Implants for sculpting, augmenting or correcting facial features such as chin

Abstract

To provide: an injectable device, comprising a hyaluronic acid-based composition, useful for long lasting facial sculpting and correction of facial features, for example, for augmenting and shaping a profile, including for example, the chin, jawline or the nose in a human being; and methods of treatment.SOLUTION: Implants provide improved volumizing and lift properties relative to other HA-based injectables, due to a combination of mechanical properties including high elasticity and high cohesivity, while still being easily injectable with a thin needle.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates generally to injectable compositions, and more specifically to injectable implants for adding structure and contour to the lower face. [Background technology]

[0002] Dermal fillers are injectable biocompatible compositions well known to correct wrinkles and folds and add volume to the face. Hyaluronic acid (HA) is still considered by many to be one of the most desirable dermal fillers because it is temporary and reversible without the risk of allergic reactions. Many hyaluronic acid-based dermal fillers have been developed specifically to treat wrinkles and folds in the skin. To be useful for facial contouring or substantial volume expansion, it would be advantageous to increase the bulking effect, also referred to as "lift", of the composition. It would also be advantageous to maximize the resistance of the composition to shear and normal deformations that occur in facial soft tissues. One drawback of maximizing these resistances, such as elasticity and cohesiveness, is that it would be expected to increase the viscosity of the composition to such an extent that it would be difficult to inject with a fine needle.

[0003] Thus, there is a great need for an injectable HA-based implant that is effective for adding substantial volume to the face, for example specifically designed for contouring the lower face, for example for expanding or correcting the chin, for example for correcting a receding chin, or for example for expanding or correcting the nose. It would be highly advantageous if such an implant, despite its high viscosity, remained easily injectable with a fine needle. Chin shape has been recognized as an important facial feature that elicits strong aesthetic values ​​that tend to accompany an individual's personality traits. A weak or insufficient chin is commonly classified as a "weak chin," while a prominent chin is classified as a "strong chin," both of which connote strong or weak personality traits. Some studies suggest that faces with average proportions are considered most attractive, and that small features, including a small chin, are interpreted as attractive in women, while enlarged chins and jaws as a result of maturation are interpreted as attractive in men. The appearance of the chin is a determining factor in perceived attractiveness and may even affect an individual's psychosocial well-being.

[0004] Chin augmentation is traditionally performed by surgically placing permanent implants on the chin. The procedure is now one of the most commonly performed aesthetic surgical procedures according to the American Society for Aesthetic Plastic Surgery (ASAPS), with a 71% increase since 2010. Receding chin is the result of changes in the growth of the lower third of the face due to maturation, trauma, or facial aging, which can exacerbate deformities or asymmetries caused by maturation and trauma. Mandibular shape affects the mouth, chin, and neck. As an individual ages, soft tissue atrophy becomes more prominent due to decreased skeletal support of this area, accentuating the chin and reducing chin projection, making the jawline appear weaker. Chin deformity is one of the most common bony anomalies of the face, the most common of which is horizontal micrognathia, characterized by the presence of normal vertical height with a receding, bony chin. Since the mandible and chin form the framework of the lower face, expansion techniques to treat aging-related chin recession and contour changes in the chin area or to treat micrognathia have been studied for decades. The approach to correct chin recession is to add volume, and procedures include chin implants, genioplasty, and injection of semi-permanent fillers such as silicone and polymethylmethacrylate microspheres, and calcium hydroxyapatite. However, all of these procedures have drawbacks. For example, chin implants and genioplasty involve painful surgery that does not necessarily result in correction of chin recession and aesthetic harmony in the area. This procedure may exacerbate bone resorption and infection, which may result in the need for implant removal. Injection of semi-permanent fillers presents a trade-off between the volume expansion potential and adverse events associated with semi-permanent fillers. Summary of the Invention

[0005] Thus, there is provided an injectable implant for facial sculpting, for example to augment, correct, restore or shape volume in the human chin and other facial features. The present invention provides a temporary and reversible HA-based structural gel that is specifically designed to provide a safe and minimally invasive method for shaping facial volume or facial contour. The combination of mechanical properties such as high elasticity and high cohesion of the implant provides improved volume expansion and lifting properties compared to other HA-based injectable materials, while still being easily injected with a thin needle. The implant can be used to inject into subcutaneous and / or supraperiosteal spaces. In many embodiments, the implant can be molded after injection, and thus can be shaped, contoured and molded over the injected area, such as the chin and jaw area.

