4%. 66.0% 9.6% 66.5% 11.9% 65.3% 9.9% model Median 58.7% 66.5% 70.0% 61.4% P = O.O346 MiniMax 41.4%.74.7% 48.4%,81.2% 43.5%.83.2% 47.4%82.9% Peri-oral N 2O 16 15 15 Mixed Mean 52.4% 13.5%. 58.9% 12.1%. 61.2% 14.8% 59.3% + 11.0% model Median SO.1% 58.4% 62.6% 61.1% P = 0.0024 MiniMax 27.4%, 79.6%. 37.1%.81.7%. 31.0%80.6% 37.6%. 79.4% Eyes N 21 16 16 14 Mixed Mean 59.6% 12.2% 62.9% 10.7% S5.8% 14.3% 61.4% 10.7% model Median 56.3% 60.6% 53.7% MiniMax 42.6%, 81.4% 45.4%. 82.6%. 19.8%. 80.8% 42.4%. 78.3%

0199 For each individual administered the fluid compo of individuals administered the fluid composition at D15, in sition using a picotage injection method, the cheek, neck, 87.5% of individuals administered the fluid composition at peri-oral and eye regions were measured for hydration (%) at D30, and in 91.3% of individuals administered the fluid com each visit from D0 to D60 by Skin Evidence for IOMATM and position at D60. Physicians using the depot injection method a mean hydration was determined at each visit. The results assessed skin hydration as “improved' or “very improved in indicated that there was no statistically significant difference 88.9% of individuals administered the fluid composition at in the hydration of the cheek, neck, peri-oral, or eye regions of D15, in 100% of individuals administered the fluid composi individuals administered the fluid compositions using the tion at D30, and in 95.7% of individuals administered the picotage injection method. fluid composition at D60. Physicians using the depot injec 0200. With respect to anisotrophy, the results indicate an tion method assessed skin appearance (color) as “improved overall improvement of skin condition from the neck and or “very improved in 48.1% of individuals administered the peri-oral regions when the fluid composition was adminis fluid composition at D15, in 91.7% of individuals adminis tered using a depot injection method. No statistically signifi tered the fluid composition at D30, and in 91.3% of individu cant difference was observed in anisotropy when the fluid als administered the fluid composition at D60. compositions were administered using a picotage injection 0205 Regarding questionnaires designed to evaluate indi method. viduals assessment of treatment, individuals administered 0201 With respect to skin roughness, the results indicate the fluid composition using the depot injection method an overall improvement of skin condition from the neck assessed skin texture (roughness) as “improved' or “very US 2011/0224164 A1 Sep. 15, 2011

improved in 72.0% of individuals administered the fluid are only illustrative of the principles of the subject matter composition at D15, in 94.7% of individuals administered the disclosed in the present specification. Therefore, it should be fluid composition at D30, and in 80.9% of individuals admin understood that the disclosed subject matter is in no way istered the fluid composition at D60. Individuals adminis limited to a particular methodology, protocol, and/or reagent, tered the fluid composition using the depot injection method etc., described herein. As such, various modifications or assessed skin brightness as “improved' or “very improved in changes to or alternative configurations of the disclosed Sub 84.0% of individuals administered the fluid composition at ject matter can be made in accordance with the teachings D15, in 84.3% of individuals administered the fluid compo herein without departing from the spirit of the present speci sition at D30, and in 85.7% of individuals administered the fication. Lastly, the terminology used herein is for the purpose fluid composition at D60. Individuals administered the fluid of describing particular embodiments only, and is not composition using the depot injection method assessed skin intended to limit the scope of the present invention, which is hydration as “improved' or “very improved in 84.0% of defined solely by the claims. Accordingly, the present inven individuals administered the fluid composition at D15, in tion is not limited to that precisely as shown and described. 94.8% of individuals administered the fluid composition at 0209 Certain embodiments of this invention are described D30, and in 95.0% of individuals administered the fluid com herein, including the best mode known to the inventors for position at D60. Individuals administered the fluid composi carrying out the invention. Of course, variations on these tion using the depot injection method assessed skin appear described embodiments will become apparent to those of ance (color) as “improved' or “very improved in 36.0% of ordinary skill in the art upon reading the foregoing descrip individuals administered the fluid composition at D15, in tion. The inventor expects skilled artisans to employ Such 42.1% of individuals administered the fluid composition at variations as appropriate, and the inventors intend for the D30, and in 42.9% of individuals administered the fluid com invention to be practiced otherwise than specifically position at D60. described herein. Accordingly, this invention includes all 0206 Regarding questionnaires