Stable hydrogel compositions including additives

0001This patent application is a partial continuation application of US Patent No. 12 / 714,377 (filed on February 26, 2010), which is a partial continuation application of US Patent Application No. 12 / 687,048 (filed on January 13, 2010). This is a partial continuation application of US Patent Application No. 12 / 956,542 (filed on November 30, 2010) (each of which is incorporated herein by reference).

0002Skin aging is a progressive phenomenon that occurs over a long period of time and can be affected by living factors such as alcohol consumption, tobacco and sun exposure. Facial skin aging can be characterized by atrophy, loosening and fattening. Atrophy corresponds to a significant reduction in the thickness of skin tissue. Loosening of the subcutaneous tissue results in excessive skin and drooping, resulting in the appearance of sagging cheeks and eyelids. Being fat refers to the increase in overweight due to swelling of the face and bottom of the neck. These changes are typically associated with dryness, loss of elasticity and rough texture.

0003Hyaluronan, also known as hyaluronic acid (HA), is a non-sulfated glycosaminoglycan that is widely distributed throughout the human body in binding, epithelial and nervous tissue. Hyaluronan is abundant in different layers of skin, where it is involved, for example, in ensuring good hydration, helping to organize extracellular matrix, acting as a filler, and in tissue remodeling mechanisms. It has multiple functions such as doing. However, with age, the amount of hyaluronan, collagen, elastin and other matrix polymers present in the skin decreases. Repeated exposure to UV light, for example from sunlight, causes both skin cells to reduce hyaluronan production and increase its rate of degradation. This hyaluronan loss results in various skin conditions such as imperfections, defects, diseases and / or disorders. For example, there is a strong correlation between water content in the skin and hyaluronan levels in the skin tissue. As the skin ages, the quantity and quality of hyaluronan in the skin is reduced. These changes cause the skin to dry and wrinkle.

0004Dermal fillers treat parenchyma to treat these skin conditions, to replace lost endogenous matrix polymers, or to enhance / promote the function of existing matrix polymers. And in other skin therapies. Traditionally, such compositions have been used to fill wrinkles, stretch marks, folds, scars, and to strengthen skin tissue, such as to make thin lips plump or to fill depressed eyes or shallow cheeks. It has been used for beauty purposes. A common matrix polymer used in dermal filler compositions is hyaluronan. Because hyaluronan is natural to the human body, it is generally well tolerated and is a fairly low risk treatment for a wide variety of skin conditions.

0005Originally, compositions containing hyaluronan were made from natural polymers, but they exist in a non-crosslinked state. Natural hyaluronan exhibits excellent biocompatibility and affinity for water molecules, but exhibits inadequate biomechanical properties as dermal fillers (Tezel and Fredrickson, The Science of Hyaluronic Acid Dermal Fillers, J. Cosmet. Laser). Ther. 10 (1): 35-42 (2008); Kablik, et al., Comparative Physical Properties of Hyaluronic Acid Dermal Fillers, Dermatol. Surg. 35 Suppl 1: 302-312 (2009); Beasley, et al., Hyaluronic Acid Fillers: A Comprehensive Review, Facial Plast. Surg. 25 (2): 86-94 (2009)) (each of these statements is incorporated herein by reference). One main reason is that this polymer is non-crosslinked and therefore highly soluble and therefore is rapidly swept away when administered to the skin area (Tezel, supra, 2008). Kablik, supra, 2009; Beasley, supra, 2009). The in vivo scavenging mainly rapid degradation of the polymer, mainly enzymatic degradation by hyaluronidase, and by chemical degradation by free radicals, are achieved Ru. Therefore, compositions containing non-crosslinked hyaluronan polymers are still commercially available, but tend to degrade within 2-3 days after administration and therefore require fairly frequent reinjections to retain skin-improving effects. And.

0006To minimize the effects of these in vivo degradation pathways, the matrix polymers are crosslinked with each other to form stabilized hydrogels. Hydrogels containing crosslinked matrix polymers are harder substances, so dermal fillers containing such hydrogels remain intact at the injection site for longer periods of time (Tezel, supra, 2008; Kablik, supra, 2009; Beasley, supra, 2009). In addition, these hydrogels are more suitable as dermal fillers as their stiffer properties improve the mechanical properties of the filler and allow the filler to lift and fill the skin area better. (Tezel, above, 2008; Kablik, above, 2009; Beasley, above, 2009). Hyaluronan polymers are typically crosslinked with a crosslinker to form covalent bonds between the hyaluronan polymers. Such crosslinked polymers are more resistant to degradation than non-crosslinked hyaluronan compositions and thus form a low water soluble hydrogel network-like structure that requires less frequent reinjection.

<p num="0007"> Current dermal fillers can be associated with a variety of side effects. For example, administration of a dermal filler to an individual is typically performed using a syringe or needle. Such administration may cause one or more unwanted side effects, such as pain and discomfort to an individual, bleeding within and below the site of administration, and pruritus around the site of administration during and after administration of the dermal filler. Can cause inflammation and irritation. The dermal fillers disclosed herein are these and other desirable by providing hydrogel compositions containing agents that reduce, stop, or prevent one or more of these side effects. Deal with no side effects.</p><p num="0008"> In addition, the skin-filled formulation must be able to withstand the stringent requirement of sterilization before the product can be sold (the product must be sterilized). Sterilization can be performed by steam sterilization, filtration, microfiltration, gamma irradiation, ETO light, or a combination of these methods. It is known that skin fillers can be vapor-sterilized (autoclaved) without substantial decomposition of physical properties, but skin-filled formulations have additional unstable components (eg, antioxidants, anti-pruritus). Agents, anti-cellulite agents, anti-scarring agents, anti-inflammatory agents, anesthetics, anti-irritants, vasoconstrictors, vasoconstrictors, anti-hemorrhagic agents such as hemostatic or anti-fibrinolytic agents, release agents, tensioning agents , Antihemorrhagic agents, pigmentation agents, antipigmentation agents or moisturizers), the whole skin filling formulation or at least additional (heat instability) agents are traditionally filtered by non-heat treatment, eg It is sterilized by the sterilization method. Therefore, known dermal filler products (REVITACARE® Bio-Revitalisation, REVITACARE® Laboratory, Saint-Ouen-I'Aumone, France) is sold in two separate vials or containers, one vial containing HA (autoclaved) and the second vial containing any additional ingredients (second). Vial contents are sterilized by filtration). Another known dermal filler product, NCTF® 135HA (Laboratories Filorga, Paris, France), is sold in a single container that holds both hyaluronan and any additional ingredients, all. , Sterilized by microfiltration. The dermal fillers disclosed herein address this issue by developing dermal fillers that are completely sterilized by heat treatment, i.e., in some embodiments of the invention, single and non-single. No component is sterilized using heat treatment, eg filtration.</p>

<p num="0009"> The present specification provides novel dermal fillers useful for treating skin conditions that are still stable after heat treatment used to sterilize compositions. One aspect of the disclosed dermal fillers, as well as a significant distinction over known dermal fillers, is that the dermal fillers disclosed herein are: 1) glucosaminoglycan polymers and the present specification. Mixing additional agents (s) disclosed therein; (2) prepared by heat treating the dermal filler composition to at least 100 ° C (without filtration sterilization of any constituents). In this case, (3) such a treatment retains the desired properties of the hydrogel composition. The disclosed hydrogel compositions do not show any significant degradation, as shown by pre- and post-autoclave treatment tests. The disclosed hydrogel composition is substantially thermally stable as determined by retention of one or more of the following properties after sterilization: clarity (transparency and translucency), homogeneity, extrusion. Force, cohesiveness, hyaluronan concentration, agent (s) concentration, permeability, pH, or other fluid properties desired for the hydrogel prior to heat treatment.</p><p num="0010"> The hydrogel compositions disclosed herein may also exhibit greater stability than hydrogel compositions without additional constituents. Without being bound by theory, the crosslinked glycosaminoglycan polymer used in our pharmaceutical metal ion blocker is made non-reactive, thereby degrading additional components (described in the Examples below). Prevents and causes decomposition of the skin-filled formulation during steam sterilization. In addition, the additional component can be hydrophilic, preventing the glycosaminoglycan polymer from degrading during steam sterilization and / or after administration of the skin-filled formulation to the patient. Without being bound by theory, the inclusion of additional ingredients in the dermal filler may suppress free radical capture at the injection / implantation site, which may extend the duration of the dermal filler after patient administration. .. After vapor sterilization, additional ingredients may be released from the skin-filled formulation for cosmetic or therapeutic effects upon administration (eg by subcutaneous injection).</p><p num="0011"> Accordingly, aspects herein include glycosaminoglycan polymers, as well as antioxidants, antipruritic agents, anti-cellulite agents, anti-scarring agents, anti-inflammatory agents, anesthetics, anti-irritants, vasoconstrictors, blood vessels. At least one agent selected from vasodilators, anti-hemorrhagic agents such as hemostatic or anti-fibrinolytic agents, release agents, tensioning agents, anti-spasmodic agents, pigmentation agents, anti-pigmentation agents or moisturizers. Provided is a hydrogel composition comprising. Glycosaminoglycan polymers useful for producing such compositions include, but are not limited to, chondroitin sulfate polymers, dermatan sulfate polymers, keratan sulfate polymers and hyaluronan polymers.</p><p num="0012"> Another aspect of the specification is a method of making a hydrogel composition disclosed herein, a) mixing a glycosaminoglycan polymer and at least one agent; and b) mixing the mixture. Provided are methods that include heat treatment, which retains the desired hydrogel properties disclosed herein.</p><p num="0013"> Yet another aspect of the specification is a method of treating a skin condition in an individual in need thereof, comprising the step of administering the hydrogel composition disclosed herein to an individual's skin area. Provided, where administration improves skin symptoms. Skin conditions treated by the disclosed compositions include, but are not limited to, enlargement, remodeling, disease, disorder, deficiency or imperfections of body parts, areas or areas. In one aspect, the cutaneous symptoms treated by the disclosed composition include, but are not limited to, facial enlargement, facial remodeling, facial disorders, facial disorders, facial defects or incompleteness. In one aspect, the skin symptoms treated by the disclosed compositions include skin dehydration, lack of skin elasticity, skin roughness, lack of skin tension, skin stretch lines or marks, skin pallor, skin. These include, but are not limited to, depressions, lumpy cheeks, thin lips, retro-orbital defects, and facial folds or wrinkles.</p>

<p num="0014"> In another aspect of the invention is provided a hydrogel composition comprising a hyaluronic acid-based polymer and at least one additional agent selected from antibacterial and vasoconstrictors, wherein the hydrogel composition is heat treated. And / or sterilized by pressure treatment, eg autoclaving, and sterilized by a process involving heat treatment at least 100 ° C. Advantageously, the heat sterilized composition is substantially stable at room temperature for at least about 3 months, for example at least 24 months, at least about 36 months.</p><p num="0015"> In some embodiments, the antihemorrhagic agent is an antifibrinolytic agent selected from the group of ε-aminocaproic acid, tranexamic acid and serpin. In some embodiments, the anti-fibrinolytic agent is tranexamic acid, which is present in an amount of about 0.1% (w / w) to about 1.0% (w / w) of the total composition.</p><p num="0016"> In some embodiments, the vasoconstrictor is naphazoline, epinephrine, methoxamine, methylnorepinephrine, norepinephrine, oxymetazoline, phenylephrine, pseudoephedrine, synephrine, silazoline, xylometazoline, analogs or derivatives thereof, or any combination thereof. is there. In some embodiments, phenylephrine is present at a concentration of about 0.001% (w / w) to about 0.1% (w / w). In some embodiments, the composition further comprises an anesthetic present in an amount of about 0.1% (w / w) to about 1.0% (w / w) of the total composition, such as lidocaine or a similar agent. .. In some embodiments, the composition further comprises an antioxidant present in an amount of about 0.01% (w / w) to about 5% (w / w) of the total composition, such as mannitol.</p><p num="0017"> In some embodiments, the hyaluronic acid-based polymer is present at a concentration of about 5 mg / g to about 40 mg / g and has an average molecular weight greater than 300,000 Da and less than about 800,000 Da, such as greater than 2,000,000 Da and about 5,000,000. Includes low molecular weight hyaluronan polymers with an average molecular weight of less than Da. In some embodiments, the hyaluronic acid-based polymer comprises both high molecular weight hyaluronan and low molecular weight hyaluronan, where the high molecular weight hyaluronan has a molecular weight greater than 2,000,000 Da and the low molecular weight hyaluronan is less than 1,000,000 Da. Has a molecular weight.</p>

0018<figref num="1">It is a figure which shows the structure of ascorbyl-2-glucoside which is also known as AA2G (Hayashibara International, Okayama, Japan).</figref><figref num="2">Procollagen (% control) for control; HA-based hydrogel with 0.3% (w / w) lidocaine, and 0.6% (w / w) ascorbyl-2-glucoside (AA2G®) in phosphate buffer. )) HA-based hydrogel with; and 0.6% (w / w) ascorbyl-2-glucoside (AA2G and 0.3% (w / w) lidocaine with HA-based hydrogel synthesis.</figref><figref num="3">Graph showing extrusion force over time (equivalent to 3 years at 25 ° C) in composition: control; HA-based hydrogel with ascorbyl-2-glucoside (AA2G ) and lidocaine; and ascorbyl-2-glucoside (equivalent to 3 years) HA-based hydrogel with AA2G , lidocaine and TPGS.</figref><figref num="4">Graph showing pH over time (equivalent to 3 years at 25 ° C) in composition: control; HA-based hydrogel with ascorbyl-2-glucoside (AA2G ) and lidocaine; and ascorbyl-2-glucoside (AA2G) ), HA-based hydrogel with lidocaine and TPGS.</figref><figref num="5">Graph showing tan δ 1 Hz over time (corresponding to 3 years at 25 ° C) in the composition: control; HA-based hydrogel with ascorbyl-2-glucoside (AA2G ); ascorbyl-2-glucoside (AA2G ) ) And HA-based hydrogels with lidocaine; and HA-based hydrogels with ascorbyl-2-glucoside (AA2G ), lidocaine and TPGS.</figref><figref num="6">HPLC analysis of ascorbyl-2-glucoside (AA2G ), lidocaine and IPA (co-eluent) after autoclaving (equivalent to 3 years at 25 ° C) (C18 column, eluent: sodium phosphate buffer (C18 column, eluent: sodium phosphate buffer) pH = 2.2) / 2-propanol 10%, 0.7 ml / min; detected at 260 nm).</figref><figref num="7">Graph comparing the properties of antioxidants in compositions: Juviderm® Ultra with lidocaine, Ascorbyl-2-glucoside (AA2G®) and Juviderm® Ultra with lidocaine relative to controls.</figref>

0019Aspects herein provide, in part, a hydrogel composition comprising a glycosaminoglycan polymer. The hydrogel compositions disclosed herein may further comprise two or more different glycosaminoglycan polymers. As used herein, the term "glycosaminoglycan" is synonymous with "GAG" and "mucopolysaccharide" and refers to a long non-branched chain polysaccharide consisting of repetitive disaccharide units. The repeating unit consists of hexose (hexose) or hexuronic acid linked with hexosamines (nitrogen-containing hexacarbonate), and a pharmaceutically acceptable salt thereof. Members of the GAG family are altered by the type of hexosamine, hexose or hexuronic acid unit they contain, such as glucuronic acid, iduronic acid, galactose, galactosamine, glucosamine, and can also vary in the form of glycosidic bonds. Any glycosaminoglycan polymer is useful in the hydrogel compositions disclosed herein, provided that the glycosaminoglycan polymer improves skin symptoms. Non-limiting examples of glycosaminoglycans include chondroitin sulfate, dermatan sulfate, keratan sulfate, and hyaluronan. Non-limiting examples of acceptable salts of glycosaminoglycans include sodium salts, potassium salts, magnesium salts, calcium salts and combinations thereof. Glycosaminoglycans and their resulting polymers useful in the hydrogel compositions and methods disclosed herein include, for example, Piron and Tholin, Polysaccharide Crosslinking, Hydrogel Preparation, Resulting Polysaccharides (s) and Hydrogel (s). ), uses Thereof, US Patent Publication 2003/0148995; Lebreton, Cross-Linking of Low and High Molecular Weight Polysaccharides Preparation of Injectable Monophase Hydrogels; Lebreton, Viscoelastic Solutions Containing Sodium Hyaluronate and Hydroxypropyl Methyl Cellulose, Preparation and Uses, US Patent Publication No. 2008/0089918; Lebreton, Hyaluronic Acid-Based Gels Including Lidocaine , U.S. Patent Publication No. 2010/0028438; and the polysaccharides and hydrogels thus obtained are U.S. Patent Publication No. 2006/0194758; and Di Napoli, Composition and Method for Intradermal Soft Tissue Augmentation, International Patent Publication WO 2004 / 073759, each of which is incorporated herein by reference. GAGs useful in the hydrogel compositions and methods disclosed herein are commercially available, such as the hyaluronan-based dermal fillers Jubiderm®, Jubiderm® 30, Jubiderm®. Ultra, Jubiderm® Ultraplus, Jubiderm® Ultra XC and Jubiderm® Ultraplus XC (Allergan Inc, Irvine, California). Table 1 lists typical GAGs. Viscoelastic Solutions Containing Sodium Hyaluronate and Hydroxypropyl Methyl Cellulose, Preparation and Uses, US Patent Publication No. 2008/0089918; Lebreton, Hyaluronic Acid-Based Gels Including Lidocaine, US Patent Publication No. 2010/0028438; Polysaccharides and hydrogels are described in US Patent Publication No. 2006/0194758; and Di Napoli, Composition and Method for Intradermal Soft Tissue Augmentation, International Patent Publication WO 2004/073759, each of which is described herein by reference. Incorporated in the book. GAGs useful in the hydrogel compositions and methods disclosed herein are commercially available, such as the hyaluronan-based dermal fillers Jubiderm®, Jubiderm® 30, Jubiderm®. Ultra, Jubiderm® Ultraplus, Jubiderm® Ultra XC and Jubiderm® Ultraplus XC (Allergan Inc, Irvine, California). Table 1 lists typical GAGs. Viscoelastic Solutions Containing Sodium Hyaluronate and Hydroxypropyl Methyl Cellulose, Preparation and Uses, US Patent Publication No. 2008/0089918; Lebreton, Hyaluronic Acid-Based Gels Including Lidocaine, US Patent Publication No. 2010/0028438; Polysaccharides and hydrogels are described in US Patent Publication No. 2006/0194758; and Di Napoli, Composition and Method for Intradermal Soft Tissue Augmentation, International Patent Publication WO 2004/073759, each of which is described herein by reference. Incorporated in the book. GAGs useful in the hydrogel compositions and methods disclosed herein are commercially available, such as the hyaluronan-based dermal fillers Jubiderm®, Jubiderm® 30, Jubiderm®. Ultra, Jubiderm® Ultraplus, Jubiderm® Ultra XC and Jubiderm® Ultraplus XC (Allergan Inc, Irvine, California). Table 1 lists typical GAGs. It is described in Composition and Method for Intradermal Soft Tissue Augmentation, WO 2004/073759, each of which is incorporated herein by reference. GAGs useful in the hydrogel compositions and methods disclosed herein are commercially available, such as the hyaluronan-based dermal fillers Jubiderm®, Jubiderm® 30, Jubiderm®. Ultra, Jubiderm® Ultraplus, Jubiderm® Ultra XC and Jubiderm® Ultraplus XC (Allergan Inc, Irvine, California). Table 1 lists typical GAGs. It is described in Composition and Method for Intradermal Soft Tissue Augmentation, WO 2004/073759, each of which is incorporated herein by reference. GAGs useful in the hydrogel compositions and methods disclosed herein are commercially available, such as the hyaluronan-based dermal fillers Jubiderm®, Jubiderm® 30, Jubiderm®. Ultra, Jubiderm® Ultraplus, Jubiderm® Ultra XC and Jubiderm® Ultraplus XC (Allergan Inc, Irvine, California). Table 1 lists typical GAGs.<tables num="1"><img id="000002" he="142" wi="159" file="JP5960894B2_D0001.tif" img-format="tif" img-content="drawing" /></tables>

0020Aspects herein provide, in part, a hydrogel composition comprising a chondroitin sulfate polymer. As used herein, the term "chondroitin sulfate polymer" is a variable length containing two monosaccharides alternating disaccharides, D-glucuronic acid (GlcA) and N-acetyl-D-galactosamine (GalNAc). Refers to the non-branched chain sulfated polymer of. The chondroitin sulfate polymer may also contain a D-glucuronic acid residue that is epilated to L-iduronic acid (IdoA), in which case the resulting disaccharide is called dermatan sulfate. Chondroitin sulfate polymers may have more than 100 individual sugar chains, each of which is sulfated at an indefinite position and amount. Chondroitin sulfate polymer is an important structural component of cartilage and provides much of its resistance to compression. Any chondroitin sulfate polymer is useful in the compositions disclosed herein, provided that it improves skin symptoms. Non-limiting examples of pharmaceutically acceptable salts of chondroitin sulfate include sodium chondroitin sulfate, potassium chondroitin sulfate, magnesium chondroitin sulfate, calcium chondroitin sulfate and combinations thereof.

0021Aspects herein provide, in part, a hydrogel composition comprising a keratan sulfate polymer. As used herein, the term "keratan sulfate polymer" refers to variable-length polymers that themselves contain disaccharide units, including β-D-galactose and N-acetyl-D-galactosamine (GalNAc). Refers to a pharmaceutically acceptable salt. The disaccharides in the repeating region of keratan sulfate can be fucosylated and N-acetylneuraminic acid caps the ends of the chain. Any keratan sulfate polymer is useful in the compositions disclosed herein, provided it ameliorate skin symptoms. Non-limiting examples of pharmaceutically acceptable salts of keratan sulfate include sodium keratan sulfate, potassium keratan sulfate, magnesium keratan sulfate, calcium keratan sulfate and combinations thereof.

0022Aspects herein provide, in part, a hydrogel composition comprising a hyaluronan polymer. As used herein, the term "hyaluronic acid polymer" is synonymous with "HA polymer," "hyaluronic acid polymer," and "hyaluronate polymer," which in themselves alternate β-1,4. Anionic non-sulfated glycosaminoglycan polymers containing disaccharide units containing D-glucuronic acid and DN-acetylglucosamine monomers linked together via β-1,3 glycosidic bonds and their pharmaceuticals. Refers to acceptable salt. Hyaluronan polymers can be purified from animal and non-animal sources. Hyaluronan polymers can range in size from about 5,000 Da to about 20,000,000 Da. Any hyaluronan polymer is useful in the compositions disclosed herein, provided it ameliorate skin symptoms. Non-limiting examples of pharmaceutically acceptable salts of hyaluronan include hyaluronan sodium, hyaluronan potassium, hyaluronan magnesium, hyaluronan calcium and combinations thereof.

0023Aspects herein provide, in part, a hydrogel composition comprising a crosslinked glycosaminoglycan polymer. As used herein, the term "crosslinking" refers to an intermolecular bond that links individual polymer molecules or monomer chains to a more stable structure, such as a gel. Thus, a crosslinked glycosaminoglycan polymer has at least one intermolecular bond that links at least one individual polymer molecule to another molecule. Cross-linking of glycosaminoglycan polymers typically produces hydrogels. Such hydrogels are highly viscous and require considerable force to be extruded through fine needles. Glycosaminoglycan polymers disclosed herein are dialdehyde and disulfide crosslinkers such as polyfunctional PEG-based crosslinkers, divinyl sulfones, diglycidyl ethers and bis-epoxides, biscarbodiimides. ) Can be crosslinked. Non-limiting examples of hyaluronan crosslinkers include polyfunctional PEG-based crosslinkers such as pentaerythritol tetraglycidyl ether (PETGE), divinylsulfone (DVS), 1,4-butanediol diglycidyl ether (BDDE), 1, 2-bis (2,3-epoxypropoxy) ethylene (EGDGE), 1,2,7,8-diepoxy octane (DEO), (phenylene bis- (ethyl) -carbodiimide and 1,6 hexamethylenebis (ethylcarbodiimide) ), Adipic acid dihydrazide (ADH), Bis (sulfosuccinimidyl) sverate (BS), Hexamethylenediamine (HMDA), 1- (2,3-Epoxypropyl) -2,3-Epoxycyclohexane or a combination thereof Other useful cross-linking agents include Stroumpoulis and Tezel, Tunably Crosslinked Polysaccharide Compositions, US Patent Application No. 12/910, It is disclosed in No. 466 (filed October 22, 2010), each of which is incorporated herein by reference. Non-limiting examples of methods for cross-linking glycosaminoglycan polymers are described, for example. Glycosaminoglycan polymers useful in the compositions and methods disclosed herein include, for example, Piron and Tholin, Polysaccharide Crosslinking, Hydrogel Preparation, Resulting Polysaccharides (s) and Hydrogel (s), uses Thereof, US Patents. Publication No. 2003/0148995; Lebreton, Cross-Linking of Low and High Molecular Weight Polysaccharides Preparation of Injectable Monophase Hydrogels; Lebreton, Viscoelastic Solutions Containing Sodium Hyaluronate and Hydroxypropyl Methyl Cellulose, Preparation and Uses, US Patent Publication No. 2008/0089918; Lebreton, Hyaluronic Acid-Based Gels Including Lidocaine, U.S. Patent Publication No. 2010/0028438; and the polysaccharides and hydrogels thus obtained are U.S. Patent Publication No. 2006/0194758; and Di Napoli, Composition and Method for Intradermal. It is described in Soft Tissue Augmentation, WO 2004/073759, each of which is incorporated herein by reference.

