ES2716396T3

Stable hydrogel compositions including additives

Abstract

Stable dermal filler formulation comprising a hyaluronic acid, a vitamin C selected from sodium ascorbyl phosphate and ascorbic acid 2-glucoside, and an aminoamide local anesthetic selected from the group consisting of articaine, bupivacaine, cinchocaine (dibucaine), etidocaine, levobupivacaine, lidocaine (lignocaine), mepivacaine, piperocaine, prilocaine, ropivacaine, and trimecaine.

ES2716396T3, drawing sheet 1 — Sheet 1 of 30

Term

4.3 yearsto projected expiry

Projected expiry 13 January 2031, counted from filing; an application has no term until it is granted.

15 claims: 1 independent, 14 dependent

1
REIVINDICACIONES i. Formulación de relleno dérmico estable que comprende un ácido hialurónico, una vitamina C seleccionada de ascorbilfosfato de sodio y
2
2-glucósido de ácido ascórbico, y un anestésico local de aminoamida seleccionado del grupo que consiste en articaína, bupivacaína, cincocaína (dibucaína), etidocaína, levobupivacaína, lidocaína (lignocaína), mepivacaína, piperocaína, prilocaína, ropivacaína y trimecaína. 2. Formulación según la reivindicación 1, en la que estabilidad de la formulación se determina sometiendo la formulación a un tratamiento térmico seleccionado del grupo que consiste en (a) esterilización por vapor a entre 120°C y 135°C, y (b) 32 días a 45°C, con conservación sustancial tras el tratamiento térmico de una o más de las características del relleno dérmico de ser claro, homogéneo y cohesivo, y sin degradación sustancial de la formulación tras el tratamiento térmico.
3
Formulación según la reivindicación 1 ó 2, en la que el ácido hialurónico está reticulado, en la que el agente de reticulación se selecciona preferiblemente de tetraglicidil éter de pentaeritritol (PETGE), divinilsulfona (DVS), diglicidil éter de 1,4-butanodiol (BDDE), 1,2-bis(2,3-epoxipropoxi)etileno (E g D g E), 1,2,7,8-diepoxioctano (DEO), fenilenbis-(etil)-carbodiimida, 1,6-hexametilen-bis(etilcarbodiimida), dihidrazida de ácido adípico (ADH), suberato de bis(sulfosuccinimidilo) (BS), hexametilendiamina (HMDA), 1-(2,3-epoxipropil)-2,3-epoxiciclohexano, o combinaciones de los mismos.
4
Formulación según una cualquiera de las reivindicaciones 1 a 3, en la que el ácido hialurónico está presente en una cantidad de 1 mg/g a 40 mg/g.
5
Formulación según una cualquiera de las reivindicaciones 1 a 4, en la que la formulación es estable, tal como se determina por la conservación sustancial a temperatura ambiente de una o más de las características del relleno dérmico de ser claro, homogéneo y cohesivo, y sin degradación sustancial de la formulación, durante un periodo de al menos 2 años.
6
Formulación según la reivindicación 5, en la que la formulación es estable durante al menos 3 años.
7
Formulación según una cualquiera de las reivindicaciones 1 a 6, en la que la vitamina C está presente en una cantidad del 0,001% p/p al 10% p/p, preferiblemente del 0,1% p/p al 10% p/p, más preferiblemente del 0,1% p/p al 3% p/p.
8
Formulación según una cualquiera de las reivindicaciones 1 a 7, en la que la vitamina C proporciona a la formulación propiedades reológicas mejoradas que dan como resultado que se requiera menos fuerza de extrusión para su administración en comparación con una formulación de gel de ácido hialurónico sin la vitamina C.
9
Formulación según una cualquiera de las reivindicaciones 1 a 8, en la que el anestésico local de aminoamida es lidocaína o una combinación de lidocaína/prilocaína que está preferiblemente presente en una cantidad del 0,1% (p/p) al 5,0% (p/p) de la composición total, más preferiblemente en una cantidad del 0,1% (p/p) al 1,0% (p/p) de la composición total, y lo más preferiblemente en una cantidad del 0,3% (p/p) de la composición total.
10
Formulación según una cualquiera de las reivindicaciones 1 a 9, en la que el ácido hialurónico es de bajo peso molecular y/o de alto peso molecular.
11
Formulación según la reivindicación 1, que es una formulación estable en esterilización por vapor que comprende un ácido hialurónico, 2-glucósido de ácido ascórbico y un anestésico local de aminoamida seleccionado del grupo que consiste en articaína, bupivacaína, cincocaína (dibucaína), etidocaína, levobupivacaína, lidocaína (lignocaína), mepivacaína, piperocaína, prilocaína, ropivacaína y trimecaína, en la que la estabilidad de la formulación se aumenta significativamente mediante la adición del 2-glucósido de ácido ascórbico.
12
Formulación según una cualquiera de las reivindicaciones 1 a 11, para su uso en un método de tratamiento de una enfermedad, en la que la formulación es preferiblemente para su uso como relleno dérmico.
13
Método no terapéutico de tratamiento de líneas finas, arrugas, agotamientos de fibroblastos o cicatrices de un paciente, comprendiendo el método la etapa de administrar la formulación según una cualquiera de las reivindicaciones 1 a 11.
14
Formulación según una cualquiera de las reivindicaciones 1 a 11 para su uso en un método de tratamiento de líneas finas, arrugas, agotamientos de fibroblastos o cicatrices de un paciente, comprendiendo el método la etapa de administrar dicha formulación.
15
Método no terapéutico según la reivindicación 13 o formulación para su uso según la reivindicación 14, en el que la formulación se administra mediante inyección, preferiblemente mediante inyección subdérmica.

Independent claims15

428 paragraphs, as filed

DESCRIPTION

Stable hydrogel compositions that include additives

Background

Skin aging is a progressive phenomenon, occurs over time and can be affected by lifestyle factors such as alcohol consumption, tobacco and sun exposure. Aging of the facial skin can be characterized by atrophy, loosening and fattening. Atrophy corresponds to a massive reduction in skin tissue thickness. Loosening of subcutaneous tissues leads to excess skin and ptosis and leads to the appearance of droopy eyelids and cheeks. Fattening refers to an increase in excess weight due to swelling of the lower part of the face and neck. These changes are normally associated with dryness, loss of elasticity and rough texture.

Hyaluronan, also known as hyaluronic acid (HA) is a non-sulfated glucosaminoglycan that is widely distributed throughout the human body in connective, epithelial and neural tissues. Hyaluronan is abundant in the different layers of the skin, where it has multiple functions such as, for example, ensuring good hydration, helping in the organization of the extracellular matrix, acting as filler material; and participate in tissue repair mechanisms. However, with age, the amount of hyaluronan, collagen, elastin, and other matrix polymers present in the skin decreases. For example, repeated exposure to ultraviolet light, for example, from the sun, causes dermal cells to both decrease their hyaluronan production as well as increase the speed of their degradation. This loss of hyaluronan results in various skin conditions such as, for example, imperfections, defects, diseases and / or disorders, and the like. For example, there is a strong correlation between the water content in the skin and the levels of hyaluronan in the dermal tissue. As the skin ages, the quantity and quality of hyaluronan in the skin is reduced. These changes lead to dry skin and wrinkles.

Dermal fillers are useful in the treatment of a soft tissue state and in other skin therapies because the charges replace lost endogenous matrix polymers, or enhance / facilitate the function of existing matrix polymers, with the In order to treat these skin states. In the past, such compositions have been used in cosmetic applications to fill wrinkles, lines, folds, scars, and to enhance dermal tissue, such as, for example, to inflate thin lips or fill sunken eyes or flat cheeks. A common matrix polymer used in dermal filler compositions is hyaluronan. Because hyaluronan is natural to the human body, it is a generally well tolerated and low-risk treatment for a wide variety of skin conditions. WO 2008/098019 A2 discloses a hyaluronan gel for filling wrinkles comprising ascorbic acid as a stabilizer and local anesthetics such as bupivacaine, lidocaine or prilocaine.

Originally, compositions comprising hyaluronan were prepared from naturally occurring polymers, which exist in an uncrosslinked state. Although they presented excellent biocompatibility and affinity for water molecules, the naturally occurring hyaluronan exhibits bad biomechanical properties as dermal filler. 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 supply 1: 302-312 (2009); Beasley, et al., Hyaluronic Acid Fillers: A Comprehensive Review, Facial Plast. Surg. 25 (2): 86-94 (2009). A main reason is that because this polymer is not crosslinked, it is highly soluble and, as such, quickly clears up when administered in a region of the skin. Tezel, cited above, 2008; Kablik, cited above, 2009; Beasley, cited above, 2009. This in vivo clearance is mainly achieved by rapid degradation of the polymers, primarily enzymatic degradation by means of hyaluronidase and chemical degradation by free radicals. Therefore, while still in commercial use, compositions comprising uncrosslinked hyaluronan polymers tend to degrade within a few days after administration and therefore require a fairly frequent reinjection to maintain their skin-enhancing effect.

To minimize the effect of these degradation pathways in vivo, the matrix polymers crosslink each other to form a stabilized hydrogel. Because hydrogels comprising crosslinked matrix polymers are a more solid substance, dermal fillers comprising such hydrogels remain in place at the implant site longer. Tezel, cited above, 2008; Kablik, cited above, 2009; Beasley, cited above, 2009. In addition, these hydrogels are more suitable as a dermal filler because their more solid nature improves the mechanical properties of the filler, allowing the filler to lift and better fill a region of the skin. Tezel, cited above, 2008; Kablik, cited above, 2009; Beasley, cited above, 2009. Hyaluronan polymers are normally crosslinked with a crosslinking agent to form covalent bonds between hyaluronan polymers. Such crosslinked polymers form a water soluble hydrogel network that is more resistant to degradation, and therefore requires less frequent reinjection, than non-crosslinked hyaluronan compositions.

Current dermal fillers may be associated with a variety of side effects. For example, the Administration of a dermal filler to an individual is usually done using a syringe or needle. Such administration could result in one or more unwanted side effects, such as, for example, pain and discomfort for the individual, bleeding in and under the site of administration, and itching, inflammation and irritation in the vicinity of the site of administration during and after administration of the dermal filler. The dermal fillers disclosed herein address these and other unwanted side effects by providing hydrogel compositions comprising agents that reduce, decrease or prevent one or more of these side effects.

Additionally, a dermal filler formulation must be able to withstand sterilization, which is a strict requirement before the product can be marketed (the product must be sterile). Sterilization can be carried out by steam sterilization, filtration, microfiltration, gamma radiation, ETO light or by a combination of these methods. It is known that a dermal filler can be steam sterilized (autoclaved) without substantial degradation of physical properties, but when a dermal filler formulation contains an additional labile component (such as an antioxidant, itching agent, an anti-cellulite agent, an agent anti-healing, an anti-inflammatory agent, an anesthetic agent, an anti-irritant agent, a vasoconstrictor, a vasodilator, an antihemorrhagic agent such as a hemostatic agent or an antifibrinolytic agent, a descaling agent, a tension agent, an anti-acne agent, a pigmentation agent, an anti-pigmentation agent or a wetting agent) the entire dermal filler formulation or at least the traditional agent (thermolabile) is traditionally sterilized by a non-thermal treatment such as by a sterilization method by filtration. Therefore, a known dermal filler product (REVITACARE® Bio-Revitalization, REVITACARE® Laboratory, Saint-Ouen-l'Aumóne, France) is marketed in two separate vials or containers, containing a vial he HA (which is autoclaved )) and the second vial containing any additional component (the content of the second vial is sterilized by filtration). Another known dermal filler product NCTF® 135HA (Laboratoires Filorga, Paris, France) is marketed in a single container containing both hyaluronan and any additional components, all of which have been sterilized by microfiltration. The dermal fillers disclosed herein address this problem by developing dermal fillers that are completely sterilized by heat treatment, that is, in some embodiments of this invention, none of the components are sterilized only using a non-thermal treatment such as, by example, filtration.

Summary

The present invention provides novel dermal fillers useful for treating skin conditions that remain stable following a heat treatment used to sterilize the compositions as set forth in the claims. One aspect of the disclosed dermal fillers, and a significant distinction with respect to known dermal fillers, is that the dermal fillers disclosed herein are prepared: 1) by mixing glycosaminoglycan polymers and the additional agent (s) ) disclosed (s) in this document, and then; (2) thermally treating the dermal filler composition to at least 100 ° C (without filtration sterilization of any component); (3) wherein such treatment maintains the desired properties of the hydrogel compositions. The hydrogel compositions of the invention as set forth in the claims do not exhibit any significant degradation as shown by tests before and after autoclaving. The disclosed hydrogel compositions are substantially thermally stable as determined by the retention of one or more of the following characteristics after sterilization: clarity (transparency and translucency), homogeneity, extrusion force, cohesiveness, hyaluronan concentration, agent concentration (s), osmolarity, pH, or other rheological characteristics desired by the hydrogel before heat treatment.

The hydrogel compositions disclosed herein may also have greater stability than a hydrogel composition without the additional constituent. Without wishing to restrict the theory, it may be that the hydrogel matrix of the crosslinked glycosaminoglycan polymers used in the sequential formulation becomes non-reactive and thereby prevents the additional component (as set forth in the following examples) from degrading and cause degradation of the dermal filler formulation during steam sterilization. Additionally, the additional component may be hydrophilic and provides protection of the glycosaminoglycan polymers against degradation during steam sterilization and / or after administration of the dermal filler formulation to a patient. Without wishing to restrict the theory, the incorporation of an additional component in the dermal filler formulation can inhibit the removal of free radicals at the injection / implant site, thereby prolonging the duration of the dermal filler after administration to the patient. After steam sterilization, the additional component, after administration (as a subdermal injection), can be released from the dermal filler formulation to achieve a cosmetic or therapeutic effect.

Therefore, the present invention provides a hydrogel composition comprising a glycosaminoglycan polymer, an antioxidant and an anesthetic agent as set forth in the claims. The glycosaminoglycan polymers of the invention are hyaluronan polymers.

Other aspects of the present specification provide a method of preparing a hydrogel composition disclosed herein, the method comprising a) mixing the polymer of glycosaminoglycan and the at least one agent; and b) heat treat the mixture; wherein the heat treatment maintains the desired hydrogel properties disclosed herein.

Still other aspects of the present specification provide formulations for use in a method of treating a skin condition in an individual in need thereof, the method comprising the steps of administering a hydrogel composition disclosed herein to a region. dermal of the individual, in which the administration improves the condition of the skin. Skin conditions treated by the disclosed compositions include, without limitation, increases, reconstructions, diseases, disorders, defects or imperfections of a part, region or area of the body. In one aspect, a condition of the skin treated by the disclosed compositions includes, without limitation, a facial augmentation, a facial reconstruction, a facial disease, a facial disorder, a facial defect or a facial imperfection. In one aspect, a condition of the skin treated by the disclosed compositions includes, without limitation, dehydration of the skin, a lack of elasticity of the skin, roughness of the skin, a lack of smoothness of the skin, a line or brand of stretching of the skin, paleness of the skin, a dermal fosita, a sunken cheek, a thin lip, a retroorbital defect, a facial crease or a wrinkle. In other aspects of the disclosure and not according to the invention, a hydrogel composition is provided comprising a polymer based on hyaluronic acid and at least one additional agent selected from the group consisting of an antihemorrhagic agent and a vasoconstrictor agent, in which The hydrogel composition is sterilized by heat treatment and / or pressure treatment, for example, by autoclaving, for example, It is sterilized in a process comprising a heat treatment of at least 100 ° C. Advantageously, the thermally sterilized composition is substantially stable at room temperature for up to at least about 3 months, for example, at least about 24 months, at least about 36 months.

In some embodiments, the antihemorrhagic agent is an antifibrinolytic agent selected from the group £ -aminocaproic acid, tranexamic acid and a serpine. In some embodiments, the antifibrinolytic agent is tranexamic acid present in an amount of about 0.1% (w / w) to about 1.0% (w / w) of the total composition.

In some embodiments, the vasoconstrictor agent is nafazolin, epinephrine, methoxamine, methylnorepinephrine, norepinephrine, oxymetazoline, phenylephrine, pseudoephedrine, synephrine, cirazoline, xylometazoline, an analogue or a derivative thereof, or any combination thereof. In some embodiments, phenylephrine is present in a concentration of about 0.001% (w / w) to about 0.1% (w / w). In some embodiments, the composition further comprises an anesthetic agent, for example, lidocaine or a similar agent, present in an amount of about 0.1% (w / w) to about 1.0% (w / w) of The total composition. In some embodiments, the composition further comprises an antioxidant agent, for example, mannitol present in an amount of about 0.01% (w / w) to about 5% (w / w) of the total composition.

In some embodiments, the hyaluronic acid based polymer is present at a concentration of about 5 mg / g to about 40 mg / g, and comprises a low molecular weight hyaluronan polymer having an average molecular weight greater than 300,000 Da and less of about 800,000 Da, for example, an average molecular weight greater than 2,000,000 Da and less than about 5,000,000 Da. In some embodiments, the hyaluronic acid based polymer comprises both high molecular weight hyaluronan and low molecular weight hyaluronan, in which the high molecular weight hyaluronan has a molecular weight greater than 2,000,000 Da and in which the hyaluronan Low molecular weight has a molecular weight of less than 1,000,000 Da.

Brief description of the drawings

Figure 1 is a representation of the structure of an ascorbyl 2-glycoside, also known as AA2G ™ (Hayashibara International, Okayama, Japan).

Figure 2 is a graph showing the synthesis of procollagen (% of control) for the control; an HA-based hydrogel with 0.3% (w / w) lidocaine and 0.6% (w / w) 2-ascorbyl glycoside (AA2G ™) in phosphate buffer; and an HA-based hydrogel with 0.6% (w / w) 2-ascorbyl glycoside (AA2G ™) and 0.3% (w / w) lidocaine.

Figure 3 is a graph showing the extrusion force over time (equivalent to 3 years at 25 ° C) in the compositions: control; an HA-based hydrogel with 2-ascorbyl glycoside (AA2G ™) and lidocaine; and an HA-based hydrogel with ascorbyl 2-glycoside (AA2G ™), lidocaine and TPGS.

Figure 4 is a graph showing the pH over time (equivalent to 3 years at 25 ° C) in the compositions: control; an HA-based hydrogel with 2-ascorbyl glycoside (AA2G ™) and lidocaine; and an HA-based hydrogel with ascorbyl 2-glycoside (AA2G ™), lidocaine and TPGS.

Figure 5 is a graph of such a delta 1 Hz over time (equivalent to 3 years at 25 ° C) in the compositions: control, a hydrogel based on HA with 2-ascorbyl glycoside (AA2G ™); an HA-based hydrogel with 2-ascorbyl glycoside (AA2G ™) and lidocaine; and an HA-based hydrogel with ascorbyl 2-glycoside (AA2G ™), lidocaine and TPGS.

Figure 6 is an HPLC analysis (column C18, eluent: 10% sodium phosphate buffer (pH = 2.2) / 2-propanol, 0.7 ml / min; detection at 260 nm) of 2-glycoside of ascorbyl (AA2G ™), lidocaine and IPA (co-eluent) after autoclaving (equivalent to 3 years at 25 ° C).

Figure 7 is a graph comparing the antioxidant properties in the compositions: control against JUVEDERM® Ultra with lidocaine, an ascorbyl 2-glycoside (AA2G ™), and JUVEDERM® Ultra with lidocaine.

Detailed description

Aspects of the present specification provide, in part, a hydrogel composition comprising a glycosaminoglycan polymer. The hydrogel composition disclosed herein may further comprise two or more different glycosaminoglycan polymers. As used herein, the term "glucosaminoglycan" is synonymous with "GAG" and "mucopolysaccharide" and refers to long unbranched polysaccharides consisting of repeat disaccharide units. The repeating unit consists of a hexose (six-carbon sugar) or a hexuronic acid, attached to a hexosamine (six-carbon sugar containing nitrogen) and pharmaceutically acceptable salts thereof. Members of the GAG family vary in the type of hexosamine, hexose or hexuronic acid unit they contain, such as, for example, glucuronic acid, iduronic acid, galactose, galactosamine, glucosamine) and may also vary in the geometry of the glycosidic union. Any glycosaminoglycan polymer is useful in the hydrogel compositions disclosed herein with the proviso that the glycosaminoglycan polymer improves a skin condition. Non-limiting examples of glycosaminoglycans include chondroitin sulfate, dermatan sulfate, queratane sulfate, hyaluronan. Non-limiting examples of an acceptable salt of a glucosaminoglycan include sodium salts, potassium salts, magnesium salts, calcium salts, and combinations thereof. Glucosaminoglycan and its resulting polymers useful in hydrogel compositions and the methods disclosed herein are described in, for example, Piron and Tholin, Polysaccharide Crosslinking, Hydrogel Preparation, Resulting Polysaccharides (s) and Hydrogel (s), uses Thereof, U.S. 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 2008/0089918; Lebreton, Hyaluronic Acid-Based Gels Including Lidocaine, US Patent Publication 2010/0028438; and Polysaccharides and Hydrogels thus Obtained, US Patent Publication 2006/0194758; and Di Napoli, Composition and Method for Intradermal Soft Tissue Augmentation, international patent publication WO 2004/073759. GAGs useful in hydrogel compositions and the methods disclosed herein are commercially available, such as, for example, hyaluronan-based dermal fillers JUVEDERM®, JUVEDERM® 30, JUVEDERM® Ultra, JUVEDERM® Ultra Plus, JUVEDERM ® Ultra XC and JUVEDERM ® Ultra Plus XC (Allergan Inc, Irvine, California).

Table 1 lists representative GAGs.

The present specification provides 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" and refers to a non-sulfated anionic glucosaminoglycan polymer comprising disaccharide units, which themselves include monomers of D-glucuronic acid and DN-acetylglucosamine, linked by means of alternate p-1,4 and p-1,3 glycosidic linkages and pharmaceutically acceptable salts thereof. 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 with the proviso that hyaluronan improves a skin condition. Non-limiting examples of pharmaceutically acceptable salts of hyaluronan include sodium hyaluronan, potassium hyaluronan, magnesium hyaluronan, calcium hyaluronan, and combinations thereof.