designed to evaluate indi modifications and equivalents of the Subject matter recited in viduals assessment of injection method, 100% of individuals the claims appended hereto as permitted by applicable law. administered the fluid composition using the depot injection Moreover, any combination of the above-described elements method assessed global aesthetic effect at day 60 of treatment in all possible variations thereof is encompassed by the inven as “improved' or “very improved', whereas only 14.3% of tion unless otherwise indicated herein or otherwise clearly individuals administered the fluid composition using the contradicted by context. picotage injection method assessed global aesthetic effect at 0210 Groupings of alternative elements or embodiments day 60 of treatment as “improved' or “very improved.” Like of the invention disclosed herein are not to be construed as wise, 100% of individuals administered the fluid composition limitations. Each group member may be referred to and using the depot injection method assessed revitalization of claimed individually or in any combination with other mem skin at day 60 of treatment as “improved' or “very improved', bers of the group or other elements found herein. It is antici whereas only 14.3% of individuals administered the fluid pated that one or more members of a group may be included composition using the picotage injection method assessed in, or deleted from, a group for reasons of convenience and/or revitalization of skin at day 60 of treatment as “improved' or patentability. When any such inclusion or deletion occurs, the “very improved.” Similarly, 78.9% of individuals adminis specification is deemed to contain the group as modified thus tered the fluid composition using the depot injection method fulfilling the written description of all Markush groups used assessed facefullness at day 60 of treatment as “improved' or in the appended claims. “very improved', whereas none of individuals administered 0211 Unless otherwise indicated, all numbers expressing the fluid composition using the picotage injection method quantities of ingredients, properties such as molecular assessed face fullness as “improved' or “very improved.” All weight, reaction conditions, and so forth used in the specifi told, 95% of individuals administered the fluid composition cation and claims are to be understood as being modified in all using the depot injection method were delighted with the instances by the term “about.” As used herein, the term treatment at day 60, whereas only 14.3% of individuals “about’ means that the item, parameter or term so qualified administered the fluid composition using the picotage injec encompasses a range of plus or minus ten percent above and tion method were delighted with the treatment at day 60. below the value of the stated item, parameter or term. Accord 0207 Overall, the fluid compositions disclosed in the ingly, unless indicated to the contrary, the numerical param present specification have significant efficacy on skin hydra eters set forth in the specification and attached claims are tion on the cheek, neck, and peri-oral regions; significant approximations that may vary depending upon the desired efficacy on skin anisotropy on the neck and peri-oral regions; properties sought to be obtained by the present invention. At and significant efficacy on skin roughness on the neck region. the very least, and not as an attempt to limit the application of In addition evaluation of questionnaires indicate physician the doctrine of equivalents to the scope of the claims, each satisfaction of aesthetic results at each visit showed that skin numerical parameter should at least be construed in light of texture, skin brightness, skin hydration and overall skin con the number of reported significant digits and by applying dition were “improved' or very improved for greater than ordinary rounding techniques. Notwithstanding that the 80% of subjects at Day 60. Similarly, subject satisfaction numerical ranges and parameters setting forth the broad indicated that skin roughness, skin brightness, skin hydration Scope of the invention are approximations, the numerical and number of fine wrinkles were “improved' or very values set forth in the specific examples are reported as pre improved for greater than 80% of subjects. cisely as possible. Any numerical value, however, inherently 0208. In closing, it is to be understood that although contains certain errors necessarily resulting from the standard aspects of the present specification have been described with deviation found in their respective testing measurements. reference to the various embodiments, one skilled in the art 0212. The terms “a” “an,” “the and similar referents used will readily appreciate that the specific examples disclosed in the context of describing the invention (especially in the US 2011/0224164 A1 Sep. 15, 2011 32 context of the following claims) are to be construed to cover 6. The fluid composition of claim 5, wherein the hyaluro both the singular and the plural, unless otherwise indicated nan polymer is present at a concentration of about 13.5 