0024According to the present specification, "%" in a pharmaceutical product is defined as a weight (ie w / w) percentage in weight units. As an example, 1% (w / w) means a concentration of 10 mg / g.

0025In one embodiment, the hydrogel composition comprises a crosslinked glycosaminoglycan polymer, wherein the crosslinked glycosaminoglycan polymer is in an amount sufficient to ameliorate skin symptoms as disclosed herein. Exists. In aspects of this embodiment, the composition comprises a crosslinked chondroitin sulfate polymer, a crosslinked dermatane sulfate polymer, a crosslinked keratane sulfate polymer, a crosslinked heparan polymer, a crosslinked heparan sulfate polymer or a crosslinked hyaluronan polymer. In another aspect of this embodiment, the composition comprises cross-linked glycosaminoglycans, wherein the cross-linked glycosaminoglycans are, for example, about 1% by weight, about 2% by weight of the total glycosaminoglycans present in the composition. , About 3% by weight, about 4% by weight, about 5% by weight, about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight or about 10% by weight. In yet another aspect of this embodiment, the composition comprises cross-linked glycosaminoglycans, wherein the cross-linked glycosaminoglycans are, for example, up to 1% by weight and up to 2% by weight of the total glycosaminoglycans present in the composition. , Up to 3% by weight, up to 4% by weight, up to 5% by weight, up to 6% by weight, up to 7% by weight, up to 8% by weight, up to 9% by weight or up to 10% by weight. In yet another aspect of this embodiment, the composition comprises cross-linked glycosaminoglycans, wherein the cross-linked glycosaminoglycans are, for example, from about 0% to about 20% by weight of the total glycosaminoglycans present in the composition. , About 1% to about 17% by weight, about 3% to about 15% by weight or about 5% to about 10% by weight, for example, about 11% by weight, about 15% by weight or about 17% by weight.

0026In aspects of this embodiment, the hydrogel composition comprises crosslinked glycosaminoglycans, which are, for example, about 2 mg / g, about 3 mg / g, about 4 mg / g, about 5 mg / g, about 6 mg. / g, about 7 mg / g, about 8 mg / g, about 9 mg / g, about 10 mg / g, about 11 mg / g, about 12 mg / g, about 13 mg / g, about 13.5 mg / g, about 14 mg / g, about It is present at concentrations of 15 mg / g, about 16 mg / g, about 17 mg / g, about 18 mg / g, about 19 mg / g or about 20 mg / g. In another aspect of this embodiment, the composition comprises a crosslinked glycosaminoglycan, wherein the crosslinked glycosaminoglycan is, for example, at least 1 mg / g, at least 2 mg / g, at least 3 mg / g, at least 4 mg / g, at least 5 mg. It is present at a concentration of / g, at least 10 mg / g, at least 15 mg / g, at least 20 mg / g or at least 25 mg / g or about 40 mg / g. In yet another aspect of this embodiment, the composition comprises cross-linked glycosaminoglycans, which are, for example, up to 1 mg / g, up to 2 mg / g, up to 3 mg / g, up to 4 mg / g, up to 4 mg / g. It is present in concentrations of 5 mg / g, up to 10 mg / g, up to 15 mg / g, up to 20 mg / g, up to 25 mg / g or up to 40 mg / g. In yet another aspect of this embodiment, the composition comprises crosslinked glycosaminoglycans, which are, for example, from about 7.5 mg / g to about 19.5 mg / g, from about 8.5 mg / g to about 18.5 mg / g. g, about 9.5 mg / g ~ about 17.5 mg / g, about 10.5 mg / g ~ about 16.5 mg / g, about 11.5 mg / g ~ about 15.5 mg / g or about 12.5 mg / g ~ about 14.5 mg / g, It is present at concentrations up to about 40 mg / g.

0027Aspects herein provide, in part, a hydrogel composition comprising a low molecular weight hyaluronan polymer, a high molecular weight hyaluronan polymer, or both low and high molecular weight hyaluronan polymers. As used herein, the term "high molecular weight" refers to a hyaluronan polymer having an average molecular weight of 1,000,000 Da or greater when referring to "hyaluronan". Non-limiting examples of high molecular weight hyaluronan polymers include hyaluronan polymers of about 1,500,000 Da, about 2,000,000 Da, about 2,500,000 Da, about 3,000,000 Da, about 3,500,000 Da, about 4,000,000 Da, about 4,500,000 Da and about 5,000,000 Da. As used herein, the term "low molecular weight" refers to a hyaluronan polymer having an average molecular weight of less than 1,000,000 Da when referring to "hyaluronan". Non-limiting examples of low molecular weight hyaluronan polymers include hyaluronan polymers of about 200,000 Da, about 300,000 Da, about 400,000 Da, about 500,000 Da, about 600,000 Da, about 700,000 Da, about 800,000 Da and about 900,000 Da.

0028In one embodiment, the composition comprises a low molecular weight crosslinked hyaluronan polymer. In aspects of this embodiment, the composition has an average molecular weight of, for example, about 100,000 Da, about 200,000 Da, about 300,000 Da, about 400,000 Da, about 500,000 Da, about 600,000 Da, about 700,000 Da, about 800,000 Da or about 900,000 Da. Includes a crosslinked hyaluronan polymer with. In yet another aspect of this embodiment, the composition is, for example, up to 100,000 Da, up to 200,000 Da, up to 300,000 Da, up to 400,000 Da, up to 500,000 Da, up to 600,000 Da, up to 700,000 Da. Includes cross-linked hyaluronan polymers with an average molecular weight of up to 800,000 Da, up to 900,000 Da or up to 950,000 Da. In yet another aspect of this embodiment, the composition is, for example, about 100,000 Da to about 500,000 Da, about 200,000 Da to about 500,000 Da, about 300,000 Da to about 500,000 Da, about 400,000 Da to about 500,000 Da, about 500,000 Da. ~ About 950,000Da ~ About 600,000Da ~ About 950,000Da, About 700,000Da ~ About 950,000Da, About 800,000Da ~ About 950,000Da, About 300,000Da ~ About 600,000Da, About 300,000Da ~ About 700,000Da, About 300,000Da ~ About It contains a crosslinked hyaluronan polymer having an average molecular weight of 800,000 Da or about 400,000 Da to about 700,000 Da.

0029In another embodiment, the composition comprises a high molecular weight crosslinked hyaluronan polymer. In aspects of this embodiment, the composition has an average molecular weight of, for example, about 1,000,000 Da, about 1,500,000 Da, about 2,000,000 Da, about 2,500,000 Da, about 3,000,000 Da, about 3,500,000 Da, about 4,000,000 Da, about 4,500,000 Da or about 5,000,000 Da. Includes a crosslinked hyaluronan polymer with. In yet another aspect of this embodiment, the composition comprises, for example, at least 1,000,000 Da, at least 1,500,000 Da, at least 2,000,000 Da, at least 2,500,000 Da, at least 3,000,000 Da, at least 3,500,000 Da, at least 4,000,000 Da, at least 4,500,000 Da or at least 5,000,000 Da. Contains a crosslinked hyaluronan polymer having an average molecular weight of. In yet another aspect of this embodiment, the composition is, for example, about 1,000,000 Da to about 5,000,000 Da, about 1,500,000 Da to about 5,000,000 Da, about 2,000,000 Da to about 5,000,000 Da, about 2,500,000 Da to about 5,000,000 Da, about 2,000,000 Da. Includes crosslinked hyaluronan polymers having an average molecular weight of ~ about 3,000,000 Da, about 2,500,000 Da ~ about 3,500,000 Da or about 2,000,000 Da ~ about 4,000,000 Da.

0030In yet another embodiment, the composition comprises a crosslinked hyaluronan polymer, wherein the crosslinked hyaluronan polymer comprises a combination of both a high molecular weight hyaluronan polymer and a low molecular weight hyaluronan polymer in various proportions. In aspects of this embodiment, the composition comprises a crosslinked hyaluronan polymer, wherein the crosslinked hyaluronan polymer is of both a high molecular weight hyaluronan polymer and a low molecular weight hyaluronan polymer, about 20: 1, about 15: 1, about 10 :. Includes combinations in the ratio of 1, about 5: 1, about 1: 1, about 1: 5, about 1:10, about 1:15 or about 1:20.

0031Aspects herein provide a hydrogel composition, in part, comprising a crosslinked glycosaminoglycan polymer having some degree of crosslinking. As used herein, the term "degree of cross-linking" refers to the percentage of glycosaminoglycan polymer monomer units, eg, hyaluronan disaccharide monomer units bound to a cross-linking agent. The degree of cross-linking is expressed as the weight percent ratio of the cross-linking agent to glycosaminoglycans.

0032Aspects herein provide, in part, a hydrogel composition comprising a non-crosslinked glycosaminoglycan polymer. As used herein, the term "non-crosslinked" refers to the lack of intermolecular bonds that link individual glycosaminoglycan polymer molecules or monomer chains. Therefore, the non-crosslinked glycosaminoglycan polymer is not linked to any other glycosaminoglycan polymer by intermolecular binding. In aspects of this embodiment, the composition comprises a non-crosslinked chondroitin sulfate polymer, a non-crosslinked dermatane sulfate polymer, a non-crosslinked keratane sulfate polymer, a non-crosslinked heparan polymer, a non-crosslinked heparan sulfate polymer or a non-crosslinked hyaluronan polymer. .. Non-crosslinked glycosaminoglycan polymers are water soluble and generally remain fluid in nature. Therefore, glycosaminoglycan polymers are often mixed as lubricants with glycosaminoglycan polymer-based hydrogel compositions to facilitate the process of extruding the composition through fine needles.

0033In one embodiment, the composition comprises a non-crosslinked glycosaminoglycan polymer, wherein the non-crosslinked glycosaminoglycan polymer is sufficient to improve the condition of the skin, as disclosed herein. Exists in quantity. In aspects of this embodiment, the composition comprises a non-crosslinked glycosaminoglycan, wherein the non-crosslinked glycosaminoglycan is, for example, about 2 mg / g, about 3 mg / g, about 4 mg / g, about 5 mg / g. , About 6mg / g, about 7mg / g, about 8mg / g, about 9mg / g, about 10mg / g, about 11mg / g, about 12mg / g, about 13mg / g, about 13.5mg / g, about 14mg / It is present at concentrations of g, about 15 mg / g, about 16 mg / g, about 17 mg / g, about 18 mg / g, about 19 mg / g or about 20 mg / g, about 40 mg / g or about 60 mg / g. In another aspect of this embodiment, the composition comprises a non-crosslinked glycosaminoglycan, in which case the non-crosslinked glycosaminoglycan is, for example, at least 1 mg / g, at least 2 mg / g, at least 3 mg / g, at least 4 mg. It is present in concentrations of / g, at least 5 mg / g, at least 10 mg / g, at least 15 mg / g, at least 20 mg / g, at least 25 mg / g, at least 35 mg / g or about 40 mg / g. In yet another aspect of this embodiment, the composition comprises a non-crosslinked glycosaminoglycan, where the non-crosslinked glycosaminoglycan is, for example, up to 1 mg / g, up to 2 mg / g, up to 3 mg / g. It is present at concentrations of g, up to 4 mg / g, up to 5 mg / g, up to 10 mg / g, up to 15 mg / g, up to 20 mg / g or up to 25 mg / g. In yet another aspect of this embodiment, the composition comprises non-crosslinked glycosaminoglycans, where the glycosaminoglycans are, for example, from about 1 mg / g to about 60 mg / g, from about 10 mg / g to about 40 mg / g. g, about 7.5 mg / g ~ about 19.5 mg / g, about 8.5 mg / g ~ about 18.5 mg / g, about 9.5 mg / g ~ about 17.5 mg / g, about 10.5 mg / g about 16.5 mg / g, about 11.5mg / g ~ about 15.

0034In one embodiment, the composition comprises a low molecular weight non-crosslinked hyaluronan polymer. In aspects of this embodiment, the composition has an average molecular weight of, for example, about 100,000 Da, about 200,000 Da, about 300,000 Da, about 400,000 Da, about 500,000 Da, about 600,000 Da, about 700,000 Da, about 800,000 Da or about 900,000 Da. Includes non-crosslinked hyaluronan with. In yet another aspect of this embodiment, the composition is, for example, up to 100,000 Da, up to 200,000 Da, up to 300,000 Da, up to 400,000 Da, up to 500,000 Da, up to 600,000 Da, up to 700,000 Da. Includes uncrosslinked hyaluronan polymers with an average molecular weight of up to 800,000 Da, up to 900,000 Da or up to 950,000 Da. In yet another aspect of this embodiment, the composition is, for example, about 100,000 Da to about 500,000 Da, about 200,000 Da to about 500,000 Da, about 300,000 Da to about 500,000 Da, about 400,000 Da to about 500,000 Da, about 500,000 Da. ~ About 950,000Da ~ About 600,000Da ~ About 950,000Da, About 700,000Da ~ About 950,000Da, About 800,000Da ~ About 950,000Da, About 300,000Da ~ About 600,000Da, About 300,000Da ~ About 700,000Da, About 300,000Da ~ About Includes a non-crosslinked hyaluronan polymer with an average molecular weight of 800,000 Da or about 400,000 Da to about 700,000 Da.

0035In another embodiment, the composition comprises a high molecular weight non-crosslinked hyaluronan polymer. In aspects of this embodiment, the composition has an average molecular weight of, for example, about 1,000,000 Da, about 1,500,000 Da, about 2,000,000 Da, about 2,500,000 Da, about 3,000,000 Da, about 3,500,000 Da, about 4,000,000 Da, about 4,500,000 Da or about 5,000,000 Da. Includes non-crosslinked hyaluronan with. In another aspect of this embodiment, the composition is, for example, at least 1,000,000 Da, at least 1,500,000 Da, at least 2,000,000 Da, at least 2,500,000 Da, at least 3,000,000 Da, at least 3,500,000 Da, at least 4,000,000 Da, at least 4,500,000 Da or at least 5,000,000 Da. Includes non-crosslinked hyaluronan polymers with average molecular weight. In yet another aspect of this embodiment, the composition is, for example, about 1,000,000 Da to about 5,000,000 Da, about 1,500,000 Da to about 5,000,000 Da, about 2,000,000 Da to about 5,000,000 Da, about 2,500,000 Da to about 5,000,000 Da, about 2,000,000 Da. Includes a non-crosslinked hyaluronan polymer having an average molecular weight of ~ about 3,000,000 Da, about 2,500,000 Da ~ about 3,500,000 Da or about 2,000,000 Da ~ about 4,000,000 Da. In yet other embodiments, the composition is, for example, greater than 2,000,000 Da and less than about 3,000,000 Da, greater than 2,000,000 Da and less than about 3,500,000 Da, greater than 2,000,000 Da and less than about 4,000,000 Da, greater than 2,000,000 Da and less than about 4,500,000 Da, and greater than 2,000,000 Da. Includes uncrosslinked hyaluronan polymers with an average molecular weight of significantly less than about 5,000,000 Da.

0036In another embodiment, the composition comprises a non-crosslinked hyaluronan polymer, wherein the non-crosslinked hyaluronan polymer comprises a combination of both a high molecular weight hyaluronan polymer and a low molecular weight hyaluronan polymer in various proportions. In aspects of this embodiment, the composition comprises a non-crosslinked hyaluronan polymer, wherein the non-crosslinked hyaluronan polymer is about 20: 1, about 15: 1, about both high molecular weight hyaluronan polymer and low molecular weight hyaluronan polymer. Includes combinations in the ratio of 10: 1, about 5: 1, about 1: 1, about 1: 5, about 1:10, about 1:15 or about 1:20.

0037Aspects herein provide, in part, a hydrogel composition comprising a substantially non-crosslinked glycosaminoglycan polymer. As used herein, the term "substantially non-crosslinked" refers to the presence of non-crosslinked glycosaminoglycan polymers in the compositions disclosed herein at a level of at least 90% by weight of the composition. The rest of the composition, at most 10% by weight, consists of other constituents, including crosslinked glycosaminoglycan polymers. In aspects of this embodiment, the composition is a substantially non-crosslinked chondroitin sulfate polymer, a substantially non-crosslinked dermatane sulfate polymer, a substantially non-crosslinked keratin sulfate polymer, a substantially non-crosslinked heparan polymer, a substantially non-crosslinked heparan Includes sulphate polymers or substantially non-crosslinked hyaluronan sulphate polymers. In another aspect of this embodiment, the composition comprises a non-bridged glycosaminoglycan, wherein the non-bridged glycosaminoglycan is, for example, about 90% by weight or about 90% by weight of the total glycosaminoglycans present in the composition. More, about 91% or more, about 92% or more, about 93% or more, about 94% or more, about 95% or more, about 96% or more , About 97% by weight or more, about 98% by weight or more, about 99% by weight or more, or about 100% by weight. In yet another aspect of this embodiment, the composition comprises non-crosslinked glycosaminoglycans, where the non-crosslinked glycosaminoglycans are, for example, about 90 to about 90 to about of the total glycosaminoglycans present in the composition. It corresponds to 100% by weight, about 93 to about 100% by weight, about 95 to about 100% by weight, or about 97 to about 100% by weight.

0038Aspects herein provide, in part, a hydrogel composition that is essentially free of crosslinked glycosaminoglycan polymers. As used herein, the term "essentially free" (or "essentially consisting of") refers to a composition in which only trace amounts of crosslinked matrix polymers can be detected. In aspects of this embodiment, the composition essentially comprises a crosslinked chondroitin sulfate polymer essentially free of chondroitin sulfate, a crosslinked dermatan sulfate polymer essentially free of dermatan sulfate, and a crosslinked heparan sulfate polymer. It contains keratane sulfate which is not contained, heparan which is essentially free of crosslinked heparan polymer, heparan sulfate which is essentially free of crosslinked heparan sulfate polymer, or hyaluronan sulfate which is essentially free of crosslinked hyaluronan polymer.

0039Aspects herein provide hydrogel compositions that, in part, do not contain any crosslinked glycosaminoglycan polymers. As used herein, the term "totally absent" means that the crosslinked glycosaminoglycan polymer cannot be detected or its presence cannot be confirmed within the detection range of the equipment or process used. Refers to the composition. In aspects of this embodiment, the composition comprises a chondroitin sulfate that does not contain any crosslinked chondroitin sulfate polymer, a dermatan sulfate that does not contain any crosslinked dermatan sulfate polymer, a keratane sulfate that does not contain any crosslinked heparan sulfate polymer, It contains heparan sulfate containing no crosslinked heparan polymer, heparan sulfate containing no crosslinked heparan sulfate polymer, or hyaluronan sulfate containing no crosslinked hyaluronan polymer.

0040Aspects herein provide, in part, a hydrogel composition comprising a proportion of crosslinked glycosaminoglycan polymers and non-crosslinked glycosaminoglycan polymers. This ratio of crosslinked and uncrosslinked glycosaminoglycan polymers is also known as the gel: fluid ratio. Any gel: fluid ratio is useful in making the compositions disclosed herein, provided that such ratios improve skin conditions as disclosed herein. Subject to producing the compositions disclosed herein. Non-limiting examples of gel: fluid ratios are 100: 0, 98: 2, 90:10, 75:25, 70:30, 60:40, 50:50, 40:60, 30:70, 25:75. , 10:90, 2:98 and 0: 100.

0041In aspects of this embodiment, the composition comprises a crosslinked glycosaminoglycan polymer and a non-crosslinked glycosaminoglycan polymer, wherein the gel: fluid ratio is, for example, about 0: 100, about 1:99, about 2: 98, about 3:97, about 4:96, about 5:95, about 6:94, about 7:93, about 8:92, about 9:91 or about 10:90. In another aspect of this embodiment, the composition comprises a crosslinked glycosaminoglycan polymer and a non-crosslinked glycosaminoglycan polymer, wherein the gel: fluid ratio is, for example, up to 1:99 and up to 2:98. , Up to 3:97, up to 4:96, up to 5:95, up to 6:94, up to 7:93, up to 8:92, up to 9:91 or up to 10:90 .. Yet another embodiment of this embodiment comprises a crosslinked glycosaminoglycan polymer and a non-crosslinked glycosaminoglycan polymer, wherein the gel: fluid ratio is, for example, from about 0: 100 to about 3:97, about 0 :. It is 100 to about 5:95, or about 0: 100 to about 10:90.

0042In another aspect of this embodiment, the composition comprises a crosslinked glycosaminoglycan polymer and a non-crosslinked glycosaminoglycan polymer, wherein the gel: fluid ratio is, for example, about 15:85, about 20:80, about. 25:75, about 30:70, about 35:65, about 40:60, about 45:55, about 50:50, about 55:45, about 60:40, about 65:35, about 70:30, about 75:25, about 80:20, about 85:15, about 90:10, about 95: 5, about 98: 2 or about 100: 0. In yet another aspect of this embodiment, the composition comprises a crosslinked visionary polymer and a non-crosslinked glycosaminoglycan polymer, in which case the gel: fluid ratio is, for example, up to 15:85 and up to 20:80. , Maximum 25:75, maximum 30:70, maximum 35:65, maximum 40:60, maximum 45:55, maximum 50:50, maximum 55:45, maximum 60:40, maximum At 65:35, up to 70:30, up to 75:25, up to 80:20, up to 85:15, up to 90:10, up to 95: 5, up to 98: 2 or up to 100 0. In yet another aspect of this embodiment, the composition comprises a crosslinked glycosaminoglycan polymer and a non-crosslinked glycosaminoglycan polymer, in which case the gel: fluid ratio is, for example, from about 10:90 to about 70:30. About 15:85 ~ about 70:30, about 10:90 ~ about 55:45, about 80:20 ~ about 95: 5, about 90:10 ~ about 100: 00, about 75:25 ~ about 100: 00 or It is about 60:40 to about 100: 0.

0043Aspects herein are in part disclosed herein which may further or optionally comprise another agent or combination of agents that provides a beneficial effect when the composition is administered to an individual. A hydrogel composition is provided. Such beneficial agents include antioxidants, antipruritic agents, anti-cellulite agents, anti-scarring agents, anti-inflammatory agents, anesthetics, anti-irritants, vasoconstrictors, vasodilators, antihemorrhagic agents, etc. Examples include, but are not limited to, hemostatic or anti-fibrinolytic agents, release agents, tensioning agents, anti-stagnation agents, pigmentation agents, anti-pigmentation agents or moisturizers.