Aspects of the present invention provide, in part, a hydrogel composition comprising a crosslinked glycosaminoglycan polymer. The glycosaminoglycan polymers of the invention are hyaluronan polymers. As used herein, the term "crosslinked" refers to intermolecular bonds that bind individual polymer molecules, or monomer chains, to give a more stable structure similar to a gel. As such, a crosslinked glycosaminoglycan polymer has at least one intermolecular bond that binds at least one individual polymer molecule to another. Crosslinking of the glycosaminoglycan polymers normally results in the formation of a hydrogel. Such hydrogels have high viscosity and require considerable force to extrude through a fine needle. The glucosaminoglycan polymers disclosed herein may be crosslinked using dialdehyde and disulfide crosslinking agents including, without limitation, cross-functional PEG crosslinking agents, divinyl sulfones, diglycidyl ethers and bis-epoxides, biscarbodiimide. Non-limiting examples of hyaluronan crosslinking agents include multifunctional PEG-based crosslinking agents such as tetraglycidyl ether of pentaerythritol (PETGE), divinylsulfone (DVS), diglycidyl ether of 1,4-butanediol (BDDE), 1,2-bis (2,3-epoxypropoxy) ethylene (EGDGE), 1,2,7,8-diepoxyoctane (DEO), (phenylenebis- (ethyl) -carbodiimide and 1.6 hexamethylenebis (ethylcarbodiimide), adipic acid dihydrazide (ADH), bis (sulfosuccinimidyl) suberate (BS), hexamethylenediamine (HMDA), 1- (2,3-epoxypropyl) -2,3-epoxycyclohexane, or combinations thereof. Other useful crosslinking agents are disclosed in Stroumpoulis and Tezel, Tunably Crosslinked Polysaccharide Compositions, U.S. Patent Application 12 / 910,466, filed October 22, 2010. Non-limiting examples of cross-linking methods of glucosaminoglycan polymers are described in, for example, Piron and Tholin, Polysaccharide Crosslinking, Hydrogel Preparation, Resulting Polysaccharide (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 2008/0089918; Lebreton, Hyaluronic Acid-Based Gels Including Lidocaine, US Patent Publication 2010/0028438; and Polysaccharides and Hydrogels thus Obtained, US Patent Publication 2006/0194758; and Di Napoli, Composition and Method for Intradermal Soft Tissue Augmentation, international patent publication WO 2004/073759.

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

In one embodiment, a hydrogel composition comprises a cross-linked glycosaminoglycan polymer in wherein the crosslinked glycosaminoglycan polymer is present in an amount sufficient to improve a skin condition disclosed herein. In aspect of this embodiment, a composition comprises a crosslinked hyaluronan polymer. In other aspects of this embodiment, a composition comprises a crosslinked glucosaminoglycan wherein the crosslinked glucosaminoglycan represents, for example, about 1% by weight, about 2% by weight, about 3% by weight, about 4% by weight , about 5% by weight, about 6% by weight, about 7% by weight, about 8% by weight, or about 9%, or about 10% by weight, of the total glucosaminoglycan present in the composition. In still other aspects of this embodiment, a composition comprises a crosslinked glucosaminoglycan wherein the crosslinked glucosaminoglycan represents, for example, at most 1% by weight, at most 2% by weight, at most 3% by weight, at most 4% by weight, a maximum of 5% by weight, a maximum of 6% by weight, a maximum of 7% by weight, a maximum of 8% by weight, a maximum of 9% by weight or a maximum of 10 % by weight, of the total glycosaminoglycan present in the composition. In still other aspects of this embodiment, a composition comprises a crosslinked glucosaminoglycan wherein the crosslinked glucosaminoglycan represents, for example, from about 0% to about 20% by weight, from about 1% to about 17% by weight, from about 3% to about 15% by weight, or from about 5% to about 10% by weight, for example, about 11% by weight, about 15% by weight or about 17% by weight, of the total glucosaminoglycan present in the composition.

In aspects of this embodiment, a hydrogel composition comprises a crosslinked glucosaminoglycan wherein the crosslinked glucosaminoglycan is present at a concentration of, 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 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 other aspects of this embodiment, a composition comprises a crosslinked glucosaminoglycan wherein the crosslinked glucosaminoglycan is present at a concentration of, for example, at least 1 mg / g, at least 2 mg / g, at least 3 mg / g, at at least 4 mg / g, at least 5 mg / 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 still other aspects of this embodiment, a composition comprises a crosslinked glucosaminoglycan wherein the crosslinked glucosaminoglycan is present at a concentration of, for example, at most 1 mg / g, at most 2 mg / g, at most 3 mg / g, maximum 4 mg / g, maximum 5 mg / g, maximum 10 mg / g, maximum 15 mg / g, maximum 20 mg / g, maximum 25 mg / g or maximum 40 mg / g. In still other aspects of this embodiment, a composition comprises a crosslinked glucosaminoglycan wherein the crosslinked glucosaminoglycan is present at a concentration of, for example, from about 7.5 mg / g to about 19.5 mg / g, from about 8.5 mg / g at about 18.5 mg / g, about 9.5 mg / g at about 17.5 mg / g, about 10.5 mg / g at about 16.5 mg / g, about 11.5 mg / g ga approximately 15.5 mg / g, or from about 12.5 mg / g to about 14.5 mg / g, to about 40 mg / g.

Aspects of the present invention provide, in part, a hydrogel composition comprising low molecular weight hyaluronan polymers, high molecular weight hyaluronan polymers, or both low and high molecular weight hyaluronan polymers. As used herein, the term "high molecular weight" when referring to "hyaluronan" refers to hyaluronan polymers having an average molecular weight of 1,000,000 Da or greater. Non-limiting examples of high molecular weight hyaluronan polymers include hyaluronan polymers of approximately 1,500,000 Da, approximately 2,000,000 Da, approximately 2,500,000 Da, approximately 3,000,000 Da, approximately 3,500,000 Da, approximately 4,000. 000 Da, approximately 4,500,000 Da and approximately 5,000,000 Da. As used herein, the term "low molecular weight" when referring to "hyaluronan" refers to hyaluronan polymers having an average molecular weight of less than 1,000,000 Da. Non-limiting examples of low molecular weight hyaluronan polymers include 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.

In one embodiment, a composition comprises crosslinked polymers of low molecular weight hyaluronan. In aspects of this embodiment, a composition comprises crosslinked hyaluronan polymers having an average molecular weight of, for example, approximately 100,000 Da, approximately 200,000 Da, approximately 300,000 Da, approximately 400,000 Da, approximately 500,000 Da, approximately 600,000 Da, approximately 700,000 Da, approximately 800,000 Da or approximately 900,000 Da. In still other aspects of this embodiment, a composition comprises crosslinked hyaluronan polymers having an average molecular weight of, for example, at most 100,000 Da, at most 200,000 Da, at most 300,000 Da, at most 400,000 Da, at most 500,000 Da , at most 600,000 Da, at most 700,000 Da, at most 800,000 Da, at most 900,000 Da or at most 950,000. In still other aspects of this embodiment, a composition comprises crosslinked hyaluronan polymers having an average molecular weight of, for example, about 100,000 Da to about 500,000 Da, about 200,000 Da a approximately 500,000 Da, from approximately 300,000 Da to approximately 500,000 Da, from approximately 400,000 Da to approximately 500,000 Da, from approximately 500,000 Da to approximately 950,000 Da, from approximately 600,000 Da to approximately 950,000 Da, from approximately 700,000 Da to approximately 950,000 Da, from approximately 800,000 Da to approximately 950,000 Da, from approximately 300,000 Da to approximately 600,000 Da, from approximately 300,000 Da to approximately 700,000 Da, from approximately 300,000 Da a approximately 800,000 Da, or from approximately 400,000 Da to approximately 700,000 Da.

In another embodiment, a composition comprises crosslinked high molecular weight hyaluronan polymers. In aspects of this embodiment, a composition comprises crosslinked hyaluronan polymers having an average molecular weight of, for example, approximately 1,000,000 Da, approximately 1,500,000 Da, approximately 2,000,000 Da, approximately 2,500,000 Da, approximately 3,000 .000 Da, approximately 3,500,000 Da, approximately 4,000,000 Da, approximately 4,500,000 Da or approximately 5,000,000 Da. In still other aspects of this embodiment, a composition comprises crosslinked hyaluronan polymers having an average molecular weight of, 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. In still other aspects of this embodiment, a composition comprises crosslinked hyaluronan polymers having an average molecular weight of, for example, about 1,000,000 Da to about 5,000,000 Da, from about 1,500,000 Da to about 5,000,000 Da , from approximately 2,000,000 Da to approximately 5,000,000 Da, from approximately 2,500,000 Da to approximately 5,000,000 Da, from approximately 2,000,000 Da to approximately 3,000,000 Da, from approximately 2,500,000 Da to approximately 3,500,000 Da or from approximately 2,000,000 Da to approximately 4,000,000 Da.

In yet another embodiment, a composition comprises crosslinked hyaluronan polymers in which crosslinked hyaluronan polymers comprise a combination of both high molecular weight hyaluronan polymers and low molecular weight hyaluronan polymers, for various reasons. In aspects of this embodiment, a composition comprises crosslinked hyaluronan polymers in which crosslinked hyaluronan polymers comprise a combination of both high molecular weight hyaluronan polymers and low molecular weight hyaluronan polymers in a ratio of about 20: 1, approximately 15: 1, approximately 10: 1, approximately 5: 1, approximately 1: 1, approximately 1: 5 approximately 1:10, approximately 1:15 or approximately 1:20.

Aspects of the present invention provide, in part, a hydrogel composition comprising a crosslinked glycosaminoglycan polymer having a degree of crosslinking. As used herein, the term "degree of crosslinking" refers to the percentage of monomeric units of glycosaminoglycan polymer, such as, for example, the hyaluronan disaccharide monomer units that are attached to a crosslinking agent. . The degree of crosslinking is expressed as the ratio of percentage by weight of crosslinking agent with respect to glycosaminoglycan.

Aspects of the present invention provide, in part, a hydrogel composition comprising a non-crosslinked glycosaminoglycan polymer. As used herein, the term "uncrosslinked" refers to a lack of intermolecular bonds that bind the individual glucosaminoglycan polymer molecules, or monomer chains. As such, a non-crosslinked glycosaminoglycan polymer is not linked to any other glycosaminoglycan polymer by an intermolecular bond. In aspects of this embodiment, a composition comprises a non-crosslinked chondroitin sulfate polymer, a non-crosslinked dermatan sulfate polymer, a non-crosslinked keratane sulfate polymer, a non-crosslinked heparan polymer, a non-heparan sulfate polymer crosslinked or an uncrosslinked hyaluronan polymer. Uncrosslinked glycosaminoglycan polymers are water soluble and generally remain fluid in nature. As such, uncrosslinked glycosaminoglycan polymers are often mixed with a hydrogel composition based on a glycosaminoglycan polymer as a lubricant to facilitate the process of extrusion of the composition through a fine needle.

In one embodiment, a composition comprises an uncrosslinked glycosaminoglycan polymer wherein the uncrosslinked glycosaminoglycan polymer is present in an amount sufficient to improve a skin condition disclosed herein. In aspects of this embodiment, a composition comprises an uncrosslinked glycosaminoglycan wherein uncrosslinked glycosaminoglycan is present at a concentration of, 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 15 mg / g, about 16 mg / g, about 17 mg / g, about 18 mg / g, about 19 mg / g, about 20 mg / g, about 40 mg / g or about 60 mg / g. In other aspects of this embodiment, a composition comprises an uncrosslinked glycosaminoglycan wherein uncrosslinked glycosaminoglycan is present at a concentration of, 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 / 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 at least 40 mg / g In still other aspects of this embodiment, a composition comprises an uncrosslinked glycosaminoglycan wherein uncrosslinked glycosaminoglycan is present at a concentration of, for example, at most 1 mg / g, at most 2 mg / g, at most 3 mg / g, maximum 4 mg / g, maximum 5 mg / g, maximum 10 mg / g, maximum 15 mg / g, maximum 20 mg / g or maximum 25 mg / g. In still other aspects of this embodiment, a composition comprises an uncrosslinked glycosaminoglycan wherein uncrosslinked glycosaminoglycan is present at a concentration of, for example, about 1 mg / g at about 60 mg / g, about 10 mg / g at about 40 mg / g, from about 7.5 mg / g to about 19.5 mg / g, from about 8.5 mg / g to about 18.5 mg / g, from about 9.5 mg / g to about 17.5 mg / g, from about 10.5 mg / g to about 16.5 mg / g, from about 11.5 mg / g to about 15.5 mg / g or from about 12.5 mg / g to about 14.5 mg / g.

In one embodiment, a composition comprises uncrosslinked low molecular weight hyaluronan polymers. In aspects of this embodiment, a composition comprises an uncrosslinked hyaluronan having an average molecular weight of, for example, approximately 100,000 Da, approximately 200,000 Da, approximately 300,000 Da, approximately 400,000 Da, approximately 500,000 Da, approximately 600,000 Da, approximately 700,000 Da, approximately 800,000 Da or approximately 900,000 Da. In still other aspects of this embodiment, a composition comprises uncrosslinked hyaluronan polymers having an average molecular weight of, for example, at most 100,000 Da, at most 200,000 Da, at most 300,000 Da, at most 400,000 Da, at most 500,000 It gives a maximum of 600,000 Da, a maximum of 700,000 Da, a maximum of 800,000 Da, a maximum of 900,000 Da or a maximum of 950,000. In still other aspects of this embodiment, a composition comprises uncrosslinked hyaluronan polymers having an average molecular weight of, for example, about 100,000 Da to about 500,000 Da, from about 200,000 Da to about 500,000 Da, from about 300,000 Da to about 500,000 Da, from approximately 400,000 Da to approximately 500,000 Da, from approximately 500,000 Da to approximately 950,000 Da, from approximately 600,000 Da to approximately 950,000 Da, from approximately 700,000 Da to approximately 950,000 Da, from approximately 800,000 Da to approximately 950,000 Da, from approximately 300,000 Da to approximately 600,000 Da, from approximately 300,000 Da to approximately 700,000 Da, from approximately 300,000 Da a approximately 800,000 Da or from approximately 400,000 Da to approximately 700,000 Da.

In another embodiment, a composition comprises uncrosslinked high molecular weight hyaluronan polymers. In aspects of this embodiment, a composition comprises an uncrosslinked hyaluronan having an average molecular weight of, for example, approximately 1,000,000 Da, approximately 1,500,000 Da, approximately 2,000. 000 Da, approximately 2,500,000 Da, approximately 3,000,000 Da, approximately 3,500,000 Da, approximately 4,000,000 Da, approximately 4,500,000 Da or approximately 5,000,000 Da. In other aspects of this embodiment, a composition comprises uncrosslinked hyaluronan polymers having an average molecular weight of, 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. In still other aspects of this embodiment, a composition comprises uncrosslinked hyaluronan polymers having an average molecular weight of, for example, about 1,000,000 Da to about 5,000,000 Da, from about 1,500,000 Da to about 5,000,000 Da, from approximately 2,000,000 Da to approximately 5,000,000 Da, from approximately 2,500,000 Da to approximately 5,000,000 Da, from approximately 2,000,000 Da to approximately 3,000,000 Da, from approximately 2,500,000 Da to approximately 3,500,000 Da or from approximately 2,000,000 Da to approximately 4,000,000 Da. In still other aspects, a composition comprises uncrosslinked hyaluronan polymers having an average molecular weight of, for example, greater than 2,000,000 Da and less than approximately 3,000,000 Da, greater than 2,000,000 Da and less than approximately 3,500 .000 Da, greater than 2,000. 000 Da and less than approximately 4,000,000 Da, greater than 2,000,000 Da and less than approximately 4,500,000 Da, greater than 2,000,000 Da and less than approximately 5,000,000 Da.

In another embodiment, a composition comprises uncrosslinked hyaluronan polymers wherein the uncrosslinked hyaluronan comprises a combination of both high molecular weight hyaluronan polymers and low molecular weight hyaluronan polymers, for various reasons. In aspects of this embodiment, a composition comprises uncrosslinked hyaluronan polymers wherein uncrosslinked hyaluronan polymers comprise a combination of both high molecular weight hyaluronan polymers and low molecular weight hyaluronan polymers in a ratio of approximately 20: 1 , about 15: 1, about 10: 1, about 5: 1, about 1: 1, about 1: 5 about 1:10, about 1:15 or about 1:20.

Aspects of the present invention provide, in part, a hydrogel composition comprising a substantially uncrosslinked glycosaminoglycan polymer. As used herein, the term "substantially uncrosslinked" refers to the presence of uncrosslinked glycosaminoglycan polymers in a composition disclosed herein at a level of at least 90% by weight of the composition, the remaining being comprised at most 10% by weight of the composition by other components including polymers of crosslinked glucosaminoglycan. In aspects of this embodiment, a composition comprises a substantially uncrosslinked chondroitin sulfate polymer, a substantially uncrosslinked dermatan sulfate polymer, a substantially uncrosslinked keratane sulfate polymer, a substantially uncrosslinked heparan polymer, a polymer of substantially uncrosslinked heparan sulfate or a substantially uncrosslinked hyaluronan polymer. In other aspects of this embodiment, a composition comprises an uncrosslinked glycosaminoglycan wherein uncrosslinked glycosaminoglycan represents, for example, about 90% or more by weight, about 91% or more by weight, about 92% or more in weight, approximately 93% or more by weight, approximately 94% or more by weight, approximately 95% or more by weight, approximately 96% or more by weight, approximately 97% or more by weight, approximately 98% or more by weight, or approximately 99% or more, or approximately 100% by weight, of the total glycosaminoglycan present in the composition. In still other aspects of this embodiment, a composition comprises an uncrosslinked glycosaminoglycan wherein uncrosslinked glycosaminoglycan represents, for example, from about 90% to about 100% by weight, from about 93% to about 100% in weight, from about 95% to about 100% by weight, or from about 97% to about 100% by weight, of the total glycosaminoglycan present in the composition.

Aspects of the present invention provide, in part, a hydrogel composition that is essentially free of a crosslinked glycosaminoglycan polymer. As used herein, the term "essentially free" (or "consisting essentially of") refers to a composition in which only trace amounts of crosslinked matrix polymers can be detected. In one aspect of this embodiment, a composition comprises a chondroitin sulfate that is essentially free of a crosslinked chondroitin sulfate polymer, a dermatan sulfate essentially free of a crosslinked dermatan sulfate polymer, a keratane sulfate essentially free of a crosslinked keratane sulfate polymer, a heparan essentially free of a crosslinked heparan polymer, a heparan sulfate essentially free of a crosslinked heparan sulfate polymer, or a hyaluronan sulfate essentially free of a crosslinked hyaluronan polymer.

Aspects of the present invention provide, in part, a hydrogel composition that is totally free of a crosslinked glycosaminoglycan polymer. As used herein, the term "totally free" refers to a composition in which within the detection range of the instrument or procedure being used, crosslinked glycosaminoglycan polymers cannot be detected or their presence cannot be confirmed. In one aspect of this embodiment, a composition comprises a hyaluronan sulfate totally free of a crosslinked hyaluronan polymer.

Aspects of the present invention provide, in part, a hydrogel composition comprising a ratio of crosslinked glycosaminoglycan polymer and uncrosslinked glycosaminoglycan polymer. This ratio of crosslinked and uncrosslinked glycosaminoglycan polymer is also known as gel: fluid ratio. Any gel: fluid ratio is useful in the preparation of the compositions disclosed herein, provided that such reasons produce a composition disclosed herein that improves a skin condition as disclosed herein. Non-limiting examples of gel: fluid ratios include 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.

In aspects of this embodiment, a composition comprises a crosslinked glycosaminoglycan polymer and an uncrosslinked glycosaminoglycan polymer wherein the gel: fluid ratio is, for example, about 0: 100, about 1:99, about 2:98, approximately 3:97, approximately 4:96, approximately 5:95, approximately 6:94, approximately 7:93, approximately 8:92, approximately 9:91, or approximately 10:90. In other aspects of this embodiment, a composition comprises a crosslinked glycosaminoglycan polymer and an uncrosslinked glycosaminoglycan polymer wherein the gel: fluid ratio is, for example, at most 1:99, at most 2:98, at most 3:97, maximum 4:96, maximum 5:95, maximum 6:94, maximum 7:93, maximum 8:92, maximum 9:91 or maximum 10:90. In still other aspects of this embodiment, a composition comprises a crosslinked glycosaminoglycan polymer and an uncrosslinked glycosaminoglycan polymer wherein the gel: fluid ratio is, for example, from about 0: 100 to about 3:97, from about 0 : 100 to about 5:95 or from about 0: 100 to about 10:90.

In other aspects of this embodiment, a composition comprises a crosslinked glycosaminoglycan polymer and an uncrosslinked glycosaminoglycan polymer wherein the gel: fluid ratio is, for example, from 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, approximately 75:25, approximately 80:20, approximately 85:15, approximately 90:10, approximately 95: 5, approximately 98: 2 or approximately 100: 0. In still other aspects of this embodiment, a composition comprises a crosslinked glycosaminoglycan polymer and an uncrosslinked glycosaminoglycan polymer wherein the gel: fluid ratio is, for example, at most 15:85, at most 20:80, as 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 65:35, maximum 70:30, maximum 75:25, maximum 80:20, maximum 85:15, maximum 90:10, maximum 95: 5, maximum 98: 2 or maximum 100: 0. In still other aspects of this embodiment, a composition comprises a crosslinked glycosaminoglycan polymer and an uncrosslinked glycosaminoglycan polymer wherein the gel: fluid ratio is, for example, from about 10:90 to about 70:30, from about 15 : 85 to about 70:30, from about 10:90 to about 55:45, from about 80:20 to about 95: 5, from about 90:10 to about 100: 0, from about 75:25 to about 100: 0 or from about 60:40 to about 100: 0.

Aspects of the present specification provide, in part, a hydrogel composition disclosed herein that may additionally and optionally comprise another agent or combination of agents that provide a beneficial effect when the composition is administered to an individual. Such beneficial agents include, without limitation, an antioxidant, an itching agent, an anti-cellulite agent, an anti-healing agent, an anti-inflammatory agent, an anesthetic agent, an anti-irritant agent, a vasoconstrictor, a vasodilator, an antihemorrhagic agent such as a hemostatic agent. or fibrinolytic agent, a descaling agent, a tension agent, an anti-acne agent, a pigmentation agent, an anti-pigmentation agent or a wetting agent.