[0006] The implant generally comprises a composition comprising hyaluronic acid (HA) crosslinked with a crosslinker selected from the group consisting of 1,4-butanediol diglycidyl ether (BDDE), 1,4-bis(2,3-epoxypropoxy)butane, 1,4-bisglycidyloxybutane, 1,2-bis(2,3-epoxypropoxy)ethylene, and 1-(2,3-epoxypropyl)-2,3-epoxycyclohexane. In some embodiments, the implant generally comprises a composition comprising hyaluronic acid (HA) crosslinked with BDDE. The composition is suitable for injection, for example, through a fine gauge needle, and can expand, correct, or create volume or lift in the face, for example, the lower face, for example, the chin or jaw, or the mid-face, for example, the nose.

[0007] In some embodiments, the HA concentration is greater than 20 mg / g. In some embodiments, the HA concentration is about 21 mg / g, or about 22 mg / g, or about 23 mg / g, or about 24 mg / g, or about 25 mg / g, or about 26 mg / g, or about 27 mg / g, or about 28 mg / g, or about 29 mg / g, or about 30 mg / g or more. In other embodiments, the composition has a HA concentration of 22.5 mg / g to 27.5 mg / g, e.g., 25.0 mg / g. In some embodiments, the method adds volume and lift to a patient's chin or jawline or nose after administration or injection into the patient's chin or jawline for a period ranging from about 9 months to about 24 months. The composition is moldable, for example, by physical manipulation of tissues near the implant for a period of time after injection. The composition may have a setting time, such that the composition is no longer moldable and substantially retains its shape after implantation or injection within about 24 to about 48 hours of implantation.

[0008] In some embodiments, the composition further comprises an anesthetic, such as lidocaine HCl. For example, the composition may comprise about 0.3% (w / w) lidocaine HCl. In a preferred embodiment, the composition comprises hyaluronic acid gel, preferably in an amount of about 25 mg, and lidocaine hydrochloride, preferably in an amount of about 3 mg, in a volume of phosphate buffer, pH 7.2, preferably in a volume of 1 mL. In some embodiments, the composition is made of a mixture of low molecular weight hyaluronic acid and high molecular weight hyaluronic acid. For example, the crosslinked hyaluronic acid may be comprised of about 50% to about 100% low molecular weight hyaluronic acid before crosslinking with a crosslinking agent. In some embodiments, the crosslinked hyaluronic acid is comprised of about 70% to about 90% low molecular weight hyaluronic acid before crosslinking with a crosslinking agent. In some embodiments, the crosslinked hyaluronic acid is comprised of about 90% low molecular weight hyaluronic acid before crosslinking with a crosslinking agent.

[0009] Using primarily low molecular weight HA, e.g., greater than about 50%, e.g., about 70% or about 90%, low molecular weight HA, prior to crosslinking, rather than primarily high molecular weight HA, results in a stronger, longer-stable, moldable hydrogel with high cohesiveness and elasticity, more particularly suited for facial shaping and expansion via subcutaneous or supraperiosteal injection. In some embodiments, the HA has a degree of cross-linking of about 4% to about 12%. For example, the HA has a degree of cross-linking of about 4%, or about 6%, or about 8%, or about 10%. In some embodiments, the HA has a degree of cross-linking of about 6.5%. In other embodiments, the HA has a degree of cross-linking of about 7.5%, or about 8.5%, or about 9.5%, or about 10.5%. In another aspect of the present invention, a method for correcting chin recession in a patient is provided. The method generally comprises administering to the periosteum of the patient's chin an effective amount of a composition comprising hyaluronic acid (HA) crosslinked with BDDE to a crosslinking degree of about 10%, the composition having an HA concentration of more than 20 mg / g. For example, in a preferred embodiment, the HA concentration is about 25 mg / g. In a specific embodiment, the composition comprises about 10% (w / w) low molecular weight hyaluronic acid (NaHA) crosslinked with BDDE, formulated with 0.3% (w / w) lidocaine hydrochloride in phosphate buffer at pH 7.2 at a concentration of about 25 mg / g and supplied in a 1 mL COC (cyclic olefin copolymer) syringe.