0044Aspects herein provide, in part, the hydrogel compositions disclosed herein which may optionally comprise an anesthetic. The anesthetic is preferably a local anesthetic, i.e. an anesthetic that causes reversible local sensory loss and pain loss, such as aminoamide local anesthetics and aminoester local anesthetics. The amount of anesthetic contained in the composition disclosed herein is an amount effective in relieving the pain experienced by an individual upon administration of the composition. Therefore, the amount of anesthetic contained in the compositions disclosed herein is about 0. 1 to about 5% by weight. Non-limiting examples of anesthetics include lidocaine, ambucaine, amoranone, amylokine, benoxinate, benzocaine, betoxicaine, biphenamine, bupivacaine, butacine, butamben, butaniricaine, butetamine, butoxycaine, culticaine, chloroprocaine, cocaine, cocaine, cocaine. , Dibucaine, dimethisokin, dimethocaine, diperodon, dicyclomine, ecgonidine, ecgonine, ethyl chloride, etidokine, beta-eucaine, euprocaine, phenalcomin, formokine, hexylcaine, hydroxytetracaine, isobutyl p-aminobenzoate, leucinocaine mesylate Levoxadorol, lidocaine, mepivacaine, meprilcaine, metabutoxycaine, methyl chloride, myrtecine, naepine, octacaine, orthocaine, oxetazain, paretoxycaine, phenacine, phenol, piperokine, pyridocaine, polydocanol, pramoxin Examples thereof include caine, pseudococaine, pyrocaine, ropivacaine, salicyl alcohol, tetracaine, tricaine, trimecaine, zoramine, combinations thereof and salts thereof. Non-limiting examples of amino ester local anesthetics include procaine, chloroprocaine, cocaine, cyclomethicine, simethocaine (lalocine), propoxycaine, procaine (novocaine), proparacaine, tetracaine (ametocaine). Non-limiting examples of aminoamide local anesthetics include articaine, bupivacaine, cincokine (dibucaine), etidocaine, levobupivacaine, lidocaine (lignocaine), mepivacaine, piperokine, prlocaine, ropivacaine and trimecaine. The compositions disclosed herein may include a single anesthetic or multiple anesthetics. A non-limiting example of a combination local anesthetic is lidocaine / prlocaine (EM).

0045Thus, in one embodiment, the compositions disclosed herein include an anesthetic and a salt thereof. In aspects of this embodiment, the compositions disclosed herein include an aminoamide local anesthetic and a salt thereof, or an aminoester local anesthetic and a salt thereof. In another aspect of this embodiment, the compositions disclosed herein are procaine, chloroprocaine, cocaine, cyclomethicine, simethocaine, propoxycaine, procaine, proparacaine, tetracaine, or salts thereof, or salts thereof. Includes any combination. In yet another aspect of this embodiment, the compositions disclosed herein are: articaine, bupivacaine, syncocaine, etidocaine, levobupivacaine, lidocaine, mepivacaine, piperocaine, prilocaine, ropivacaine, trimecaine, or salts thereof. Or any combination thereof. In yet another aspect of this embodiment, the compositions disclosed herein include a lidocaine / prlocaine combination.

0046In another aspect of this embodiment, the compositions disclosed herein are, for example, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6 by weight of the total composition. %, Approx. 0.7%, Approx. 0.8%, Approx. 0.9%, Approx. 1.0%, Approx. 2.0%, Approx. 3.0%, Approx. 4.0%, Approx. 5.0%, Approx. 6.0%, Approx. 7.0%, Approx. 8.0%, Approx. 9.0% or Includes anesthetic in an amount of about 10%. In yet another aspect, the compositions disclosed herein are, for example, at least 0.1%, at least 0.2%, at least 0.3%, at least 0.4%, at least 0.5%, at least 0.6%, at least of the weight of the total composition. 0.7%, at least 0.8%, at least 0.9%, at least 1.0%, at least 2.0%, at least 3.0%, at least 4.0%, at least 5.0%, at least 6.0%, at least 7.0%, at least 8.0%, at least 9.0% or at least 10% Includes anesthetic in the amount of. In yet another aspect, the compositions disclosed herein are, for example, up to 0.1%, up to 0.2%, up to 0.3%, up to 0.4%, up to 0.5%, by weight of the total composition. Up to 0.6%, up to 0.7%, up to 0.8%, up to 0.9%, up to 1.0%, up to 2.0%, up to 3.0%, up to 4.0%, up to 5.0%, up to 6.0%, Includes anesthetic in amounts up to 7.0%, up to 8.0%, up to 9.0% or up to 10%. In a further aspect, the compositions disclosed herein are, for example, about 0.1% to about 0.5%, about 0.1% to about 1.0%, about 0.1% to about 2.0%, about 0.1% of the total weight of the composition. ~ About 3.0%, about 0.1% ~ about 4.0%, about 0.1% ~ about 5.0%, about 0.2% ~ about 0.9%, about 0.2% ~ about 1.0%, about 0.2% ~ about 2.0%, about 0.5% ~ about Contains anesthetic in an amount of 1.0% or about 0.5% to about 2.0%.

0047In another embodiment, the compositions disclosed herein do not include an anesthetic.

0048Aspects herein provide, in part, the hydrogel compositions disclosed herein which may optionally contain an antioxidant. The amount of antioxidant contained in the compositions disclosed herein reduces or reduces the degradation of the compositions disclosed herein, eg, enzymatic and / or chemical degradation of the composition. It is an effective amount to prevent. Therefore, the amount of antioxidant contained in the compositions disclosed herein is from about 0.1% to about 10% by weight of the total composition. Non-limiting examples of antioxidants include polyols, flavonoids, phytoarexins, ascorbic acids, tocopherols, tocotrienols, lipoic acid, melatonins, carotenoids, analogs or derivatives thereof, and any combination thereof. The compositions disclosed herein include a single oxidant or multiple oxidants, retinol, coenzymes, idebenone, allopurinol, glutathione, sodium selenite.

0049Aspects herein provide, in part, the hydrogel compositions disclosed herein which may optionally contain polyols. As used herein, the term "polyol" is synonymous with "sugar alcohol," "polyol," and "polyalcohol," and refers to a hydrogenated form of a carbohydrate whose carbonyl group (aldehyde). Or ketones, reducing sugars) have been reduced to primary or secondary hydroxyl groups (hence alcohols), such as from mannose to mannitol, from xylose to xylitol, and from lacturose to lactitol. The polyol is of the general formula H (HCHO)._nHas + 1H. Both monosaccharides and disaccharides can form polyols; however, disaccharide-derived polyols are not completely hydrogenated because only one aldehyde group is available for reduction. Non-limiting examples of polyols include glycerol, erythritol, threitol, arabitol, erythritol, ribitol, xylitol, galactitol (or zulucitol), glucthiol (or sorbitol), iditol, inositol, mannitol, isomalt, lactitol, maltitol and poly. Glythritol can be mentioned. Other non-limiting examples of polyols include, for example, Pharmaceutical Dosage Forms and Drug Delivery Systems (Howard C. Ansel et al., Eds., Lippincott Williams &amp; Wilkins Publishers, 7).^th ed. 1999); Remington: The Science and Practice of Pharmacy (Alfonso R. Gennaro ed., Lippincott, Williams &amp; Wilkins, 20^th ed. 2000); Goodman &amp; Gilman's The Pharmacological Basis of Therapeutics (Joel G. Hardman et al., eds., McGraw-Hill Professional, 10^th ed. 2001); and Handbook of Pharmaceutical Excipients (Raymond C. Rowe et al., APhA Publications, 4^th It may be found in edition 2003), each of which is incorporated herein by reference.

0050Aspects herein provide, in part, the hydrogel compositions disclosed herein that optionally include flavonoids (Table 2). Flavonoids (or bioflavonoids) refer to a class of polyphenolic ketone-containing and non-ketone-containing secondary metabolites found in plants that are known to have a variety of beneficial biochemical and antioxidant effects. Non-limiting examples of flavonoids include C-methylated flavonoids, O-methylated flavonoids, isoflavonoids, neoflavonoids, flavonoids, flanoflavonoids, pyranoflavonoids, methylenedioxyflavonoids, prenylated flavonoids, auron, flavonoids, flavonoids. , Flavonones, flavanonols, flavan-3-ols, flavon-4-ols, leukoanthocyanidins (flavon-3,4-diols), anthocyanidins and tannins. It is understood that these and other substances known in the pharmaceutical industry may be included in the compositions disclosed herein (eg, Remington's Pharmaceutical Sciences Mac Publishing Company, Easton, PA 16^th See Edition 1980).

0051Aurone is a compound derived from 2-benzylidene-1-benzofuran-3-one. Non-limiting examples of aurone include 4,5,6-trihydroxy-auron, auroicidine, hispidol, leptosidin, maritimetin and sulfretin.

0052The three main classes of ketone-containing flavonoids are flavones, which are compounds derived from 2-phenylchromen-4-one (2-phenyl-1,4-benzopyrone); 3-phenylchromen-4-one (3-phenyl-). Isoflavone, which is a compound derived from 1,4-benzopyrone; and neoflavon, which is a compound derived from 4-phenylcoumarin (4-phenyl-1,2-benzopyrone) (Table 2). Flavons are themselves divided into four groups based on the presence or absence of 3-hydroxyl 2,3-dihydro functional groups: 2-phenylchromen-4-one lacking both functional groups: Flavon, a compound of origin; flavonol (3-hydroxyflavon), a compound derived from 3-hydroxy-2-phenylchromen-4-one, which has a 3-hydroxyl group but lacks a 2,3-dihydro group; Flabanone, a compound derived from 2,3-dihydro-2-phenylchromen-4-one that has a 2,3-dihydro group but lacks a 3-hydroxyl group; and 3-hydroxy with both functional groups Flavanonol (3-hydroxyflabanone or 2,3-dihydroflavonol) is a compound derived from -2,3-dihydro-2-phenylchromen-4-one.

0053Non-limiting examples of flavones include acasetin, apiin, apigetrin, apigetrin, altindonin P, baikarain, baikarin, chrysin, cynaroside, diosmethine, diosmin, eupatilin, flavoxate, 6-hydroxyflavon, genquanin, hindrosmin, luteolin, nepetin, Examples include nepetrin (nepetin 7-glucoside), nobiletin, orientin (isoorientin), oroxylin gin, oroxylin A, leufolin, scutellarain, scutellaline, tangeritin, techtochrysin, tetin, tricin, veronicastroside, vitexin (isobitexin) and wagonin. .. Non-limiting examples of flavonols include 3-hydroxyflavon, azaleaatin, fisetin, galangin, gosipetin, kenferide, kenferol, isorhamnetin, morin, mylicetin, natsudaidain, pachipodor, quercetin, rhamnazin, ramnetin and sophorin. Non-limiting examples of flavanones include butin, eriodictyol, hesperetin, hesperidin, homoeriodictyol, isosakuranetin, naringenin, naringin, pinosembulin, poncirin, sakuranetin, sakuranin and sterbin. Non-limiting examples of flavanonol include taxifolin (dihydroquercetin) and aromadedrin (dihydrokaempferol).

0054Isoflavonoids include isoflavones and isoflavane (Table 2). Non-limiting examples of isoflavonoids include alpinumisoflavones, anagiloidisoflavones A and B, calicocin, daidozein, daidin, delrubone, di-O-methylalpinumisoflavones, formononetin, genistein, genistein, glycitein, ipriflavones, Irigenin, irigen, irilon, 4'-methyl-alpinumisoflavone, 5-O-methylgenistein, luteon, ononin, olobol, prtensein, purnetin, pseudobaptigenin, psai-tectrigenin, puerulin, letscin, tectrigenin, tectrigenin And Witeon.

0055Neoflavonoids include 4-arylcoumarin (neoflavone), 4-arylchroman, d'Albergion and d'Alberginol (Table 2). Neoflavon is a compound derived from 4-phenylcoumarin (or 4-aryl-coumarin); neoflaben is a compound derived from 4-phenylchromen. Non-limiting examples of neoflavonoids include carophyllolide, kutareagenin, dalbergichromene, dalbergin and nibetin.

0056Non-ketone-containing flavonoids include flavan-3-ols and catechins. Flavan-3-ols (flavanols) are a class of flavonoids derived from the 2-phenyl3,4-dihydro-2H chromen-3-ol skeleton. Catkin has two benzene rings (called A and B rings) and a dihydropyran heterocycle (C ring) with a hydroxyl group on carbon 3. Ring A resembles the resorcinol moiety, while ring B resembles the catechol moiety. There are two chiral centers on the molecule on carbons 2 and 3. Therefore, it has four diastereoisomers. Two of the isomers exist in the trans configuration and are called catechins, and the other two exist in the cis configuration and are called epicatechins. Non-limiting examples of non-ketone-containing flavonoids include afzelechin, altromerin A, altromerin B, catechin, epicatechin, epigallocatechin, epicatechin gallate, epigallocatechin gallate, epigallocatechin gallate, epigallocatechin, fisetinidol, galocatechin, galocatechin. Galate, guiburtinidol, mesiadanol (3-O-methylcatechin), mesquitol, propyl gallate, robinechinidol and thealbigin.

0057Flavan-4-ol (3-to oxyflavonoid) is a flavon-induced alcohol derived from 2-phenylchroman-4-ol. Non-limiting examples of flavan-4-ol include apiforol and luteoforol.

0058Leucoanthocyanidin (flavan-3,4-diol) is a compound derived from 2-phenyl-3,4-dihydro-2H-chromen-3,4-diol. Non-limiting examples of flavan-3,4-diols include leucocyanidin, leucodelfinidin, leucopelargonidin, leucopelargonidin, leucopelargonidin, leucopelarginidine and melacacidin.

0059Anthocyanidins are compounds derived from 2-phenylchromenilium. Non-limiting examples of anthocyanidins include antilinin, apigenidin, aurantidinin, capencinidin, chrysantenin, cormunidin, comelinin, cyanidin, 6-hydroxycyanidin, cyanidin-3- (di-p-malvidin glucoside) -5-glucoside, cyano Salbianin, Delphinidin, Diosmethocyanidin, Europinidin, Phycetinidin, Gesneridin, Guibrutinidin, Hirstidine, Luteolinidin, Malvidin, 5-Desoxy-Malvidin, Malvidin, Miltilin, Oenin, Peonidin, Miltilin, Oenin, Peonidin, 5-Desoxy-Peonidin, Peonidin, Peonidin, Peonidin Included are protodelphin, pulkeridine, pulkeridin 3-glucoside, pulkeridin 3-ramnoside, robinetinidin, rosinidin, trisetinidin, tulipanin and violdelphin.

0060Tannin is a compound derived from 2-phenylchromenilium. There are three main classes of tannins: hydrolyzed tannins; non-hydrolyzed tannins (condensed tannins; proanthocyanidins); and pseudotannins.

0061Hydrolyzed tannins themselves fall into four groups: oligomeric tannins, such as aglycone tannins and glycoside tannins; elagitannins; gallotannins, and unclassified tannins. Non-limiting examples of aglycone tannins include ellagic acid, galactic acid and gallic acid. Non-limiting examples of glycoside tannins include glucose, kinin acid and shikimic acid. Non-limiting examples of ellagitannins include castaragin (vescaragin), castarin, casalitin, casariin, casalinin, cornucine E, grangenin, pedunclagin, punicacortein C, punigluconin, punicalin, punicalagin alfa, punicalin, 2-O-galloyl- Examples include punicalin, stakiurin, strictinin and terimagrangin II. Non-limiting examples of gallotannin include corilagin, galloyl glucose, jigaroyl glucose, triggerloyl glucose, tetragalloyl glucose, pentagalloyl glucose, hexagalloyl glucose, heptagaloyl glucose, octagalloyl glucose and tannic acid. Can be mentioned. Non-limiting examples of non-classified tannins include acticimin A, acticimin B, kebulinic acid, chebulinic acid, cinnamtannin B1, combreglutinin, geraniin, granatin B, lobulin A, lobulin B, lobulin C, lobulin D, Robrin E, stakiurin, telcatin, terflavin A, terflavin B, tergaragin, vescarin, 1,3,4-tri-O-galloylkinic acid, 3,5-di-O-galloyl-shikimic acid and 3,4,5-tri -O-galloyl shikimic acid can be mentioned.

0062Condensed tannins (proanthocyanidins) are essentially flavonoid polymer chains, such as catechin. Non-limiting examples of condensed tannins include proanthocyanidins, prodelphinidins, profisetinidins, progabletinidins and prolobinetidine.<tables num="2-1"><img id="000003" he="155" wi="158" file="JP5960894B2_D0001.tif" img-format="tif" img-content="drawing" /></tables><tables num="2-2"><img id="000004" he="211" wi="158" file="JP5960894B2_D0001.tif" img-format="tif" img-content="drawing" /></tables><tables num="2-3"><img id="000005" he="186" wi="159" file="JP5960894B2_D0001.tif" img-format="tif" img-content="drawing" /></tables><tables num="2-4"><img id="000006" he="112" wi="158" file="JP5960894B2_D0001.tif" img-format="tif" img-content="drawing" /></tables>

0063Aspects herein provide, in part, the hydrogel compositions disclosed herein which may optionally comprise phytoalexin. Phytoalexin refers to a class of antibacterial molecules with antioxidant activity that are synthesized in de novo by plants that respond to incompatible pathogen infections. Non-limiting examples of phytoalexins include resveratrol (3,5,4'-trihydroxy-trans-stilbene) and alixin (3-hydroxy-5-methoxy-6-methyl-2-pentyl-4H-pyran). -4-one), glyceolin, phaseolin and medical pin.

0064Aspects herein provide, in part, the hydrogel compositions disclosed herein which may optionally comprise an ascorbic acid agent. Ascorbic acid (vitamin C), (5R)-[(1S) -1,2-dihydroxyethyl] -3,4-dihydroxyfuran-2 (5H) -one reduces reactive oxygen species, such as hydrogen peroxide. It is a monosaccharide redox catalyst found in both animals and plants that neutralizes it. Ascorbic acid also interconverts into two unstable ketone tautomers by proton transfer, but it is the most stable in the enol form. The hydroxyl protons of the enol are removed. The resulting pair of electrons from the oxide anion is then pushed down to form a ketone at position 2 or 3, and the electrons from the double bond move to position 3 or 2, respectively, to form a carbanion. , This picks up the protons and gives rise to two possible forms: 1-carboxy-2-ketone and 1-carboxy-3-ketone. Non-limiting examples of ascorbic acid agents include ascorbic acid and sodium, potassium and calcium salts of ascorbic acid, fat-soluble esters of ascorbic acid with long-chain fatty acids (ascorbyl palmitate or ascorbyl stearate), magnesium ascorbyl phosphate (MAP). , Sodium ascorbyl phosphate (SAP) and ascorbic acid 2-glucoside (AA2G)^TM), Disodium ascorbyl sulfate, and Vitagen.

0065Aspects herein provide the hydrogel compositions disclosed herein, in part which may optionally include tocopherols and / or tocotrienols. Tocopherols and tocotrienols contain a group of antioxidants collectively called vitamin E. All feature a chromanol ring, with a hydroxyl group that can impart hydrogen atoms to reduce free radicals, as well as hydrophobic side chains that allow permeation into biological membranes. Both tocopherols and tocotrienols occur in alpha, beta, gamma and delta forms and are determined by the number and position of methyl groups on the chromanol ring. Tocotrienols have the same methyl structure in the ring, but are similar and different from cophenols due to the presence of three double bonds in the hydrophobic side chain. Tail unsaturatedity provides tocotrienol with only a single stereoisomeric carbon (thus two possible isomers per structural formula, one of which is naturally occurring), while tocopherols have three centers. (And eight possible steric isomers per structural formula, one of which is naturally occurring). In general, the unnatural I-isomers of tocotrienols lack almost all vitamin activity, and half of the eight possible isomers of tocopherols (those with 2S chirality at the ring-tail junction) are also vitamin-active. Lacking. Of the active stereoisomers, increased methylation, especially complete methylation to the alpha form, increases vitamin activity. Non-limiting examples of vitamin E include tocopherols (eg, α-tocopherol, β-tocopherol, γ-tocopherol and δ-tocopherol), tocopherol analogs and derivatives (eg, tocopheryl acetate, sodium tocopheryl phosphate (STP),). Polyoxyethanyl-α-tocopheryl sebacate and tocopherol polyethylene glycol 1000 succinate (TPGS)), tocotrienols (eg, α-tocotrienols, β-tocotrienols, γ-tocotrienols and δ-tocotrienols),

0066Aspects herein provide, in part, the hydrogel compositions disclosed herein which may optionally comprise lipoic acid (LA). Lipoic acid (R) -5- (1,2-dithiolan-3-yl) pentanoic acid contains two adjacent sulfur atoms (of C6 and C8) that are attached via disulfide bonds and is therefore oxidized. It is an organic sulfur compound derived from octanoic acid that is said to be present (but one of the sulfur atoms can be present in a higher oxidation state). The carbon atom of C6 is chiral and the molecule is as two enantiomers R-(+)-lipoic acid (RLA) and S-(-)-lipoic acid (SLA), as well as the racemic mixture R / S-lipoic acid (R). / S-LA) can exist. Only R- (+)-enantiomer is naturally present and is an essential cofactor for the four mitochondrial enzyme complexes.

0067Aspects herein provide, in part, the hydrogel compositions disclosed herein which may optionally contain melatonin. Melatonin, N-acetyl-5-methoxytryptamine, is a powerful widespread antioxidant found in animals, plants and microorganisms.

0068Aspects herein provide, in part, the hydrogel compositions disclosed herein which may optionally contain carotenoids. Carotenoids are naturally occurring tetras in plants, as well as some other photosynthetic organisms such as algae, some types of fungi, some bacteria and at least one species of aphid chloroplasts and chromoplasts. It is a terpenoid. Structurally, tetraterpenes are biochemically synthesized from eight isoprene units that give rise to a 40 carbon skeleton that can be terminated by a hydrocarbon ring. There are over 600 known carotenoids; they fall into two classes: xanthophylls (containing oxygen) and carotenes (pure hydrocarbons, containing no oxygen).

0069Chemically, carotene, such as lycopene, is a polyunsaturated hydrocarbon containing 40 carbon atoms per molecule, a variable number of hydrogen atoms, and no other elements. Some carotenes are terminated by hydrocarbon rings at one or both ends of the molecule. Non-limiting examples of carotene include α-carotene, β-carotene, γ-carotene, δ-carotene, ε-carotene, zeta-carotene and lycopene.

0070Xanthophyll hydrocarbons, which contain 40 carbon atoms per molecule, contain a pair of hydroxyl groups and / or hydrogen atoms (substituted by oxygen atoms). For this reason, they are more polar than pure hydrocarbon carotene. Some xanthophylls are terminated by hydrocarbon rings at one or both ends of the molecule. Non-limiting examples of xanthophylls include lutein, zeaxatin, neoxanthin, violaxanthin, α-cryptoxanthin and β-cryptoxanthin.

0071Aspects herein provide, in part, the hydrogel compositions disclosed herein which may optionally comprise Vitamin A. Vitamin A includes retinol, retinal and retinoic acid, and retinol due to the trans or cis configuration of four of the five double bonds found in the polyene chain [(2E, 4E, 6E, 8E) -3. , 7-Dimethyl-9- (2,6,6-trimethylcyclohexe-1-enyl) nona-2,4,6,8-tetraene-1-ol], retinal and different geometric isomers of retinoic acid listed Be done. Non-limiting examples of vitamin A include retinol, retinal, retinoic acid, retinoic isomers, retinal isomers, retinoic acid isomers, tretinoin, iso and retinoic acid and retinyl palmitate.

0072In one embodiment, the compositions disclosed herein contain an antioxidant in an amount sufficient to reduce or prevent the degradation of the glycosaminoglycan polymer. In aspects of this embodiment, the compositions disclosed herein are polyols, flavonoids, phytoarexins, ascorbic acid agents, tocopherols, tocotrienols, lipoic acid, melatonin, carotenoids, analogs or derivatives thereof, or derivatives thereof. Includes any combination.

0073In another aspect of this embodiment, the compositions disclosed herein are about 0.01%, for example, about 0.01% of the total weight of the composition. 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1.0%, about 2.0%, about 3.0%, about 4.0% , About 5.0%, about 6.0%, about 7.0%, about 8.0%, about 9.0% or about 10% containing antioxidants. In yet another aspect, the compositions disclosed herein are, for example, at least 0.1%, at least 0.2%, at least 0.3%, at least 0.4%, at least 0.5%, at least 0.6% of the weight of the total composition. At least 0.7%, at least 0.8%, at least 0.9%, at least 1.0%, at least 2.0%, at least 3.0%, at least 4.0%, at least 5.0%, at least 6.0%, at least 7.0%, at least 8.0%, at least 9.0% or at least 10 In the amount of%, it contains an antioxidant. In yet another aspect, the compositions disclosed herein are, for example, up to 0.1%, up to 0.2%, up to 0.3%, up to 0.4%, up to 0.5% of the weight of the total composition. %, Maximum 0.6%, Maximum 0.7%, Maximum 0.8%, Maximum 0.9%, Maximum 1.0%, Maximum 2.0%, Maximum 3.0%, Maximum 4.0%, Maximum 5.0%, Maximum 6.0 %, Up to 7.0%, Up to 8.0%, Up to 9.0% or Up to 10% containing antioxidants. In a further aspect, the compositions disclosed herein are, for example, about 0.1% to about 0.5%, about 0.1% to about 1.0%, about 0.1% to about 2.0%, about the weight of the total composition. 0.1% to about 3.0%, about 0.1% to about 4.0%, about 0.1% to about 5.0%, about 0.2% to about 0.9%, about 0.2% to about 1.0%, about 0.2% to about 2.0%, about 0.5% Contains antioxidants in an amount of ~ about 1.0% or about 0.5% ~ about 2.0%.