The invention provides a hydrogel composition disclosed herein comprising an anesthetic agent as set forth in the claims. The anesthetic agent is a local anesthetic agent of aminoamide, that is, an anesthetic agent that causes reversible local anesthesia and a loss of nociception. The amount of anesthetic agent included in a composition disclosed herein is an amount effective to mitigate the pain experienced by an individual after administration of the composition. As such, the amount of the anesthetic agent included in a composition disclosed herein is between about 0.1% and about 5% by weight of the total composition. Non-limiting examples of local aminoamide anesthetics include articaine, bupivacaine, cincocaine (dibucaine), etidocaine, levobupivacaine, lidocaine (lignocaine), mepivacaine, piperocaine, prilocaine, ropivacaine and trimecaine. A composition disclosed herein may comprise a single anesthetic agent or a plurality of anesthetic agents. A non-limiting example of a local anesthetic combination is lidocaine / prilocaine (EMLA).

Therefore, in one embodiment, a composition disclosed herein comprises a local aminoamide anesthetic and salts thereof. In other aspects of this embodiment, a composition disclosed herein comprises articaine, bupivacaine, cincocaine, etidocaine, levobupivacaine, lidocaine, mepivacaine, piperocaine, prilocaine, ropivacaine, trimecaine, or salts thereof, or any combination thereof. In still other aspects of this embodiment, a composition disclosed herein comprises a combination of lidocaine / prilocaine.

In other aspects of this embodiment, a composition disclosed herein comprises an anesthetic agent in an amount of, for example, about 0.1%, about 0.2%, about 0.3%, about 0 , 4%, approximately 0.5%, approximately 0.6%, approximately 0.7%, approximately 0.8% approximately 0.9%, approximately 1.0%, approximately 2.0 %, approximately 3.0%, approximately 4.0%, approximately 5.0%, approximately 6.0%, approximately 7.0%, approximately 8.0%, approximately 9.0% or approximately 10% by weight of the total composition. In still other aspects, a composition disclosed herein comprises an anesthetic agent in an amount of, 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 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% by weight of the total composition. In still other aspects, a composition disclosed herein comprises an anesthetic agent in an amount of, for example, at most 0.1%, at most 0.2%, at most 0.3%, at most 0.4%, maximum 0.5%, 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%, maximum 7.0% , at most 8.0%, at most 9.0% or at most 10% by weight of the total composition. In additional aspects, a composition disclosed herein comprises an anesthetic agent in an amount of, for example, about 0.1% to about 0.5%, from about 0.1% to about 1.0 %, from about 0.1% to about 2.0%, from about 0.1% to about 3.0%, from about 0.1% to about 4.0%, from about 0.1% to about 5.0%, from about 0.2% to about 0.9%, from about 0.2% to about 1.0%, from about 0.2% to about 2.0%, from about 0, 5% to about 1.0% or from about 0.5% to about 2.0% by weight of the total composition.

The invention provides a hydrogel composition disclosed herein comprising an antioxidant agent as set forth in the claims. The amount of an antioxidant agent included in a composition disclosed herein is an amount effective to reduce or prevent degradation of a composition disclosed herein, such as, for example, enzymatic degradation and / or chemical degradation of the composition. As such, the amount of an antioxidant agent included in a composition disclosed herein is between about 0.1% and about 10% by weight of the total composition. A composition disclosed herein may comprise a single antioxidant agent or a plurality of antioxidant agents, a retinol, coenzyme, idebenone, allopurinol, glutathione, sodium selenite.

Aspects of the present specification provide, in part, a hydrogel composition disclosed herein that may optionally comprise a polyol. As used herein, the term "polyol" is synonymous with "sugar alcohol", "polyhydric alcohol" and "polyalcohol" and refers to a hydrogenated form of carbohydrate, whose carbonyl group (aldehyde or ketone , reducing sugar) has been reduced to a primary or secondary hydroxyl group (eg alcohol), such as, for example, mannitol from mannose, xylitol from xylose and lactitol from lactulose. Polyols have the general formula H (HCHO) n + 1H. Both monosaccharides and disaccharides can form polyols; however, polyols derived from disaccharides are not fully hydrogenated because only one aldehyde group is available for reduction. Non-limiting examples of polyols include glycerol, erythritol, treitol, arabitol, erythritol, ribitol, xylitol, galactitol (or dulcitol), gluctiol (or sorbitol), iditol, inositol, mannitol, isomalt, lactitol, maltitol and polyglycol. Other non-limiting examples of polyols can be found in, for example, Pharmaceutical Dosage Forms and Drug Delivery Systems (Howard C. Ansel et al., Eds., Lippincott Williams & Wilkins Publishers, 7th ed. 1999); Remington: The Science and Practice of Pharmacy (Alfonso R. Gennaro ed., Lippincott, Williams & Wilkins, 20th ed. 2000); Goodman & 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).

Aspects of the present specification provide, in part, a hydrogel composition disclosed herein that may optionally comprise a flavonoid (Table 2). A flavonoid (or bioflavonoid) refers to the class of secondary metabolites that contain polyphenolic ketones and that do not contain ketones found in plants that are well known to have various beneficial antioxidant and biochemical effects. Non-limiting examples of flavonoids include C-methylated flavonoids, O-methylated flavonoids, isoflavonoids, neoflavonoids, flavonolignans, furanoflavonoids, pyranoflavonoids, methylenedioxyfonoonoids, pre-piled flavonoids, aurones, flavones, flavanols, flavanones, flavanones, flavanones, flavanones, flavanones, flavanones, flavanones, flavanones, flavanones, flavanones, flavanones, flavanones, flavanones, flavanones, flavanones, flavanones, flavanones, flavanones, flavanones, flavanones, flavanones, flavanones, flavanones 4-oles, leucoanthocyanidin (flavan-3,4-diols), anthocyanidins and tannins. It is understood that these and other substances known in the art of pharmacology may be included in a composition disclosed herein. See for example, Remington's Pharmaceutical Sciences Mac Publishing Company, Easton, PA 16th edition 1980.

Aurones are compounds derived from 2-benzylidene-1-benzofuran-3-one. Non-limiting examples of aurones include 4,5,6-trihydroxy-aurone, aureusidine, hispidol, leptosidine, maritimetin and sulfuretin.

Three important classes of flavonoids containing ketones are flavones, compounds derived from 2-phenylchromen-4-one (2-phenyl-1,4-benzopirone); isoflavones, compounds derived from 3-phenylchromen-4-one (3-phenyl-1,4-benzopirone); and neoflavones, compounds derived from 4-phenylcoumarin (4-phenyl-1,2-benzopirone) (table 2). Flavones divide themselves into four groups based on the presence or absence of 3-hydroxyl, 2,3-dihydro functional groups: flavones, compounds derived from 2-phenylchromen-4-one, lack both functional groups; flavonols (3-hydroxyflavone), compounds derived from 3-hydroxy-2-phenylchromen-4-one have the 3- hydroxyl group, but lack the 2,3-dihydro group; flavanones, compounds derived from 2,3-dihydro-2-phenylchromen-4- one have the 2,3-dihydro group, but lack the 3-hydroxyl group; and flavanonols (3-hydroxyflavanone or 2,3-dihydroflavonol), compounds derived from 3-hydroxy-2,3-dihydro-2-phenylchromen-4-one have both functional groups.

Non-limiting examples of flavones include acacetin, apiin, apigenin, apigetrin, artoindonesianin P, baicalein, baicalin, chrysin, cinaroside, diosmentin, diosmin, eupatilin, flavoxate, 6-hydroxyfllavone, genkwanina, hydrosmine, luteolin (nepetine, 7- epitin nepetine glycoside), nobiletin, orientine (isoorientin), oroxindin, oroxylin A, roifolin, escutelarein, escutelarin, tangeritine, tectocrisin, tetuine, tricine, veronicastroside, Vitexin (isovitexin) and wogonin. Non-limiting examples of flavonols include 3-hydroxyfllavone, azaleatin, fisetin, galangina, gosipetin, kaempferida, kaempferol, isorramnetine, morina, myricetin, natsudaidaine, paquipodol, quercetin, ramnazine, ramnetine and sophorin. Non-limiting examples of flavanones include butin, eriodictiol, hesperetin, hesperidin, homoeriodictiol, isosakuranetin, naringenin, naringin, pinocembrine, poncirin, sakuranetin, sakuranin and sterubicin. Non-limiting examples of flavanols include taxifoline (dihydroquercetin) and aromadedrin (dihydrokaempferol).

Isoflavonoids include isoflavones and isoflavans (table 2). Non-limiting examples of isoflavonoids include alpinumisoflavone, anagiroidisoflavone A and B, kaleicosin, daidzein, daidzine, derrubone, di-O-methylalpinumisoflavone, formononetin, genistein, genistin, glycytein, ipriflavone, irysteine, iridine, iridine, iridine, iridine, iridine, iridine, iridine, iridine, iridine, iridine, iridine, iridine, iridine, iridine, iridine, iridine, iridine, iridine, iridine, iridone, iridine, iridine, iridine, iridine, iridine, iridine, iridine, iridine, iridine, iridine, iridine, iridine, iridine-5 -O-methylgenisteína, luteona, ononina, orobol, pratenseína, prunetina, pseudobaptigenina, psitectorigenina, puerarina, retusina, tectoridina, tectorigenina and wighteona.

Neoflavonoids include 4-aryl coumarins (neoflavones), 4-arylchroman, dalbergionas and dalbergiquinoles (table 2). Neoflavones are compounds derived from 4-phenylcoumarin (or 4-aryl-coumarin); neoflaven compounds 4-phenylchromen derivatives. Non-limiting examples of neoflavonoids include calofilolide, coutareagenin, dalbergicromen, dalbergine and levelin.

Flavonoids that do not contain ketones include flavan-3-oles and catechins. Flavan-3-olos (flavanols) are a class of flavonoids derived from a skeleton of 2-phenyl-3,4-dihydro-2H-chromen-3-ol. The catechin has two benzene rings (called rings A and B) and a dihydropyran heterocycle (ring C) with a hydroxyl group on carbon 3. Ring A is similar to a resorcinol moiety while ring B is similar to a catechol rest. There are two chiral centers in the molecule at carbons 2 and 3. It therefore has four diastereoisomers. Two of the isomers are in the trans configuration and are called catechin and the other two are in cis configuration and are called epicatechin. Nonlimiting examples of flavonoids which contain ketones flavonoids include afzelechin, artromerina A, artromerina B, catechin, epicatechin, epigallocatechin, epicatechin gallate, epigallocatechin gallate, epigallocatechin gallate, epiafzelechin, fisetinaidol, gallocatechin, gallocatechin gallate, guibourtinidol, meciadanol (3-O-methylcatechin), mesquitol, propyl gallate, robinetinidol, and tearubigin.

Flavan-4-oles (3-deoxiflavonoids) are flavone-derived alcohols derived from 2-phenylchroman-4-ol. Non-limiting examples of flavan-4-oles include apiforol and luteoforol.

Leucoanthocyanidin (flavan-3,4-diols) are compounds derived from 2-phenyl-3,4-dihydro-2H-chromene-3,4-diol. Non-limiting examples of flavan-3,4-diols include leucocyanidin, leucodelfinidine, leucomalvidin, leucopelargonidine, leucopeonidine, leukocobinetinidine and melacacidine.

Anthocyanidins are compounds derived from 2-phenylchromenilio. Non-limiting examples of anthocyanidins include antirrinin, apigeninaidine, aurantinidine, capensinidine, chrysanthenine, columnidine, commelinin, cyanidine, 6-hydroxycyanidine, cyanidine-3- (di-p-coumarylglucoside) -5-glucoside, cyaninealine, cyanaline , fisetinaidine, gesneridine, guibourtinidine, hirsutidine, luteolinidine, malvidin, 5-deoxy-malvidin, malvina, mirtiline, oenin, peonidine, 5-deoxy-peonidine, pelargonidine, petunidine, primulin, protocyanine, protodelfine, pulquelidine, pulquelidine 3-glycoside, pulquelidine 3-ramnoside, robinetinidine, rosinidine, tricetinidine, tulipanin and violdelfine

Tannins with compounds derived from 2-phenylchromenilio. There are three main classes of tannins: hydrolysable tannins; non-hydrolysable tannins (condensed tannins; proanthocyanidins); and pseudotannins.

Hydrolysable tannins are divided into four groups by themselves: oliomer tannins including aglycone tannins and glycoside tannins; elagitannins; galotaninos and unclassified tannins. Non-limiting examples of aglycone tannins include ellagic acid, gallic acid and gallic acid. Non-limiting examples of glycoside tannins include glucose, quinic acid and shikimic acid. Non-limiting examples of elagitannins include castalagina (vescalagina), castalina, casuarictina, casuariina, casuarinina, cornusiina E, grandinina, pedunculagina, punicacorteína C, punigluconina, punicalagina, punicalagina alpha, punicalina, 2-O-galoil-punicalina, estaquiur and telimagrandina II. Non-limiting examples of gallotannins include corylagin, galoylglucose, digaloylglucose, trigaloylglucose, tetragaloylglucose, pentagaloylglucose, hexagaloylglucose, heptagaloylglucose, octagaloylglucose and tannic acid. Non-limiting examples of unclassified tannins include acutisimine A, acutisimine B, quebulágico acid, quebulínico acid, cinnamtanina B1, combreglutinina, geraniina, granatina B, roburina A, roburina B, roburina C, roburina D, roburina E, estaquiurina, tercatina, terflavins A, terflavins B, tergalagina, vescalin, 1,3,4-tri-O-galoylquinic acid, 3,5-di-O-galoyl-shikimic acid and 3,4,5-tri-O-galoylshikimic acid.

Condensed tannins (proanthocyanidins) are essentially polymer chains of flavonoids such as catechins. Non-limiting examples of condensed tannins include proanthocyanidin, prodelfinidine, profisetinaidine, proguibourtinidine and prorobinetidine.

Aspects of the present specification provide, in part, a hydrogel composition disclosed herein that may optionally comprise a phytoalexin. A phytoalexin refers to the class of antimicrobial molecules with antioxidant effects synthesized de novo by plants in response to an incompatible pathogen infection. Non-limiting examples of phytoalexins include resveratrol (3,5,4'-trihydroxy-transestylbeno), alixin (3-hydroxy-5-methoxy-6-methyl-2-pentyl-4H-pyran-4-one), glyceoline, phaseolin and medicarpine.

The present invention provides a hydrogel composition disclosed herein comprising an ascorbic acid agent as set forth in the claims. Ascorbic acid (vitamin C), (5R) - [(1 S) -1,2-dihydroxyethyl] -3,4-dihydroxyfuran-2 (5H) -one, is an oxidation-reduction (redox) catalyst for monosaccharides found both in animals and in plants that reduce, and thereby neutralize, reactive oxygen species such as hydrogen peroxide. Ascorbic acid is interconverted into two unstable ketone tautomers by proton transfer, although the enol form is the most stable. The enol hydroxyl proton is removed. Then a pair of electrons from the resulting oxide anion press to form the ketone in position 2 or 3 and the electrons of the double bond move to position 3 or 2, respectively, forming the carbanion, which collects the proton resulting in two Possible forms: 1-carboxy-2-ketone and 1-carboxy-3-ketone. Non-limiting examples of ascorbic acid agents include ascorbic acid agents including 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 2-glucoside of ascorbic acid (AA2G ™), disodium ascorbyl sulfate, Vitagen.

Aspects of the present specification provide, in part, a hydrogel composition disclosed herein that may optionally comprise a tocopherol and / or a tocotrienol. Tocopherols and tocotrienols comprise a group of antioxidant agents collectively referred to as vitamin E. All are characterized by a chromanol ring, with a hydroxyl group that can donate a hydrogen atom to reduce free radicals and a hydrophobic side chain that allows penetration into biological membranes. Both tocopherols and tocotrienols appear in alpha, beta, gamma and delta forms, determined by the number and position of methyl groups in the chromanol ring. Tocotrienols have the same methyl structure in the ring, but differ from analog tocopherols by the presence of three double bonds in the hydrophobic side chain. The unsaturation of the tails provides tocotrienols only a single stereoisomeric carbon (and therefore two possible isomers by structural formula, one of which occurs naturally), while tocopherols have 3 centers (and eight possible stereoisomers per formula structural, one of which occurs naturally). In general, the unnatural isomers I of tocotrienols lack almost all vitamin activity, and half of the 8 possible isomers of tocopherols (those with 2S chirality at the ring-tail junction) also lack vitamin activity. Of the stereoisomers that retain activity, increasing methylation, especially complete methylation to the alpha form, increases vitamin activity. Non-limiting examples of vitamin E include tocopherols (such as a-tocopherol, p-tocopherol, and-tocopherol and 8-tocopherol), analogs of tocopherols and derivatives (such as tocopheryl acetate, sodium tocopheryl phosphate (STP), polyoxyetanyl sebacate) a-tocopheryl and tocopherol-polyethylene glycol 1000 succinate (TPGS)), tocotrienols (such as a-tocotrienol, ptocotrienol, and-tocotrienol and 8-tocotrienol), tocotrienol analogs and derivatives.

Aspects of the present specification provide, in part, a hydrogel composition disclosed herein that may optionally comprise a lipoic acid (LA). Lipoic acid, (R) -5- (1,2-dithiolan-3-yl) pentanoic acid, is an organo-sulfur compound derived from octanoic acid that contains two neighboring sulfur atoms (at C6 and C8) linked by a disulfide bond and is therefore considered to be oxidized (although any sulfur atom may exist in higher oxidation states). The carbon acid in C6 is chiral and the molecule exists as two enantiomers R - (+) - lipoic acid (RLA) and S - (-) - lipoic acid (SLA) and as a racemic mixture of R / S-lipoic acid (R / S-LA). Only the R - (+) enantiomer exists in nature and is an essential cofactor of four mitochondrial enzyme complexes.

Aspects of the present specification provide, in part, a hydrogel composition disclosed herein that may optionally comprise a melatonin. Melatonin, N-acetyl-5-methoxytryptamine, is a powerful and penetrating antioxidant found in animals, plants and microbes.

Aspects of the present specification provide, in part, a hydrogel composition disclosed herein that may optionally comprise a carotenoid. Carotenoids are organic tetraterpenoid pigments that occur naturally in plant chloroplasts and chromoplasts and some other photosynthetic organisms such as algae, some types of fungi, some bacteria and at least one species of aphids. Structurally, tetraterpenes are biochemically synthesized from eight isoprene units that result in a 40-carbon skeleton that can be terminated by hydrocarbon rings. There are more than 600 known carotenoids; They are divided into two classes, xanthophiles (which contain oxygen) and carotenes (which are purely hydrocarbons, and do not contain oxygen).

Chemically, carotenes, including lycopene, are polyunsaturated hydrocarbons containing 40 carbon atoms per molecule, varying numbers 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 carotenes include a-carotene, p-carotene, and-carotene, 8-carotene, g-carotene, ^ -carotene, lycopene.

Xanthophilic hydrocarbons containing 40 carbon atoms per molecule that either contain hydroxyl groups and / or pairs of hydrogen atoms that are replaced by oxygen atoms. For this reason there are more polar carotenes than purely hydrocarbons. Some xanthophiles are terminated by hydrocarbon rings, at one or both ends of the molecule. Non-limiting examples of xanthophiles include lutein, zeaxanthin, neoxanthin, violaxanthin, a-cryptoxanthin and p-cryptoxanthin.

Aspects of the present specification provide, in part, a hydrogel composition disclosed herein that may optionally comprise a vitamin A. Vitamin A includes retinol, retinal and retinoic acid and the different geometric isomers of retinol [(2E, 4E, 6E, 8E) -3,7-dimethyl-9- (2,6,6-trimethylcyclohex-1-enyl) nona -2,4,6,8-tetraen-1-ol], retinal and retinoic acid resulting from either a trans or cis configuration of four of the five double bonds found in the polyene chain. Non-limiting examples of vitamin A include retinol, retinal, retinoic acid, retinol isomers, retinal isomers, retinoic acid isomers, tretinoin, isotretinoin and retinyl palmitate.

In one embodiment, a composition disclosed herein comprises an antioxidant agent in an amount sufficient to reduce or prevent the degradation of a glycosaminoglycan polymer. In aspects of this embodiment, a composition disclosed herein comprises a polyol, a flavonoid, a phytoalexin, an ascorbic acid agent, a tocopherol, a tocotrienol, a lipoic acid, a melatonin, a carotenoid, an analogue or derivative thereof, or any combination thereof.

In other aspects of this embodiment, a composition disclosed herein comprises an antioxidant agent in an amount of, for example, about 0.01%, about 0.1%, about 0.2%, about 0 , 3%, approximately 0.4%, approximately 0.5%, approximately 0.6%, approximately 0.7%, approximately 0.8% approximately 0.9%, approximately 1.0 %, approximately 2.0%, approximately 3.0%, approximately 4.0%, approximately 5.0%, approximately 6.0%, approximately 7.0%, approximately 8.0%, approximately 9.0% or approximately 10% by weight of the total composition In still other aspects, a composition disclosed herein comprises an antioxidant agent in an amount of, 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 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% by weight of the total composition. In still other aspects, a composition disclosed herein comprises an antioxidant agent in an amount of, for example, at most 0.1%, at most 0.2%, at most 0.3%, at most 0.4%, maximum 0.5%, 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%, maximum 7.0% , at most 8.0%, at most 9.0% or at most 10% by weight of the total composition. In additional aspects, a composition disclosed herein comprises an antioxidant agent in an amount of, for example, about 0.1% to about 0.5%, from about 0.1% to about 1.0 %, from about 0.1% to about 2.0%, from about 0.1% to about 3.0%, from about 0.1% to about 4.0%, from about 0.1% to about 5.0%, from about 0.2% to about 0.9%, from about 0.2% to about 1.0%, from about 0.2% to about 2.0%, from about 0, 5% to about 1.0% or from about 0.5% to about 2.0% by weight of the total composition.