herein or clearly contradicted by context. Recitation of ranges mg/mL. of values herein is merely intended to serve as a shorthand 7. The fluid composition of claim 1, wherein the hyaluro methodofreferring individually to each separate value falling nan polymer has a mean molecular weight greater than 2,000, within the range. Unless otherwise indicated herein, each 000 Da and less than about 5,000,000 Da. individual value is incorporated into the specification as if it 8. The fluid composition of claim 1, wherein the hyaluro were individually recited herein. All methods described nan polymer comprises both high molecular weight hyaluro herein can be performed in any suitable order unless other nan and low molecular weight hyaluronan. wise indicated herein or otherwise clearly contradicted by 9. The fluid composition of claim 8, wherein the high context. The use of any and all examples, or exemplary lan molecular weight hyaluronan has a molecular weight grater guage (e.g., “such as') provided herein is intended merely to than 2,000,000 Da and wherein the low molecular weight better illuminate the invention and does not pose a limitation hyaluronan has a molecular weight of less than 1,000,000 Da. on the scope of the invention otherwise claimed. No language 10. The fluid composition of claim 1, wherein the mannitol in the specification should be construed as indicating any is present in at most 5.0% (w/v) of the composition. non-claimed element essential to the practice of the invention. 11. The fluid composition of claim 1, wherein the mannitol 0213 Specific embodiments disclosed herein may be fur is present in at about 0.5% (w/v) to about 5% (w/v) of the ther limited in the claims using consisting of or consisting composition. essentially of language. When used in the claims, whether as 12. The fluid composition of claim 11, wherein the man filed or added per amendment, the transition term “consisting nitol is present in at about 0.8% (w/v) to about 1.2% (w/v). of excludes any element, step, or ingredient not specified in 13. The fluid composition of claim 12, wherein the man the claims. The transition term "consisting essentially of lim nitol is present in at about 1% (w/v). its the scope of a claim to the specified materials or steps and 14. The fluid composition of claim 1, wherein the mannitol those that do not materially affect the basic and novel char is presentata concentration of about 0.06 mg/mL to about 0.7 acteristic(s). Embodiments of the invention so claimed are mg/mL. inherently or expressly described and enabled herein. 15. The fluid composition of claim 1, wherein the fluid 0214 All patents, patent publications, and other publica composition has an osmolarity of about 270 mOsm/L to about tions referenced and identified in the present specification are 390 mOsm/L. individually and expressly incorporated herein by reference 16. The fluid composition of claim 1, wherein the fluid in their entirety for the purpose of describing and disclosing, composition the hyaluronan polymer is present at a concen for example, the methodologies described in Such publica tration of about 13.5 mg/mL and the mannitol is present in at tions that might be used in connection with the present inven tion. These publications are provided solely for their disclo about 1% (w/v). Sure prior to the filing date of the present application. Nothing 17. A fluid composition comprising: in this regard should be construed as an admission that the a) a hyaluronan polymer, wherein the hyaluronan polymer inventors are not entitled to antedate such disclosure by virtue is present at a concentration of about 11.5 mg/mL to of prior invention or for any other reason. All statements as to about 15.5 mg/mL, and wherein the hyaluronan polymer the date or representation as to the contents of these docu is Substantially uncrosslinked; and ments is based on the information available to the applicants b) a mannitol; wherein the mannitol is present in at about and does not constitute any admission as to the correctness of 0.5% (w/v) to about 5% (w/v) of the composition. the dates or contents of these documents. 18. The fluid composition of claim 17, wherein the hyalu roman polymer is at least 95% by weight of the total hyaluro nan polymer present in the composition. What is claimed: 19. The fluid composition of claim 17, wherein the hyalu 1. A fluid composition comprising: roman polymer is essentially free of a crosslinked hyaluronan a) a hyaluronan polymer, wherein the hyaluronan polymer polymer. is Substantially uncrosslinked; and 20. The fluid composition of claim 19, wherein the hyalu b) a mannitol; roman polymer is entirely free of a crosslinked hyaluronan wherein the fluid composition has a dynamic viscosity of polymer. about 50 Pa's to about 150 Pas; and 21. The fluid composition of claim 20, wherein the hyalu wherein the fluid composition has a osmolarity of about roman polymer is present at a concentration of about 13.5 200 mOsm/L to about 400 mOsm/L. mg/mL. 2. The fluid composition of claim 1, wherein the 22. The fluid composition of claim 17, wherein the hyalu uncrosslinked hyaluronan polymer is at least 95% by weight roman polymer has a mean molecular weight greater than of the total hyaluronan polymer present in the composition. 