0074In another embodiment, the compositions disclosed herein are free of antioxidants.

0075Aspects herein provide, in part, the hydrogel compositions disclosed herein which may optionally comprise a vasoconstrictor. The amount of vasoconstrictor contained in the composition disclosed herein is effective in reducing, stopping, and / or preventing bleeding experienced by an individual during or after administration of the composition. The amount. Non-limiting examples of vasoconstrictors include α1 receptor agonists such as 2- (1-naphthylmethyl) -2-imidazoline (nafazoline), (R) -4- (1-hydroxy-2- (methylamino) ethyl). ) Benzene-1,2-diol (epinephrine), 2-amino-1- (2,5-dimethoxyphenyl) propan-1-ol (methoxamine), 4-[(1R, 2S) -2-amino-1- Hydroxypropyl] benzene-1,2-diol (methyl norepinephrine), 4-[(1R) -2-amino-1-hydroxyethyl] benzene-1,2-diol (norepinephrine), 3- (4,5-dihydro) -1H-imidazol-2-ylmethyl) -2,4-dimethyl-6-tert-butyl-phenol (oxymethazoline), (R) -3- [-1-hydroxy-2- (methylamino) ethyl] phenol (Phenilefrin or Neo-Cinefrin), (R^*, R^*)-2-Methylamino-1-phenylpropan-1-ol (pseudoephedrine), 4- [1-hydroxy-2- (methylamino) ethyl] phenol (cinefurin or oxedrin), 2-[(2-cyclopropyl) Phenoxy) Methyl] -4,5-dihydro-1H-imidazole (silazoline), 2-[(4-tert-butyl-2,6-dimethylphenyl) methyl] -4,5-dihydro-1H-imidazole (xylometazoline) , Its analogs or derivatives, and any combination thereof. The compositions disclosed herein may include a single vasoconstrictor or multiple vasoconstrictors.

0076Thus, in one embodiment, the compositions disclosed herein may comprise a vasoconstrictor. In aspects of this embodiment, the compositions disclosed herein include an α1 receptor agonist. In aspects of this embodiment, the compositions disclosed herein are naphazoline, epinephrine, methoxamine, methylnorepinephrine, norepinephrine, oxymetazoline, phenylephrine, pseudoephedrine, synephrine, silazoline, xylometazoline, analogs or derivatives thereof. , Or any combination thereof.

0077In another aspect of this embodiment, the compositions disclosed herein are of, for example, about 0.001%, about 0.01%, about 0.1%, about 0.2%, about 0.3%, about the weight of the total composition. 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, Vasoconstrictor in amounts of about 0.9%, about 1.0%, about 2.0%, about 3.0%, about 4.0%, about 5.0%, about 6.0%, about 7.0%, about 8.0%, about 9.0% or about 10% including. In yet another aspect, the compositions disclosed herein are, for example, at least 0.1%, at least 0.2%, at least 0.3%, at least 0.4%, at least 0.5%, at least 0.6% of the weight of the total composition. , At least 0.7%, at least 0.8%, at least 0.9%, at least 1.0%, at least 2.0%, at least 3.0%, at least 4.0%, at least 5.0%, at least 6.0%, at least 7.0%, at least 8.0%, at least 9.0% or at least Contains a vasoconstrictor in an amount of 10%. In yet another aspect, the compositions disclosed herein are, for example, up to 0.1%, up to 0.2%, up to 0.3%, up to 0.4%, up to 0.5% of the weight of the total composition. , Maximum 0.6%, maximum 0.7%, maximum 0.8%, maximum 0.9%, maximum 1.0%, maximum 2.0%, maximum 3.0%, maximum 4.0%, maximum 5.0%, maximum 6.0% Includes vasoconstrictor in amounts of up to 7.0%, up to 8.0%, up to 9.0% or up to 10%. In a further aspect, the compositions disclosed herein are about 0.1% to about 0.5%, about 0.1% to about 1.0%, about 0.1% to about 2.0%, about 0.1 of the total weight of the composition. % ~ About 3.0%, about 0.1% ~ about 4.0%, about 0.1% ~ about 5.0%, about 0.2% ~ about 0.9%, about 0.2% ~ about 1.0%, about 0.2% ~ about 2.0%, about 0.5% ~ Includes vasoconstrictor in an amount of about 1.0% or about 0.5% to about 2.0%.

0078In another embodiment, the compositions disclosed herein do not include a vasoconstrictor.

0079Aspects herein provide, in part, the hydrogel compositions disclosed herein which may optionally comprise an antihemorrhagic agent. Anti-bleeding agents include hemostatic agents and anti-fibrinolytic agents. Hemostatic agents are molecules that act to reduce, stop, and / or prevent bleeding in the event of a ruptured blood vessel. A class of hemostatic agents is vitamin K and its analogs or derivatives. Vitamin K and its 2-methyl-1,4-naphthoquinone derivatives are required for post-translational modification of certain proteins and primarily for blood coagulation, but metabolism in bone and other tissues. It is a group of lipophilic and hydrophobic vitamins that are also involved in the pathway. The function of vitamin K in cells is to convert glutamate in proteins to gamma-carboxyglutamate (gla). Antifibrinolytic agents are molecules that act to promote clot formation. Anti-fibrinolytic agents include aminocaproic acid (ε-aminocaproic acid) and tranexamic acid. These lysine-like agents prevent the formation of the fibrinolytic enzyme plasmin from its precursor plasminogen by plasminogen activators (mainly t-PA and u-PA). These agents reversibly block the lysine binding site of the enzyme or plasminogen, thus arresting plasmin formation, thereby preventing fibrinolysis and clot degradation. The amount of antihemorrhagic agent contained in the composition disclosed herein is effective in reducing, stopping, and / or preventing the bleeding experienced by an individual during or after administration of the composition. The amount. Etancilate (disinen / disinone) is another hemostatic agent. Non-limiting examples of anti-hemorrhagic agents include hemostatic agents such as chitosan, ethanecillate, desmopressin, vitamin K or vitamin K analogs such as vitamin K.₁(Phytonadione, Phytomenadione or Phytonadione), Vitamin K₂(Menaquinone or Menatetrenone), Vitamin K₃(Menadione), Vitamin K₄(Menadiol), Vitamin K₅(4-Amino-2-mefil-1-naphthol hydrochloride), Vitamin K₆, Vitamin K₇, Vitamin K₈, Vitamin K₉And Vitamin K₁₀, Anti-fibrinolytic agents such as aminocaproic acid (ε-aminocaproic acid), tranexamic acid, serpins such as aprotinin, α1-antitrypsin, C1-inhibitors, camostat, analogs or derivatives thereof, and any combination thereof. Be done. The compositions disclosed herein may include a single antihemorrhagic agent or multiple antihemorrhagic agents.

0080Thus, in one embodiment, the compositions disclosed herein include an antihemorrhagic agent. In aspects of this embodiment, the compositions disclosed herein include a hemostatic agent or an anti-fibrinolytic agent. In aspects of this embodiment, the compositions disclosed herein are vitamin K or vitamin K analogs, such as vitamin K.₁, Vitamin K₂, Vitamin K₃, Vitamin K₄, Vitamin K₅, Vitamin K₆, Vitamin K₇, Vitamin K₈, Vitamin K₉And Vitamin K₁₀, Ε-Aminocaproic acid, tranexamic acid, serpins such as aprotinin, α1-antitrypsin, C1-inhibitors, camostat, analogs or derivatives thereof, and any combination thereof.

0081In another aspect of this embodiment, the compositions disclosed herein are of, for example, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about the weight of the total composition. 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1.0%, about 2.0%, about 3.0%, about 4.0%, about 5.0%, about 6.0%, about 7.0%, about 8.0%, about 9.0% Or in about 10% dose, containing antihemorrhagic agent. In yet another aspect, the compositions disclosed herein are, for example, at least 0.1%, at least 0.2%, at least 0.3%, at least 0.4%, at least 0.5%, at least 0.6% of the weight of the total composition. At least 0.7%, at least 0.8%, at least 0.9%, at least 1.0%, at least 2.0%, at least 3.0%, at least 4.0%, at least 5.0%, at least 6.0%, at least 7.0%, at least 8.0%, at least 9.0% or at least 10 Includes antihemorrhagic agent in% amount. In yet another aspect, the compositions disclosed herein are, for example, up to 0.1%, up to 0.2%, up to 0.3%, up to 0.4%, up to 0.5% of the weight of the total composition. , Maximum 0.6%, maximum 0.7%, maximum 0.8%, maximum 0.9%, maximum 1.0%, maximum 2.0%, maximum 3.0%, maximum 4.0%, maximum 5.0%, maximum 6.0% Contains antihemorrhagic agents in amounts of up to 7.0%, up to 8.0%, up to 9.0% or up to 10%. In a further aspect, the compositions disclosed herein are about 0.1% to about 0.5%, about 0.1% to about 1.0%, about 0.1% to about 2.0%, about 0.1 of the total weight of the composition. % ~ About 3.0%, about 0.1% ~ about 4.0%, about 0.1% ~ about 5.0%, about 0.2% ~ about 0.9%, about 0.2% ~ about 1.0%, about 0.2% ~ about 2.0%, about 0.5% ~ Includes antihemorrhagic agent in an amount of about 1.0% or about 0.5% to about 2.0%.

0082In another embodiment, the compositions disclosed herein do not include an antihemorrhagic agent.

0083Aspects herein provide, in part, the hydrogel compositions disclosed herein which may optionally comprise an antipruritic agent. The amount of antipruritic agent contained in the composition disclosed herein is an amount effective for alleviating the pruritic response experienced by an individual upon administration of the composition. Non-limiting examples of antipruritic agents include methylsulfonylmethane, sodium bicarbonate, calamine, allantin, kaolin, peppermint, tea tree oil, camphor, menthol, hydrocortisone, analogs or derivatives thereof, and any combination thereof. .. The compositions disclosed herein may include a single antipruritic agent or multiple antipruritic agents.

0084Thus, in one embodiment, the compositions disclosed herein include an antipruritic agent. In aspects of this embodiment, the compositions disclosed herein are methylsulfonylmethane, sodium bicarbonate, calamine, allantoin, kaolin, peppermint, tea tree oil, camphor, menthol, hydrocortisone, analogs or derivatives thereof. , As well as any combination thereof.

0085In another aspect of this embodiment, the compositions disclosed herein are of, for example, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about the weight of the total composition. 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1.0%, about 2.0%, about 3.0%, about 4.0%, about 5.0%, about 6.0%, about 7.0%, about 8.0%, about 9.0% Or in an amount of about 10%, it contains an antipruritic agent. In yet another aspect, the compositions disclosed herein are, for example, at least 0.1%, at least 0.2%, at least 0.3%, at least 0.4%, at least 0.5%, at least 0.6% of the weight of the total composition. At least 0.7%, at least 0.8%, at least 0.9%, at least 1.0%, at least 2.0%, at least 3.0%, at least 4.0%, at least 5.0%, at least 6.0%, at least 7.0%, at least 8.0%, at least 9.0% or at least 10 In the amount of%, it contains an antipruritic agent. In yet another aspect, the compositions disclosed herein are, for example, up to 0.1%, up to 0.2%, up to 0.3%, up to 0.4%, up to 0.5% of the weight of the total composition. , Maximum 0.6%, maximum 0.7%, maximum 0.8%, maximum 0.9%, maximum 1.0%, maximum 2.0%, maximum 3.0%, maximum 4.0%, maximum 5.0%, maximum 6.0% Includes antipruritic agents in amounts of up to 7.0%, up to 8.0%, up to 9.0% or up to 10%. In a further aspect, the compositions disclosed herein are about 0.1% to about 0.5%, about 0.1% to about 1.0%, about 0.1% to about 2.0%, about 0.1 of the total weight of the composition. % ~ About 3.0%, about 0.1% ~ about 4.0%, about 0.1% ~ about 5.0%, about 0.2% ~ about 0.9%, about 0.2% ~ about 1.0%, about 0.2% ~ about 2.0%, about 0.5% ~ Includes antipruritic agent in an amount of about 1.0% or about 0.5% to about 2.0%.

0086In another embodiment, the compositions disclosed herein do not contain antipruritic agents.

0087Aspects herein provide, in part, the hydrogel compositions disclosed herein which may optionally comprise an anti-cellulite agent. The amount of anti-cellulite agent contained in the composition disclosed herein is an effective amount to alleviate the fat deposits experienced by an individual upon administration of the composition. Non-limiting examples of anti-cellulite agents include, but are not limited to, forskolin, xanthine compounds such as caffeine, theophylline, theobromine and aminophylline, analogs or derivatives thereof, and any combination thereof. The compositions disclosed herein may include a single anti-cellulite agent or multiple anti-cellulite agents.

0088Thus, in one embodiment, the compositions disclosed herein include an anti-cellulite agent. In aspects of this embodiment, the compositions disclosed herein include forskolin, xanthine compounds, analogs or derivatives thereof, or any combination thereof.

0089In another aspect of this embodiment, the compositions disclosed herein are of, for example, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about the weight of the total composition. 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1.0%, about 2.0%, about 3.0%, about 4.0%, about 5.0%, about 6.0%, about 7.0%, about 8.0%, about 9.0% Or in an amount of about 10%, it contains an anti-cellulite agent. In yet another aspect, the compositions disclosed herein are, for example, at least 0.1%, at least 0.2%, at least 0.3%, at least 0.4%, at least 0.5%, at least 0.6% of the weight of the total composition. At least 0.7%, at least 0.8%, at least 0.9%, at least 1.0%, at least 2.0%, at least 3.0%, at least 4.0%, at least 5.0%, at least 6.0%, at least 7.0%, at least 8.0%, at least 9.0% or at least 10 Includes anti-cellulite in an amount of%. In yet another aspect, the compositions disclosed herein are, for example, up to 0.1%, up to 0.2%, up to 0.3%, up to 0.4%, up to 0.5% of the weight of the total composition. , Maximum 0.6%, maximum 0.7%, maximum 0.8%, maximum 0.9%, maximum 1.0%, maximum 2.0%, maximum 3.0%, maximum 4.0%, maximum 5.0%, maximum 6.0% Contains anti-cellulite in amounts of up to 7.0%, up to 8.0%, up to 9.0% or up to 10%. In a further aspect, the compositions disclosed herein are about 0.1% to about 0.5%, about 0.1% to about 1.0%, about 0.1% to about 2.0%, about 0.1 of the total weight of the composition. % ~ About 3.0%, about 0.1% ~ about 4.0%, about 0.1% ~ about 5.0%, about 0.2% ~ about 0.9%, about 0.2% ~ about 1.0%, about 0.2% ~ about 2.0%, about 0.5% ~ Includes anti-cellulite in an amount of about 1.0% or about 0.5% to about 2.0%.

0090In another embodiment, the compositions disclosed herein do not contain anti-cellulite agents.

0091Aspects herein provide, in part, the hydrogel compositions disclosed herein which may optionally comprise an anti-scarring agent. The amount of anti-scarring agent contained in the composition disclosed herein is an amount effective to alleviate the scarring response experienced by an individual upon administration of the composition. Non-limiting examples of anti-scarring agents include IFN-γ, fluorouracil, poly (lactic-co-glycolic acid), methylated polyethylene glycol, polylactic acid, polyethylene glycol, analogs or derivatives thereof, and any combination thereof. Can be mentioned. The compositions disclosed herein may include a single anti-scarring agent or multiple anti-scarring agents.

0092Thus, in one embodiment, the compositions disclosed herein include an anti-scarring agent. In aspects of this embodiment, the compositions disclosed herein are IFN-γ, fluorouracil, poly (lactic-co-glycolic acid), methylated polyethylene glycol, polylactic acid, polyethylene glycol, analogs thereof or Includes derivatives, or any combination thereof.

0093In another aspect of this embodiment, the compositions disclosed herein are of, for example, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about the weight of the total composition. 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1.0%, about 2.0%, about 3.0%, about 4.0%, about 5.0%, about 6.0%, about 7.0%, about 8.0%, about 9.0% Or in an amount of about 10%, it contains an anti-scarring agent. In yet another aspect, the compositions disclosed herein are, for example, at least 0.1%, at least 0.2%, at least 0.3%, at least 0.4%, at least 0.5%, at least 0.6% of the weight of the total composition. At least 0.7%, at least 0.8%, at least 0.9%, at least 1.0%, at least 2.0%, at least 3.0%, at least 4.0%, at least 5.0%, at least 6.0%, at least 7.0%, at least 8.0%, at least 9.0% or at least 10 In an amount of%, it contains an anti-scarring agent. In yet another aspect, the compositions disclosed herein are, for example, up to 0.1%, up to 0.2%, up to 0.3%, up to 0.4%, up to 0.5% of the weight of the total composition. , Maximum 0.6%, maximum 0.7%, maximum 0.8%, maximum 0.9%, maximum 1.0%, maximum 2.0%, maximum 3.0%, maximum 4.0%, maximum 5.0%, maximum 6.0% Contains anti-scarring agents in amounts of up to 7.0%, up to 8.0%, up to 9.0% or up to 10%. In a further aspect, the compositions disclosed herein are about 0.1% to about 0.5%, about 0.1% to about 1.0%, about 0.1% to about 2.0%, about 0.1 of the total weight of the composition. % ~ About 3.0%, about 0.1% ~ about 4.0%, about 0.1% ~ about 5.0%, about 0.2% ~ about 0.9%, about 0.2% ~ about 1.0%, about 0.2% ~ about 2.0%, about 0.5% ~ It contains an anti-scarring agent in an amount of about 1.0% or about 0.5% to about 2.0%.

0094In another embodiment, the compositions disclosed herein do not include anti-scarring agents.

0095Aspects herein provide, in part, the hydrogel compositions disclosed herein which may optionally comprise an anti-inflammatory agent. The amount of anti-inflammatory agent contained in the composition disclosed herein is an amount effective for alleviating the inflammatory and / or stimulating response experienced by an individual upon administration of the composition. Non-limiting examples of anti-inflammatory drugs include dexamethacin, prednisolone, corticosterone, budesonide, estrogen, sulfasalazine, mesalamine, cetidine, diphenhydramine, antipyrine, methylsalicylate, loratazine, timol (2-isopropyl-5-methylphenol). , Carbacrol (5-isopropyl-2-methylphenol), Visabolol (6-methyl-2- (4-methylcyclohexe-3-enyl) hept-5-en-2-ol), allantin, eucalyptor, phenazone ( Antipyrine), propifenazone, and non-steroidal anti-inflammatory drugs (NSAIDs) include, but are not limited to, propionic acid derivatives such as ibuprofen, naproxen, phenoprofen, ketoprofen, flurbiprofen and oxaprodin; acetic acid derivatives. , For example indomethacin, slindac, etodrac, ketoprofen, diclofenac and nabmeton; enolic acid (oxycam) derivatives such as pyroxicum, meroxycam, tenoxycam, droxycam, lornoxycam, isoxycam; phenamic acid derivatives such as mefenamic acid, meclofenamic acid, flurbenamic acid and tolphenamic acid. Also include selective COX-2 inhibitors (coxibs) such as selecoxib, lofecoxib, valdecoxyb, parecoxyb, lumiracoxib, etricoxyb and phyllocoxyb, analogs or derivatives thereof, and any combination thereof. The compositions disclosed herein may include a single anti-inflammatory agent or multiple anti-inflammatory agents.

0096Thus, in one embodiment, the compositions disclosed herein include an anti-inflammatory agent. In aspects of this embodiment, the compositions disclosed herein are dexamethasone, prednisolone, corticosterone, budesonide, estrogen, sulfasalazine, mesalamine, cetirizine, diphenhydramine, antipyrine, methylsalicylate, loratadine, thymol ( 2-Isopropyl-5-methylphenol), carvacrol (5-isopropyl-2-methylphenol), bisabolol (6-methyl-2- (4-methylcyclohexe-3-enyl) hept-5-en-2- All), allantin, eucarvacrol, phenazone (antipyrine), propiphenazone, NSAID, analogs or derivatives thereof, or any combination thereof.

0097In another aspect of this embodiment, the compositions disclosed herein are, for example, at least about 0.001%, at least about 0.01%, about 0.1%, about 0.2%, about 0.3% of the weight of the total composition. , About 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1.0%, about 2.0%, about 3.0%, about 4.0%, about 5.0%, about 6.0%, about Contains anti-inflammatory agents in amounts of 7.0%, about 8.0%, about 9.0% or about 10%. In yet another aspect, the compositions disclosed herein are, for example, at least 0.1%, at least 0.2%, at least 0.3%, at least 0.4%, at least 0.5%, at least 0.6% of the weight of the total composition. At least 0.7%, at least 0.8%, at least 0.9%, at least 1.0%, at least 2.0%, at least 3.0%, at least 4.0%, at least 5.0%, at least 6.0%, at least 7.0%, at least 8.0%, at least 9.0% or at least 10 In the amount of%, it contains an anti-inflammatory agent. In yet another aspect, the compositions disclosed herein are, for example, up to 0.1%, up to 0.2%, up to 0.3%, up to 0.4%, up to 0.5% of the weight of the total composition. , Maximum 0.6%, maximum 0.7%, maximum 0.8%, maximum 0.9%, maximum 1.0%, maximum 2.0%, maximum 3.0%, maximum 4.0%, maximum 5.0%, maximum 6.0% Includes anti-inflammatory agents in amounts of up to 7.0%, up to 8.0%, up to 9.0% or up to 10%. In a further aspect, the compositions disclosed herein are about 0.1% to about 0.5%, about 0.1% to about 1.0%, about 0.1% to about 2.0%, about 0.1 of the total weight of the composition. % ~ About 3.0%, about 0.1% ~ about 4.0%, about 0.1% ~ about 5.0%, about 0.2% ~ about 0.9%, about 0.2% ~ about 1.0%, about 0.2% ~ about 2.0%, about 0.5% ~ Contains anti-inflammatory agents in an amount of about 1.0% or about 0.5% to about 2.0%.

0098In another embodiment, the compositions disclosed herein do not include anti-inflammatory agents.

0099Aspects herein provide the hydrogel compositions disclosed herein, in part exhibiting complex modulus, modulus, viscosity and / or tangent delta (tan δ). The compositions disclosed herein are elastic constituents (solid-like, eg crosslinked glycosaminoglycan polymers) and viscous constituents (liquid-like, eg non-bridging) when a force is applied (stress, deformation). It is viscoelastic in that it has a glycosaminoglycan polymer or carrier phase). The rheological attribute that describes this property is the complex modulus (G).^*), Which defines the total resistance of the composition to deformation. Complex modulus is a composite number with real and imaginary parts: G^*= G'+ iG ". G^*The absolute value of is Abs (G)^*) = Sqrt (G'²+ G "²). Complex modulus is defined as the sum of elastic modulus (G') and viscosity (G ) (Falcone, et al., Temporary Polysaccharide Dermal Fillers: A Model for Persistence Based on Physical Properties, Dermatol Surg. 35 (8): 1238-1243 (2009); Tezel, supra, 2008; Kablik, supra, 2009; Beasley, supra, 2009; each of these statements is incorporated herein by reference).