Aspects of the present specification provide, in part, a hydrogel composition disclosed herein that may optionally comprise a vasoconstrictor agent. The amount of a vasoconstrictor agent included in a composition disclosed herein is an amount effective to reduce, stop and / or prevent bleeding experienced by an individual with or after administration of the composition. Non-limiting examples of vasoconstrictor agents include a1 receptor agonists such as 2- (1-nanaphthylmethyl) -2-imidazoline (nafazolin), (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 (methylnorepinephrine), 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 (oxymetazoline), (R) -3 - [- 1-hydroxy-2- (methylamino) ethyl] phenol (phenylephrine or neosinephrine), (R *, R *) - 2-methylamino-1-phenylpropan-1-ol (pseudoephedrine), 4 - [1-hydroxy-2- (methylamino) ethyl] phenol (synephrine or oxedrine), 2 - [(2-cyclopropylphenoxy) methyl] -4,5-dihydro-1H-imidazole (cirazoline), 2 - [(4- tert-butyl-2,6-dimethylphenyl) methyl] -4,5-dihydro-1H-imidazole (xylometazoline), analogs or derivatives thereof, and any combination thereof.

A composition disclosed herein may comprise a single vasoconstrictor agent or a plurality of vasoconstrictor agents.

Therefore, in one embodiment, a composition disclosed herein comprises a vasoconstrictor agent. In aspects of this embodiment, a composition disclosed herein comprises an a1 receptor agonist. In aspects of this embodiment, a composition disclosed herein comprises nafazolin, epinephrine, methoxamine, methylnorepinephrine, norepinephrine, oxymetazoline, phenylephrine, pseudoephedrine, synephrine, cirazoline, xylometazoline, an analogue or a derivative thereof, or any combination thereof. same.

In other aspects of this embodiment, a composition disclosed herein comprises a vasoconstrictor agent in an amount of, for example, about 0.001%, about 0.01%, about 0.1%, about 0.2 %, approximately 0.3%, approximately 0.4%, approximately 0.5%, approximately 0.6%, approximately 0.7%, approximately 0.8% approximately 0.9%, about 1.0%, about 2.0%, approximately 3.0%, approximately 4.0%, approximately 5.0%, approximately 6.0%, approximately 7.0%, approximately 8.0%, approximately 9.0% or approximately 10% by weight of the total composition.

In still other aspects, a composition disclosed herein comprises a vasoconstrictor agent in an amount of, 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 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% by weight of the total composition. In still other aspects, a composition disclosed herein comprises a vasoconstrictor agent in an amount of, for example, a maximum of 0.1%, a maximum of 0.2%, a maximum of 0.3%, a maximum 0.4%, maximum 0.5%, maximum 0.6%, maximum 0.7%, maximum 0.8% maximum 0.9%, maximum 1, 0%, as maximum 2.0%, maximum 3.0%, maximum 4.0%, maximum 5.0%, maximum 6.0%, maximum 7.0%, at most 8.0%, at most 9.0% or at most 10% by weight of the total composition. In additional aspects, a composition disclosed herein comprises a vasoconstrictor agent in an amount of, for example, about 0.1% to about 0.5%, from about 0.1% to about 1.0 %, from about 0.1% to about 2.0%, from about 0.1% to about 3.0%, about 0.1% to about 4.0%, from about 0.1% to about 5.0%, from about 0.2% to about 0.9%, from about 0.2% to about 1.0%, from about 0.2% to about 2.0%, from about 0, 5% to about 1.0% or from about 0.5% to about 2.0% by weight of the total composition.

In another embodiment, a composition disclosed herein does not comprise a vasoconstrictor agent.

Aspects of the present specification provide, in part, a hydrogel composition disclosed herein that may optionally comprise an antihemorrhagic agent. An antihemorrhagic agent includes hemostatic agents and antifibrinolytic agents. A hemostatic agent is a molecule that acts by reducing, stopping and / or preventing bleeding in the case of a broken blood vessel. One class of hemostatic agents is vitamin K and its analogues or derivatives. Vitamin K and its derivatives of 2-methyl-1,4-naphthoquinone derivatives is a group of lipophilic, hydrophobic vitamins that are necessary for the post-translational modification of certain proteins, mainly required for blood coagulation but also involved in metabolic pathways in bone and other tissue. The function of vitamin K in the cell is to convert the glutamate of the proteins into gamma-carboxyglutamate (gla). An antifibrinolytic agent is a molecule that acts by promoting the formation of blood clots. Antifibrinolytics include aminocaproic acid (g-aminocaproic acid) and tranexamic acid. These lysine-like drugs interfere with the formation of plasmin fibrinolytic enzyme from its plasminogen precursor by plasminogen activators (mainly t-PA and u-PA). These drugs reversibly block the lysine binding sites of enzymes or plasminogen and therefore stop plasmin formation thereby preventing fibrinolysis and the breakdown of a blood clot. The amount of an antihemorrhagic agent included in a composition disclosed herein is an amount effective to reduce, stop and / or prevent bleeding experienced by an individual with or after administration of the composition. Ethamsylate (dicineno / dicinone) is another hemostatic agent. Non-limiting examples of antihemorrhagic agents include hemostatic agents such as chitosan, ethamsylate, desmopressin, a vitamin K or a vitamin K analogue, such as, for example, a vitamin K1 (phylloquinone, phytomenadione or phytonadione), a vitamin K2 (menaquinone or menatetrenone), a vitamin K3 (menadione), a vitamin K4 (menadiol), a vitamin K5 (4-amino-2-methyl-1-naphthol hydrochloride), a vitamin K6, a vitamin K7, a vitamin Ka, a vitamin Kg and a vitamin K10, antifibrinolytic agents such as aminocaproic acid (gaminocaproic acid), tranexamic acid, serpins such as aprotinin, a1-antitrypsin, C1 inhibitor, camostat, analogues or derivatives thereof, and any combination thereof. A composition disclosed herein may comprise a single antihemorrhagic agent or a plurality of antihemorrhagic agents.

Therefore, in one embodiment, a composition disclosed herein comprises an antihemorrhagic agent. In aspects of this embodiment, a composition disclosed herein comprises a hemostatic agent or an antifibrinolytic agent. In aspects of this embodiment, a composition disclosed herein comprises vitamin K or a vitamin K analog, such as, for example, a vitamin K1, a vitamin K2, a vitamin K3, a vitamin K4, a vitamin K5 , a vitamin K6, a vitamin K7 , a vitamin Ka, a vitamin Kg and a vitamin K10, g-aminocaproic acid, tranexamic acid, serpins such as aprotinin, a1-antitrypsin, C1 inhibitor, camostat, an analogue or a derivative thereof, or any combination thereof.

In other aspects of this embodiment, a composition disclosed herein comprises an antihemorrhagic agent in an amount of, for example, about 0.1%, about 0.2%, about 0.3%, about 0, 4%, approximately 0.5%, approximately 0.6%, approximately 0.7%, approximately 0.8% approximately 0.9%, approximately 1.0%, approximately 2.0% , about 3.0%, about 4.0%, approximately 5.0%, approximately 6.0%, approximately 7.0%, approximately 8.0%, approximately 9.0% or approximately 10% by weight of the total composition. In still other aspects, a composition disclosed herein comprises antihemorrhagic agent in an amount of, 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 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% by weight of the total composition. In still other aspects, a composition disclosed herein comprises an antihemorrhagic agent in an amount of, for example, a maximum of 0.1%, a maximum of 0.2%, a maximum of 0.3%, a maximum of 0.4%, maximum 0.5%, maximum 0.6%, maximum 0.7%, maximum 0.8% maximum 0.9%, maximum 1.0 %, at most 2.0%, at most 3.0%, at most 4.0%, at most 5.0%, at most 6.0%, at most 7.0%, at most 8.0%, at most 9.0% or at most 10% by weight of the total composition. In additional aspects, a composition disclosed herein comprises antihemorrhagic agent in an amount of, for example, about 0.1% to about 0.5%, from about 0.1% to about 1.0%, from about 0.1% to about 2.0%, from about 0 , 1% to approximately 3.0%, from approximately 0.1% to approximately 4.0%, from approximately 0.1% to approximately 5.0%, from about 0.2% to about 0.9%, from about 0.2% to about 1.0%, from about 0.2% to about 2.0%, from about 0, 5% to about 1.0% or from about 0.5% to about 2.0% by weight of the total composition.

In another embodiment, a composition disclosed herein does not comprise antihemorrhagic agent. Aspects of the present specification provide, in part, a hydrogel composition disclosed herein that may optionally comprise an itching agent. The amount of an itching agent included in a composition disclosed herein is an amount effective to mitigate an itching response experienced by an individual following administration of the composition. Non-limiting examples of itching agents include methylsulfonylmethane, sodium bicarbonate, calamine, allantoin, kaolin, peppermint, tea tree oil, camphor, menthol, hydrocortisone, analogs or derivatives thereof, and any combination thereof. A composition disclosed herein may comprise a single agent against itching or a plurality of agents against itching.

Therefore, in one embodiment, a composition disclosed herein comprises an itching agent. In aspects of this embodiment, a composition disclosed herein comprises methylsulfonylmethane, sodium bicarbonate, calamine, allantoin, kaolin, mint, tea tree oil, camphor, menthol, hydrocortisone, an analogue or derivative thereof, or any combination thereof.

In other aspects of this embodiment, a composition disclosed herein comprises an itching agent in an amount of, for example, about 0.1%, about 0.2%, about 0.3%, about 0.4%, approximately 0.5%, approximately 0.6%, approximately 0.7%, approximately 0.8% approximately 0.9%, approximately 1.0%, approximately 2 , 0%, approximately 3.0%, approximately 4.0%, approximately 5.0%, approximately 6.0%, approximately 7.0%, approximately 8.0%, approximately 9.0% or approximately 10% by weight of the total composition. In still other aspects, a composition disclosed herein comprises an itching agent in an amount of, 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 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% by weight of the total composition. In still other aspects, a composition disclosed herein comprises an itching agent in an amount of, for example, at most 0.1%, at most 0.2%, at most 0.3%, maximum 0.4%, maximum 0.5%, 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%, maximum 7 , 0%, at most 8.0%, at most 9.0% or at most 10% by weight of the total composition. In additional aspects, a composition disclosed herein comprises an itching agent in an amount of, for example, about 0.1% to about 0.5%, from about 0.1% to about 1 , 0%, from about 0.1% to about 2.0%, from about 0.1% to about 3.0%, from about 0.1% to about 4.0%, of about 0.1% to about 5.0%, from about 0.2% to about 0.9%, from about 0.2% to about 1.0%, from about 0.2% to about 2.0%, from about 0, 5% to about 1.0% or from about 0.5% to about 2.0% by weight of the total composition.

In another embodiment, a composition disclosed herein does not comprise an itching agent. Aspects of the present specification provide, in part, a hydrogel composition disclosed herein that may optionally comprise an anti-cellulite agent. The amount of an anti-cellulite agent included in a composition disclosed herein is an amount effective to mitigate a fatty deposit experienced by an individual after administration of the composition. Non-limiting examples of anti-cellulite agents include forskolin, xanthine compounds such as, but not limited to, caffeine, theophylline, theobromine, and aminophylline, analogs or derivatives thereof, and any combination thereof. A composition disclosed herein may comprise a single anti-cellulite agent or a plurality of anti-cellulite agents.

Therefore, in one embodiment, a composition disclosed herein comprises an anti-cellulite agent. In aspects of this embodiment, a composition disclosed herein comprises forskolin, a xanthine compound, an analogue or derivative thereof, or any combination thereof. In other aspects of this embodiment, a composition disclosed herein comprises an agent. anti-cellulite in an amount of, for example, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6% , approximately 0.7%, approximately 0.8%, approximately 0.9%, approximately 1.0%, approximately 2.0%, approximately 3.0%, approximately 4.0%, approximately 5.0%, approximately 6.0%, approximately 7.0%, approximately 8.0%, approximately 9.0% or approximately 10% by weight of the total composition. In still other aspects, a composition disclosed herein comprises an anti-cellulite agent in an amount of, 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 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% by weight of the total composition. In still other aspects, a composition disclosed herein comprises an anti-cellulite agent in an amount of, for example, at most 0.1%, at most 0.2%, at most 0.3%, at most 0.4%, maximum 0.5%, 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%, maximum 7.0% , at most 8.0%, at most 9.0% or at most 10% by weight of the total composition. In additional aspects, a composition disclosed herein comprises an anti-cellulite agent in an amount of, for example, about 0.1% to about 0.5%, from about 0.1% to about 1.0 %, from about 0.1% to about 2.0%, from about 0.1% to about 3.0%, from about 0.1% to about 4.0%, from about 0.1% to about 5.0%, from about 0.2% to about 0.9%, from about 0.2% to about 1.0%, from about 0.2% to about 2.0%, from about 0, 5% to about 1.0%, or from about 0.5% to about 2.0% by weight of the total composition.

In another embodiment, a composition disclosed herein does not comprise an anti-cellulite agent.

Aspects of the present specification provide, in part, a hydrogel composition disclosed herein that may optionally comprise an anti-healing agent. The amount of an anti-healing agent included in a composition disclosed herein is an amount effective to mitigate a healing response experienced by an individual following administration of the composition. Non-limiting examples of anti-healing agents include IFN-y, fluorouracil, poly (lactic-co-glycolic acid), methylated polyethylene glycol, poly (lactic acid), polyethylene glycol, analogs or derivatives thereof, and any combination thereof. A composition disclosed herein may comprise a single anti-healing agent or a plurality of anti-healing agents.

Therefore, in one embodiment, a composition disclosed herein comprises an anti-healing agent. In aspects of this embodiment, a composition disclosed herein comprises IFN-y, fluorouracil, poly (lactic-co-glycolic acid), methylated polyethylene glycol, poly (lactic acid), polyethylene glycol, an analogue or derivative thereof, or Any combination thereof.

In other aspects of this embodiment, a composition disclosed herein comprises an anti-healing agent in an amount of, for example, about 0.1%, about 0.2%, about 0.3%, about 0 , 4%, approximately 0.5%, approximately 0.6%, approximately 0.7%, approximately 0.8% approximately 0.9%, approximately 1.0%, approximately 2.0 %, approximately 3.0%, approximately 4.0%, approximately 5.0%, approximately 6.0%, approximately 7.0%, approximately 8.0%, approximately 9.0% or approximately 10% by weight of the total composition. In still other aspects, a composition disclosed herein comprises an anti-healing agent in an amount of, 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 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% by weight of the total composition. In still other aspects, a composition disclosed herein comprises an anti-healing agent in an amount of, for example, at most 0.1%, at most 0.2%, at most 0.3%, at most 0.4%, maximum 0.5%, 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%, maximum 7.0% , at most 8.0%, at most 9.0% or at most 10% by weight of the total composition. In additional aspects, a composition disclosed herein comprises an anti-healing agent in an amount of, for example, about 0.1% to about 0.5%, from about 0.1% to about 1.0 %, from about 0.1% to about 2.0%, from about 0.1% to about 3.0%, from about 0.1% to about 4.0%, from about 0.1% to about 5.0%, from about 0.2% to about 0.9%, from about 0.2% to about 1.0%, from about 0.2% to about 2.0%, from about 0, 5% to about 1.0% or from about 0.5% to about 2.0% by weight of the total composition.

In another embodiment, a composition disclosed herein does not comprise an anti-healing agent.

Aspects of the present specification provide, in part, a hydrogel composition disclosed herein that may optionally comprise an anti-inflammatory agent. The amount of an anti-inflammatory agent included in a composition disclosed herein is an amount effective to mitigate an inflammatory and / or irritating response experienced by an individual following administration of the composition. Non-limiting examples of anti-inflammatory agents include dexamethasone, prednisolone, corticosterone, budesonide, estrogen, sulfasalazine, mesalamine, cetirizine, diphenhydramine, antipyrine, methyl salicylate, loratadine, thymol (2-isopropyl-5-methylpropyl). -2-methylphenol), bisabolol (6-methyl-2- (4-methylcyclohex-3-enyl) hept-5-en-2-ol), allantoin, eucalyptol, phenazone (antipyrine), propifenazone, and non-steroidal anti-inflammatory drugs (NSAID) including, without limitation, propionic acid derivatives such as ibuprofen, naproxen, fenoprofen, ketoprofen, flurbiprofen and oxaprozin; acetic acid derivatives such as indomethacin, sulindac, etodolac, ketorolac, diclofenac and nabumetone; Enolic acid derivatives (oxicam) such as piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, isoxicam; derivatives of phenolic acid such as mefenamic acid, meclofenamic acid, flufenamic acid and tolfenamic acid; and selective COX-2 inhibitors (coxibs) such as celecoxib, rofecoxib, valdecoxib, parecoxib, lumiracoxib, etoricoxib and firocoxib, analogs or derivatives thereof, and any combination thereof. A composition disclosed herein may comprise a single anti-inflammatory agent or a plurality of anti-inflammatory agents.

Therefore, in one embodiment, a composition disclosed herein comprises an anti-inflammatory agent. In aspects of this embodiment, a composition disclosed herein comprises dexamethasone, prednisolone, corticosterone, budesonide, estrogen, sulfasalazine, mesalamine, cetirizine, diphenhydramine, antipyrine, methyl salicylate, loratadine, thymol (2-isopropyl-5-methylphenol) , carvacrol (5-isopropyl-2-methylphenol), bisabolol (6-methyl-2- (4-methylcyclohex-3-enyl) hept-5-en-2-ol), allantoin, eucalyptol, phenazone (antipyrine), propifenazone , an NSAID, an analogue or derivative thereof, or any combination thereof.

In other aspects of this embodiment, a composition disclosed herein comprises an anti-inflammatory agent in an amount of, for example, at least about 0.001%, at least about 0.01%, about 0.1%, about 0.2%, approximately 0.3%, approximately 0.4%, approximately 0.5%, approximately 0.6%, approximately 0.7%, approximately 0.8% approximately 0 , 9%, approximately 1.0%, approximately 2.0%, approximately 3.0%, approximately 4.0%, approximately 5.0%, approximately 6.0%, approximately 7.0%, approximately 8.0%, approximately 9.0% or about 10% by weight of the total composition.

In still other aspects, a composition disclosed herein comprises an anti-inflammatory agent in an amount of, 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 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% by weight of the total composition. In still other aspects, a composition disclosed herein comprises an anti-inflammatory agent in an amount of, for example, at most 0.1%, at most 0.2%, at most 0.3%, at most 0.4%, maximum 0.5%, 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%, maximum 7.0% , at most 8.0%, at most 9.0% or at most 10% by weight of the total composition. In additional aspects, a composition disclosed herein comprises an anti-inflammatory agent in an amount of, for example, about 0.1% to about 0.5%, from about 0.1% to about 1.0 %, from about 0.1% to about 2.0%, from about 0.1% to about 3.0%, from about 0.1% to about 4.0%, from about 0.1% to about 5.0%, from about 0.2% to about 0.9%, from about 0.2% to about 1.0%, from about 0.2% to about 2.0%, from about 0, 5% to about 1.0% or from about 0.5% to about 2.0% by weight of the total composition.

Aspects of the present specification provide, in part, a hydrogel composition disclosed herein that presents a complex module, an elastic module, a viscous module and / or a tan 8. The compositions as disclosed herein are viscoelastic because the composition has an elastic component (similar to a solid such as, for example, crosslinked glucosaminoglycan polymers) and a viscous component (similar to a liquid such as, for example, non-crosslinked glycosaminoglycan polymers or a carrier phase) when a force (tension, deformation) is applied. The rheological attribute that describes this property is the complex module (G *), which defines the total resistance of a deformation composition. The complex module is a complex number with a real and an imaginary part: G * = G '+ iG ”. The absolute value of G * is Abs (G *) = Sqrt (G'2 + G ”2). The complex module can be defined as the sum of the elastic module (G ') and the viscous module (G ”). Falcone, et al., Temporary Polysaccharide Dermal Fillers: A Model for Persistence Based on Physical Properties, Dermatol Surg. 35 (8): 1238-1243 (2009); Tezel, cited above, 2008; Kablik, cited above, 2009; Beasley, cited above, 2009.

The elastic modulus or modulus of elasticity refers to the ability of a hydrogel material to resist

deformation or, conversely, the tendency of an object to deform non-permanently when a

strength to it. The elastic module characterizes the firmness of a composition and is also known as the modulus of

storage because it describes the storage of energy from the movement of the composition. He

elastic modulus describes the interaction between elasticity and resistance (G '= tension / deformation) and, as such,

provides a quantitative measurement of the hardness or softness of a composition. The elastic modulus of an object

It is defined as the slope of its stress-strain curve in the region of elastic deformation: X =

tension / deformation, where X is the elastic modulus in pascals; tension is the force that causes the

deformation divided by the area to which the force is applied; and deformation is the reason for the change caused

by the tension with respect to the original state of the object. Although depending on the speed at which the

strength, a more rigid composition will have a superior elastic modulus and will need more force to deform

the material a given distance, such as, for example, an injection. The specification of how to measure

Tensions, including directions, allow many types of elastic modules to be defined. The three modules

Main elastics are the tensile module, shear module and compressibility module.

The viscous module is also known as the loss module because it describes the energy lost as

viscous dissipation. So 8 is the reason for the viscous module and the elastic module, so 8 = G ”/ G '. Falcone, cited

previously, 2009. For values of tan 8 disclosed in this specification, a tan 8 is obtained

starting from the dynamic module at a frequency of 1 Hz. A lower tan 8 corresponds to a more rigid composition,

harder or more elastic.

In another embodiment, a hydrogel composition disclosed herein has an elastic modulus.