2,000,000 Da and less than about 5,000,000 Da. 3. The fluid composition of claim 1, wherein the hyaluro 23. The fluid composition of claim 17, wherein the hyalu nan polymer is essentially free of a crosslinked hyaluronan roman polymer comprises both high molecular weight hyalu polymer. roman and low molecular weight hyaluronan. 4. The fluid composition of claim 3, wherein the hyaluro 24. The fluid composition of claim 23, wherein the high nan polymer is entirely free of a crosslinked hyaluronan poly molecular weight hyaluronan has a molecular weight grater C. than 2,000,000 Da and wherein the low molecular weight 5. The fluid composition of claim 1, wherein the hyaluro hyaluronan has a molecular weight of less than 1,000,000 Da. nan polymer is present at a concentration of about 11.5 25. The fluid composition of claim 17, wherein the man mg/mL to about 15.5 mg/mL. nitol is present in at about 0.8% (w/v) to about 1.2% (w/v). US 2011/0224164 A1 Sep. 15, 2011

26. The fluid composition of claim 25, wherein the man a) combining mannitol with a physiologically-acceptable nitol is present in at about 1% (w/v). buffer to make a mannitol-buffered solution, wherein the 27. The fluid composition of claim 17, wherein the fluid mannitol is present in at about 0.5% (w/v) to about 5% composition the hyaluronan polymer is present at a concen (w/v) of the solution: tration of about 13.5 mg/mL and the mannitol is present in at b) combining a hyaluronan polymer with the mannitol about 1% (w/v). 28. A fluid composition comprising: buffered solution to hydrate the hyaluronan polymer, a) a hyaluronan polymer, wherein the hyaluronan polymer wherein the hyaluronan polymer is present at a concen is present at a concentration of about 11.5 mg/mL to tration of about 11.5 mg/mL to about 15.5 mg/mL and about 15.5 mg/mL, and wherein the hyaluronan polymer wherein the hyaluronan polymer is substantially is Substantially uncrosslinked; and uncrosslinked, and; b) a mannitol; wherein the mannitol is present in at most c) sizing the fluid composition by recirculating the fluid 5.0% (w/v) of the composition. composition between a first vessel and a second vessel 29. The fluid composition of claim 28, wherein the hyalu through a narrow aperture; roman polymer is at least 95% by weight of the total hyaluro wherein the fluid composition has a dynamic viscosity of nan polymer present in the composition. about 50 Pa's to about 150 Pars; and 30. The fluid composition of claim 28, wherein the hyalu roman polymer is essentially free of a crosslinked hyaluronan wherein the fluid composition has a osmolarity of about polymer. 200 mOsm/L to about 400 mOsm/L. 31. The fluid composition of claim 30, wherein the hyalu 40. A method of improving a condition of skin in an indi roman polymer is entirely free of a crosslinked hyaluronan vidual in need thereof, the method comprising the steps of polymer. administering a fluid composition of claim 1 into a dermal 32. The fluid composition of claim 28, wherein the hyalu region of the individual, wherein the administration improves roman polymer is present at a concentration of about 13.5 the condition. mg/mL. 41. The method of claim 40, wherein the skin conditions 33. The fluid composition of claim 28, wherein the hyalu treated is skin dehydration, a lack of skin elasticity, skin roman polymer has a mean molecular weight greater than 2,000,000 Da and less than about 5,000,000 Da. roughness, a lack of skin tautness, a skin stretch line or mark, 34. The fluid composition of claim 28, wherein the hyalu skin paleness, or skin wrinkles. roman polymer comprises both high molecular weight hyalu 42. A fluid composition comprising: roman and low molecular weight hyaluronan. a) an uncrosslinked hyaluronan polymer, wherein the 35. The fluid composition of claim 34, wherein the high uncrosslinked hyaluronan polymer is present at a con molecular weight hyaluronan has a molecular weight grater centration of about 11.5 mg/mL to about 15.5 mg/mL, than 2,000,000 Da and wherein the low molecular weight b) A crosslinked hyaluronan polymer, hyaluronan has a molecular weight of less than 1,000,000 Da. 36. The fluid composition of claim 28, wherein the man c) a mannitol; wherein the mannitol is present in at most nitol is present in at about 0.8% (w/v) to about 1.2% (w/v). 5.0% (w/v) of the composition. 37. The fluid composition of claim 36, wherein the man 43. The fluid composition of claim 42, wherein the gel: fluid nitol is present in at about 1% (w/v). ratio is at most 10:90. 38. The fluid composition of claim 28, wherein the fluid 44. The fluid composition of claim 42, wherein the gel: fluid composition the hyaluronan polymer is present at a concen ratio is at about 55:45 to about 80:20. tration of about 13.5 mg/mL and the mannitol is present in at 45. The fluid composition of claim 42, wherein the gel: fluid about 1% (w/v). ratio is at about 85:15 to about 100:0. 39. A method of making a fluid composition, the method comprising the steps of c c c c c