0100The modulus of elasticity or coefficient of elasticity refers to the ability of a hydrogel material to resist deformation, or conversely, the tendency of an object to be deformed non-permanently when a force is applied to it. The modulus of elasticity is also known as the modulus of storage because it characterizes the stiffness of the composition and it describes the storage of energy from the movement of the composition. Modulus describes the interaction between elasticity and strength (G'= stress / strain) and thus provides a quantitative measure of the hardness or flexibility of the composition. The modulus of elasticity of an object is defined as the slope of its stress-strain curve in the elastic deformation region: λ = stress / strain (where λ is the modulus of elasticity (the unit of Pascal); stress is the force that causes the deformation. Is the value obtained by dividing the force by the area to which the force is applied; and the strain is the ratio of the change caused by the stress to the original state of the object). Depending on the speed at which the force is applied, the stiffer composition has a higher modulus and requires greater force to deform the material to a given distance, for example in injection. The modulus of elasticity of many types can be defined by specifically describing the method by which the stress should be measured, including the direction. The three main elastic moduli are tensile modulus, shear modulus and bulk modulus.

0101Viscosity is also known as loss modulus because it describes the energy lost as viscous dissipation. tan δ is the ratio of viscosity to elastic modulus: tan δ = G "/ G'(Falcone, supra, 2009). With respect to the tan δ values disclosed herein, tan δ is dynamic at a frequency of 1 Hz. The lower the .tan δ obtained from the modulus of elasticity, the harder, harder, or more elastic the composition.

0102In another embodiment, the compositions disclosed herein exhibit a certain elastic modulus. In aspects of this embodiment, the hydrogel composition is, for example, about 25Pa, about 50Pa, about 75Pa, about 100Pa, about 125Pa, about 150Pa, about 175Pa, about 200Pa, about 250Pa, about 300Pa, about 350Pa, about 400Pa, about. 450Pa, about 500Pa, about 550Pa, about 600Pa, about 650Pa, about 700Pa, about 750Pa, about 800Pa, about 850Pa, about 900Pa, about 950Pa, about 1,000Pa, about 1,200Pa, about 1,300Pa, about 1,400Pa, about 1,500 It shows elastic modulus of Pa, about 1,600Pa, about 1700Pa, about 1800Pa, about 1900Pa, about 2,000Pa, about 2,100Pa, about 2,200Pa, about 2,300Pa, about 2,400Pa or about 2,500Pa. In another aspect of this embodiment, the hydrogel composition is, for example, at least 25Pa, at least 50Pa, at least 75Pa, at least 100Pa, at least 125Pa, at least 150Pa, at least 175Pa, at least 200Pa, at least 250Pa, at least 300Pa, at least 350Pa, at least 400Pa. , At least 450Pa, at least 500Pa, at least 550Pa, at least 600Pa, at least 650Pa, at least 700Pa, at least 750Pa, at least 800Pa, at least 850Pa, at least 900Pa, at least 950Pa, at least 1,000Pa, at least 1,200Pa, at least 1,300Pa, at least 1,400Pa, At least 1,500 Pa, at least 1,600 Pa, at least 1700 Pa, at least 1800 Pa, at least 1900 Pa, at least 2,000 Pa, at least 2,100 Pa, at least 2,200 Pa, at least 2,300 Pa, at least 2,400 Pa or at least 2, It shows an elastic modulus of 500 Pa. In yet another aspect of this embodiment, the hydrogel composition is, for example, up to 25 Pa, up to 50 Pa, up to 75 Pa, up to 100 Pa, up to 125 Pa, up to 150 Pa, up to 175 Pa, up to 200 Pa, up to 200 Pa. 250Pa, maximum 300Pa, maximum 350Pa, maximum 400Pa, maximum 450Pa, maximum 500Pa, maximum 550Pa, maximum 600Pa, maximum 650Pa, maximum 700Pa, maximum 750Pa, maximum 800Pa, maximum 850Pa, The elastic modulus is 900 Pa at the maximum, 950 Pa at the maximum, 1,000 Pa at the maximum, 1,200 Pa at the maximum, 1,300 Pa at the maximum, 1,400 Pa at the maximum, 1,500 Pa at the maximum, or 1,600 Pa at the maximum. In yet another aspect of this embodiment, the hydrogel composition is, for example, about 25Pa to about 150Pa, about 25Pa to about 300Pa, about 25Pa to about 500Pa, about 25Pa to about 800Pa, about 125Pa to about 300Pa, about 125Pa to about 125Pa. 500Pa, about 125Pa ~ about 800Pa, about 500Pa ~ about 1,600Pa, about 600Pa ~ about 1,600Pa, about 700Pa ~ about 1,600Pa, about 800Pa ~ about 1,600Pa, about 900Pa ~ about 1,600Pa, about 1,000Pa ~ about 1,600Pa , About 1,100Pa ~ about 1,600Pa, about 1,200Pa ~ about 1,600Pa, about 500Pa ~ about 2,500Pa, about 1,000Pa ~ about 2,500Pa, about 1,500Pa ~ about 2,500Pa, about 2,000Pa ~ about 2,500Pa, about 1,300 Pa ~ about 1,600Pa, about 1,400Pa ~ about 1,700Pa, about 1,500Pa ~ about 1,800Pa, about 1,600Pa ~ about 1,900Pa, about 1,700Pa ~ about 2,000Pa, about 1,800Pa ~ about 2,100Pa, about 1,900Pa ~ It exhibits an elastic modulus of about 2,200 Pa, about 2,000 Pa to about 2,300 Pa, about 2,100 Pa to about 2,400 Pa, or about 2,200 Pa to about 2,500 Pa. It has an elastic modulus of 300 Pa, a maximum of 1,400 Pa, a maximum of 1,500 Pa, or a maximum of 1,600 Pa. In yet another aspect of this embodiment, the hydrogel composition is, for example, about 25Pa to about 150Pa, about 25Pa to about 300Pa, about 25Pa to about 500Pa, about 25Pa to about 800Pa, about 125Pa to about 300Pa, about 125Pa to about 125Pa. 500Pa, about 125Pa ~ about 800Pa, about 500Pa ~ about 1,600Pa, about 600Pa ~ about 1,600Pa, about 700Pa ~ about 1,600Pa, about 800Pa ~ about 1,600Pa, about 900Pa ~ about 1,600Pa, about 1,000Pa ~ about 1,600Pa , About 1,100Pa ~ about 1,600Pa, about 1,200Pa ~ about 1,600Pa, about 500Pa ~ about 2,500Pa, about 1,000Pa ~ about 2,500Pa, about 1,500Pa ~ about 2,500Pa, about 2,000Pa ~ about 2,500Pa, about 1,300 Pa ~ about 1,600Pa, about 1,400Pa ~ about 1,700Pa, about 1,500Pa ~ about 1,800Pa, about 1,600Pa ~ about 1,900Pa, about 1,700Pa ~ about 2,000Pa, about 1,800Pa ~ about 2,100Pa, about 1,900Pa ~ It exhibits an elastic modulus of about 2,200 Pa, about 2,000 Pa to about 2,300 Pa, about 2,100 Pa to about 2,400 Pa, or about 2,200 Pa to about 2,500 Pa. It has an elastic modulus of 300 Pa, a maximum of 1,400 Pa, a maximum of 1,500 Pa, or a maximum of 1,600 Pa. In yet another aspect of this embodiment, the hydrogel composition is, for example, about 25Pa to about 150Pa, about 25Pa to about 300Pa, about 25Pa to about 500Pa, about 25Pa to about 800Pa, about 125Pa to about 300Pa, about 125Pa to about 125Pa. 500Pa, about 125Pa ~ about 800Pa, about 500Pa ~ about 1,600Pa, about 600Pa ~ about 1,600Pa, about 700Pa ~ about 1,600Pa, about 800Pa ~ about 1,600Pa, about 900Pa ~ about 1,600Pa, about 1,000Pa ~ about 1,600Pa , About 1,100Pa ~ about 1,600Pa, about 1,200Pa ~ about 1,600Pa, about 500Pa ~ about 2,500Pa, about 1,000Pa ~ about 2,500Pa, about 1,500Pa ~ about 2,500Pa, about 2,000Pa ~ about 2,500Pa, about 1,300 Pa ~ about 1,600Pa, about 1,400Pa ~ about 1,700Pa, about 1,500Pa ~ about 1,800Pa, about 1,600Pa ~ about 1,900Pa, about 1,700Pa ~ about 2,000Pa, about 1,800Pa ~ about 2,100Pa, about 1,900Pa ~ It exhibits an elastic modulus of about 2,200 Pa, about 2,000 Pa to about 2,300 Pa, about 2,100 Pa to about 2,400 Pa, or about 2,200 Pa to about 2,500 Pa.

0103In another embodiment, the hydrogel compositions disclosed herein exhibit a certain viscosity. In aspects of this embodiment, the hydrogel composition is, for example, about 10 Pa, about 20 Pa, about 30 Pa, about 40 Pa, about 50 Pa, about 60 Pa, about 70 Pa, about 80 Pa, about 90 Pa, about 100 Pa, about 150 Pa, about 200 Pa, about 200 Pa. It shows a viscosity of 250Pa, about 300Pa, about 350Pa, about 400Pa, about 450Pa, about 500Pa, about 550Pa, about 600Pa, about 650Pa or about 700Pa. In another aspect of this embodiment, the hydrogel composition is, for example, up to 10 Pa, up to 20 Pa, up to 30 Pa, up to 40 Pa, up to 50 Pa, up to 60 Pa, up to 70 Pa, up to 80 Pa, up to 90 Pa. , Maximum 100Pa, maximum 150Pa, maximum 200Pa, maximum 250Pa, maximum 300Pa, maximum 350Pa, maximum 400Pa, maximum 450Pa, maximum 500Pa, maximum 550Pa, maximum 600Pa, maximum 650Pa or maximum Shows a viscosity of 700 Pa. In yet another aspect of this embodiment, the hydrogel composition is, for example, about 10Pa to about 30Pa, about 10Pa to about 50Pa, about 10Pa to about 100Pa, about 10Pa to about 150Pa, about 70Pa to about 100Pa, about 50Pa to about 50Pa. 350Pa, about 150Pa ~ about 450Pa, about 250Pa ~ about 550Pa, about 350Pa ~ about 700Pa, about 50Pa ~ about 150Pa, about 100Pa ~ about 200Pa, about 150Pa ~ about 250Pa, about 200Pa ~ about 300Pa, about 250Pa ~ about 350Pa, It shows a viscosity of about 300 Pa to about 400 Pa, about 350 Pa to about 450 Pa, about 400 Pa to about 500 Pa, about 450 Pa to about 550 Pa, about 500 Pa to about 600 Pa, about 550 Pa to about 650 Pa, or about 600 Pa to about 700 Pa.

0104In another embodiment, the hydrogel compositions disclosed herein exhibit a tan δ. In aspects of this embodiment, the hydrogel composition is, for example, about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1.0, about 1.1, about 1.2, about. It shows tan α of 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, about 2.0, about 2.1, about 2.2, about 2.3, about 2.4 or about 2.5. In another aspect of this embodiment, the hydrogel composition is, for example, up to 0.1, up to 0.2, up to 0.3, up to 0.4, up to 0.5, up to 0.6, up to 0.7, up to 0.8, up to 0.9. , Maximum 1.0, maximum 1.1, maximum 1.2, maximum 1.3, maximum 1.4, maximum 1.5, maximum 1.6, maximum 1.7, maximum 1.8, maximum 1.9, maximum 2.0, maximum 2.1, maximum Indicates a tan α of 2.2, a maximum of 2.3, a maximum of 2.4, or a maximum of 2.5. In yet another aspect of this embodiment, the hydrogel composition is, for example, about 0.1-0.3, about 0.3-about 0.5, about 0.5-about 0.8, about 1.1-about 1.4, about 1.4-about 1.7, about 0.3-about 0.6. , About 0.1 to about 0.5, about 0.5 to about 0.9, about 0.1 to about 0.6, about 0.1 to about 1.0, about 0.5 to about 1.5, about 1.0 to about 2.0, or about 1.5 to about 2.5 tan α.

0105Aspects herein provide, in part, the hydrogel compositions disclosed herein that are transparent and / or translucent. Transparency (also called clarity or transparency) is a physical property that allows light to pass through a substance, while translucency (semi-transparent or translucent) only allows light to pass through in a scattered manner. Is. The opposite property is opacity. Transparent material is transparent, while translucent material is not clearly transparent through it. The silk fibroin hydrogels disclosed herein may or may not exhibit optical properties such as transparency and translucency. In some cases, it may be beneficial to have an opaque hydrogel, for example for the filling of stretch marks on the surface. In other cases, for example in the development of lenses or "body fluids" to fill the eye, it would be beneficial to have a translucent hydrogel. These properties can be modified by affecting the structural distribution of the hydrogel material. Factors used to control the optical properties of hydrogels include, but are not limited to, polymer concentration, gel crystallinity and hydrogel homogeneity.

0106When light hits a substance, it can interact with it in several different ways. This interaction depends on the nature of light (its wavelength, frequency, energy, etc.) and the nature of matter. Light waves interact with an object by some combination of reflection and transmission and transmission with refraction. Therefore, an optically transparent substance transmits most of the light that hits it, and the light is hardly reflected. A substance that does not transmit light is called optically opaque or simply opaque.

0107In one embodiment, the hydrogel compositions disclosed herein are optically transparent. In aspects of this embodiment, the hydrogel composition transmits, for example, about 75% light, about 80% light, about 85% light, about 90% light, about 95% light or about 100% light. To do. In another aspect of this embodiment, the hydrogel composition transmits, for example, at least 75% light, at least 80% light, at least 85% light, at least 90% light or at least 95% light. In yet another aspect of this embodiment, the hydrogel composition is, for example, about 75% to about 100% light, about 80% to about 100% light, about 85% to about 100% light, about 90% to. It transmits about 100% light or about 95% to about 100% light.

0108In another embodiment, the hydrogel compositions disclosed herein are optically opaque. In aspects of this embodiment, the hydrogel composition is, for example, about 5% light, about 10% light, about 15% light, about 20% light, about 25% light, about 30% light, about. It transmits 35% light, about 40% light, about 45% light, about 50% light, about 55% light, about 60% light, about 65% light or about 70% light. In another aspect of this embodiment, the hydrogel composition comprises, for example, up to 5% light, up to 10% light, up to 15% light, up to 20% light, up to 25% light, Up to 30% light, up to 35% light, up to 40% light, up to 45% light, up to 50% light, up to 55% light, up to 60% light, up to Transmits 65% light, up to 70% light or up to 75% light. In another aspect of this embodiment, the hydrogel composition is, for example, about 5% to about 15%, about 5% to about 20%, about 5% to about 25%, about 5% to about 30%, about 5%. ~ About 35%, about 5% ~ about 40%, about 5% ~ about 45%, about 5% ~ about 50%, about 5% ~ about 55%, about 5% ~ about 60%, about 5% ~ about 65%, about 5% to about 70%, about 5% to about 75%, about 15% to about 20%, about 15% to about 25%, about 15% to about 30%, about 15% to about 35% , About 15% to about 40%, about 15% to about 45%, about 15% to about 50%, about 15% to about 55%, about 15% to about 60%, about 15% to about 65%, about 15% to about 70%, about 15% to about 75%, about 25% to about 35%, about 25% to about 40%, about 25% to about 45%, about 25% to about 50%, about 25% ~ About 55%, about 25% ~ about 60%, about 25% ~ about 65%, about 25% ~ about 70% or about 25% ~ about 75% of light is transmitted.

0109In one embodiment, the hydrogel compositions disclosed herein are optically translucent. In aspects of this embodiment, the hydrogel composition scatters, for example, about 75% light, about 80% light, about 85% light, about 90% light, about 95% light or about 100% light. Is transparent. In another aspect of this embodiment, the hydrogel composition scatters, for example, at least 75% light, at least 80% light, at least 85% light, at least 90% light or at least 95% light. .. In yet another aspect of this embodiment, the hydrogel composition is, for example, about 75% to about 100% light, about 80% to about 100% light, about 85% to about 100% light, about 90% to. It scatters and transmits about 100% light or about 95% to about 100% light.

0110The hydrogel compositions disclosed herein grind the hydrogel into particles and optionally mix with a carrier phase, eg water or physiological saline solution, to inject or local substances such as solutions, oils. It can be further processed by producing lotions, gels, ointments, creams, slurries, ointments or pastes. Therefore, the disclosed hydrogel composition can be a single-phase or polyphase composition. Hydrogels have a diameter of about 10 μm to about 1000 μm, for example, about 15 μm to about 30 μm, about 50 μm to about 75 μm, about 100 μm to about 150 μm, about 200 μm to about 300 μm, about 450 μm to about 550 μm, about 600 μm to about 700 μm, about 750 μm ~. It can be ground to a particle size of about 850 μm or about 900 μm to about 1,000 μm.

0111Aspects herein provide compositions disclosed herein that are injectable in part. As used herein, the term "injectable" refers to a substance that has the properties necessary to administer a composition to an individual's skin area using an injectable tool with a fine needle. As used herein, the term "fine needle" refers to a needle of 27 gauge or smaller. The injectability of the compositions disclosed herein can be achieved by making hydrogel particles as described above to a certain size.

0112In aspects of this embodiment, the hydrogel compositions disclosed herein can be injected through a fine needle. In another aspect of this embodiment, the hydrogel compositions disclosed herein can be injected through, for example, a needle of about 27 gauge, about 30 gauge or about 32 gauge. In yet another aspect of this embodiment, the hydrogel compositions disclosed herein can be injected through, for example, 22 gauge or less, 27 gauge or less, 30 gauge or less or 32 gauge or less needles. In yet another aspect of this embodiment, the hydrogel compositions disclosed herein are, for example, from about 22 gauge to about 35 gauge, from 22 gauge to about 34 gauge, from 22 gauge to about 33 gauge, from 22 gauge to about. It can be injected through a 32 gauge, about 22 gauge to about 27 gauge or about 27 gauge to about 32 gauge needle.

0113In aspects of this embodiment, the hydrogel compositions disclosed herein are about 60N, about 55N, about 50N, about 45N, about 40N, about 35N, about 30N, about 25N at a rate of 100 mm / min. Can be injected with an extrusion of about 20N or about 15N. In another aspect of this embodiment, the hydrogel compositions disclosed herein are about 60 N or less, about 55 N or less, about 50 N or less, about 45 N or less, about 40 N or less, about 35 N or less, about 30 N or less, It can be injected through a 27 gauge needle with a push force of about 25 N or less, about 20 N or less, about 15 N or less, about 10 N or less or about 5 N or less. In yet another aspect of this embodiment, the hydrogel compositions disclosed herein are about 60N or less, about 55N or less, about 50N or less, about 45N or less, about 40N or less, about 35N or less, about 30N or less. Can be injected through a 30 gauge needle with an extrusion force of about 25N or less, about 20N or less, about 15N or less, about 10N or less or about 5N or less. In yet another aspect of this embodiment, the hydrogel compositions disclosed herein are about 60N or less, about 55N or less, about 50N or less, about 45N or less, about 40N or less, about 35N or less, about 30N or less. Can be injected through a 32 gauge needle with an extrusion force of about 25 N or less, about 20 N or less, about 15 N or less, about 10 N or less or about 5 N or less.

0114Aspects herein provide, in part, the hydrogel compositions disclosed herein that exhibit cohesivity. Cohesiveness (also called cohesion, cohesive attraction, cohesion or compressive force) is a physical property of a substance caused by intermolecular attraction between molecular-like substances in a substance that acts to bind molecules together. Cohesiveness is expressed in grams and force (gmf). Aggregation, among other factors, is the initial molecular weight ratio of the free glycosaminoglycan polymer, the degree of cross-linking of the glycosaminoglycan polymer, the amount of residual free glycosaminoglycan polymer after cross-linking, and the hydrogel composition. Affected by the pH of. The composition should be sufficiently cohesive to remain localized at the site of administration. Moreover, in certain applications, in the event of mechanical load circulation, sufficient cohesiveness is important for the composition to retain its shape and thus its function. Thus, in one embodiment, the hydrogel compositions disclosed herein exhibit cohesiveness comparable to water. In yet another embodiment, the hydrogel compositions disclosed herein exhibit sufficient cohesiveness to remain localized at the site of administration. In yet another embodiment, the hydrogel compositions disclosed herein exhibit sufficient cohesiveness to retain their shape. In a further embodiment, the hydrogel compositions disclosed herein exhibit sufficient cohesiveness to retain their shape and function.

0115Aspects herein provide, in part, the hydrogel compositions disclosed herein that exhibit physiologically acceptable osmolality. As used herein, the term "osmotic pressure" refers to the concentration of osmotic active solute in solution. As used herein, the term "physiologically acceptable osmotic pressure" refers to osmotic pressure that is consistent with or characteristic of the normal functioning of a living organism. Thus, administration of the hydrogel compositions disclosed herein exhibits osmotic pressure that, when administered to mammals, has substantially no long-term or permanent adverse effects. Osmotic pressure is expressed in osmoles (osmoles / L or Osm / L) of osmotic active solutes per liter of solvent. The osmotic pressure is different from the molar concentration because it measures the number of moles of osmotic active solute particles rather than the number of moles of solute. Differences occur because some compounds can dissociate in solution, while others cannot. The osmotic pressure of the solution can be calculated from the following formula: osmol / L = Σφ_iη_iC_i(In the equation, φ is the permeation coefficient, which describes the degree of non-ideality of the solution; η is the number of particles (eg, ions) at which the molecule dissociates; and C is the molar concentration of the solute. Yes; and i is an index of which particular solute is). The osmotic pressure of the hydrogel compositions disclosed herein can be measured using conventional methods of measuring the solution.

0116In one embodiment, the hydrogel compositions disclosed herein exhibit physiologically acceptable osmotic pressure. In aspects of this embodiment, the hydrogel composition is, for example, about 100 mOsm / L, about 150 mOsm / L, about 200 mOsm / L, about 250 mOsm / L, about 300 mOsm / L, about 350 mOsm / L, about 400 mOsm / L, about 450 mOsm. It shows an osmotic pressure of / L or about 500 mOsm / L. In another aspect of this embodiment, the hydrogel composition is, for example, at least 100 mOsm / L, at least 150 mOsm / L, at least 200 mOsm / L, at least 250 mOsm / L, at least 300 mOsm / L, at least 350 mOsm / L, at least 400 mOsm / L, It exhibits an osmotic pressure of at least 450 mOsm / L or at least 500 mOsm / L. In yet another aspect of this embodiment, the hydrogel composition is, for example, up to 100 mOsm / L, up to 150 mOsm / L, up to 200 mOsm / L, up to 250 mOsm / L, up to 300 mOsm / L, up to 350 mOsm / It shows an osmotic pressure of L, a maximum of 400 mOsm / L, a maximum of 450 mOsm / L or a maximum of 500 mOsm / L. In yet another aspect of this embodiment, the hydrogel composition is, for example, about 100 mOsm / L to about 500 mOsm / L, about 200 mOsm / L to about 500 mOsm / L, about 200 mOsm / L to about 400 mOsm / L, about 300 mOsm / L. ~ 400mOsm / L, 270mOsm / L ~ 390mOsm / L, 225mOsm / L ~ 350mOsm / L, 250mOsm / L ~ 325mOsm / L, 275mOsm / L ~ 300mOsm / L or 285mOsm / L ~ Shows an osmotic pressure of about 290 mOsm / L.

0117Aspects herein provide, in part , the hydrogel compositions disclosed herein that exhibit physiologically acceptable osmolality. As used herein, the term "osmotic pressure" refers to the concentration of osmotic active solute per kilogram of solvent in the body. As used herein, the term "physiologically acceptable osmotic pressure" refers to osmotic pressure that is consistent with or characteristic of the normal functioning of a living organism. Thus, administration of the hydrogel compositions disclosed herein exhibits osmotic pressure that, when administered to mammals, has substantially no long-term or permanent adverse effects. The osmotic pressure is expressed in osmoles (osmol / kg or Osm / kg) of the osmotic active solute per kilogram of solvent and is equal to the sum of the number of moles of the total solute present in the solution. The osmolality of the solution can be measured using an osmotic meter. The most commonly used instrument in modern laboratories is the freezing point drop osmotic meter. This instrument measures the change in freezing point that occurs in the solution as the osmotic pressure increases (freezing point drop type osmotic pressure gauge), or the change in vapor pressure that occurs in the solution as the osmotic pressure increases (vapor pressure drop type osmotic pressure gauge). To do.