In aspects of this embodiment, a hydrogel composition has an elastic modulus of, for example,

approximately 25 Pa, approximately 50 Pa, approximately 75 Pa, approximately 100 Pa

approximately 125 Pa, approximately 150 Pa, approximately 175 Pa, approximately 200 Pa

approximately 250 Pa, approximately 300 Pa, approximately 350 Pa, approximately 400 Pa

approximately 450 Pa, approximately 500 Pa, approximately 550 Pa, approximately 600 Pa

approximately 650 Pa, approximately 700 Pa, approximately 750 Pa, approximately 800 Pa

approximately 850 Pa, approximately 900 Pa, approximately 950 Pa, approximately 1,000 Pa

approximately 1,200 Pa, approximately 1,300 Pa, approximately 1,400 Pa, approximately 1,500 Pa,

approximately 1,600 Pa, approximately 1700 Pa, approximately 1800 Pa, approximately 1900 Pa,

approximately 2,000 Pa, approximately 2,100 Pa, approximately 2,200 Pa, approximately 2,300 Pa,

approximately 2,400 Pa or approximately 2,500 Pa. In other aspects of this embodiment, a composition

Hydrogel has an elastic modulus of, for example, at least 25 Pa, at least 50 Pa, at least 75 Pa, at

at least 100 Pa, at least 125 Pa, at least 150 Pa, at least 175 Pa, at least 200 Pa, at least 250 Pa, at least

300 Pa, at least 350 Pa, at least 400 Pa, at least 450 Pa, at least 500 Pa, at least 550 Pa, at least 600 Pa,

at least 650 Pa, at least 700 Pa, at least 750 Pa, at least 800 Pa, at least 850 Pa, at least 900 Pa, at

at least 950 Pa, at least 1,000 Pa, at least 1,200 Pa, at least 1,300 Pa, at least 1,400 Pa, 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 2,500 Pa. In still other aspects of this

embodiment, a hydrogel composition has an elastic modulus of, for example, a maximum of 25 Pa, as

maximum 50 Pa, maximum 75 Pa, maximum 100 Pa, maximum 125 Pa, maximum 150 Pa, as

maximum 175 Pa, maximum 200 Pa, maximum 250 Pa, maximum 300 Pa, maximum 350 Pa, as

maximum 400 Pa, maximum 450 Pa, maximum 500 Pa, maximum 550 Pa, maximum 600 Pa, as

650 Pa maximum, 700 Pa maximum, 750 Pa maximum, 800 Pa maximum, 850 Pa maximum, as

maximum 900 Pa, maximum 950 Pa, maximum 1,000 Pa, maximum 1,200 Pa, maximum 1,300 Pa,

a maximum of 1,400 Pa, a maximum of 1,500 Pa or a maximum of 1,600 Pa. In still other aspects of this

embodiment, a hydrogel composition has an elastic modulus of, for example, approximately 25 Pa a

about 150 Pa, from about 25 Pa to about 300 Pa, from about 25 Pa to about 500 Pa, from about 25 Pa to about 800 Pa, from about 125 Pa to

approximately 300 Pa, from approximately 125 Pa to approximately 500 Pa, from approximately 125 Pa to approximately 800 Pa, from approximately 500 Pa to approximately 1,600 Pa, from approximately 600 Pa to approximately 1,600 Pa, from approximately 700 Pa to approximately 1,600 Pa, from approximately 800

Pa at approximately 1,600 Pa, from approximately 900 Pa to approximately 1,600 Pa, from approximately

1,000 Pa at approximately 1,600 Pa, from approximately 1,100 Pa to approximately 1,600 Pa, from

approximately 1,200 Pa to approximately 1,600 Pa, from approximately 500 Pa to approximately

2,500 Pa, from approximately 1,000 Pa to approximately 2,500 Pa, from approximately 1,500 Pa a

approximately 2,500 Pa, from approximately 2,000 Pa to approximately 2,500 Pa, from approximately

1,300 Pa to approximately 1,600 Pa, from approximately 1,400 Pa to approximately 1,700 Pa, from

approximately 1,500 Pa to approximately 1,800 Pa, from approximately 1,600 Pa to approximately

1,900 Pa, from approximately 1,700 Pa to approximately 2,000 Pa, from approximately 1,800 Pa a

approximately 2,100 Pa, from approximately 1,900 Pa to approximately 2,200 Pa, from approximately

2,000 Pa at approximately 2,300 Pa, from approximately 2,100 Pa to approximately 2,400 Pa or from

approximately 2,200 Pa to approximately 2,500 Pa.

In another embodiment, a hydrogel composition disclosed herein has a viscous module.

In aspects of this embodiment, a hydrogel composition has a viscous modulus of, 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 , approximately 90 Pa, approximately 100 Pa, approximately 150 Pa, approximately 200 Pa, approximately 250 Pa, approximately 300 Pa, approximately 350 Pa, approximately 400 Pa, approximately 450 Pa, approximately 500 Pa, approximately 550 Pa, approximately 600 Pa, approximately 650 Pa or approximately 700 Pa. In other aspects of this embodiment, a hydrogel composition has a viscous modulus of, for example, a maximum of 10 Pa, a maximum of 20 Pa, a maximum of 30 Pa, a maximum of 40 Pa, a maximum of 50 Pa, a maximum of 60 Pa, maximum 70 Pa, maximum 80 Pa, maximum 90 Pa, maximum 100 Pa, maximum 150 Pa, maximum 200 Pa, maximum 250 Pa, maximum 300 Pa, maximum 350 Pa, maximum 400 Pa, a maximum of 450 Pa, a maximum of 500 Pa, a maximum of 550 Pa, 600 Pa maximum, 650 Pa maximum or 700 Pa maximum. In still other aspects of this embodiment, a hydrogel composition has a viscous modulus of, for example, about 10 Pa to about 30 Pa, from about 10 Pa to about 50 Pa, from about 10 Pa to about 100 Pa, from about 10 Pa at about 150 Pa, from about 70 Pa to about 100 Pa, from about 50 Pa to about 350 Pa, from about 150 Pa to about 450 Pa, from about 250 Pa to about 550 Pa, from about 350 Pa to about 700 Pa, from about 50 Pa to about 150 Pa, from about 100 Pa to about 200 Pa, from about 150 Pa to about 250 Pa, from about 200 Pa to approximately 300 Pa, from approximately 250 Pa to approximately 350 Pa, from approximately 300 Pa to approximately 400 Pa, from approximately 350 Pa to approximately 450 Pa, from about 400 Pa to about 500 Pa, from about 450 Pa to about 550 Pa, from about 500 Pa to about 600 Pa, from about 550 Pa to about 650 Pa or from about 600 Pa to about 700 Pa.

In another embodiment, a hydrogel composition disclosed herein has a tan 8. In aspects of this embodiment, a hydrogel composition has a tan 8 of, 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 1.3, about 1.4, about 1.5, about 1.6, about 1, 7, about 1.8, about 1.9, approximately 2.0, approximately 2.1, approximately 2.2, approximately 2.3, approximately 2.4 or approximately 2.5. In other aspects of this embodiment, a hydrogel composition has a tan of 8, for example, at most 0.1, at most 0.2, at most 0.3, at most 0.4, at most 0.5, maximum 0.6, maximum 0.7, maximum 0.8, maximum 0.9, maximum 1.0, maximum 1.1, maximum 1.2, maximum 1.3, maximum 1.3 1.4, maximum 1.5, maximum 1.6, maximum 1.7, maximum 1.8, maximum 1.9, maximum 2.0, maximum 2.1, maximum 2, 2, maximum 2.3, maximum 2.4 or maximum 2.5. In still other aspects of this embodiment, a hydrogel composition has a tan 8 of, for example, about 0.1 to about 0.3, from about 0.3 to about 0.5, from about 0.5 to about 0 , 8, from about 1.1 to about 1.4, from about 1.4 to about 1.7, from about 0.3 to about 0.6, from about 0.1 to about 0.5, from about 0 , 5 to about 0.9, from about 0.1 to about 0.6, from about 0.1 to about 1.0, from about 0.5 to about 1.5, from about 1.0 to about 2.0 or from about 1.5 to about 2.5

Aspects of the present specification provide, in part, a hydrogel composition disclosed herein that has transparency and / or translucency. Transparency (also called clarity or diafanity) is the physical property of allowing light to pass through a material, while translucency (also called translucency or translucency quality) also allows light to diffuse through it. The opposite property is opacity. Transparent materials are clear, while translucent ones cannot be seen clearly. The silk fibroin hydrogels disclosed herein may or may not have optical properties such as transparency and translucency. In certain cases, for example, filling of surface lines, it would be an advantage to have an opaque hydrogel. In other cases such as developing a lens or a "mood" to fill the eye, it would be an advantage to have a translucent hydrogel. These properties could be modified by affecting the structural distribution of the hydrogel material.

Factors used to control the optical properties of a hydrogel include, without limitation, polymer concentration, gel crystallinity and hydrogel homogeneity.

When light meets a material, it can interact with it in several different ways. These interactions depend on the nature of the light (its wavelength, frequency, energy, etc.) and the nature of the material. Light waves interact with an object through some combination of reflection, and transmittance with refraction. As such, an optically transparent material allows much of the light that falls on it to be transmitted, reflecting little light. Materials that do not allow light transmission are called optically opaque or simply opaque.

In one embodiment, a hydrogel composition disclosed herein is optically transparent.

In aspects of this embodiment, a hydrogel composition transmits, for example, about 75% of the

light, about 80% of the light, about 85% of the light, about 90% of the light, about 95% of the light or about 100% of the light. In other aspects of this embodiment, a hydrogel composition transmits, for example, at least 75% of the light, at least 80% of the light, at least the

85% of the light, at least 90% of the light or at least 95% of the light. In still other aspects of this embodiment, a hydrogel composition transmits, for example, from about 75% to about 100% of the light, from about 80% to about 100% of the light, from about 85% at about 100% of the light, from about 90% to about 100% of the light or from about 95% to about 100% of the light.

In another embodiment, a hydrogel composition disclosed herein is optically opaque. In aspects of this embodiment, a hydrogel composition transmits, for example, about 5% of the light, about 10% of the light, about 15% of the light, about 20% of the light, about 25 % of the light, about 30% of the light, about 40% of the light, about 45% of the light, about 55% of the light, about 60% of the light, about 65% of the light or about 70% of the light. In other aspects of this embodiment, a hydrogel composition transmits, for example, at most 5% of the light, at most 10% of the light, at most 15% of the light, at most 20% of the light, at most 25% of the light, at most 30% of the light, at most 35% of the

light, a maximum of 40% of the light, a maximum of 45% of the light, a maximum of 50% of the light, a maximum of

55% of the light, a maximum of 60% of the light, a maximum of 65% of the light, a maximum of 70% of the light or a maximum of 75% of the light. In other aspects of this embodiment, a hydrogel composition transmits, for example,

from about 5% to about 15%, from about 5% to about 20%, from about 5% to about 25%, from about 5% to about 30%, about 5% to about 35%, from about 5% to about 40%, about 5% to about 45%, from about 5% to about 50%, about 5% to about 55%, from about 5 % to about 60%, approximately 5% to approximately 65%, from approximately 5% to approximately 70%, approximately 5% to approximately 75%, from approximately 15% to approximately 20%, from approximately 15% to approximately 25 %, from about 15% to about 30%, from about 15% to about 35%, from about 15% to about 40%, from about 15% to about 45%, from about 15% to about 50%, from about 15% to about 55%, from about 15% to about 60%, from about 15% to about 65%, from about 15% to about 70%, from about 15% to about 75%, from about 25% to about 35%, from about 25% to about 40%, from about 25% to about 45%, from about 25% to about 50%, from about 25% to about 55%, from about 25% to about 60%, from about 25% to about 65%, from about 25% to about 70% or about 25% to about 75% of the

light.

In one embodiment, a hydrogel composition disclosed herein is optically translucent. In aspects of this embodiment, a hydrogel composition diffuses, for example, about 75% of the light, about 80% of the light, about 85% of the light, about 90% of the light, approximately 95% of the light or approximately 100% of the light. In

other aspects of this embodiment, a hydrogel composition transmits diffusely, for example, at least

75% of the light, at least 80% of the light, at least 85% of the light, at least 90% of the light or at least 95% of the light.

In still other aspects of this embodiment, a hydrogel composition diffuses, for example, from about 75% to about 100% of the light, from about 80% to about

100% of the light, from about 85% to about 100% of the light, from about 90% to about 100% of the light or from about 95% to about 100% of the light.

A hydrogel composition disclosed herein can be further processed by spraying the hydrogel to give particles and optionally mixing with a carrier phase such as, for example, water or a saline solution to form an injectable or topical substance such as a solution, an oil. , a lotion, a gel, an ointment, a cream, a suspension, an ointment or a paste. As such, the disclosed hydrogel compositions may be single-phase or multi-phase compositions. A hydrogel can be milled to a particle size of from about 10 | im to about 1000 | im in diameter, such as from about 15 | im to about 30 | im, from about 50 | im to about 75 | im, about 100 | im to about 150 | im, from about 200 | im to about 300 | im,

from about 450 | im to about 550 | im, from about 600 | im to about

Aspects of the present specification provide, in part, a composition disclosed herein that is injectable. As used herein, the term "injectable" refers to a material that has the necessary properties to administer composition to a region of an individual's skin using an injection device with a fine needle. As used herein, the term "fine needle" refers to a needle that is 27 gauge or smaller. The injectability of a composition disclosed herein can be achieved by sizing the hydrogel particles as discussed above.

In one aspect of this embodiment, a hydrogel composition disclosed herein is injectable through a fine needle. In other aspects of this embodiment, a hydrogel composition disclosed herein is injectable through a needle of, for example, about 27 gauge, about 30 gauge or about 32 gauge. In still other aspects of this embodiment, a hydrogel composition disclosed herein is injectable through a needle of, for example, size 22 or smaller, size 27 or smaller, size 30 or smaller, or size 32 or smaller. In still other aspects of this embodiment, a hydrogel composition disclosed herein is injectable through a needle of, for example, about 22 gauge to about 35 gauge, 22 gauge to about 34 gauge, 22 gauge to approximately 33 caliber, from 22 caliber to approximately 32 caliber, from approximately 22 caliber to approximately 27 caliber or from approximately 27 caliber to approximately 32 caliber.

In aspects of this embodiment, a hydrogel composition disclosed herein can be injected with an extrusion force of about 60 N, about 55 N, about 50 N, about 45 N, about 40 N, about 35 N, about 30 N , about 25 N, about 20 N or about 15 N at speeds of 100 mm / min. In other aspects of this embodiment, a hydrogel composition disclosed herein may be injected through a 27 gauge needle with an extrusion force of 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, 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 still other aspects of this embodiment, a hydrogel composition disclosed herein can be injected through a 30 gauge needle with an extrusion force of 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, 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 still other aspects of this embodiment, a hydrogel composition disclosed herein can be injected through a 32 gauge needle with an extrusion force of 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 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.

Aspects of the present specification provide, in part, a hydrogel composition disclosed herein that is cohesive. Cohesiveness, also called cohesive attraction of cohesion, cohesive force or compression force is a physical property of a material, caused by the intermolecular attraction between similar molecules within the material that acts by joining the molecules. Cohesiveness is expressed in terms of grams-force (gmf). Cohesiveness is affected by, among other factors, the molecular weight ratio of the initial free glycosaminoglycan polymer, the degree of cross-linking of glycosaminoglycan polymers, the amount of residual free glycosaminoglycan polymers after cross-linking and the pH of the composition of hydrogel A composition must be cohesive enough to remain located at an administration site. Additionally, in certain applications, sufficient cohesiveness is important for a composition to retain its shape, and therefore functionality, in the case of mechanical loading cycles. As such, in one embodiment, a hydrogel composition disclosed herein exhibits cohesiveness, along with water. In yet another embodiment, a hydrogel composition disclosed herein has sufficient cohesiveness to remain localized at an administration site. In yet another embodiment, a hydrogel composition disclosed herein has sufficient cohesiveness to retain its shape. In a further embodiment, a hydrogel composition disclosed herein has sufficient cohesiveness to retain its shape and functionality.

Aspects of the present specification provide, in part, a hydrogel composition disclosed herein that has a physiologically acceptable osmolarity. As used herein, the term "osmolarity" refers to the concentration of osmotically active solutes in solution. As used herein, the term "a physiologically acceptable osmolarity" refers to an osmolarity consistent with, or characteristic of, the normal functioning of a living organism. As such, the administration of a hydrogel composition as disclosed herein has an osmolarity that has substantially no permanent or long-term detrimental effect when administered to a mammal. Osmolarity is expressed as osmoles of osmotically active solute per liter of solvent (Osmol / lu Osm / l). Osmolarity is different from molarity because it measures moles of osmotically active solute particles instead of moles of solute. The distinction arises because some compounds can dissociate in solution, while others cannot. The osmolarity of a solution can be calculated from the following expression: Osmol / l = Z ^ C i, where9 it is the osmotic coefficient, which represents the degree of non-ideality of the solution; ^ is the number of particles (eg ions) in which a molecule dissociates; and C is the molar concentration of the solute; ei is the index that represents the identity of a particular solute. The osmolarity of a hydrogel composition disclosed herein can be measured using a conventional method that measures solutions.

In one embodiment, a hydrogel composition disclosed herein has a physiologically acceptable osmolarity. In aspects of this embodiment, a hydrogel composition has an osmolarity of, 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 / l or about 500 mOsm / l. In other aspects of this embodiment, a hydrogel composition has an osmolarity of, 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, at least 450 mOsm / l or at least 500 mOsm / l. In still other aspects of this embodiment, a hydrogel composition has an osmolarity of, for example, a maximum of 100 mOsm / l, a maximum of 150 mOsm / l, a maximum of 200 mOsm / l, a maximum of 250 mOsm / l, a maximum 300 mOsm / l, maximum 350 mOsm / l, maximum 400 mOsm / l, maximum 450 mOsm / l or maximum 500 mOsm / l. In still other aspects of this embodiment, a hydrogel composition has an osmolarity of, for example, about 100 mOsm / about 500 mOsm / l, about 200 mOsm / about 500 mOsm / l, about 200 mOsm / la 400 mOsm / l, approximately 300 mOsm / approximately 400 mOsm / l, approximately 270 mOsm / approximately 390 mOsm / l, approximately 225 mOsm / approximately 350 mOsm / l, from about 250 mOsm / about 325 mOsm / l, about 275 mOsm / about 300 mOsm / l or about 285 mOsm / about 290 mOsm / l.

Aspects of the present specification provide, in part, a hydrogel composition disclosed herein that has a physiologically acceptable osmolality. As used herein, the term "osmolality" refers to the concentration of osmotically active solutes per kilo of solvent in the body. As used herein, the term "a physiologically acceptable osmolality" refers to an osmolality consistent with, or characteristic of, the normal functioning of a living organism. As such, the administration of a hydrogel composition disclosed herein has an osmolality that does not substantially have a permanent or long-term detrimental effect when administered to a mammal. Osmolality is expressed as osmoles of osmotically active solute per kilogram of solvent (osmol / kg or Osm / kg) and is equal to the sum of the molalities of all solutes present in that solution. The osmolality of a solution can be measured using an osmometer. The most commonly used instrument in modern laboratories is a freezing point depression osmometer. This instrument measures the change in the freezing point that occurs in a solution with increasing osmolality (freezing point depression osmometer) or the change in vapor pressure that occurs in a solution with increasing osmolality (osmometer vapor pressure depression).

In one embodiment, a hydrogel composition disclosed herein has a physiologically acceptable osmolality. In aspects of this embodiment, a hydrogel composition has an osmolality of, for example, approximately 100 mOsm / kg, approximately 150 mOsm / kg, approximately 200 mOsm / kg, approximately 250 mOsm / kg, approximately 300 mOsm / kg, approximately 350 mOsm / kg, approximately 400 mOsm / kg, approximately 450 mOsm / kg or approximately 500 mOsm / kg. In other aspects of this embodiment, a hydrogel composition has an osmolality of, 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, at least 450 mOsm / kg or at least 500 mOsm / kg. In still other aspects of this embodiment, a hydrogel composition has an osmolality of, for example, a maximum of 100 mOsm / kg, a maximum of 150 mOsm / kg, a maximum of 200 mOsm / kg, a maximum of 250 mOsm / kg, a maximum 300 mOsm / kg, maximum 350 mOsm / kg, maximum 400 mOsm / kg, maximum 450 mOsm / kg or maximum 500 mOsm / kg. In still other aspects of this embodiment, a hydrogel composition has an osmolality of, for example, about 100 mOsm / kg to about 500 mOsm / kg, from about 200 mOsm / kg to about 500 mOsm / kg, from about 200 mOsm / kg at about 400 mOsm / kg, from about 300 mOsm / kg to about 400 mOsm / kg, from about 270 mOsm / kg to about 390 mOsm / kg, from about 225 mOsm / kg to about 350 mOsm / kg, from about 250 mOsm / kg to about 325 mOsm / kg, from about 275 mOsm / kg to about 300 mOsm / kg or from about 285 mOsm / kg to about 290 mOsm / kg.

Aspects of the present specification provide, in part, a hydrogel composition disclosed herein that has substantial stability. As used herein, the term "Stability" or "stable" when referring to a hydrogel composition disclosed herein refers to a composition that is not prone to degradation, breakdown or breakdown to any substantial or significant degree while stored before administration to An individual. As used herein, the term "substantial thermal stability", "substantially thermally stable", "stable in autoclave" or "stable in steam sterilization" refers to a hydrogel composition disclosed herein which is substantially stable when subjected to heat treatment as disclosed herein.

The stability of a hydrogel composition disclosed herein can be determined by subjecting a hydrogel composition to heat treatment, such as, for example, steam sterilization at normal pressure or pressure (for example, autoclaving). Preferably the heat treatment is carried out at a temperature of at least about 100 ° C for between about one minute and about 10 minutes. The substantial stability of a hydrogel composition disclosed herein can be assessed 1) by determining the change in extrusion force (AF) of a hydrogel composition disclosed herein after sterilization, wherein the change in extrusion force less than 2 N is indicative of a substantially stable hydrogel composition as measured by (the extrusion force of a hydrogel composition with the specified additives) less (the extrusion force of a hydrogel composition without additives added); and / or 2) determining the change in the rheological properties of a hydrogel composition disclosed herein after sterilization, wherein the change in tan 8 1 Hz of less than 0.1 is indicative of a substantially stable hydrogel composition as measured by (so 81 Hz of gel formulation with additives) less (so 81 Hz of gel formulation without additives). As such, a substantially stable hydrogel composition disclosed herein retains one or more of the following characteristics after sterilization: homogeneity, extrusion force, cohesivity, hyaluronan concentration, agent (s) concentration, osmolarity, pH or other rheological characteristics desired by the hydrogel before heat treatment.