0118In one embodiment, the hydrogel compositions disclosed herein exhibit physiologically acceptable osmotic pressure. In aspects of this embodiment, the hydrogel composition is, for example, about 100 mOsm / kg, about 150 mOsm / kg, about 200 mOsm / kg, about 250 mOsm / kg, about 300 mOsm / kg, about 350 mOsm / kg, about 400 mOsm / kg, about 450 mOsm. It shows an osmotic pressure of / kg or about 500 mOsm / kg. In another aspect of this embodiment, the hydrogel composition is, for example, at least 100 mOsm / kg, at least 150 mOsm / kg, at least 200 mOsm / kg, at least 250 mOsm / kg, at least 300 mOsm / kg, at least 350 mOsm / kg, at least 400 mOsm / kg, It exhibits an osmotic pressure of at least 450 mOsm / kg or at least 500 mOsm / L. In yet another aspect of this embodiment, the hydrogel composition is, for example, up to 100 mOsm / kg, up to 150 mOsm / kg, up to 200 mOsm / kg, up to 250 mOsm / kg, up to 300 mOsm / kg, up to 350 mOsm /. It shows an osmotic pressure of kg, maximum 400 mOsm / kg, maximum 450 mOsm / kg or maximum 500 mOsm / kg. In yet another aspect of this embodiment, the hydrogel composition is, for example, about 100 mOsm / kg to about 500 mOsm / kg, about 200 mOsm / kg to about 500 mOsm / kg, about 200 mOsm / kg to about 400 mOsm / kg, about 300 mOsm / kg. ~ 400mOsm / kg, 270mOsm / kg ~ 390mOsm / kg, 225mOsm / kg ~ 350mOsm / kg, 250mOsm / kg ~ 325mOsm / kg, 275mOsm / kg ~ 300mOsm / kg or 285mOsm / kg ~ Shows an osmotic pressure of about 290 mOsm / kg.

0119Aspects herein provide, in part, the hydrogel compositions disclosed herein that exhibit substantial stability. As used herein, the term "stable" or "stable" as used herein refers to any of the hydrogel compositions disclosed herein, as long as they are stored prior to administration to an individual. Refers to a composition that does not tend to deteriorate, decompose, or destroy substantially or significantly. As used herein, the terms "substantially thermostable," "substantially thermostable," "autoclave-stable," or "sterilized stability" are disclosed herein. Refers to the hydrogel compositions disclosed herein that are substantially stable when subjected to such heat treatments.

0120The stability of the hydrogel compositions disclosed herein can be determined by subjecting the hydrogel compositions to heat treatment, eg steam sterilization, at normal pressure or under pressure (eg, autoclaving). Preferably the heat treatment is carried out for about 1 minute to about 10 minutes at a temperature of at least about 100 ° C. Substantial stability of the hydrogel composition disclosed herein is determined by 1) determining the change in extrusion (ΔF) of the hydrogel composition disclosed herein after sterilization (in this case). , (Extrusion of hydrogel composition with specific additives)-(Extrusion of hydrogel composition without additional additives), hydrogel with substantially stable changes in extrusion below 2N The composition is shown); and / or 2) by establishing changes in the fluid properties of the hydrogel composition disclosed herein after sterilization (in this case, tan δ 1 Hz of the gel formulation with the additive). )-(A change of tan δ 1 Hz less than 0.1, as measured by (tan δ 1 Hz of gel formulation without additives), indicates a substantially stable hydrogel composition), can be evaluated. Thus, the substantially stable hydrogel compositions disclosed herein retain one or more of the following properties after sterilization: homogeneity, osmolality, cohesiveness, hyaluronan concentration, agent (single or). Multiple) Concentration, osmotic pressure, pH, or other rheological properties desired by hydrogel prior to heat treatment.

0121In one embodiment, the hydrogel composition comprising the glycosaminoglycan polymer and at least one agent disclosed herein uses a heat treatment that maintains the desired hydrogel properties disclosed herein. , Processed. In aspects of this embodiment, the hydrogel composition comprising the glycosaminoglycan polymer and at least one agent disclosed herein is, for example, about 100 ° C, about 105 ° C, about 110 ° C, about. It is processed using heat treatment at 115 ° C, about 120 ° C, about 125 ° C or about 130 ° C. In another aspect of this embodiment, the hydrogel composition comprising the glycosaminoglycan polymer and at least one agent disclosed herein is, for example, at least 100 ° C, at least 105 ° C, at least 110 ° C. , At least 115 ° C, at least 120 ° C, at least 125 ° C or at least 130 ° C. In yet another aspect of this embodiment, the hydrogel composition comprising the glycosaminoglycan polymer and at least one agent disclosed herein is, for example, from about 100 ° C to about 120 ° C, about 100 °. C ~ about 125 ° C, about 100 ° C ~ about 130 ° C, about 100 ° C ~ about 135 ° C, about 110 ° C ~ about 120 ° C, about 110 ° C ~ about 125 ° C, about 110 ° C ~ about 130 ° C, about 110 ° C ~ about 135 ° C, about 120 ° C ~ about 125 ° C, about 120 ° C ~ about 130 ° C, about 120 ° C ~ about 135 ° C, about 125 ° It is processed using a heat treatment of C to about 130 ° C or about 125 ° C to about 135 ° C.

0122The long-term stability of the hydrogel composition disclosed herein can be determined by subjecting the hydrogel composition to heat treatment, eg, storage in an environment of about 45 ° C. for about 60 days. The long-term stability of the hydrogel compositions disclosed herein is determined by 1) assessing the clarity and color of the hydrogel composition after 45 ° C heat treatment (clear and colorless hydrogel compositions are stable in parenchymal solution). Hydrogel composition is shown); 2) By determining the change in extrusion (ΔF) of the hydrogel composition disclosed herein after 45 ° C heat treatment (in this case, before (45 ° C heat treatment)). Changes in hydrogel composition with specific additives as measured by (Ejection of hydrogel composition with specific additives after 45 ° C heat treatment) are substantially stable. Hydrogel compositions are shown); and / or 3) by establishing changes in the fluid properties of the hydrogel compositions disclosed herein after sterilization (in this case (before 45 ° C heat treatment). A hydrogel composition in which a change of less than 0.1 tan δ 1 Hz, as measured by tan δ 1 Hz for gel formulations with specific additives)-(tan δ 1 Hz for gel formulations with specific additives after 45 ° C heat treatment), is substantially stable. Show), can be evaluated. Therefore, the long-term stability of the hydrogel compositions disclosed herein is assessed by retention of one or more of the following properties after 45 ° C heat treatment: transparency (transparency and translucency). , Homogeneity and cohesiveness.

0123In aspects of this embodiment, the hydrogel composition is, for example, about 3 months, about 6 months, about 9 months, about 12 months, about 15 months, about 18 months, about 21 months, about 24 months, about 27 months, about. It is substantially stable at room temperature for 30 months, about 33 months or about 36 months. In another aspect of this embodiment, the hydrogel composition is, for example, at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, at least 21 months, at least 24 months, at least 27 months. It is substantially stable at room temperature for at least 30 months, at least 33 months or at least 36 months. In another aspect of this embodiment, the hydrogel composition is, for example, about 3 months to about 12 months, about 3 months to about 18 months, about 3 months to about 24 months, about 3 months to about 30 months, about 3 months. ~ About 36 months, about 6 months ~ about 12 months, about 6 months ~ about 18 months, about 6 months ~ about 24 months, about 6 months ~ about 30 months, about 6 months ~ about 36 months, about 9 months ~ about 12 months, about 9 months to about 18 months, about 9 months to about 24 months, about 9 months to about 30 months, about 9 months to about 36 months, about 12 months to about 18 months, about 12 months to about 24 months , Approximately 12 to 30 months, 12 to 36 months, 18 to 24 months, 18 to 30 months or 18 to 36 months, substantially stable at room temperature is there.

0124Aspects herein provide the hydrogel compositions disclosed herein, in part being pharmaceutically acceptable compositions. As used herein, the term "pharmaceutically acceptable" refers to any molecular entity or composition that does not cause harmful, allergic, or other adverse reactions when administered to an individual. means. Pharmaceutically acceptable hydrogel compositions are useful for medical and veterinary applications. The pharmaceutically acceptable hydrogel composition can be administered to an individual alone or in combination with other supplemental active ingredients, agents, agents or hormones.

0125Aspects herein provide, in part, the hydrogel compositions disclosed herein that include pharmaceutically acceptable excipients. As used herein, the term "pharmacologically acceptable excipient" is synonymous with "pharmacological excipient" or "excipient" when administered to a mammal. Refers to any excipient that has virtually no long-term or permanent adverse effects, and refers to, for example, stabilizers, bulking agents, cryoprotectants, lysis protectants, additives, vehicles, carriers, diluents or Includes compounds such as adjuvants. Excipients can generally be mixed with the active ingredient or diluted or encapsulated with the active ingredient and can be a solid, semi-solid or liquid substance. Pharmaceutical compositions as disclosed herein may contain one or more pharmaceutically acceptable excipients that facilitate the processing of the active ingredient into a pharmaceutically acceptable composition. It is also assumed. Unless any pharmacologically acceptable excipient is incompatible with the active ingredient, its use in a pharmaceutically acceptable composition is intended. Non-limiting examples of pharmacologically acceptable excipients include, for example, Pharmaceutical Dosage Forms and Drug Delivery Systems. (Howard C. Ansel et al., eds., Lippincott Williams &amp; Wilkins Publishers, 7th ed. 1999); Remington: The Science and Practice of Pharmacy (Alfonso R. Gennaro ed., Lippincott, Williams &amp; Wilkins, 20th ed. 2000) ); Goodman &amp; Gilman's The Pharmacological Basis of Therapeutics (Joel G. Hardman et al., Eds., McGraw-Hill Professional, 10th ed. 2001); and Handbook of Pharmaceutical Excipients (Raymond C. Rowe et al., APhA Publications, 4th edition 2003) (each of which is incorporated herein by reference).

0126The hydrogel compositions disclosed herein are optionally other pharmaceutically acceptable constituents such as buffers, preservatives, isotonic agents, salts, antioxidants, osmoregulators, emulsifiers. , Wetting agents, sweetening agents or flavoring agents, etc. (but not limited to these) may also be included.

0127A pharmaceutically acceptable buffer is a buffer that can be used to prepare the hydrogel compositions disclosed herein, provided that the resulting preparation is pharmaceutically acceptable. It is a condition. Non-limiting examples of pharmaceutically acceptable buffers include acetate buffers, borate buffers, citrate buffers, neutral buffered physiological saline, phosphate buffers and phosphate buffers. Phosphate solution can be mentioned. Any concentration of pharmaceutically acceptable buffer may be useful in formulating the pharmaceutical compositions disclosed herein, provided that a therapeutically effective amount of active ingredient buffers this effective concentration. The condition is that it is recovered using an agent. Non-limiting examples of physiologically acceptable buffer concentrations range from about 0.lmM to about 900 mM. The pH of the pharmaceutically acceptable buffer can be adjusted, provided that the resulting preparation is pharmaceutically acceptable. It is understood that the acid or base can be used to adjust the pH of the pharmaceutical composition, if desired. Any buffered pH level may be useful in formulating pharmaceutical compositions, provided that this effective pH level is used to recover a therapeutically effective amount of the matrix polymer active ingredient. .. Non-limiting examples of physiologically acceptable pH are in the range of about pH 5.0 to about pH 8.5. For example, the pH of the hydrogel compositions disclosed herein can be from about 5.0 to about 8.0, or from about 6.5 to about 7.5, from about 7.0 to about 7.4 or from about 7.1 to about 7.3.

0128Pharmaceutically acceptable preservatives include, but are not limited to, sodium metabisulfite, sodium thiosulfite, butylated hydroxyanisole and butylated hydroxytoluene. Pharmaceutically acceptable preservatives include benzalkonium chloride, chlorobutanol, thimerosal, phenylmercury acetate, phenylmercury nitrate, stabilized oxychloro compositions such as PURITE® (Allergan, Inc. Irvine, CA), And chelating agents such as, but not limited to, DTPA or DTPA-bisamide, calcium DTPA and CaNa DTPA-bisamide.

0129Pharmaceutically acceptable isotonic agents useful in the hydrogel compositions disclosed herein include, but are not limited to, salts such as sodium chloride and potassium chloride; and glycerin. The composition can be provided as a salt and can be produced using a number of acids such as, but not limited to, hydrochloric acid, sulfuric acid, acetic acid, lactic acid, tartaric acid, malic acid, succinic acid and the like. Salts tend to be more soluble in aqueous or other protic solvents than their corresponding free base forms. It is understood that these and other substances known in the pharmaceutical industry may be included in the hydrogel compositions disclosed herein. Other non-limiting examples of pharmacologically acceptable components include, eg, Ansel, supra, (1999); Gennaro, supra, (2000); Hardman, supra, (2001); and Rowe, supra, (2003). (Each of these statements is incorporated herein by reference).

0130Aspects herein, in part, provide a method of treating an individual's parenchyma symptoms by administering the hydrogel composition disclosed herein. As used herein, does the term "treating" reduce the cosmetic or clinical manifestations of soft tissue symptoms characterized by soft tissue imperfections, defects, diseases and / or disorders in individuals? Or to eliminate; or to delay or prevent the onset of cosmetic or clinical symptoms of symptoms characterized by soft tissue imperfections, defects, diseases and / or disorders in an individual. For example, the term "treating" refers to symptoms of symptoms characterized by parenchyma defects, diseases and / or disorders, eg at least 20%, at least 30%, at least 40%, at least 50%, at least 60%. , At least 70%, at least 80%, at least 90% or at least 100% reduction. The effectiveness of the hydrogel compositions disclosed herein in treating symptoms characterized by parenchyma defects, diseases and / or disorders is one or more cosmetic, clinical symptoms, and / or. It can be determined by observing the physiological indicators associated with the condition. Improvements in parenchyma defects, disease and / or disorders can also be demonstrated by reducing the need for combination therapy. One of ordinary skill in the art will be aware of the appropriate symptoms or indicators associated with a particular parenchyma defect, disease and / or disorder, and for treatment by an individual with a compound or composition disclosed herein. You will find out how to determine if you are a candidate for.

0131The hydrogel composition is administered to the individual. An individual is typically a human of any age, gender or race. Typically, any individual who is a candidate for conventional methods for treating parenchyma symptoms is a candidate for the methods disclosed herein. Subjects experiencing signs of aging skin are adults, but subjects experiencing premature aging or other skin symptoms suitable for treatment (eg, scarring) are also disclosed herein. It can be treated with a hydrogel composition. In addition, the disclosed hydrogel compositions and methods are small / moderate enlargements, shapes of parts or areas of the body that may not be technically possible or aesthetically acceptable with current parenchyma transplantation techniques. Applicable to individuals seeking change or contour changes. Preoperative assessment typically includes routine medical history and physical examination, as well as sufficient informed consent to disclose all relevant risks and benefits of the procedure.

0132The hydrogel compositions and methods disclosed herein are useful in treating parenchyma symptoms. Parenchyma symptoms include, but are not limited to, parenchyma imperfections, defects, diseases and / or disorders. Non-limiting examples of soft tissue symptoms include incompleteness, defects, disease and / or disorders of the breast, such as breast enlargement, breast remodeling, breast fixation, small breasts, thoracic dysplasia, Polish syndrome, capsular contraction and / or rupture. Defects due to implant complications such as; facial imperfections, defects, diseases and / or disorders such as facial enlargement, facial remodeling, mesotherapy, Parry Lomberg syndrome, deep erythema, skin depressions, Scars, sick cheeks, thin lips, incomplete or defective nose, post-orbital incompleteness or defect, facial folds, lines and / or wrinkles, such as eyebrows, nasal lip line, peri-mouth line and / or marionette line , And / or other contour deformities or imperfections of the face; neck imperfections, defects, diseases and / or disorders; skin imperfections, defects, diseases and / or disorders; other soft tissue imperfections, Defects, diseases and / or disorders, such as upper arms, forearms, hands, shoulders, back, torso, such as abdomen, buttocks, thighs, lower limbs, such as calves, feet, such as sole fat pads, eyes, genitals, or others. Diseases or disorders that affect a part, area or area of the body, or these parts, areas or areas; urinary incontinence, fecal incontinence, other types of incontinence; and reflux esophagitis (GERD). .. As used herein, the term "mesotherapy" refers to non-surgical cosmetic treatment techniques for the skin, such as agents administered as small multiplex droplets into the epidermis, dermis-epidermis junction and / or dermis. Refers to intraepidermal, intradermal and / or subcutaneous injection.

0133The amount of hydrogel composition used with any of the methods disclosed herein is typically the modification and / or improvement desired by the individual and / or physician, the desired parenchyma condition. It is determined based on the reduction and / or elimination of symptoms, the desired clinical and / or cosmetic effect, and the part or area of the body being treated. The effectiveness of composition administration may be manifested by one or more of the following clinical and / or cosmetic measurements: parenchyma shape modification and / or improvement, parenchyma size modification and / or improvement, Parenchyma contour changes and / or improvements, tissue function changes and / or improvements, tissue internal growth instructions and / or new collagen deposition, sustained composition engraftment, improved patient satisfaction and / or quality of life, And reduced use of transplantable foreign substances.

0134For example, for breast enlargement techniques, the effectiveness of the composition and method can be demonstrated by one or more of the following clinical and / or cosmetic measurements: breast size increase, breast shape modification, breast contour modification. , Persistent engraftment, reduced risk of capsular contraction, reduced rate of fat necrosis cyst formation, improved patient satisfaction and / or quality of life, and reduced use of breast transplants.

0135As another example, the effectiveness of compositions and methods in the treatment of facial soft tissue can be demonstrated by one or more of the following clinical and / or cosmetic measurements: the size, shape and / of facial features. Or an increase in contour, eg, an increase in the size, shape and / or contour of the lip, cheek or eye area; a change in the size, shape and / or contour of a facial feature, eg, a change in the size, shape and shape of the lip, cheek or eye area shape and / Or contour changes; reduction or elimination of skin wrinkles, folds or lines; resistance to skin wrinkles, folds or lines; skin rehydration; increased elasticity to skin; reduction or elimination of skin roughness; skin Increased tension and / or improvement; Reduced or eliminated stretch lines or marks; Increased and / or improved skin tone, luster, gloss and / or shine; Increased and / or improved skin color, pale skin Reduction or elimination; Persistence of composition; Side effects; Improvement of patient satisfaction and / or quality of life.

0136As yet another example, for urinary incontinence techniques, the effectiveness of compositions and methods for sphincter support can be demonstrated by one or more of the following clinical measurements: reduced incontinence frequency, engraftment. Persistence, patient satisfaction and / or quality of life improvement, and reduced use of implantable outpatient fillers.

0137In aspects of this embodiment, the amount of hydrogel composition administered is, for example, about 0.01 g, about 0.05 g, about 0.1 g, about 0.5 g, about 1 g, about 5 g, about 10 g, about 20 g, about 30 g, about. 40g, about 50g, about 60g, about 70g, about 80g, about 90g, about 100g, about 150g or about 200g. In another aspect of this embodiment, the amount of hydrogel composition administered is, for example, about 0.01 g to about 0.1 g, about 0.1 g to about 1 g, about 1 g to about 10 g, about 10 g to about 100 g or about 50 g to. It is about 200g. In yet another aspect of this embodiment, the amount of hydrogel composition administered is, for example, about 0.01 mL, about 0.05 mL, about 0.1 mL, about 0.5 mL, about 1 mL, about 5 mL, about 10 mL, about 20 mL, about. 30 mL, about 40 mL, about 50 mL, about 60 mL, about 70 g, about 80 mL, about 90 mL, about 100 mL, about 150 mL or about 200 mL. In another aspect of this embodiment, the amount of hydrogel composition administered is, for example, about 0.01 mL to about 0.1 mL, about 0.1 mL to about 1 mL, about 1 mL to about 10 mL, about 10 mL to about 100 mL, or about 50 mL to. It is about 200 mL.

0138The duration of treatment is typically determined based on the cosmetic and / or clinical effect desired by the individual and / or physician, as well as the part or area of the body being treated. In aspects of this embodiment, the hydrogel compositions disclosed herein are, for example, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about. Parenchyma symptoms can be treated for 13 months, about 14 months, about 15 months, about 18 months or about 24 months. In another aspect of this embodiment, administration of the hydrogel composition disclosed herein is, for example, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least. Parenchyma symptoms can be treated for 12 months, at least 13 months, at least 14 months, at least 15 months, at least 18 months or at least 24 months. In a further aspect of this embodiment, the administration of the hydrogel composition disclosed herein is, for example, about 6 months to about 12 months, about 6 months to about 15 months, about 6 months to about 18 months, about 6 months. ~ About 21 months, about 6 months ~ about 24 months, about 9 months ~ about 12 months, about 9 months ~ about 15 months, about 9 months ~ about 18 months, about 9 months ~ about 21 months, about 6 months ~ about 24 months, about 12 months to about 15 months, about 12 months to about 18 months, about 12 months to about 21 months, about 12 months to about 24 months, about 15 months to about 18 months, about 15 months to about 21 months , About 15 months to about 24 months, about 18 months to about 21 months, about 18 months to about 24 months, or about 21 months to about 24 months, parenchyma symptoms can be treated.

0139Aspects herein provide, in part, to administer the hydrogel compositions disclosed herein. As used herein, the term "administering" may produce any clinically, therapeutically or experimentally beneficial outcome that provides an individual with the compositions disclosed herein. Means a delivery mechanism with. The actual delivery mechanism used to administer the composition to an individual is, for example, the type of skin condition, the location of the skin condition, the cause of the skin condition, the severity of the skin condition, the desired degree of relief, the desired duration of relief. , Specific composition used, discharge rate of specific composition used, pharmacokinetics of specific composition used, nature of other compounds contained in specific composition used, specific route of administration, specific individual It can be determined by those skilled in the art by taking into account factors such as characteristics, medical history and risk factors such as age, weight, general health, or any combination thereof (but not limited to these). In one aspect of this embodiment, the compositions disclosed herein are administered by injection to an individual's skin area.

0140The route of administration of the hydrogel composition to an individual patient is typically determined based on the cosmetic and / or clinical effect desired by the individual and / or the physician, as well as the part or area of the body being treated. To. The compositions disclosed herein can be surgically performed topically or directly by any means known to those of skill in the art, eg, by a syringe with a needle, a pistol (eg, a hydropneumatic compression pistol), a catheter. It can be administered by implantation. The hydrogel compositions disclosed herein can be administered to a skin area, such as the dermis area or the subcutaneous tissue area. For example, the hydrogel compositions disclosed herein can be injected using a needle about 0.26 mm to about 0.4 mm in diameter and about 4 mm to about 14 mm in length. Alternatively, the needle is 21-32G and can have a length of about 4mm-about 70mm. Preferably, the needle is a disposable needle. The needle can be combined with a syringe, catheter and / or pistol.

0141In addition, the compositions disclosed herein can be administered once or in multiple doses. After all, the time of day used follows quality control standards. For example, the hydrogel compositions disclosed herein can be administered once or over several times with intervals of days or weeks. For example, an individual may be administered the hydrogel composition disclosed herein every 1, 2, 3, 4, 5, 6 or 7 days, or every 1, 2, 3 or 4 weeks. Administration of the hydrogel composition disclosed herein to an individual can be on a monthly or bimonthly basis, or every 3, 6, 9 or 12 months.

0142For breast parenchyma replacement techniques, the route of administration includes the axilla, perareolar and / or inflammatory route. Alternatively, or in addition, the composition can be delivered through a transaxillary endoscopic subpectoralis major approach. For facial parenchyma replacement techniques, the route of administration can be frontal, temporal, cheekbone, periocular, mandible, perioral or jaw route. In urinary incontinence techniques, the route of administration may include the transurethral or periurethral route. Alternatively or in addition, administration can be delivered via an antegrade route. The pathways disclosed herein do not preclude the use of multiple pathways to achieve the desired clinical effect.

0143Aspects herein provide, in part, the dermis region. As used herein, the term "dermis region" refers to the region of the skin that includes the dermis, including the epidermis-dermis junction, superficial dermis (papillary dermis region) and deep dermis (reticular region). .. The skin is composed of three main layers: the epidermis (which provides waterproofing and serves as a barrier against infection), the dermis (which serves as a place for skin appendages), and the subcutaneous tissue (subcutaneous adipose tissue). The epidermis does not contain blood vessels and is nourished by diffusion from the dermis. The main types of cells that make up the epidermis are keratinocytes, melanocytes, Langerhans cells and Merkel cells.

0144The dermis is a layer of skin under the epidermis that consists of connective tissue and protects the body from stress and strain. The dermis is firmly attached to the epidermis by the basement membrane. It also possesses a number of mechanical receptors / nerve endings that provide tactile and warm sensations. It contains hair follicles, sweat glands, sebaceous glands, apocrine glands, lymph vessels and blood vessels. Blood vessels in the dermis provide nutrients and waste products from their own cells, as well as from the basal layer of the epidermis. The dermis is structurally divided into two areas: the superficial area adjacent to the epidermis (called the papilla area), and the deeper, thicker area known as the reticular area.

0145The papillary region consists of sparse ring-shaped connective tissue. It is named after its finger-like process, called the papilla, which extends in the direction of the epidermis. The papilla mates with the epidermis and provides the dermis with a "bumpy" surface that strengthens the bond between the two layers of skin. The reticular region lies deep in the papillary region and is usually much thicker than the papillary region. It consists of dense connective tissue and is named after the dense concentrations of collagen, elastic and reticulated fibers that make up its entire body. These protein fibers give the dermis its properties of strength, extensibility and elasticity. Hair roots, sebaceous glands, sweat glands, receptors, nails and blood vessels are also present within the reticular region. The tattoo ink is retained in the dermis. Stretch marks are also located in the dermis.

0146The subcutaneous tissue lies beneath the dermis. Its purpose is to attach the dermis area of the skin to the underlying bones and muscles, as well as to supply blood vessels and nerves to it. It consists of loose connective tissue and elastin. The main cell types are fibroblasts, macrophages and adipocytes (subcutaneous tissue contains 50% of body fat). Fat serves as a padding and insulator for the body.

0147In aspects of this embodiment, the hydrogel compositions disclosed herein are administered to an individual's skin area by injection into the dermis or subcutaneous tissue area. In aspects of this embodiment, the hydrogel compositions disclosed herein are administered to an individual's dermis region, for example by injection into the epidermis-dermis junction region, papillary region, reticular region or any combination thereof. Will be done.

0148Aspects of the present specification are, in part, a method of treating an individual's parenchyma symptoms, wherein the hydrogel composition disclosed herein is administered to the site of the individual's parenchyma symptoms, and the composition is administered. Discloses methods that include steps to improve parenchyma symptoms and thereby treat parenchyma symptoms. In aspects of this embodiment, the soft tissue symptoms are breast tissue symptoms, facial tissue symptoms, neck symptoms, skin symptoms, upper arm symptoms, forearm symptoms, hand symptoms, shoulder symptoms, back symptoms, body, eg abdominal symptoms, buttocks symptoms, A thigh symptom, a lower limb symptom, such as a calf symptom, a foot symptom, such as a sole fat pad symptom, an eye symptom, a genital symptom, or a symptom that acts on another body part, area or area.

0149Another aspect of the present specification is, in part, a method of treating the skin, wherein the hydrogel composition disclosed herein is administered to an individual suffering from skin symptoms, and the composition is administered. Disclosed are methods that include steps to improve skin symptoms and thereby treat skin symptoms. In aspects of this embodiment, the skin symptom is dehydration of the skin, a method of treating it, the individual suffering from skin dehydration is administered the hydrogel composition disclosed herein. However, administration of the composition discloses a method comprising rehydrating the skin, thereby treating skin dehydration. In another aspect of this embodiment, a method of treating a skin elastic deficiency administers a hydrogel composition disclosed herein to an individual suffering from a skin elastic deficiency. It involves the steps of increasing the elasticity of the skin and thereby treating the elastic deficiency of the skin. In yet another aspect of this embodiment, the method of treating the texture of the skin administers and composes the hydrogel composition disclosed herein to an individual suffering from the roughness of the skin. Administration of a substance comprises the steps of reducing the texture of the skin, thereby treating the texture of the skin. In yet another aspect of this embodiment, the method of treating skin tension deficiency administers the hydrogel composition disclosed herein to an individual suffering from skin tension deficiency (in this case, composition). Administration of a substance creates skin tension), thereby including the step of treating the lack of skin tension.

0150In a further aspect of this embodiment, the method of treating skin stretch lines or marks administers the hydrogel composition disclosed herein to an individual suffering from skin stretch lines or marks, and the composition. Administration involves reducing or eliminating the skin, thereby treating stretch lines or marks on the skin. In another aspect of this embodiment, the method of treating flesh-colored skin administers the hydrogel composition disclosed herein to an individual suffering from flesh-colored skin and administers the composition. Includes steps to increase skin tone or radiance, thereby treating poor skin tone. In another aspect of this embodiment, a method of treating skin wrinkles administers a hydrogel composition disclosed herein to an individual suffering from skin wrinkles, and administration of the composition administers skin wrinkles. Includes steps to reduce and eliminate, thereby treating wrinkles on the skin. In yet another aspect of this embodiment, a method of treating skin wrinkles administers the hydrogel composition disclosed herein to an individual, and administration of the composition resists the skin against skin wrinkles. As having sex, it involves the steps of treating wrinkles on the skin.

0151In another aspect of the invention, hyaluronic acid (HA) and at least one additional component selected from the group consisting of wrinkle reduction, antioxidant, hemostatic, vasoconstriction, antipruritic, anti-inflammatory, and anti-irritating components. A stable skin-filled formulation containing is provided, wherein the stability of the skin-filled formulation is (a) steam sterilized at about 120 ° C to about 135 ° C, and (b) from about 32 days at about 45 ° C. The heat treatment selected from the group consists of substantially retaining one or more of the skin filler properties of being transparent, homogeneous and cohesive after the heat treatment, and the skin after the heat treatment. It does not involve substantial decomposition of the filled product. The additional ingredient can be Vitamin C or Vitamin E.

0152In this aspect of the invention, the formulation substantially retains at room temperature one or more of the dermal filler properties of being clear, homogeneous and cohesive for at least two years, resulting in substantial degradation of the dermal filler. It is stable as confirmed by not being accompanied. In some embodiments, the formulation is stable for at least 3 years.

0153The additional component provides the formulation with improved rheological properties as compared to the HA gel formulation without the additional component, resulting in lower extrusions required for administration.

0154In yet another aspect of the invention is a method of treating fine lines, wrinkles, fibroblast depletion or scarring in a patient with hyaluronic acid (HA), as well as wrinkle reduction, antioxidant, hemostatic, vasoconstriction, antipruritic. A method comprising the step of administering to a patient an effective amount of a steam sterilized stable skin filling formulation comprising at least one additional ingredient selected from the group consisting of anti-inflammatory and anti-irritating ingredients is provided, wherein the formulation is transparent. Homogeneous, monophasic, cohesive, stable, not degraded after steam sterilization, reduced appearance of fine lines, wrinkles, fibroblast depletion or scarring

0155In yet another aspect of the invention is a method of treating fine lines, wrinkles, fibroblast depletion or scarring of a patient, from about 1 to about 40 mg / g of crosslinked hyaluronic acid (HA), as well as wrinkle reduction, oxidation. A method comprising the step of topical injection into a patient of a vapor-sterilized stable skin-filled formulation containing at least one additional ingredient selected from the group consisting of anti-inflammatory, vasoconstrictive, vasoconstrictive, anti-pruritic, anti-inflammatory and anti-irritating ingredients. Provided, the formulation is clear, homogeneous, cohesive, stable, does not decompose after steam sterilization, and the appearance of fine lines, wrinkles, fibroblast depletion or scarring is reduced by injection.

0156In a further aspect of the present invention, a steam-sterilized stable skin-filled preparation comprising hyaluronic acid and at least one additional ingredient selected from the group consisting of AA2G and dexpantenol, which adds to the stability of the skin-filled preparation. Provided are formulations that are significantly increased by the addition of the ingredients of.