In one embodiment, a hydrogel composition comprising a glycosaminoglycan polymer and the at least one agent disclosed herein is processed using a heat treatment that maintains the desired hydrogel properties disclosed herein. In aspects of this embodiment, a hydrogel composition comprising a glycosaminoglycan polymer and the at least one agent disclosed herein is processed using a heat treatment of, for example, about 100 ° C, about 105 ° C, about 110 ° C, approximately 115 ° C, approximately 120 ° C, approximately 125 ° C or approximately 130 ° C. In other aspects of this embodiment, a hydrogel composition comprising a glycosaminoglycan polymer and the at least one agent disclosed herein is processed using a heat treatment of, 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 still other aspects of this embodiment, a hydrogel composition comprising a glycosaminoglycan polymer and the at least one agent disclosed herein is processed using a heat treatment of, for example, about 100 ° C to about 120 ° C, from about 100 ° C to about 125 ° C, from about 100 ° C to about 130 ° C, from about 100 ° C to about 135 ° C, from about 110 ° C to about 120 ° C, from about 110 ° C to about 125 ° C, from about 110 ° C to about 130 ° C, from about 110 ° C to about 135 ° C, from about 120 ° C to about 125 ° C, from about 120 ° C to approximately 130 ° C, approximately 120 ° C to approximately 135 ° C, approximately 125 ° C to approximately 130 ° C or approximately 125 ° C to approximately 135 ° C.

The long-term stability of a hydrogel composition disclosed herein can be determined by subjecting a hydrogel composition to a heat treatment, such as, for example, storage in an environment at about 45 ° C for about 60 days. Long-term stability of a hydrogel composition disclosed herein can be assessed 1) by evaluating the clarity and color of a hydrogel composition after heat treatment at 45 ° C, being a clear and colorless hydrogel composition indicative of a composition of substantially stable hydrogel; 2) determining the change in extrusion force (AF) of a hydrogel composition disclosed herein after heat treatment at 45 ° C, wherein the change in extrusion force less than 2 N is indicative of a substantially stable hydrogel composition as measured by (the extrusion force of a hydrogel composition with the additives specified before heat treatment at 45 ° C) less (the extrusion force of a hydrogel composition with the additives specified after heat treatment at 45 ° C); and / or 3) determining the change in the rheological properties of a hydrogel composition disclosed herein after sterilization, wherein the change in tan 8 1 Hz of less than 0.1 is indicative of a substantially stable hydrogel composition as measured by (tan 8 1 Hz of a gel formulation with the specified additives before heat treatment at 45 ° C) less (so 81 Hz of a gel formulation with the additives specified after heat treatment at 45 ° C). As such, the long-term stability of a hydrogel composition disclosed herein is evaluated by the preservation of one or more of the following characteristics after heat treatment at 45 ° C: clarity (transparency and translucency), homogeneity and cohesiveness .

In aspects of this embodiment, a hydrogel composition is substantially stable at room temperature for, 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, approximately 27 months, approximately 30 months, approximately 33 months or approximately 36 months. In other aspects of this embodiment, a hydrogel composition is substantially stable at room temperature for, 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, at least 30 months, at least 33 months or at least 36 months. In other aspects of this embodiment, a hydrogel composition is substantially stable at room temperature for, for example, from about 3 months to about 12 months, from about 3 months to about 18 months, from about 3 months to about 24 months, of approximately 3 months to approximately 30 months, approximately 3 months to approximately 36 months, approximately 6 months to approximately 12 months, from about 6 months to about 18 months, from about 6 months to about 24 months, from about 6 months to about 30 months, from about 6 months to about 36 months, from about 9 months to about 12 months, from 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, from about 12 months to about 18 months, from about 12 months to about 24 months, from about 12 months to about 30 months, from about 12 months to about 36 months, from about 18 months to about 24 months, from about 18 months to approximately 30 months or approximately 18 months to approximately 36 months.

Aspects of the present specification provide, in part, a hydrogel composition disclosed herein that is a pharmaceutically acceptable composition. As used herein, the term "pharmaceutically acceptable" means any molecular entity or composition that does not produce an adverse, allergic or other harmful or unwanted reaction when administered to an individual. A pharmaceutically acceptable hydrogel composition is useful for medical and veterinary applications. A pharmaceutically acceptable hydrogel composition can be administered to an individual alone, or in combination with other active ingredients, agents, drugs or complementary hormones.

Aspects of the present specification provide, in part, a hydrogel composition as disclosed herein comprising a pharmacologically acceptable excipient. As used herein, the term "pharmacologically acceptable excipient" is synonymous with "pharmacological excipient" or "excipient" and refers to any excipient that does not substantially have a permanent or long-term detrimental effect when administered to a mammal. and encompasses compounds such as, for example, stabilizing agent, a loading agent, a cryoprotectant, a lioprotective, an additive, a vehicle, a carrier, a diluent or an auxiliary. An excipient is generally mixed with an active ingredient, or it is allowed to be diluted to enclose the active ingredient and can be a solid, semi-solid or liquid agent. It is also envisioned that a pharmaceutical composition as disclosed herein may include one or more pharmaceutically acceptable excipients that facilitate the processing of an active ingredient to give pharmaceutically acceptable compositions. As long as any pharmacologically acceptable excipient is not incompatible with the active substance, its use in pharmaceutically acceptable compositions is contemplated. Non-limiting examples of pharmacologically acceptable excipients can be found in, for example, Pharmaceutical Dosage Forms and Drug Delivery Systems (Howard C. Ansel et al., Eds., Lippincott Williams & Wilkins Publishers, 7th ed. 1999); Remington: The Science and Practice of Pharmacy (Alfonso R. Gennaro ed., Lippincott, Williams & Wilkins, 20th ed. 2000); Goodman & 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).

It is further envisioned that a hydrogel composition disclosed herein may optionally include, without limitation, other pharmaceutically acceptable components, including, without limitation, buffers, preservatives, tonicity adjusting agents, salts, antioxidants, osmolality, emulsifying agents, wetting agents, sweetening or flavoring agents, and the like.

A pharmaceutically acceptable buffer is a buffer that can be used to prepare a hydrogel composition disclosed herein, provided the resulting preparation is pharmaceutically acceptable. Non-limiting examples of pharmaceutically acceptable buffers include acetate buffers, borate buffers, citrate buffers, neutral buffered saline solutions, phosphate buffers and phosphate buffered saline solutions. Any concentration of a pharmaceutically acceptable buffer can be useful in the formulation of a pharmaceutical composition disclosed herein, with the proviso that a therapeutically effective amount of the active ingredient is recovered using this effective buffer concentration. Non-limiting examples of physiologically acceptable buffer concentrations occur within the range of about 0.1 mM to about 900 mM. The pH of pharmaceutically acceptable buffers can be adjusted, provided the resulting preparation is pharmaceutically acceptable. It is understood that acids or bases can be used to adjust the pH of a pharmaceutical composition as needed. Any level of buffered pH may be useful in the formulation of a pharmaceutical composition, provided that a therapeutically effective amount of the matrix polymer active ingredient is recovered using this effective pH level. Non-limiting examples of physiologically acceptable pH occur within the range of about pH 5.0 to about pH 8.5. For example, the pH of a hydrogel composition disclosed herein may 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.

Pharmaceutically acceptable preservatives include, without limitation, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene. Pharmaceutically acceptable preservatives include, without limitation, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate, phenylmercuric nitrate, a stabilized oxychloro composition, such as, for example, PURITE® (Allergan, Inc. Irvine, CA) and chelants, such as, for example, DTPA or DTPA-bisamide, DTPA calcium and CaNaDTPA-bisamide.

Pharmaceutically acceptable tonicity adjusting agents useful in a hydrogel composition disclosed herein include, without limitation, salts such as, for example, sodium chloride and potassium chloride; and glycerin. The composition can be provided as a salt and can be formed with many acids, including but not limited to, hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous solvents or other protons than the corresponding free base forms. It is understood that these and other substances known in the art of pharmacology may be included in a pharmaceutical composition disclosed herein. Other non-limiting examples of pharmacologically acceptable components can be found in, for example, Ansel, cited above, (1999); Gennaro, cited above, (2000); Hardman, cited above, (2001); and Rowe, cited above, (2003).

Aspects of the present specification provide, in part, a method of treating a soft tissue state of an individual by administering a hydrogel composition disclosed herein. As used herein, the term "treat" refers to reducing or eliminating in an individual a clinical or cosmetic symptom of a soft tissue state characterized by an imperfection, a defect, a disease and / or a disorder. soft tissue; or delay or prevent in an individual the appearance of a clinical or cosmetic symptom of a condition characterized by an imperfection, a defect, a disease and / or a soft tissue disorder. For example, the term "treat" may mean reducing a symptom of a condition characterized by a defect, a disease and / or a soft tissue disorder in, for example, 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%. The efficacy of a hydrogel composition disclosed herein in the treatment of a condition characterized by a defect, a disease and / or a soft tissue disorder can be determined by observing one or more clinical, cosmetic, and / or associated physiological indicators. with the state. An improvement in a defect, a disease and / or a soft tissue disorder can also be indicated by a reduced need for concurrent therapy. Those skilled in the art will know the appropriate symptoms or indicators associated with a specific defect, disease and / or soft tissue disorder and will know how to determine if an individual is a candidate for treatment with a compound or composition disclosed herein. document.

A hydrogel composition is administered to an individual. An individual is normally a human of any age, gender or race. Normally, any individual who is a candidate for a conventional procedure to treat a soft tissue state is a candidate for a method disclosed herein. Although a subject experiencing the signs of aging is an adult, subjects experiencing premature aging or other skin conditions suitable for treatment (eg, a scar) can also be treated with a hydrogel composition disclosed herein. In addition, the hydrogel compositions and methods disclosed herein may be applied to individuals seeking a small / moderate elongation, change in shape or alteration of the contour of a part or region of the body, which may not be technically possible or aesthetically Acceptable with existing soft tissue implant technology. The preoperative evaluation usually includes a physical examination and a routine history, as well as a thorough informed consent, spreading all the relevant risks and benefits of the procedure.

The hydrogel composition and methods disclosed herein are useful in the treatment of a soft tissue state. A soft tissue state includes, without limitation, an imperfection, a defect, a disease and / or a soft tissue disorder. Non-limiting examples of a soft tissue state include imperfection, defect, disease and / or breast disorder, such as, for example, breast augmentation, breast reconstruction, mastopexy, micromastia, thoracic hypoplasia, Poland syndrome , defects due to implant complications such as contraction and / or capsular rupture; an imperfection, a defect, a disease or a facial disorder, such as, for example, a facial increase, a facial reconstruction, a mesotherapy, Parry-Romberg syndrome, deep lupus erythematosus, dermal pits, scars, sunken cheeks, thin lips , imperfections or nasal defects, imperfections or retroorbital defects, a crease, a line and / or a facial wrinkle such as a glabellar line, a nasolabial line, a perioral line and / or a puppet line and / or other deformities or imperfections of the contour of the face; an imperfection, a defect, a disease or a neck disorder; an imperfection, a defect, a disease and / or a skin disorder; other imperfections, defects, diseases and / or soft tissue disorders, such as, for example, an increase or reconstruction of the upper arm, lower arm, hand, shoulder, back, torso including the abdomen, the buttocks, the upper leg, the lower leg including the calves, foot including the plantar fat pad, the eye, the genitals or other, region or area of the body, or a disease or disorder that affects these parts, regions or areas of the body; urinary incontinence, fecal incontinence, other forms of incontinence; and gastroesophageal reflux disease (GERD). As used herein, the term "mesotherapy" refers to a technique of non-surgical cosmetic treatment of the skin that involves intraepidermal, intradermal and / or subcutaneous injection of an agent administered as multiple small droplets into the epidermis, dermo-epidermal junction, and / or the dermis.

The amount of a hydrogel composition used with any of the methods disclosed herein will normally be determined based on the desired alteration and / or improvement, the reduction and / or elimination of a desired soft tissue condition symptom, the clinical effect. and / or cosmetic desired by the individual and / or physician, and the part or region of the body being treated. The effectiveness of the administration of the composition can be manifested by one or more of the following clinical and / or cosmetic measures: altered and / or improved soft tissue shape, altered and / or improved soft tissue size, altered and / or improved soft tissue contour, altered and / or improved soft tissue function, internal tissue growth support and / or deposition again collagen, sustained grafting of the composition, patient satisfaction and / or improved quality of life, and decreased use of implantable foreign material.

For example, for breast augmentation procedures, the effectiveness of the compositions and methods may be manifested by one or more of the following clinical and / or cosmetic measures: enlarged breast size, altered breast shape, altered breast contour , sustained grafting, reduction in the risk of capsular contraction, decrease in the rate of formation of liponecrotic cyst, patient satisfaction and / or improved quality of life, and decrease in the use of breast implants.

As another example, the effectiveness of the compositions and methods in the treatment of facial soft tissue may be manifested by one or more of the following clinical and / or cosmetic measures: size, shape and / or increased contour of a facial feature such as size, enlarged shape and / or contour of a region of the eye, cheek or lip; altered size, shape and / or contour of a facial feature such as size, shape and / or altered contour of the shape of a region of the eye, cheek or lip; reduction or elimination of a wrinkle, a crease or a line on the skin; resistance to a wrinkle, a crease or a line on the skin; skin rehydration; increased skin elasticity; reduction or elimination of skin roughness; increased and / or improved skin smoothness; reduction or elimination of stretch lines or marks; increase and / or improvement of the tone, the brightness, the brightness and / or the luminosity of the skin; increase and / or improvement of skin color, reduction or elimination of skin paleness; sustained grafting of the composition; diminished side effects; patient satisfaction and / or improved quality of life.

As yet another example, for urinary incontinence procedures, the efficacy of the compositions and methods for sphincter support can be manifested by one or more of the following clinical measures: decreased frequency of incontinence, sustained grafting, patient satisfaction and / or Improved quality of life and decreased use of implantable foreign fill.

In aspects of this embodiment, the amount of a 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 40 g, about 50 g, about 60 g, about 70 g, about 80 g, about 90 g, about 100 g, approximately 150 g or approximately 200 g. In other aspects of this embodiment, the amount of a 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, from about 10 g to about 100 g or from about 50 g to about 200 g. In still other aspects of this embodiment, the amount of a hydrogel composition administered is, for example, about 0.01 ml, approximately 0.05 ml, approximately 0.1 ml, approximately 0.5 ml, approximately 1 ml, approximately 5 ml, approximately 10 ml, approximately 20 ml, approximately 30 ml, approximately 40 ml, approximately 50 ml, approximately 60 ml, approximately 70 g, approximately 80 ml, approximately 90 ml, approximately 100 ml, approximately 150 ml or approximately 200 ml. In other aspects of this embodiment, the amount of a hydrogel composition administered is, for example, from about 0.01 ml to about 0.1 ml, from about 0.1 ml to about 1 ml, from about 1 ml to about 10 ml, approximately 10 ml to approximately 100 ml or approximately 50 ml to approximately 200 ml.

The duration of treatment will normally be determined based on the cosmetic and / or clinical effect desired by the individual and / or doctor and the region or part of the body being treated. In aspects of this embodiment, the administration of a hydrogel composition disclosed herein may treat a state of soft tissues for, for example, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 12 months, about 13 months, about 14 months, about 15 months, about 18 months or about 24 months. In other aspects of this embodiment, administration of a hydrogel composition disclosed herein may treat a soft tissue condition for, 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 12 months, at least 13 months, at least 14 months, at least 15 months, at least 18 months or at least 24 months. In still aspects of this embodiment, administration of a hydrogel composition disclosed herein may treat a soft tissue condition for, for example, from about 6 months to about 12 months, from about 6 months to about 15 months, of approximately 6 months to approximately 18 months, approximately 6 months to approximately 21 months, approximately 6 months to approximately 24 months, from about 9 months to about 12 months, from about 9 months to about 15 months, from about 9 months to about 18 months, from about 9 months to about 21 months, from about 6 months to about 24 months, from about 12 months to approximately 15 months, approximately 12 months to approximately 18 months, approximately 12 months to approximately 21 months, approximately 12 months to approximately 24 months, approximately 15 months to approximately 18 months, approximately 15 months to approximately 21 months, approximately 15 months to approximately 24 months, approximately 18 months to approximately 21 months, approximately 18 months to approximately 24 months or approximately 21 months to approximately 24 months

Aspects of the present specification provide, in part, the administration of a hydrogel composition disclosed herein. As used herein, the term "administration" means any delivery mechanism that provides a composition disclosed herein to an individual that potentially results in a clinical, therapeutic or experimentally beneficial outcome. The actual delivery mechanism used to administer a composition to an individual can be determined by a person skilled in the art taking into account factors, including, without limitation, the type of skin condition, the location of the skin condition, the cause of the skin condition, severity of skin condition, degree of relief desired, duration of relief desired, the particular composition used, the rate of excretion of the particular composition used, the pharmacodynamics of the particular composition used, the nature of the other compounds included in the particular composition used, the particular route of administration, the particular characteristics, the history and the risk factors of the individual, such as, for example, age, weight, general health and the like, or any combination thereof. In one aspect of this embodiment, a composition disclosed herein is administered to a region of an individual's skin by injection.

The route of administration of a hydrogel composition to an individual patient will normally be determined based on the cosmetic and / or clinical effect desired by the individual and / or physician and the region or part of the body being treated. A composition disclosed herein may be administered by any means known to those of ordinary skill in the art including, without limitation, needle syringe, a gun (e.g., a hydropneumatic compression gun), a catheter, topically or by direct surgical implant. The hydrogel composition disclosed herein can be administered to a region of the skin such as, for example, a dermal region or a hypodermic region. For example, a hydrogel composition disclosed herein can be injected using needles with a diameter of about 0.26 mm to about 0.4 mm and a length ranging from about 4 mm to about 14 mm. Alternatively, the needles can be from 21 to 32 G and have a length of about 4 mm to about 70 mm. Preferably, the needle is a single use needle. The needle can be combined with a syringe, a catheter and / or a gun.

In addition, a composition disclosed herein may be administered once, or over a plurality of times. Ultimately, the moment used will follow the standards of quality care. For example, a hydrogel composition disclosed herein may be administered once or over several sessions, the sessions being separated by a few days, or weeks. For example, a hydrogel composition disclosed herein may be administered to an individual every 1, 2, 3, 4, 5, 6 or 7 days or every 1, 2, 3 or 4 weeks. The administration of a hydrogel composition disclosed herein to an individual may be on a monthly or bi-monthly basis or administered every 3, 6, 9 or 12 months.

For a soft breast tissue replacement procedure, the route of administration may include the axillary, periareolar and / or inframammary pathways. Alternatively or in addition, a composition can be administered through a transaxillary endoscopic subpectoral approach. For a procedure of facial soft tissue replacement, the route of administration may be the frontal, temporal, zygomatic, periocular, mandibular, perioral or chin. In urinary incontinence procedures, the route of administration may include the transurethral or periurethral routes. Alternatively or in addition, administration may be delivered by an antegrade route. The pathways discussed in this document do not exclude the use of multiple pathways to achieve the desired clinical effect.

Aspects of the present specification provide, in part, a dermal region. As used herein, the term "dermal region" refers to the region of the skin comprising the epidermal dermal junction and the dermis including the superficial dermis (papillary region) and the 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 location for skin appendages; and the hypodermis (subcutaneous fat layer). The epidermis does not contain blood vessels, and is nourished by diffusion from the dermis. The main cell type that constitutes the epidermis are keratinocytes, melanocytes, Langerhans cells and Merkel cells.

The dermis is the layer of skin below the epidermis that consists of connective tissue and protects the body from stress and deformation. The dermis is closely connected to the epidermis by a basement membrane. It also houses a lot of mechanoreceptors / nerve endings that provide touch and heat detection. It contains hair follicles, sweat glands, sebaceous glands, approcrine glands, lymphatic vessels and blood vessels. The blood vessels in the dermis provide nutrition and waste disposal from their own cells as well as the basal stratum of the epidermis. The dermis is structurally divided into two zones: a surface area adjacent to the epidermis, called the papillary region, and a thicker, deeper zone known as the reticular region.

The papillary region is composed of loose areolar connective tissue. Its name comes from its finger-like projections called papillae that extend into the epidermis. The papillae provide the dermis with an "uneven" surface that fits the epidermis, reinforcing the connection between the two layers of the skin. The reticular region is deeper in the papillary region and is usually much thicker. It is made up of dense irregular connective tissue, and is named after the dense concentration of collagenous, elastic and reticular fibers that interweave throughout it. These protein fibers give the dermis its strength, extensibility and elasticity properties. Also located within the reticular region are the hair roots, sebaceous glands, sweat glands, receptors, nails and blood vessels. Tattoo ink is contained in the dermis. Stretch marks of pregnancy are also located in the dermis.

The hypodermis is below the dermis. Its purpose is to bind the dermal region of the skin to the underlying bone and muscle as well as supply blood vessels and nerves. It consists of loose connective tissue and elastin. The main cell types are fibroblasts, macrophages and adipocytes (the hypodermis contains 50% of body fat). Fat serves as cushioning and insulation for the body.

In one aspect of this embodiment, a hydrogel composition disclosed herein is administered a region of the skin of an individual by injection into a dermal region or a hypodermic region. In aspects of this embodiment, a hydrogel composition disclosed herein is administered to a dermal region of an individual by injection into, for example, an epidermal-dermal junction region, a papillary region, a reticular region, or any combination. the same.

Aspects of the present specification disclose, in part, a method of treating a soft tissue state of an individual, the method comprising the steps of administering a hydrogel composition disclosed herein to a site of the soft tissue state of the individual, in which the administration of the composition improves the state of soft tissues, thereby treating the state of soft tissues. In aspects of this embodiment, a soft tissue state is a state of the breast tissue, a state of the facial tissue, a state of the neck, a state of the skin, a state of the upper arm, a state of the part lower arm, a state of the hand, a state of the shoulder, a state of the back, a state of the torso including abdominal, a state of the buttocks, a state of the upper leg, a state of the lower leg including a state of the calves, a state of the foot including a state of the plantar fat pad, a state of the eye, a genital state or a state that affects another part, region or area of the body.