<p num="0157"> The following examples illustrate the representative embodiments currently intended, but do not limit the disclosed hydrogel compositions, as well as the methods of parenchyma augmentation using such hydrogel compositions.</p><p num="0158"> Example 1 Method for determining gel cohesive force This example illustrates the tests that can be performed to demonstrate and quantify the cohesiveness of HA-based gel compositions.</p><p num="0159"> First, 0.2 g or 0.4 g of gel composition to be tested is placed in a glass syringe. Next, 0.2 g or more of phosphate buffer is added to the syringe and the mixture is thoroughly mixed for about 1 hour to obtain a homogeneous mixture. The homogenized mixture is then centrifuged at 2000 tr / min for 5 minutes to remove air bubbles and decant the arbitrary particles. The syringe is then held in a vertical position and a drop of eosin colorant is deposited on the surface of the gel using the syringe and an 18G needle. After 10 minutes, the dye gradually diffused throughout the gel.</p><p num="0160"> After gel dilution, homogenization and decantation, gels with relatively low cohesion show phase separation (upper diluted low viscous phase without particles and lower part consisting of decanted particles visible to the naked eye or under a microscope. phase). Under the same conditions, the highly cohesive gel exhibits substantially no phase separation and the dye is prevented from dispersing in the cohesive formulation. On the other hand, the relative low cohesive gel shows clear phase separation.</p><p num="0161"> Example 2 Effect of water-soluble molecules on the extrudability of HA-based gel formulations The active ingredient was mixed into an HA-based gel matrix and autoclaved by steam sterilization at a temperature of about 130 ° C to about 135 ° C for about 1 to about 10 minutes. After autoclaving and after a period corresponding to 3 years at room temperature, hydrogel properties, aspect (ie, color / transparency / homogeneity) and extrusion were analyzed. All formulations were transparent, homogeneous, and colorless and had acceptable extrusion properties after autoclaving and at the time equivalent to 3 years (Table 3). These results indicate that the test gel did not show degradation, indicating that the gel was stable and that contamination with the components did not affect the properties and structure of the hydrogel.<tables num="3"><img id="000007" he="158" wi="158" file="JP5960894B2_D0001.tif" img-format="tif" img-content="drawing" /></tables></p><p num="0162"> Example 3 Effect of Vitamin C Derivatives on Extrudability and Stability of HA-Based Gel Formulas Ascorbic acid was mixed into the HA-based gel matrix at a concentration of 1% (w / w), adjusting the pH of the gel to about 7, and then a temperature of about 130 ° C to about 135 ° C. Then, it was autoclaved by steam sterilization for about 1 minute to about 10 minutes. The gel was clear but colorless before the autoclave treatment, but the gel was clear but yellow after the autoclave treatment, indicating that the test gel had decomposed.</p><p num="0163"> Example 4 Effect of Vitamin C Derivatives on Extrudability and Stability of HA-Based Gel Formulas Ascorbyl magnesium phosphate (MAP) is mixed into the HA-based gel matrix at concentrations of 0.6% (w / w), 1% (w / w) or 2% (w / w) to adjust the pH of the gel. It was adjusted to about 7, and then autoclaved in the same manner as in Example 3. The gel was clear and colorless both before and after the autoclave treatment. Both extrusion and degradation were used to assess the rheological properties of the gel. Decomposition was measured as a function of time using a controlled stress flowmeter according to the following method: Frequency sweep from 0.05 Hz to 10 Hz at 0.8% (w / w) controlled strain. ΔTanδ 1Hz = (Tanδ 1Hz test gel)-(Tanδ 1Hz control gel) (In the formula, Tanδ 1Hz is the ratio of viscosity to elastic modulus). ΔTanδ less than 0.1 1 Hz demonstrates the absence of detectable degradation, which indicates that the test gel was stable. Rheological analysis showed that the test gel had acceptable extrusion properties, but the test gel showed degradation after autoclaving, indicating that the gel was unstable (Table). Four).<tables num="4"><img id="000008" he="57" wi="159" file="JP5960894B2_D0001.tif" img-format="tif" img-content="drawing" /></tables></p><p num="0164"> Example 5 Effect of Vitamin C Derivatives on Extrudability and Stability of HA-Based Gel Formulas Ascorbyl sodium phosphate (SAP) is mixed into the HA-based gel matrix at concentrations of 0.6% (w / w), 1% (w / w) or 2% (w / w) to adjust the pH of the gel. It was adjusted to about 7, and then autoclaved in the same manner as in Example 3. The gel was clear and colorless both before and after the autoclave treatment. Rheological analysis shows that the test gel has acceptable extrusion properties, and that the test gel showed no degradation compared to the control, indicating that the gel was stable. Shown (Table 5).<tables num="5"><img id="000009" he="57" wi="158" file="JP5960894B2_D0001.tif" img-format="tif" img-content="drawing" /></tables></p><p num="0165"> Example 6 Effects of Vitamin C Derivatives on Extrudability and Stability of HA-Based Gel Formulas Ascorbic acid 2-glucoside (AA2G ) was mixed into the HA-based gel matrix at concentrations of 0.6% (w / w), 1% (w / w) or 2% (w / w). The pH of the gel was adjusted to about 7, and then autoclaved in the same manner as in Example 3. The gel was clear and colorless both before and after the autoclave treatment. Rheological analysis shows that the test gel has acceptable extrusion properties, and that the test gel showed no degradation compared to the control, indicating that the gel was stable. Shown (Table 6). Degradation of the test gel decreased with increasing ascorbic acid 2-glucoside concentration, indicating that higher ascorbic acid 2-glucoside concentration increased gel stability.<tables num="6"><img id="000010" he="53" wi="159" file="JP5960894B2_D0001.tif" img-format="tif" img-content="drawing" /></tables></p><p num="0166"> Example 7 Effects of Vitamin C Derivatives on Long-Term Stability of HA-Based Gel Formulas The formulation prepared in Example 6 was tested for a shelf life of 32 days at 45 ° C. and compared to an HA-based gel matrix without any additives. After the test period, the gel was clear and colorless. Surprisingly, rheological analysis showed that not only did all test gels with ascorbic acid 2-glucoside (AA2G ) show degradation during the test period, but these gels also increased stability over time. (Compare the ΔTanδ 1Hz value from Table 4 with the ΔTanδ 1Hz value from Table 7).<tables num="7"><img id="000011" he="55" wi="117" file="JP5960894B2_D0001.tif" img-format="tif" img-content="drawing" /></tables></p><p num="0167"> Example 8 Effect of Vitamin E Derivatives on Extrudability and Stability of HA-Based Gel Formulas Tocopheryl acetate was mixed into the HA-based gel matrix at a concentration of 0.5% (w / w) or 1.2% (w / w) and the gel was autoclaved as in Example 3. After autoclaving, the gel was opaque and white.</p><p num="0168"> Example 9 Effect of Vitamin E Derivatives on Extrudability and Stability of HA-Based Gel Formulas Sodium tocopheryl phosphate (STP) was mixed into the HA-based gel matrix at a concentration of 0.4% (w / w) or 1.2% (w / w) and the gel was autoclaved as in Example 3. .. After autoclaving, the gel was opaque and white.</p><p num="0169"> Example 10 Effect of Vitamin E Derivatives on Extrudability and Stability of HA-Based Gel Formulas 0.7% (w / w) of polyoxyethanyl sebacate-α-tocopheryl was mixed into the HA-based gel matrix and the gel was autoclaved in the same manner as in Example 3. After autoclaving, the gel was clear but heterogeneous.</p><p num="0170"> Example 11 Effect of Vitamin E Derivatives on Extrudability and Stability of HA-Based Gel Formulas Tocopherol polyethylene glycol 1000 succinate (TPGS) is mixed into the HA-based gel matrix at 1% (w / w), 3.5% (w / w) or 7% (w / w) concentrations to give the gel. It was autoclaved in the same manner as in Example 3. The gel was clear and colorless both before and after the autoclave treatment. Rheological analysis shows that the test gel has acceptable extrusion properties, and that the test gel showed no degradation compared to the control, indicating that the gel was stable. Shown (Table 8).<tables num="8"><img id="000012" he="54" wi="158" file="JP5960894B2_D0001.tif" img-format="tif" img-content="drawing" /></tables></p><p num="0171"> Example 12 Effects of Vitamin C Derivatives, Vitamin E Derivatives and Anesthetics on Extrudability and Stability of HA-Based Gel Formulas Lidocaine at a concentration of 0.3% (w / w), 0.6% (w / w) ascorbic acid 2-glucoside (AA2G ) or 0.6% (w / w) ascorbic acid 2-glucoside (AA2G ) ) And 1.5% (w / w) TPGS in an HA-based gel matrix, and the gel was autoclaved in the same manner as in Example 3. The gel was clear and colorless both before and after the autoclave treatment. Rheological analysis shows that the test gel has acceptable extrusion properties, and that the test gel showed no degradation compared to the control, indicating that the gel was stable. Shown (Table 9).<tables num="9"><img id="000013" he="57" wi="159" file="JP5960894B2_D0001.tif" img-format="tif" img-content="drawing" /></tables></p><p num="0172"> Example 13 Effects of Vitamin C Derivatives, Vitamin E Derivatives and Anesthetics on Long-Term Stability of HA-Based Gel Formulas The formulation prepared in Example 12 was tested for a 48 day shelf life at 45 ° C. and compared to an HA-based gel matrix without any additives. After the test period, the gel was clear and colorless. Surprisingly, fluid analysis showed 0.3% (w / w) lidocaine, as well as 0.6% (w / w) ascorbic acid 2-glucoside (AA2G ) or 0.6% (w / w) ascorbic acid 2-. It was shown that test gels containing glucosides (AA2G ) and 1.5% (w / w) TPGS not only showed no degradation during the test period (Table 10).<tables num="10"><img id="000014" he="54" wi="147" file="JP5960894B2_D0001.tif" img-format="tif" img-content="drawing" /></tables></p><p num="0173"> Push power, pH and decomposition stability are shown over time in Figures 3, 4 and 5, respectively. HPLC analysis (C18 column; eluent: sodium phosphate buffer (pH 2.2), 2-propanol 10%, 0.7 ml / min; detected at 260 nm) confirmed components after autoclaving and 3 year shelf life. (Fig. 6).</p><p num="0174"> Example 14 Vitamin C derivatives promote collagen synthesis Human skin fibroblasts were cultured in 12-well plates. At confluence, 100 μL of each compound: HA-based gel matrix + 0.3% (w / w) lidocaine; HA-based gel matrix + 0.3 (w / w) lidocaine and 0.6% (w / w) ascorbic acid 2-glucoside (AA2G ) was deposited in a culture insert (porous 0.4 μm) and placed itself on a fibroblast monolayer. In parallel, untreated controls were performed. The cultures were incubated for 72 hours and each experimental condition was performed in a triple repeat experiment. At the end of the incubation, cell viability was demonstrated by microscopic observation and MTT reduction assay. Procollagen I secretion was measured using an ELISA kit. The presence of 0.6% (w / w) ascorbic acid 2-glucoside (AA2G ) in hyaluronic acid containing 0.3% (w / w) lidocaine increased procollagen synthesis by the third factor (+292). %), On the other hand, gels with 0.3% (w / w) lidocaine showed a 40% increase in procollagen secretion (see Figure 2).</p><p num="0175"> Example 15 Vitamin C derivatives protect HA-based gel formulations from oxidative degradation The effect of ascorbic acid 2-glucoside (AA2G ) on HA-based gel matrix oxidative degradation was tested. Oxidation tests were used as they allow testing of the resistance of HA-based gel matrices to free radicals. 1/7 ratio H of the surface of the diffusion gel measured with a controlled stress flowmeter according to the following method₂O₂With 30% addition, free radical decomposition was simulated with a flow meter (Haake Rheostress 600): 1 Hz frequency with 0.8% control distortion in 3600 s at 35 ° C. The time value is obtained at 5 Pa / s.</p><p num="0176"> In addition, HA-based gel matrix + 0.3 (w / w) lidocaine and 0.6% (w / w) ascorbic acid 2-glucoside (AA2G ) (15 800 s) vs. HA-based gel matrix + 0.3% (w) / w) Comparison of antioxidant properties for lidocaine (4 942 s) shows that gels containing ascorbic acid 2-glucoside (AA2G ) and lidocaine are more stable with respect to free radical activity. (Fig. 7). Ascorbic acid 2-glucoside (AA2G ) protected against oxidative degradation by a third factor.</p><p num="0177"> Example 16 Implantation test A gel containing 0.6% (w / w) ascorbic acid 2-glucoside (AA2G ) was implanted in the deep dermis and subcutaneous tissue of rats. Histological evaluation at week 1 showed some mononuclear cells (lymphocytes and plasma cells) around the implant at all implantation sites (tests and controls). They were also accompanied by macrophages. Gels containing ascorbic acid 2-glucoside (AA2G ) appeared to be hypoinflammatory. The stimulation index in the test sample (sodium HA with AA2G ) was 9.9, compared to 12.3 in the control (sodium HA only). Table 11 shows the histological results of the 1st week, 1st month and 3rd month. The stimulation score of the test gel for each implantation time was lower than that of the control.<tables num="11"><img id="000015" he="58" wi="136" file="JP5960894B2_D0001.tif" img-format="tif" img-content="drawing" /></tables></p><p num="0178"> Example 17 Moisturizer's effect on the extrudability and stability of HA-based gel formulations Dexapanthenol was mixed into an HA-based gel matrix containing 0.3% (w / w) lidocaine at a concentration of 1% (w / w) and the gel was autoclaved as in Example 3. The gel was clear and colorless both before and after the autoclave treatment. Rheological analysis showed that the test gel had acceptable extrusion properties, and the test gel showed no degradation compared to the control, indicating that the test gel was stable. Was shown (Table 12).<tables num="12"><img id="000016" he="54" wi="159" file="JP5960894B2_D0001.tif" img-format="tif" img-content="drawing" /></tables></p><p num="0179"> Example 18 Moisturizer effect on long-term stability of HA-based gel formulations The formulation prepared in Example 17 was tested for a shelf life of 30 days at 45 ° C. and compared to an HA-based gel matrix without any additives. After the test period, the gel was clear and colorless. Surprisingly, rheological analysis showed that not only did test gels with dexapanthenol show no degradation during the test period, but these gels also showed increased stability over time (Table). Compare the ΔTan δ 1Hz value from 12 with the ΔTan δ 1Hz value from Table 13).<tables num="13"><img id="000017" he="43" wi="115" file="JP5960894B2_D0001.tif" img-format="tif" img-content="drawing" /></tables></p><p num="0180"> Example 19 Effect of vasoconstrictor on the extrudability and stability of HA-based gel formulations Epinephrine bitartrate was mixed into the HA-based gel matrix at a concentration of 10 ppm (1 ppm is about 0.1 mg / g) and the gel was autoclaved in the same manner as in Example 3. The gel was clear and colorless both before and after the autoclave treatment. Rheological analysis showed that the test gel containing 10 ppm epinephrine bitartrate had acceptable extrusion properties, but the test gel showed degradation after autoclaving, indicating that the gel was unstable. , (Table 14).<tables num="14"><img id="000018" he="41" wi="158" file="JP5960894B2_D0001.tif" img-format="tif" img-content="drawing" /></tables></p><p num="0181"> Example 20 Effects of vasoconstrictors and anesthetics on the extrudability and stability of HA-based gel formulations Epinephrine bitartrate was mixed into an HA-based gel matrix containing 0.3% (w / w) lidocaine at a concentration of 10 ppm and the gel was autoclaved as in Example 3. The gel obtained before the autoclave treatment was transparent and colorless, while the gel obtained after the autoclave treatment was transparent but colored. Rheological analysis showed that the test gel had acceptable extrusion properties (Table 15).<tables num="15"><img id="000019" he="47" wi="158" file="JP5960894B2_D0001.tif" img-format="tif" img-content="drawing" /></tables></p><p num="0182"> Example 21 Effects of vasoconstrictors and anesthetics on the long-term stability of HA-based gel formulations The formulation prepared in Example 20 was tested for a shelf life of 60 days at 45 ° C. and compared to an HA-based gel matrix without any additives. After the test period, the gel was clear and slightly colored. Rheological analysis showed that gels with 0.3% (w / w) lidocaine and 10 ppm bitartrate epinephrine showed degradation of the test gel during the test period, indicating that the gel was unstable over time. (Compare the ΔTanδ 1Hz value from Table 13 with the ΔTanδ 1Hz value from Table 16).<tables num="16"><img id="000020" he="36" wi="118" file="JP5960894B2_D0001.tif" img-format="tif" img-content="drawing" /></tables></p><p num="0183"> Example 22 Effects of vasoconstrictors and antioxidants on the extrudability and stability of HA-based gel formulations Epinephrine was mixed into an HA-based gel matrix containing 0.9 (w / w) or 4.5% (w / w) mannitol at a concentration of 10 ppm and the gel was autoclaved as in Example 3. Gels with 4.5% (w / w) mannitol were clear and colorless before and after autoclaving, while gels with 0.9% (w / w) mannitol were slightly colored. Rheological analysis showed that test gels with 0.3% (w / w) lidocaine, 10 ppm bitartrate epinephrine, and 0.9 (w / w) or 4.5% (w / w) mannitol had acceptable extrusion properties. , And the test gel showed no degradation compared to the control, indicating that the gel was stable (Table 17).<tables num="17"><img id="000021" he="56" wi="159" file="JP5960894B2_D0001.tif" img-format="tif" img-content="drawing" /></tables></p><p num="0184"> Example 23 Effects of vasoconstrictors and antioxidants on the long-term stability of HA-based gel formulations The formulation prepared in Example 22 was tested for a shelf life of 60 days at 45 ° C. and compared to an HA-based gel matrix without any additives. After the test period, the gel was clear and slightly colored. Rheological analysis showed that gels with 0.3% (w / w) lidocaine and 10 ppm bitartrate epinephrine, and 0.9 (w / w) or 4.5% (w / w) mannitol showed no degradation during the study period. This indicates that the gel was stable over time (Table 18). Gels with 4.5% (w / w) mannitol were more stable over time (compare the ΔTan δ 1 Hz values from Table 17 with the ΔTan δ 1 Hz values from Table 18).<tables num="18"><img id="000022" he="44" wi="119" file="JP5960894B2_D0001.tif" img-format="tif" img-content="drawing" /></tables></p><p num="0185"> Example 24 Effects of vasoconstrictors, antioxidants and anesthetics on the extrudability and stability of HA-based gel formulations Epinephrine bitartrate was mixed into an HA-based gel matrix containing 0.3% (w / w) lidocaine and 4.5% (w / w) mannitol at a concentration of 20 ppm and the gel was autoclaved as in Example 3. .. The gel was clear and colorless before the autoclave treatment, but was slightly colored after the autoclave treatment. Fluid analysis showed that test gels with 20 ppm epinephrine bitartrate, 0.3% (w / w) lidocaine and 4.5% (w / w) mannitol had acceptable extrusion properties, and the test gels were compared to controls. It did not show any degradation, indicating that the gel was stable (Table 19).<tables num="19"><img id="000023" he="52" wi="159" file="JP5960894B2_D0001.tif" img-format="tif" img-content="drawing" /></tables></p><p num="0186"> Example 25 Effects of vasoconstrictors, antioxidants and anesthetics on the long-term stability of HA-based gel formulations The formulation prepared in Example 24 was tested for a shelf life of 60 days at 45 ° C. and compared to an HA-based gel matrix without any additives. After the test period, the gel was clear and slightly colored. Fluid analysis showed that test gels with 20 ppm epinephrine bitartrate, 0.3% (w / w) lidocaine and 4.5% (w / w) mannitol did not show degradation of the test gels during the test period. Indicated.<tables num="20"><img id="000024" he="42" wi="117" file="JP5960894B2_D0001.tif" img-format="tif" img-content="drawing" /></tables></p><p num="0187"> Example 26 Effects of vasoconstrictors and anesthetics on the extrudability and stability of HA-based gel formulations Synephrine was mixed into an HA-based gel matrix containing 0.3% (w / w) lidocaine at a concentration of 100 ppm and the gel was autoclaved in the same manner as in Example 3. The gel was clear and colorless both before and after the autoclave treatment. Rheological analysis showed that the test gel with 100 ppm synephrine and 0.3% (w / w) lidocaine had acceptable push-out properties, and the test gel showed no degradation compared to the control. It was shown that the gel was stable (Table 21).<tables num="21"><img id="000025" he="45" wi="158" file="JP5960894B2_D0001.tif" img-format="tif" img-content="drawing" /></tables></p><p num="0188"> Example 27 Effects of vasoconstrictors and anesthetics on the long-term stability of HA-based gel formulations The formulation prepared in Example 26 was tested for a shelf life of 60 days at 45 ° C. and compared to an HA-based gel matrix with 0.3% (w / w) lidocaine. After the test period, the gel was clear and colorless. Rheological analysis showed that test gels with 100 ppm synephrine and 0.3% (w / w) lidocaine did not show degradation during the test period.<tables num="22"><img id="000026" he="40" wi="118" file="JP5960894B2_D0001.tif" img-format="tif" img-content="drawing" /></tables></p><p num="0189"> Example 28 Effects of vasoconstrictors and anesthetics on the extrudability and stability of HA-based gel formulations Phenylephrine was mixed into an HA-based gel matrix containing 0.3% (w / w) lidocaine at a concentration of 100 ppm and the gel was autoclaved in the same manner as in Example 3. The gel was clear and colorless both before and after the autoclave treatment. Rheological analysis showed that the test gel with 100 ppm phenylephrine and 0.3% (w / w) lidocaine had acceptable push-out properties, and the test gel showed no degradation compared to the control. It was shown that the gel was stable (Table 23).<tables num="23"><img id="000027" he="45" wi="158" file="JP5960894B2_D0001.tif" img-format="tif" img-content="drawing" /></tables></p><p num="0190"> Example 29 Effects of vasoconstrictors and anesthetics on the long-term stability of HA-based gel formulations The formulation prepared in Example 28 was tested for a shelf life of 60 days at 45 ° C. and compared to an HA-based gel matrix with 0.3% (w / w) lidocaine. After the test period, the gel was clear and colorless. Fluid analysis showed that the test gel with 100 ppm phenylephrine and 0.3% (w / w) lidocaine did not show degradation during the test period.<tables num="24"><img id="000028" he="37" wi="154" file="JP5960894B2_D0001.tif" img-format="tif" img-content="drawing" /></tables></p><p num="0191"> Example 30 Effects of vasoconstrictors and anesthetics on the extrudability and stability of HA-based gel formulations Naphazoline was mixed into an HA-based gel matrix containing 0.3% (w / w) lidocaine at a concentration of 100 ppm and the gel was autoclaved as in Example 3. The gel was clear and colorless both before and after the autoclave treatment. Rheological analysis showed that the test gel with 100 ppm naphazoline and 0.3% (w / w) lidocaine had acceptable extrusion properties, and the test gel showed no degradation compared to the control. It was shown that the gel was stable (Table 25).<tables num="25"><img id="000029" he="44" wi="159" file="JP5960894B2_D0001.tif" img-format="tif" img-content="drawing" /></tables></p><p num="0192"> Example 31 Effects of vasoconstrictors and anesthetics on the long-term stability of HA-based gel formulations The formulation prepared in Example 30 was tested for a shelf life of 60 days at 45 ° C. and compared to an HA-based gel matrix with 0.3% (w / w) lidocaine. After the test period, the gel was clear and colorless. Rheological analysis showed that test gels with 100 ppm naphazoline and 0.3% (w / w) lidocaine did not show degradation during the test period.<tables num="26"><img id="000030" he="32" wi="142" file="JP5960894B2_D0001.tif" img-format="tif" img-content="drawing" /></tables></p><p num="0193"> Example 32 Effect of antihemorrhagic agents and anesthetics on the extrudability and stability of HA-based gel formulations Tranexamic acid was mixed into an HA-based gel matrix containing 0.3% (w / w) lidocaine at a concentration of 0.4% (w / w) and the gel was autoclaved as in Example 3. The gel was clear and colorless both before and after the autoclave treatment. Rheological analysis showed that the test gel with 0.4% (w / w) tranexamic acid and 0.3% (w / w) lidocaine had acceptable extrusion properties, and the test gel degraded compared to the control. Although not shown, this indicates that the gel was stable (Table 27).<tables num="27"><img id="000031" he="51" wi="157" file="JP5960894B2_D0001.tif" img-format="tif" img-content="drawing" /></tables></p><p num="0194"> Example 33 Effects of antihemorrhagic agents and anesthetics on the long-term stability of HA-based gel formulations The formulation prepared in Example 32 was tested for a shelf life of 60 days at 45 ° C. and compared to an HA-based gel matrix with 0.3% (w / w) lidocaine. After the test period, the gel was clear and colorless. Rheological analysis showed that the gel was stable during the test period.<tables num="28"><img id="000032" he="38" wi="119" file="JP5960894B2_D0001.tif" img-format="tif" img-content="drawing" /></tables></p><p num="0195"> Example 34 Use of dermal filler compositions for the treatment of wrinkles This example illustrates the use of the compositions and methods disclosed herein to treat wrinkles.</p><p num="0196"> A 37-year-old woman presents with fine lines around the eyes and deep wrinkles on the sides of the oral cavity. The person's preoperative assessment includes routine medical history and physical examination, as well as sufficient informed consent to disclose all of the risks and benefits associated with the procedure. The physician assessing the individual determines that she is a candidate for parenchyma treatment using the compositions and methods disclosed herein. One of the hydrogel compositions as disclosed herein, eg, the compositions of Examples 11, 12, 17, 22, 14, 26, 28, 30 and 32, is superficial in the affected area. Under the muscular system, once a week for 3 weeks; about 1.0 mL to about 2.0 mL of the composition is subcutaneously administered to the affected area. The individual is then monitored for about 7 days. The doctor evaluates the facial area and determines that the procedure was successful. Both the woman and her doctor are pleased with the results of the procedure as she looks younger. Approximately one month after the procedure, women show improved quality of life.</p><p num="0197"> Example 35 Use of dermal filler compositions for the treatment of wrinkles This example illustrates the use of the compositions and methods disclosed herein to treat wrinkles.</p><p num="0198"> A 59-year-old man has wrinkles between his eyebrows and on his nasolabial folds. The person's preoperative assessment includes routine medical history and physical examination, as well as sufficient informed consent to disclose all of the risks and benefits associated with the procedure. The physician assessing the individual determines that he is a candidate for parenchyma treatment using the compositions and methods disclosed herein. Hydrogel compositions as disclosed herein, such as the compositions of Examples 11, 12, 17, 22, 24, 26, 28, 30 and 32, are applied under the superficial muscular system of the affected area. Once every 3 months; about 1.5 mL to about 3.0 mL of the composition is subcutaneously administered to each affected area. The individual is then monitored for about 7 days. The doctor evaluates the facial area and determines that the procedure was successful. Both the man and his doctor are pleased with the results of the procedure as he looks younger. Approximately one month after the procedure, men show improved quality of life.</p><p num="0199"> Example 36 Use of dermal filler compositions for the treatment of wrinkles This example illustrates the use of the compositions and methods disclosed herein to treat wrinkles.</p><p num="0200"> A 35-year-old woman presents a fine line across her forehead. The person's preoperative assessment includes routine medical history and physical examination, as well as sufficient informed consent to disclose all of the risks and benefits associated with the procedure. The teacher assessing the individual determines that she is a candidate for parenchyma treatment using the compositions and methods disclosed herein. Hydrogel compositions as disclosed herein, such as the compositions of Examples 11, 12, 17, 22, 24, 26, 28, 30 and 32, are applied under the superficial muscular system of the affected area. Once weekly, for 2 weeks; about 1.0 mL to about 2.0 mL of the composition is subcutaneously administered to the affected area. The individual is then monitored for about 7 days. The doctor evaluates the facial area and determines that the procedure was successful. Both the woman and her doctor are pleased with the results of the procedure as she looks younger. Approximately one month after the procedure, women show improved quality of life.</p><p num="0201"> Example 37 Use of dermal filler compositions for the treatment of wrinkles This example illustrates the use of the compositions and methods disclosed herein to treat wrinkles.</p><p num="0202"> A 44-year-old woman presents with an uneven texture on the right buccal surface due to the loss of collagen due to aging. The person's preoperative assessment includes routine medical history and physical examination, as well as sufficient informed consent to disclose all of the risks and benefits associated with the procedure. The physician assessing the individual determines that she is a candidate for parenchyma treatment using the compositions and methods disclosed herein. Hydrogel compositions as disclosed herein, such as the compositions of Examples 11, 12, 17, 22, 24, 26, 28, 30 and 32, are applied under the superficial muscular system of the affected area. Once weekly, for 3 weeks; about 3.0 mL to about 4.0 mL of the composition is subcutaneously administered to the affected area. The individual is then monitored for about 7 days. The doctor evaluates the facial area and determines that the procedure was successful. Both the woman and her doctor are pleased with the results of the procedure as she looks younger. Approximately one month after the procedure, women show improved quality of life.</p><p num="0203"> Example 38 Use of dermal filler compositions for the treatment of wrinkles This example illustrates the use of the compositions and methods disclosed herein to treat wrinkles.</p><p num="0204"> A 62-year-old woman presents with wrinkles across the forehead, on the sides of the eyes, and on the nasolabial folds. The person's preoperative assessment includes routine medical history and physical examination, as well as sufficient informed consent to disclose all of the risks and benefits associated with the procedure. The physician assessing the individual determines that she is a candidate for parenchyma treatment using the compositions and methods disclosed herein. Hydrogel compositions as disclosed herein, such as the compositions of Examples 11, 12, 17, 22, 24, 26, 28, 30 and 32, are applied under the superficial muscular system of the affected area; A composition of about 1.5 mL to about 2.5 mL is subcutaneously administered to each affected area. The individual is then monitored for about 7 days. The doctor evaluates the facial area and determines that the procedure was successful. Both the woman and her doctor are pleased with the results of the procedure as she looks younger. Approximately one month after the procedure, women show improved quality of life.</p><p num="0205"> Example 39 Use of dermal filler compositions for the treatment of scars This example illustrates the use of the compositions and methods disclosed herein for treating scarring.</p><p num="0206"> A 35-year-old man presents with a deep scar that traverses his mandible. The person's preoperative assessment includes routine medical history and physical examination, as well as sufficient informed consent to disclose all of the risks and benefits associated with the procedure. The physician assessing the individual determines that he is a candidate for parenchyma treatment using the compositions and methods disclosed herein. Hydrogel compositions as disclosed herein, such as the compositions of Examples 11, 12, 17, 22, 24, 26, 28, 30 and 32, are applied under the superficial muscular system of the affected area; A composition of about 1.0 mL to about 2.0 mL is subcutaneously administered to the affected area. The individual is then monitored for about 7 days. The doctor evaluates the facial area and determines that the procedure was successful. Both the man and his doctor are pleased with the results of the procedure as he looks younger. Approximately one month after the procedure, men show improved quality of life.</p><p num="0207"> Example 40 Use of dermal filler compositions for the treatment of facial defects on the cheeks This example illustrates the use of the compositions and methods disclosed herein for treating buccal facial defects.</p><p num="0208"> A 28-year-old woman presents a lean face. Her cheeks weren't very plump, so she felt her face aged, sad, and moody. The person's preoperative assessment includes routine medical history and physical examination, as well as sufficient informed consent to disclose all of the risks and benefits associated with the procedure. The physician assessing the individual determines that she is a candidate for parenchyma treatment using the compositions and methods disclosed herein. Hydrogel compositions as disclosed herein, such as the compositions of Examples 11, 12, 17, 22, 24, 26, 28, 30 and 32, are placed under the superficial muscular system of the matching region; Approximately 15 mL of the composition is administered subcutaneously to the left and right cheeks. The individual is then monitored for about 7 days. The doctor evaluates the facial area and determines that the procedure was successful. Both the woman and her doctor are pleased with the results of the procedure as she looks younger. Approximately one month after the procedure, women show improved quality of life.</p><p num="0209"> Example 41 Use of dermal filler compositions for the treatment of facial imperfections in the eyelids This example illustrates the use of the compositions and methods disclosed herein to treat facial imperfections in the eyelids.</p><p num="0210"> A 37-year-old woman presents with depressed eyes, and this appearance makes her look old and rugged. The person's preoperative assessment includes routine medical history and physical examination, as well as sufficient informed consent to disclose all of the risks and benefits associated with the procedure. The physician assessing the individual determines that she is a candidate for parenchyma treatment using the compositions and methods disclosed herein. Hydrogel compositions as disclosed herein, such as the compositions of Examples 11, 12, 17, 22, 24, 26, 28, 30 and 32, are applied under the superficial muscular system of the upper eyelid region. Approximately 2.5 mL of the composition is administered subcutaneously to the left and right eyelid areas. The individual is then monitored for about 7 days. The doctor evaluates the eyelid area and determines that the procedure was successful. Both the woman and her doctor are pleased with the results of the procedure as she looks younger. Approximately one month after the procedure, women show improved quality of life.</p><p num="0211"> Example 42 Use of dermal filler compositions for the treatment of wrinkles This example illustrates the use of the compositions and methods disclosed herein to treat wrinkles.</p><p num="0212"> A 55-year-old woman presents with wrinkles around the eye and cheek areas. The person's preoperative assessment includes routine medical history and physical examination, as well as sufficient informed consent to disclose all of the risks and benefits associated with the procedure. The physician assessing the individual determines that she is a candidate for parenchyma treatment using the compositions and methods disclosed herein. Hydrogel compositions as disclosed herein, such as the compositions of Examples 11, 12, 17, 22, 24, 26, 28, 30 and 32, are applied to the superficial muscular system of the upper eyelid and buccal region. Below; about 1.5 mL of composition is administered subcutaneously to the left and right eyelid and buccal areas. The individual is then monitored for about 7 days. The doctor evaluates the facial area and determines that the procedure was successful. Both the woman and her doctor are pleased with the results of the procedure as she looks younger. Approximately one month after the procedure, women show improved quality of life.</p><p num="0213"> Example 43 Use of dermal filler compositions for the treatment of breast defects This example illustrates the use of the compositions and methods disclosed herein to treat breast defects.</p><p num="0214"> A 32-year-old woman complains that the medical part of her breast transplant is visible, which highlights the "boney" appearance of her sternum. In addition, she felt her breasts were too far apart. The person's preoperative assessment includes routine medical history and physical examination, as well as sufficient informed consent to disclose all of the risks and benefits associated with the procedure. The physician assessing the individual determines that she is a candidate for parenchyma treatment using the compositions and methods disclosed herein. Hydrogel compositions as disclosed herein, such as the compositions of Examples 11, 12, 17, 22, 24, 26, 28, 30 and 32, are applied bilaterally to the entire lateral sternum and medial breast. Administer subcutaneously in 15 mL on the right and 10 mL on the left. The composition is administered in a tear-like manner to increase the surface area body volume ratio. The individual is then monitored for about 7 days. The doctor evaluates the breast and determines that the procedure was successful. Both the woman and her doctor are pleased with the results of the procedure. Approximately one month after the procedure, women show improved quality of life.</p><p num="0215"> Example 44 Use of dermal filler compositions for breast enlargement This example illustrates the use of the compositions and methods disclosed herein for breast enlargement.</p><p num="0216"> A 28-year-old woman presents with small breasts or breast hypoplasia. The person's preoperative assessment includes routine medical history and physical examination, as well as sufficient informed consent to disclose all of the risks and benefits associated with the procedure. The physician assessing the individual determines that she is a candidate for parenchyma treatment using the compositions and methods disclosed herein. Hydrogel compositions as disclosed herein, such as the compositions of Examples 11, 12, 17, 22, 24, 26, 28, 30 and 32, using the axillary, peri-areola and submammary pathways. Administer subcutaneously in 90 mL to the right and 145 mL to the left on both sides. The composition is administered in a tear-like manner to increase the surface area body volume ratio. The individual is then monitored for about 7 days. The doctor evaluates the breast and determines that the procedure was successful. Both the woman and her doctor are pleased with the results of the procedure. Approximately one month after the procedure, women show improved quality of life.</p><p num="0217"> In conclusion, although aspects of this specification have been described for various embodiments, one of ordinary skill in the art will readily recognize that the disclosed embodiments are merely illustrations of the principles of the objects disclosed herein. It should be understood to do. Therefore, it should be understood that the objects disclosed are not limited in any way to the particular methods, protocols and / or reagents described herein. Accordingly, according to the teachings herein, one of ordinary skill in the art may, without departing from the spirit of the present specification, make numerous and various modifications or changes to the disclosure object, or create alternative forms thereof. obtain. Changes can be made in detail without departing from the spirit of the invention as defined in the appended claims. Finally, the terms used herein are for illustration purposes only and are not intended to limit the scope of the invention, the invention is limited only by the claims. Will be done. Furthermore, the content included in the above description or shown in the accompanying drawings is only to be construed as an example and is not limiting. Therefore, the present invention is not limited to what is clearly illustrated and described.</p><p num="0218"> Certain embodiments of the invention are described herein, including the best methods known to the inventors to carry out the invention. Of course, modifications relating to these described embodiments will be apparent to those skilled in the art upon reading the above description. The inventors of the invention anticipate that such modifications will be used by those skilled in the art where appropriate, and the inventors of the invention are separate from those specifically described herein. Intended to be performed in the manner of. Accordingly, the present invention includes all modifications and equivalents of the objects listed in the claims attached thereto, where permitted by applicable rules. Further, unless otherwise stated herein, or otherwise expressly denied by the text, any combination of the above elements in all possible variants thereof is included in the invention.</p><p num="0219"> The grouping of alternative elements or embodiments of the invention disclosed herein should not be construed as limiting. Members of each group may be referred to and claimed individually or in any combination with other members of the group or other elements found herein. For convenience and / or for patentability reasons, it is expected that one or more members of a group may be included or removed from the group. If any such inclusion or deletion occurs, it is considered to contain a group that is amended and therefore satisfies the text of all Markush groups used in the appended claims.</p><p num="0220"> Unless otherwise stated, it is understood that all numerical values representing quantities of components, properties, such as molecular weight, reaction conditions, etc., used herein and in the claims are all modified by the term "about". Should be. As used herein, the term "about" is such a limited item, parameter or term, plus or minus 10, preferably 5, most, plus or minus the value of the item, parameter or advocacy described. It means that it preferably covers a range above or below 1%. Therefore, unless otherwise indicated, the parameter values described in the specification and the appended claims are approximations that may vary depending on the desired properties sought to be obtained by the present invention. At a minimum, and not as limiting the application of views equivalent to the claims, each parameter number applies, at least in light of the number of significant figures reported, and ordinary rounding techniques. By doing so, it should be interpreted. Although the numerical ranges and parameters that describe a wide range of inventions are approximate values, the numerical values described in the specific examples are reported as accurately as possible. However, any number will necessarily contain certain errors due to the standard deviation found in their respective test measurements.</p><p num="0221"> The terms "one (a)", "one (an)", "the", and similar as used in the context of describing the invention (particularly in the context of the claims below). The demonstrative terms should be construed to include both singular and plural, unless otherwise stated herein or expressly denied in the context. The enumeration of the range of values herein is intended to serve merely as an abbreviation for individually referring to each distinct value within that range. Unless otherwise stated, each individual value is incorporated herein as if it were listed individually herein. All of the methods described herein may be performed in any suitable order unless otherwise stated or expressly denied by the context. Any and all examples, or representations of the illustrations provided herein (eg, "such") are merely for the purpose of better elucidating the present invention and in other circumstances. It does not limit the scope of the claimed invention. None of the expressions in the specification should be construed as indicating any non-patentable element essential to the practice of the present invention.</p><p num="0222"> Specific embodiments disclosed herein may be further limited within the scope of the claims, using the expression consisting of, or essentially consisting of. When used in the claims, whether filed or added by amendment, the transitional term "consisting of" excludes any element, step or component not specified in the claims. .. The transitional term "essentially consists of" limits the claims to a particular substance or step and to those that do not substantially affect the basic and novel qualities (s). The embodiments of the invention so claimed are inherently or explicitly described and enabled herein.</p><p num="0223"> All patents, patent publications and other publications referred to and specified in the specification of the present invention are, for example, the compositions and methods described in such publications which may be used in conjunction with the present invention. The content of which is incorporated herein by reference, individually and expressly, for the purposes of description and disclosure. These publications are provided exclusively for their disclosure prior to the filing date of this application. In this regard, what should be construed as an acknowledged fact that the inventors, etc. are not entitled to prior to such disclosure, based on conventional inventions or for any other reason. nothing. All date statements, or expressions relating to the content of these documents, are based on the information available to the applicant, etc. and do not give any acceptance regarding the accuracy of the date or content of these documents.</p>