Other aspects of the present specification disclose, in part, a method of treating a skin condition comprising the step of administering to a person suffering from a skin condition a hydrogel composition disclosed herein, in the that the administration of the composition improves the condition of the skin, thereby treating the condition of the skin. In one aspect of this embodiment, a skin condition is a method of treating skin dehydration comprising the step of administering to an individual suffering from skin dehydration a hydrogel composition disclosed herein, in the that the administration of the composition rehydrates the skin, thereby treating the dehydration of the skin. In another aspect of this embodiment, a method of treating a lack of elasticity of the skin comprises the step of administering to an individual suffering from a lack of elasticity of the skin a hydrogel composition disclosed herein, in which the Administration of the composition increases the elasticity of the skin, thereby treating a lack of elasticity of the skin. In yet another aspect of this embodiment, a method of treating skin roughness comprises the step of administering to an individual suffering from skin roughness a hydrogel composition disclosed herein, in which the administration of the composition It reduces the roughness of the skin, thus treating the roughness of the skin. In yet another aspect of this embodiment, a method of treating a lack of smoothness of the skin comprises the step of administering to an individual suffering from a lack of smoothness of the skin a hydrogel composition disclosed herein. document, in which the administration of the composition makes the skin more smooth, thereby treating a lack of smoothness of the skin.

In a further aspect of this embodiment, a method of treating a skin stretch line or mark comprises the step of administering to an individual suffering from a skin stretch line or mark a hydrogel composition disclosed herein. , in which the administration of the composition reduces or eliminates the skin stretch mark or line, thereby treating a skin stretch line or mark. In another aspect of this embodiment, a method of treating skin paleness comprises the step of administering to an individual suffering from skin paleness a hydrogel composition disclosed herein, in which the administration of the composition increases the tone or luminosity of the skin, thereby treating the paleness of the skin. In another aspect of this embodiment, a method of treating skin wrinkles comprises the step of administering to an individual suffering from skin wrinkles a hydrogel composition disclosed herein, wherein the administration of the composition reduces or eliminates skin wrinkles, thereby treating skin wrinkles. In yet another aspect of this embodiment, a method of treating skin wrinkles comprises the step of administering to an individual a hydrogel composition disclosed herein, in which the administration of the composition makes the skin resistant. to skin wrinkles, thereby treating skin wrinkles.

In another aspect of the invention, a stable dermal filler formulation is provided as set forth in claim 1, wherein the stability of the dermal filler formulation is determined by subjecting the dermal filler formulation to a heat treatment selected from the group. consisting of (a) steam sterilization at between approximately 120 ° C and approximately 135 ° C, and (b) approximately 32 days at approximately 45 ° C, with substantial preservation after heat treatment of one or more of the dermal filler characteristics of being clear, homogeneous and cohesive, and without substantial degradation of the dermal filler formulation after heat treatment.

In this aspect of the invention, the formulation is stable, as determined by the substantial preservation at room temperature of one or more of the dermal filler characteristics of being clear, homogeneous and cohesive, and without substantial degradation of the filler formulation. dermal, for a period of at least 2 years. In some embodiments, the formulation is stable for a period of at least 3 years.

The additional component provides the formulation with improved rheological properties that result in less extrusion force being required for administration compared to an HA gel formulation without the additional constituent.

In yet another aspect of the invention, a method of treating fine lines, wrinkles, depletion of fibroblasts or scars of a patient is provided in which the method comprises the step of administering to the patient an effective amount of a stable dermal filler formulation. in steam sterilization comprising a hyaluronic acid (HA) and at least one additional component selected from the group consisting of wrinkle reduction components, antioxidant, hemostatic, of vasoconstriction, against itching, anti-inflammatory and anti-irritant, in which the formulation is clear, homogeneous, monophasic, cohesive, stable and does not degrade after steam sterilization and in which the appearance of fine lines, wrinkles, Depletion of fibroblasts or scars decreases.

In yet another aspect of the specification, a method of treating fine lines, wrinkles, is provided. depletion of fibroblasts or scars of a patient in which the method comprises the stage of local injection to the patient of a stable dermal filler formulation in steam sterilization comprising from about 1 mg / g to about 40 mg / g of a hyaluronic acid ( HA) cross-linked and at least one additional component selected from the group consisting of wrinkle reduction, antioxidant, hemostatic, vasoconstriction, anti-itch components, anti-inflammatory and anti-irritant, in which the formulation is clear, homogeneous, cohesive, stable and does not degrade after steam sterilization and in which the appearance of fine lines, wrinkles, depletion of fibroblasts or scars is reduced by injection.

In still a further aspect of the invention, a stable dermal filler formulation is provided in steam sterilization in which the formulation comprises a hyaluronic acid and an additional component that is AA2G, in which the stability of the dermal filler formulation is increases significantly by adding the additional component.

Examples

From the following examples, only examples 12-16 and 34-44 refer to compositions according to the invention. The other examples are either preparatory examples, comparative examples or examples showing the use of both the examples of the invention and the comparative ones.

Example 1

Method to determine gel cohesiveness

This example illustrates tests that can be performed in order to demonstrate or quantify the cohesiveness of a HA-based gel composition.

First, 0.2 g or 0.4 g of a gel composition to be tested is placed in a glass syringe. Then, 0.2 g or more of phosphate buffer is added to the syringe and the mixture is thoroughly mixed for approximately 1 hour to obtain a homogeneous mixture. Then, the homogenized mixture is centrifuged for 5 min at 2000 tr / min to remove air bubbles and allow the decantation of any particle. The syringe is then held in an upright position and a drop of eosin dye is deposited on the surface of the gel by means of a syringe and an 18G needle. After 10 min, the dye has slowly diffused through the gel.

After dilution of the gel, homogenization and decantation, a relatively low cohesiveness gel shows a phase separation (a less viscous diluted phase without particles and a lower one composed of decanted particles that are visible to the naked eye or under a microscope). Under the same conditions, a highly cohesive gel does not show substantially phase separation, and the dye is prevented from diffusing into the cohesive formulation. A relatively less cohesive gel, on the other hand, shows a clear phase separation. Example 2

Effect of water soluble molecules on the extrusion capacity of a HA based gel formulation The gels of Example 2 are not according to the invention.

The active ingredient was incorporated into a HA-based gel matrix and autoclaved by steam sterilization at a temperature between about 130 ° C and about 135 ° C for between about one minute and about 10 minutes. Hydrogel properties, appearance (i.e. color / clarity / homogeneity) and extrusion force after autoclaving were analyzed and at 3 years equivalent to room temperature. All formulations were clear, homogeneous, non-colored and had acceptable extrusion force properties after autoclaving and at the equivalent 3-year mark (Table 3). These results show that the test gels had no degradation, indicating that the gels were stable and the incorporation of the components had no impact on the properties and structure of the hydrogel.

Comparative Example 3

Effect of vitamin C derivative on the extrusion capacity and stability of the HA based gel formulation

Ascorbic acid, at a concentration of 1% (w / w), was incorporated into a gel matrix based on HA, and the pH of the gel was adjusted to approximately 7 and then autoclaved by steam sterilization at a temperature between about 130 ° C and about 135 ° C for between about one minute and about 10 minutes. Although it was clear and not colored before autoclaving, the gel was clear but yellowed after autoclaving indicating that the test gel degraded.

Comparative Example 4

Effect of vitamin C derivative on the extrusion capacity and stability of the HA based gel formulation

Magnesium ascorbyl phosphate (MAP), at a concentration of 0.6% (w / w), 1% (w / w) or 2% (w / w), was incorporated into a HA based gel matrix , and the pH of the gel was adjusted to approximately 7 and then autoclaved as in Example 3. The gel was clear and not colored both before and after autoclaving. Both extrusion force and degradation were used to access the rheological properties of a gel. Degradation was determined as a function of time using a controlled voltage rheometer according to the following method: frequency sweep from 0.05 Hz to 10 Hz with a controlled strain of 0.8% (w / w).

At Tan 81 Hz = (Tan 81 Hz test gel) - (Tan 81 Hz control gel) where Tan 81 Hz is the ratio of viscous modulus to elastic modulus. An A Tan 8 1 Hz of less than 0.1 demonstrates that there is no detectable degradation, indicating that the test gel was stable. The rheology analysis showed that although the test gels have acceptable extrusion force properties, the test gels exhibited degradation after autoclaving indicating that the gel was unstable (Table 4).

Example 5

Effect of vitamin C derivative on the extrusion capacity and stability of the HA based gel formulation

This example is not according to the invention.

Sodium ascorbyl phosphate (SAP), at a concentration of 0.6% (w / w), 1% (w / w) or 2% (w / w), was incorporated into a HA based gel matrix , and the pH of the gel was adjusted to approximately 7 and then autoclaved as in Example 3. The gel was clear and not colored both before and after autoclaving. The rheology analysis showed that the test gels had acceptable extrusion force properties, and that the test gels showed no degradation in relation to the controls indicating that the gels were stable (Table 5).

Example 6

Effect of vitamin C derivative on the extrusion capacity and stability of the HA based gel formulation

This example is not according to the invention.

Ascorbic acid 2-glycoside (AA2G ™), at a concentration of 0.6% (w / w), 1% (w / w) or 2% (w / w), was incorporated into a gel matrix based on HA, and the pH of the gel was adjusted to approximately 7 and then autoclaved as in example 3. The gel was clear and not colored both before and after autoclaving. The rheology analysis showed that the test gels had acceptable extrusion force properties, and that the test gels had no degradation in relation to the controls indicating that the gels were stable (Table 6). The degradation of the test gels decreased as the concentration of 2-glycoside of ascorbic acid increased indicating that higher concentrations of 2-glycoside of ascorbic acid increased the stability of the gel.

Example 7

Effect of vitamin C derivative on the long-term stability of the HA based gel formulation

This example is not according to the invention.

The formulations prepared in Example 6 were tested to determine the shelf life at 45 ° C for 32 days and compared with a HA-based gel matrix without any additive. After the test period, the gel was clear and not colored. Surprisingly, the rheology analysis showed that all test gels with ascorbic acid 2-glycoside (AA2G ™) not only did not show degradation during the test period, but that these gels showed increased stability over time (compare the values of A Tan 81 Hz of table 4 with the values of A Tan 81 Hz of table 7).

Comparative Example 8

Effect of vitamin E derivative on the extrusion capacity and stability of the HA based gel formulation

Tocopheryl acetate, at a concentration of 0.5% (w / w) or 1.2% (w / w), was incorporated into a gel matrix based on HA and the gel was autoclaved as in the Example 3. The gel was unclear and white after autoclaving.

Comparative Example 9

Effect of vitamin E derivative on the extrusion capacity and stability of the HA based gel formulation

Sodium tocopheryl phosphate (STP), at a concentration of 0.4% (w / w) or 1.2% (w / w), was incorporated into an HA-based gel matrix and the gel was autoclaved as in example 3. The gel was unclear and white after autoclaving.

Comparative Example 10

Effect of vitamin E derivative on the extrusion capacity and stability of the HA based gel formulation

0.7% (w / w) polyoxyetanyl-a-tocopheryl sebacate was incorporated into an HA-based gel matrix and treated in autoclave the gel as in example 3. The gel was clear, but heterogeneous after autoclaving.

Comparative Example 11

Effect of vitamin E derivative on the extrusion capacity and stability of the HA based gel formulation

Tocopherol-polyethylene glycol 1000 succinate (TPGS) was incorporated at a concentration of 1% (w / w), 3.5% (w / w) or 7% (w / w) in a gel matrix based on HA and the gel was autoclaved as in Example 3. The gel was clear and not colored both before and after autoclaving. The rheology analysis showed that the test gels had acceptable extrusion force properties, and that the test gels showed no degradation in relation to the controls indicating that the gels were stable (Table 8).

Example 12

Effect of vitamin C derivative, vitamin E derivative and anesthetic agent on the extrusion capacity and stability of the HA based gel formulation

Lidocaine, at a concentration of 0.3% (w / w), was incorporated into an HA-based gel matrix comprising either 0.6% ascorbic acid (AA2G ™) 2-glycoside (w / w ) or 0.6% (w / w) ascorbic acid (AA2G ™) 2-glycoside and 1.5% (w / w) TPGS, and the gels were autoclaved as in example 3. Gels were clear and not colored both before and after autoclaving. The rheology analysis showed that the test gels had acceptable extrusion force properties, and that the test gels showed no degradation in relation to the controls indicating that the gels were stable (Table 9).

Example 13

Effect of vitamin C derivative, vitamin E derivative and anesthetic agent on the long-term stability of the HA-based gel formulation

The formulations prepared in Example 12 were tested to determine the shelf life at 45 ° C for 48 days and compared with a HA-based gel matrix without any additive. After the test period, the gel was clear and not colored. Surprisingly, the rheology analysis showed that the test gel comprising 0.3% (w / w) lidocaine and either 0.6% ascorbic acid (AA2G ™) 2-glycoside (w / w) or 0.6% (w / w) ascorbic acid (AA2G ™) 2-glycoside and 1.5% (w / w) TPGS not only showed no degradation during the test period (Table 10).

The stability of extrusion force, pH and degradation are shown over time in Figures 3, 4 and 5, respectively. HPLC analysis (column C18; eluent: sodium phosphate buffer (pH 2.2), 10% propanol, 0.7 ml / min; detection at 260 nm) confirmed the components after autoclaving and the 3 year shelf life as shown in figure 6.

Example 14

Vitamin C derivative promotes collagen synthesis

Human skin fibroblasts were cultured in a 12-well plate. At the confluence, 100 µl of each HA-based gel matrix compound was deposited with 0.3% lidocaine (w / w); HA-based gel matrix with 0.3% lidocaine (w / w) and 0.6% ascorbic acid (AA2G ™) -glucoside (w / w); and phosphate buffer with 0.6% (w / w) ascorbic acid (AA2G ™) 2-glycoside was deposited in a culture insert (0.4 | im porosity), which was itself on the monolayers of fibroblasts. In parallel, a control without treatment was performed. Cultures were incubated for 72 hours and each experimental condition was performed in triplicate. At the end of the incubation, cell viability was verified 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-glycoside (w / w) in a hyaluronic acid gel containing 0.3% lidocaine (w / w) increased procollagen synthesis by a factor 3 (+ 292%), while the gel with 0.3% lidocaine (w / w) showed a 40% increase in procollagen secretion (see Figure 2).

Example 15

The vitamin C derivative protects the HA-based gel formulation from oxidative degradation

The effect of 2-glycoside of ascorbic acid (AA2G ™) on oxidative degradation of the HA-based gel matrix was studied. Oxidation tests were used as they allow testing the resistance of a HA-based gel matrix to free radicals. Degradation by free radicals in a rheometer (Haake Rheostress 600) was simulated by adding a ratio 1/7 of H2OR2 at 30% on the surface of an extension gel measured with a controlled voltage rheometer according to the following method: frequency of 1 Hz with a controlled deformation of 0.8%, for 3600 s at 35 ° C. The time value is taken at 5 Pa / s.

In addition, a comparison of the antioxidant properties for a HA-based gel matrix with 0.3% lidocaine (w / w) and ascorbic acid 2-glycoside (AA2G ™) 0.06% (w / w) (15800 s) versus an HA-based gel matrix with 0.3% lidocaine (w / w) (4942 s) showed that the gel containing 2-glycoside of ascorbic acid (AA2G ™) and lidocaine is more stable with respect to free radical activity (figure 7). Ascorbic acid 2-glycoside (AA2G ™) protected against oxidative degradation by a factor of 3.

Example 16

Implant study

A gel containing 0.6% (w / w) ascorbic acid 2-glycoside (AA2G ™) was implanted in the deep dermis and subcutaneous tissues in rats. The 1-week histological evaluation showed some mononuclear cells (lymphocytes and plasma cells) around the implants at all implant sites (test and control). They were also associated with macrophages. The gel containing 2-glycoside of ascorbic acid (AA2G ™) appeared to be less inflammatory. The irritation index in the test samples (sodium HA with AA2G ™) was 9.9 compared to 12.3 in the controls (sodium HA only). Table 11 shows the histological results at 1 week, 1 month and 3 months. The test gel irritation scores for each implant time are lower than the control.

Example 17

Effect of wetting agent on the extrusion capacity and stability of the HA based gel formulation This example is not according to the invention.

Dexpanthenol, at a concentration of 1% (w / w), was incorporated into a HA-based gel matrix comprising 0.3% lidocaine (w / w) and the gel was autoclaved as in Example 3 The gel was clear and not colored both before and after autoclaving. The rheology analysis showed that the test gel had acceptable extrusion force properties, and that the test gel showed no degradation in relation to the controls indicating that the test gel was stable (Table 12).

Example 18

Effect of wetting agent on the long-term stability of the HA based gel formulation

This example is not according to the invention.

The formulations prepared in Example 17 were tested to determine the shelf life at 45 ° C for 30 days and compared with a HA-based gel matrix without any additive. After the test period, the gel was clear and not colored. Surprisingly, the rheology analysis showed that the test gel with dexpanthenol not only showed no degradation during the test period, but that this gel showed increased stability over time (compare the value of A Tan 81 Hz from the table 12 with the value of A Tan A 1 Hz from table 13).

Example 19

Effect of vasoconstrictor agent on the extrusion capacity and stability of the HA based gel formulation

This example is not according to the invention.

Epinephrine bitartrate was incorporated, at a concentration of 10 ppm (1 ppm is approximately 0.1 mg / g), in a HA-based gel matrix) and the gel was autoclaved as in Example 3. The gel obtained both before and after the autoclave treatment was clear and not colored. The rheology analysis showed that although the test gel comprising 10 ppm of epinephrine bitartrate had acceptable extrusion force properties, the test gel exhibited degradation after autoclaving indicating that the gel was unstable (Table 14).

Example 20

Effect of vasoconstrictor agent and anesthetic agent on the extrusion capacity and stability of the HA based gel formulation

This example is not according to the invention.

Epinephrine bitartrate was incorporated, at a concentration of 10 ppm, in a HA-based gel matrix comprising 0.3% lidocaine (w / w) and the gel was autoclaved as in Example 3. Although the gel obtained before of the autoclave treatment was clear and not colored, the gel obtained after the autoclave treatment was clear but not colored. The rheology analysis showed that although the test gels have acceptable extrusion force properties (table 15).

Example 21

Effect of vasoconstrictor agent and anesthetic agent on the long-term stability of the HA based gel formulation

This example is not according to the invention.

The formulations prepared in Example 20 were tested to determine the shelf life at 45 ° C for 60 days and compared with an HA-based gel matrix without any additive. After the test period, the gel was clear and slightly colored. The rheology analysis showed that gels with 0.3% lidocaine (w / w) and 10 ppm epinephrine bitartrate exhibited test gel degradation during the test period indicating that the gel was unstable over time ( compare the value of A Tan 81 Hz in table 13 with the value of A Tan 81 Hz in table 16).

Example 22

Effect of vasoconstrictor and antioxidant agent on the extrusion capacity and stability of the HA based gel formulation

This example is not according to the invention.

Epinephrine, at a concentration of 10 ppm, was incorporated into an HA-based gel matrix comprising either mannitol either 0.9 (w / w) or 4.5% (w / w) and treated in autoclave the gel as in example 3. The gel with 4.5% mannitol (w / w) was clear and not colored before and after autoclaving while the gel with 0.9% mannitol (w / w ) was slightly colored. The rheology analysis showed that the test gels with 0.3% lidocaine (w / w), 10 ppm epinephrine bitartrate and mannitol either 0.9 (w / w) or 4.5% (w / w) had acceptable extrusion force properties, and that the test gels showed no degradation in relation to the controls indicating that the gels were stable (table 17).

Example 23

Effect of vasoconstrictor and antioxidant agent on the long-term stability of the HA based gel formulation

This example is not according to the invention.

The formulations prepared in Example 22 were tested to determine the shelf life at 45 ° C for 60 days and compared with a HA-based gel matrix without any additive. After the test period, the gel was clear and slightly colored. The rheology analysis showed that gels with 0.3% lidocaine (w / w), 10 ppm epinephrine bitartrate and mannitol either 0.9 (w / w) or 4.5% (w / p) showed no degradation during the test period indicating that the test gels were stable over time (table 18). The gel with 4.5% mannitol (w / w) was more stable over time (compare the value of A Tan 81 Hz in table 17 with the value of A Tan 81 Hz in table 18).

Example 24

Effect of vasoconstrictor agent, antioxidant and anesthetic agent on the extrusion capacity and stability of the HA based gel formulation

This example is not according to the invention.

Epinephrine bitartrate, at a concentration of 20 ppm, was incorporated into an HA-based gel matrix comprising 0.3% lidocaine (w / w) and 4.5% (w / w) mannitol and treated autoclave the gel as in example 3. The gel was clear and not colored before autoclaving, but was slightly colored after autoclaving. The rheology analysis showed that the test gel with 20 ppm epinephrine bitartrate, 0.3% lidocaine (w / w) and 4.5% mannitol (w / w) had acceptable extrusion force properties, and that the test gel showed no degradation in relation to the controls indicating that the gel was stable (table 19).

Example 25

Effect of vasoconstrictor agent, antioxidant and anesthetic agent on the long-term stability of the HA-based gel formulation

This example is not according to the invention.

The formulation prepared in Example 24 was tested to determine the shelf life at 45 ° C for 60 days and compared to a HA based gel matrix without any additive. After the test period, the gel was clear and slightly colored. The rheology analysis showed that the test gel with 20 ppm epinephrine bitartrate, 0.3% lidocaine (w / w) and 4.5% (w / w) mannitol did not show degradation during the trial period .

Example 26

Effect of vasoconstrictor agent and anesthetic agent on the extrusion capacity and stability of the HA based gel formulation

This example is not according to the invention.

Synephrine, at a concentration of 100 ppm, was incorporated into an HA-based gel matrix comprising 0.3% lidocaine (w / w) and the gel was autoclaved as in Example 3. The gel was clear. and not colored both before and after autoclaving. The rheology analysis showed that the test gel with 100 ppm of synephrine and 0.3% lidocaine (w / w) had acceptable extrusion force properties, and that the test gel showed no degradation in relation to the controls indicating that the gel was stable (table 21).

Example 27

Effect of vasoconstrictor agent and anesthetic agent on the long-term stability of the HA based gel formulation

This example is not according to the invention.

The formulations prepared in Example 26 were tested for storage shelf life at 45 ° C for 60 days and compared with a HA-based gel matrix with 0.3% lidocaine (w / w). After the test period, the gel was clear and not colored. The rheology analysis showed that the test gel with 100 ppm of synephrine and 0.3% lidocaine (w / w) showed no degradation during the test period.

Example 28

Effect of vasoconstrictor agent and anesthetic agent on the extrusion capacity and stability of the HA based gel formulation

This example is not according to the invention.

Phenylephrine, at a concentration of 100 ppm, was incorporated into a HA-based gel matrix comprising 0.3% lidocaine (w / w) and the gel was autoclaved as in Example 3. The gel was clear. and not colored both before and after autoclaving. The rheology analysis showed that the test gel with 100 ppm of phenylephrine and 0.3% lidocaine (w / w) had acceptable extrusion force properties, and that the test gel showed no degradation in relation to the controls indicating that the gel was stable (table 23).

Example 29

Effect of vasoconstrictor agent and anesthetic agent on the long-term stability of the HA based gel formulation

This example is not according to the invention.

The formulations prepared in Example 28 were tested for storage shelf life at 45 ° C for 60 days and compared with a HA-based gel matrix with 0.3% lidocaine (w / w). After the test period, the gel was clear and not colored. The rheology analysis showed that the test gel with 100 ppm of phenylephrine and 0.3% lidocaine (w / w) showed no degradation during the test period.

Table 24

Example 30

Effect of vasoconstrictor agent and anesthetic agent on the extrusion capacity and stability of the HA based gel formulation

This example is not according to the invention.

Nafazolin, at a concentration of 100 ppm, was incorporated into a HA-based gel matrix comprising 0.3% lidocaine (w / w) and the gel was autoclaved as in Example 3. The gel was clear. and not colored both before and after autoclaving. The rheology analysis showed that the test gel with 100 ppm nafazoline and 0.3% lidocaine (w / w) had acceptable extrusion force properties, and that the test gel showed no degradation in relation to the controls indicating that the gel was stable (table 25).

Example 31

Effect of vasoconstrictor agent and anesthetic agent on the long-term stability of the HA based gel formulation

This example is not according to the invention.

The formulations prepared in Example 30 were tested to determine the shelf life at 45 ° C for 60 days and compared with a HA-based gel matrix with 0.3% lidocaine (w / w). After the test period, the gel was clear and not colored. The rheology analysis showed that the test gel with 100 ppm of nafazoline and 0.3% lidocaine (w / w) showed no degradation during the test period.

Example 32

Effect of antihemorrhagic agent and anesthetic agent on the extrusion capacity and stability of the HA based gel formulation

This example is not according to the invention.

Tranexamic acid, at a concentration of 0.4% (w / w), was incorporated into an HA-based gel matrix comprising 0.3% lidocaine (w / w) and the gel was autoclaved as in Example 3. The gel was clear and not colored both before and after autoclaving. Rheology analysis showed that the test gel with 0.4% tranexamic acid (w / w) and 0.3% lidocaine (w / w) had acceptable extrusion strength properties, and that the test gel showed no degradation in relation to the controls indicating that the gel was stable (table 27).

Example 33

Effect of antihemorrhagic agent and anesthetic agent on the long-term stability of the HA-based gel formulation

This example is not according to the invention.

The formulations prepared in Example 32 were tested to determine the shelf life at 45 ° C for 60 days and compared with an HA-based gel matrix with 0.3% lidocaine (w / w). After the test period, the gel was clear and not colored. The rheology analysis showed that the gel is stable during the test period.

Example 34

Use of the dermal filler composition to treat wrinkles

This example illustrates the use of compositions and methods disclosed herein to treat wrinkles. A 37-year-old woman has fine lines around her eyes and deeper wrinkles on the sides of her mouth. The preoperative evaluation of the person includes physical examination and routine history in addition to thorough informed consent disclosing all the relevant risks and benefits of the procedure. The physician who evaluates the individual determines that she is a candidate for the treatment of soft tissues using the compositions and methods disclosed herein. A hydrogel composition disclosed herein, such as, for example, one of the compositions of examples 11, 12, 17, 22, 14, 26, 28, 30 and 32 (of these, only the composition of example 12 is according to the invention), it is administered subcutaneously and under the superficial muscles of the affected regions once a week for three weeks; from about 1.0 ml to about 2.0 ml of composition in the affected cheek region. The individual is then monitored for approximately 7 days. The doctor evaluates the facial regions and determines that the treatment was satisfactory. Both the woman and her doctor are satisfied with the results of the procedure because she looks younger. Approximately one month after the procedure, the woman indicates that her quality of life has improved. Example 35

Use of the dermal filler composition to treat wrinkles

This example illustrates the use of compositions and methods disclosed herein to treat wrinkles. A 59-year-old man has wrinkles between his eyebrows and nasolabial folds. The preoperative evaluation of the person includes physical examination and routine history in addition to thorough informed consent disclosing all the relevant risks and benefits of the procedure. The physician evaluating the individual determines that he is a candidate for the treatment of soft tissues using the compositions and methods disclosed herein. A hydrogel composition disclosed herein, such as, for example, the compositions of examples 11, 12, 17, 22, 24, 26, 28, 30 and 32 (of these, only the composition of example 12 is according to the invention), is administered subcutaneously and under the superficial musculature of the affected regions once every 3 months; from about 1.5 ml to about 3.0 ml of composition in each affected region. The individual is then monitored for approximately 7 days. The doctor evaluates the facial regions and determines that the treatment was satisfactory. Both the man and his doctor are satisfied with the results of the procedure because he seems younger. Approximately one month after the procedure, the man indicates that his quality of life has improved.

Example 36

Use of the dermal filler composition to treat wrinkles

This example illustrates the use of compositions and methods disclosed herein to treat wrinkles. A 35-year-old woman has fine lines across her forehead. The preoperative evaluation of the person includes physical examination and routine history in addition to thorough informed consent disclosing all the relevant risks and benefits of the procedure. The doctor who evaluates the individual determines that she is a candidate for the treatment of soft tissues using the compositions and methods disclosed herein. A hydrogel composition disclosed herein, such as, for example, the compositions of examples 11, 12, 17, 22, 24, 26, 28, 30 and 32 (of these, only the composition of example 12 is according to the invention), is administered subcutaneously and under the superficial musculature of the affected regions once a week for two weeks; from about 1.0 ml to about 2.0 ml of composition in the affected cheek region. The individual is then monitored for approximately 7 days. The doctor evaluates the facial regions and determines that the treatment was satisfactory. Both the woman and her doctor are satisfied with the results of the procedure because she looks younger. Approximately one month after the procedure, the woman indicates that her quality of life has improved.

Example 37

Use of the dermal filler composition to treat wrinkles

This example illustrates the use of compositions and methods disclosed herein to treat wrinkles. A 44-year-old woman has a non-uniform texture on her right cheek resulting from a loss of collagen due to aging. The preoperative evaluation of the person includes physical examination and routine history in addition to thorough informed consent disclosing all the relevant risks and benefits of the procedure. The physician who evaluates the individual determines that she is a candidate for the treatment of soft tissues using the compositions and methods disclosed herein. A hydrogel composition disclosed herein, such as, for example, the compositions of examples 11, 12, 17, 22, 24, 26, 28, 30 and 32 (of these, only the composition of example 12 is according to the invention), is administered subcutaneously and under the superficial muscles of the affected regions once a week for three weeks; from about 3.0 ml to about 4.0 ml of composition in the affected cheek region. The individual is then monitored for approximately 7 days. The doctor evaluates the facial regions and determines that the treatment was satisfactory. Both the woman and her doctor are satisfied with the results of the procedure because she looks younger. Approximately one month after the procedure, the woman indicates that her quality of life has improved.

Example 38

Use of the dermal filler composition to treat wrinkles

This example illustrates the use of compositions and methods disclosed herein to treat wrinkles. A 62-year-old woman has wrinkles across her forehead, on the sides of her eyes, and on the nasolabial folds. The preoperative evaluation of the person includes physical examination and routine history in addition to thorough informed consent disclosing all the relevant risks and benefits of the procedure. The physician who evaluates the individual determines that she is a candidate for the treatment of soft tissues using the compositions and methods disclosed herein. A hydrogel composition disclosed herein, such as, for example, the compositions of examples 11, 12, 17, 22, 24, 26, 28, 30 and 32 (of these, only the composition of example 12 is according to the invention), is administered subcutaneously and under the superficial musculature of the affected regions; from about 1.5 ml to about 2.5 ml of composition in each affected region. The individual is then monitored for approximately 7 days. The doctor evaluates the facial regions and determines that the treatment was satisfactory. Both the woman and her doctor are satisfied with the results of the procedure because she looks younger. Approximately one month after the procedure, the woman indicates that her quality of life has improved.

Example 39

Use of the dermal filler composition to treat a scar

This example illustrates the use of compositions and methods disclosed herein to treat a scar.

A 35-year-old man has a deep scar across his chin. The preoperative evaluation of the person includes physical examination and routine history in addition to thorough informed consent disclosing all the relevant risks and benefits of the procedure. The physician evaluating the individual determines that he is a candidate for the treatment of soft tissues using the compositions and methods disclosed herein. A hydrogel composition disclosed herein, such as, for example, the compositions of examples 11, 12, 17, 22, 24, 26, 28, 30 and 32 (of these, only the composition of example 12 is according to the invention), is administered subcutaneously and under the superficial musculature of the affected regions; from about 1.0 ml to about 2.0 ml of composition in the affected region. The individual is then monitored for approximately 7 days. The doctor evaluates the facial regions and determines that the treatment was satisfactory. Both the man and his doctor are satisfied with the results of the procedure because He looks younger. Approximately one month after the procedure, the man indicates that his quality of life has improved.

Example 40

Use of the dermal filler composition to treat a facial cheek defect

This example illustrates the use of compositions and methods disclosed herein to treat a facial cheek defect.

A 28-year-old woman has a lean face. He feels that his face looks older, sad and bitter because the contour of his cheeks is less complete. The preoperative evaluation of the person includes physical examination and routine history in addition to thorough informed consent disclosing all the relevant risks and benefits of the procedure. The physician who evaluates the individual determines that she is a candidate for the treatment of soft tissues using the compositions and methods disclosed herein. A hydrogel composition disclosed herein, such as, for example, the compositions of examples 11, 12, 17, 22, 24, 26, 28, 30 and 32 (of these, only the composition of example 12 is according to the invention), is administered subcutaneously and under the superficial musculature of the cheek regions; approximately 15 ml of composition on the left and right cheeks. The individual is then monitored for approximately 7 days. The doctor evaluates the cheek tissue and determines that the treatment was satisfactory. Both the woman and her doctor are satisfied with the results of the procedure because she looks younger. Approximately one month after the procedure, the woman indicates that her quality of life has improved.

Example 41

Use of the dermal filler composition to treat a facial imperfection of the eyelids

This example illustrates the use of compositions and methods disclosed herein to treat a facial imperfection of the eyelids.

A 37-year-old woman has sunken eyes and this aspect makes her look old and violent. The preoperative evaluation of the person includes physical examination and routine history in addition to thorough informed consent disclosing all the relevant risks and benefits of the procedure. The physician who evaluates the individual determines that she is a candidate for the treatment of soft tissues using the compositions and methods disclosed herein. A hydrogel composition disclosed herein, such as, for example, the compositions of examples 11, 12, 17, 22, 24, 26, 28, 30 and 32 (of these, only the composition of example 12 is according to the invention), is administered subcutaneously and under the superficial musculature of the upper eyelid regions; approximately 2.5 ml of composition the regions of the left and right eyelids. The individual is then monitored for approximately 7 days. The doctor evaluates the eyelid regions and determines that the treatment was satisfactory. Both the woman and her doctor are satisfied with the results of the procedure because she looks younger. Approximately one month after the procedure, the woman indicates that her quality of life has improved.

Example 42

Use of the dermal filler composition to treat wrinkles

This example illustrates the use of compositions and methods disclosed herein to treat wrinkles. A 55-year-old woman has wrinkles around her eyes and cheek areas. The preoperative evaluation of the person includes physical examination and routine history in addition to thorough informed consent disclosing all the relevant risks and benefits of the procedure. The physician who evaluates the individual determines that she is a candidate for the treatment of soft tissues using the compositions and methods disclosed herein. A hydrogel composition disclosed herein, such as, for example, the compositions of examples 11, 12, 17, 22, 24, 26, 28, 30 and 32 (of these, only the composition of example 12 is according to the invention), is administered subcutaneously and under the superficial musculature of the cheek and upper eyelid regions; approximately 1.5 ml of composition in the cheek and left and right eyelid regions. The individual is then monitored for approximately 7 days. The doctor evaluates the facial regions and determines that the treatment was satisfactory. Both the woman and her doctor are satisfied with the results of the procedure because she looks younger. Approximately one month after the procedure, the woman indicates that her quality of life has improved.

Example 43

Use of the dermal filler composition to treat a breast defect

This example illustrates the use of compositions and methods disclosed herein to treat a breast defect.

A 32-year-old woman complains that the middle portions of her breast implants are visible, which accentuated the "bony" aspect of her breastbone. He also feels that his breasts are too far apart. The preoperative evaluation of the person includes physical examination and routine history in addition to thorough informed consent disclosing all the relevant risks and benefits of the procedure. The physician who evaluates the individual determines that she is a candidate for the treatment of soft tissues using the compositions and methods disclosed herein. A hydrogel composition disclosed herein, such as, for example, the compositions of examples 11, 12, 17, 22, 24, 26, 28, 30 and 32 (of these, only the composition of example 12 is according to the invention), is administered subcutaneously on the lateral sternum and the middle part of the breasts bilaterally, 15 ml on the right side and 10 ml on the left. The composition is administered in a similar manner to tears to increase the ratio of surface area to volume. The individual is then monitored for approximately 7 days. The doctor evaluates the breasts and determines that the treatment was satisfactory. Both the woman and her doctor are satisfied with the results of the procedure. Approximately one month after the procedure, the woman indicates that her quality of life has improved. Example 44

Use of the dermal filler composition for breast augmentation

This example illustrates the use of compositions and methods disclosed herein for breast augmentation.

A 28-year-old woman has micromastia or breast hypoplasia. The preoperative evaluation of the person includes physical examination and routine history in addition to thorough informed consent disclosing all the relevant risks and benefits of the procedure. The physician who evaluates the individual determines that she is a candidate for the treatment of soft tissues using the compositions and methods disclosed herein. A hydrogel composition disclosed herein, such as, for example, the compositions of examples 11, 12, 17, 22, 24, 26, 28, 30 and 32 (of these, only the composition of example 12 is according to the invention), is administered subcutaneously using the axillary, periareolar and inframammary routes bilaterally, 90 ml on the right side and 145 ml on the left. The composition is administered in a similar manner to tears to increase the ratio of surface area to volume. The individual is then monitored for approximately 7 days. The doctor evaluates the breasts and determines that the treatment was satisfactory. Both the woman and her doctor are satisfied with the results of the procedure. Approximately one month after the procedure, the woman indicates that her quality of life has improved.

Finally, the terminology used in this document is solely for the purpose of describing particular embodiments.

As used herein, the term "approximately" means that the element, parameter or term qualified in this way covers a range of plus or minus ten, preferably 5 and most preferably 1 percent above and below the value of the mentioned element, parameter or term. At a minimum, and not in an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter must be interpreted at least in view of the number of significant digits notified and applying usual rounding techniques. Regardless of whether the ranges and numerical parameters that expose the wide scope of the invention are approximations, the numerical values set forth in the specific examples are reported as accurately as possible. However, any numerical value inherently contains certain errors that necessarily result from the standard deviation found in their respective test measurements.

It should be interpreted that the terms "a", "a", "the" and similar references used in the context of describing the invention (especially in the context of the following claims) cover both the singular and the plural, unless otherwise indicated in this document or is clearly contradicted by the context. It is intended that the mention of ranges of values in this document simply serve as an abbreviated method of individually referring to each independent value that is within the range. All methods described herein may be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by the context. It is intended that the use of each and every one of the examples, or example terms (for example, "as") provided herein simply clarifies the invention better and does not imply a limitation as to the scope of the claimed invention. else.

The specific embodiments disclosed herein may be further limited in the claims using the expressions consisting of or consisting essentially of. When used in the claims, either as presented or added according to a modification, the transition term "consisting of" excludes any element, step or component not specified in the claims. The term of Transition "consisting essentially of" limits the scope of a claim to the specified materials or stages and those that do not significantly affect the basic (s) and new (s) characteristic (s). This document describes and allows the inherent or express realization of the embodiments of the invention thus claimed. All patents, patent publications and other publications referred to and identified herein are provided solely by their disclosure prior to the filing date of this application. Nothing in this regard should be construed as an admission that the inventors have no right to precede such disclosure thanks to a prior invention or for any other reason. All statements regarding the date or representation regarding the content of these documents are based on the information available to applicants and does not constitute any admission as to the accuracy of the dates or content of those documents.

87 members in 10 offices

This recordMember, by publication datePriority claim

Priority claims6

Priority claims
Document	Office	Kind	Date
687048	United States of America	–	2010-01-13
68704810	United States of America	A	2010-01-13
714377	United States of America	–	2010-02-26
71437710	United States of America	A	2010-02-26
956542	United States of America	–	2010-11-30
95654210	United States of America	A	2010-11-30

Members87

Family members, oldest first
Document	Office	Kind
US2011171286A1	United States of America	A1	2011-07-14
US2011171310A1	United States of America	A1	2011-07-14
US2011171311A1	United States of America	A1	2011-07-14
US2011172180A1	United States of America	A1	2011-07-14
CA2786968A1	Canada	A1	2011-07-21
CA2905371A1	Canada	A1	2011-07-21
WO2011086458A1	World Intellectual Property Organization (WIPO)	A1	2011-07-21
CA2824483A1	Canada	A1	2012-07-19
WO2012097272A1	World Intellectual Property Organization (WIPO)	A1	2012-07-19
AU2011206389A1	Australia	A1	2012-08-09
US2012208890A1	United States of America	A1	2012-08-16
US2012225842A1	United States of America	A1	2012-09-06
US2012232030A1	United States of America	A1	2012-09-13
WO2012097272A8	World Intellectual Property Organization (WIPO)	A8	2012-09-20
KR20120125293A	Republic of Korea	A	2012-11-14
EP2523701A1	European Patent Office (EPO)	A1	2012-11-21
AU2012101836A4	Australia	A4	2013-01-17
US2013072453A1	United States of America	A1	2013-03-21
JP2013517263A	Japan	A	2013-05-16
AU2012205418A1	Australia	A1	2013-08-01
EP2663342A1	European Patent Office (EPO)	A1	2013-11-20
KR20140033337A	Republic of Korea	A	2014-03-18
JP2014513988A	Japan	A	2014-06-19
US8946192B2	United States of America	B2	2015-02-03
US2015038456A1	United States of America	A1	2015-02-05
AU2012205418B2	Australia	B2	2015-03-26
AU2011206389B2	Australia	B2	2015-07-02
AU2015203482A1	Australia	A1	2015-07-16
US9114188B2	United States of America	B2	2015-08-25
JP5788412B2	Japan	B2	2015-09-30
AU2015234293A1	Australia	A1	2015-10-22
US2015306280A1	United States of America	A1	2015-10-29
US2015314040A1	United States of America	A1	2015-11-05
JP2015205921A	Japan	A	2015-11-19
EP2959923A1	European Patent Office (EPO)	A1	2015-12-30
US9333160B2	United States of America	B2	2016-05-10
JP5960894B2	Japan	B2	2016-08-02
US2016220729A1	United States of America	A1	2016-08-04
CA2905371C	Canada	C	2016-08-16
CA2824483C	Canada	C	2016-08-30
EP2523701B1	European Patent Office (EPO)	B1	2016-09-07
JP2016166254A	Japan	A	2016-09-15
EP2959923B1	European Patent Office (EPO)	B1	2016-11-09
PT2523701T	Portugal	T	2016-12-20
EP3138585A1	European Patent Office (EPO)	A1	2017-03-08
HK1219240A	Hong Kong, China	A	2017-03-31
HK1219240A1	Hong Kong, China	A1	2017-03-31
AU2015234293B2	Australia	B2	2017-04-27
US9655991B2	United States of America	B2	2017-05-23
ES2613528T3	Spain	T3	2017-05-24
ES2614434T3	Spain	T3	2017-05-31
JP6152345B2	Japan	B2	2017-06-21
US2017216488A1	United States of America	A1	2017-08-03
AU2017206247A1	Australia	A1	2017-08-10
KR20170094463A	Republic of Korea	A	2017-08-17
KR101768733B1	Republic of Korea	B1	2017-08-30
JP6208293B2	Japan	B2	2017-10-04
JP2017210491A	Japan	A	2017-11-30
US9855367B2	United States of America	B2	2018-01-02
KR101830591B1	Republic of Korea	B1	2018-02-20
CA2786968C	Canada	C	2018-02-27
US2018078674A1	United States of America	A1	2018-03-22
KR20180101613A	Republic of Korea	A	2018-09-12
EP3138585B1	European Patent Office (EPO)	B1	2018-11-21
US10220113B2	United States of America	B2	2019-03-05
AU2017206247B2	Australia	B2	2019-03-28
AU2019201589A1	Australia	A1	2019-04-04
JP6509979B2	Japan	B2	2019-05-08
ES2716396T3This record	Spain	T3	2019-06-12
US2019192732A1	United States of America	A1	2019-06-27
EP3511028A1	European Patent Office (EPO)	A1	2019-07-17
JP2019131586A	Japan	A	2019-08-08
US10449268B2	United States of America	B2	2019-10-22
EP2663342B1	European Patent Office (EPO)	B1	2020-03-25
KR102111170B1	Republic of Korea	B1	2020-05-15
KR102127060B1	Republic of Korea	B1	2020-06-26
KR20200078672A	Republic of Korea	A	2020-07-01
AU2019201589B2	Australia	B2	2020-07-09
EP3682911A1	European Patent Office (EPO)	A1	2020-07-22
US10806821B2	United States of America	B2	2020-10-20
AU2020250203A1	Australia	A1	2020-11-05
ES2805329T3	Spain	T3	2021-02-11
US2021077658A1	United States of America	A1	2021-03-18
EP3511028B1	European Patent Office (EPO)	B1	2021-04-07
EP3862029A1	European Patent Office (EPO)	A1	2021-08-11
US2023158203A1	United States of America	A1	2023-05-25
US2025288718A1	United States of America	A1	2025-09-18

Stable hydrogel compositions including additives

Abstract

Term

Priority claims6

Members87

Numbers

Titles2

Classification