[0010] The composition can be extruded through a fine gauge needle, for example a needle having a gauge of 25 G, 26 G, 27 G, 28 G, 29 G or 30 G. In a particular embodiment, the needle is a 27 Gauge x 13 mm / 27G1 / 2 x 26 mm needle. The extrusion force is the force (in Newtons, N) required to extrude a composition from the syringe at a certain rate. For example, using a 1 mL COC syringe provided and a TSK 27G×13 mm needle, the extrusion force of some of the compositions of the present invention may be about 4N to about 15N at 13 mm / min, which is considered extremely small. For example, the extrusion force may be about 7N to about 12N, preferably about 8N to about 10N. In another aspect of the invention, a method is provided for contouring or correcting a facial feature, such as a receding chin, in an individual. The method includes, for example, administering subcutaneously to a treatment area of ​​a patient an effective amount, such as about 1.0 ml or more, such as about 2.0 ml or more, such as about 3.0 ml or more, such as 4.0 ml, of a composition of the invention. The facial feature to be improved or contoured may be the patient's chin, such as a receding chin. The treatment area includes an area selected from the group consisting of the pogonion, the mentum, the left premaxillary groove, the right premaxillary groove, and the wrinkles under the lip. The treatment may include administering the composition to two or more treatment areas. Every feature described in this specification, and every combination of two or more such features, is included within the scope of the present invention, unless the features included in such a combination are mutually inconsistent. [Brief description of the drawings]

[0011] [Figure 1]FIG. 1 illustrates facial contours and landmarks for calculating the patient's G-Sn-Pog angle. [Diagram 2] FIG. 1 shows the average Burstone angle of the chin. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0012] Certain terms used herein are intended to refer to the following definitions, which are set forth in detail below. In the event that a definition of a term differs from the commonly used meaning of that term, applicants intend to use the definition set forth below, unless otherwise indicated. The term "about" in relation to a numerical value is readily understood by one of ordinary skill in the art and preferably means that the particular value may vary by ±10%. With respect to the endpoints of a range, the modifier "about" preferably means that the lower endpoint may be decreased by 10% and the upper endpoint may be increased by 10%. It is also intended that each numerical value or range disclosed in this application may be an absolute value, i.e., the modifier "about" may be omitted.

[0013] All numbers herein referring to the "molecular weight" of HA should be understood to refer to the weight average molecular weight (Mw) in Daltons. The molecular weight of HA is calculated from intrinsic viscosity measurements using the Mark Houwink relationship: Intrinsic viscosity (L / g)=9.78×10 -5 ×Mw0.690 Intrinsic viscosity is determined according to the European Pharmacopoeia (HA Monograph N o The measurement shall be performed according to the procedure defined in IEC 1472, 01 / 2009.

[0014] Unless otherwise stated, molecular weight refers to weight average molecular weight (Mw). The HA used to prepare the compositions of the present invention may comprise a mixture of high molecular weight HA, low molecular weight HA, and / or medium molecular weight HA, with the high molecular weight HA having a molecular weight greater than about 2,000,000 Da (or an intrinsic viscosity greater than 2.2 L / g) and the low molecular weight HA having a molecular weight less than about 1,000,000 Da (or an intrinsic viscosity less than 1.4 L / g). For example, the high molecular weight HA in the compositions of the present invention may have an average molecular weight in the range of about 2 MDa to about 4.0 MDa, such as about 3.0 MDa (2.9 L / g). In another example, the high molecular weight HA may have an average molecular weight of about 2.4 MDa to about 3.6 MDa, such as about 3.0 MDa. The high molecular weight HA may have an intrinsic viscosity greater than about 2.2 L / g, such as about 2.5 L / g to about 3.3 L / g.

[0015] The low molecular weight HA may have a molecular weight of about 200,000 Da (0.2 MDa) to less than 1.0 MDa, such as about 300,000 Da (0.3 MDa) to about 750,000 Da (1.1 L / g), up to but not exceeding 0.99 MDa (1.4 L / g). The low molecular weight HA may have an intrinsic viscosity of less than about 1.40 L / g, such as about 0.6 L / g to about 1.2 L / g. Preferably, there is no overlap between the molecular weight distributions of the low and high molecular weight HA materials. Preferably, the mixture of low and high molecular weight HA has a bimodal molecular weight distribution. The mixture may have a multimodal distribution. In one embodiment of the invention, the composition comprises HA having a high molecular weight component and a low molecular weight component, the high molecular weight component having a weight average molecular weight at least twice the weight average molecular weight of the low molecular weight component.

[0016] As used herein, "degree of crosslinking" refers to the intermolecular linkages that connect individual HA polymer molecules or monomer chains into a permanent structure or soft tissue filler composition disclosed herein. Furthermore, for purposes of this disclosure, the degree of crosslinking is further defined as the percent weight ratio of crosslinker to HA monomer units in the crosslinked portion of the HA-based composition, as measured by the weight ratio of crosslinker to HA monomer. As used herein, "uncrosslinked HA" refers to individual HA polymer molecules that are not crosslinked. Uncrosslinked HA generally remains water soluble. An uncrosslinked HA fraction may be included in the composition, for example to act as a lubricant and facilitate injection into facial tissue. Such compositions may include an uncrosslinked HA fraction, and the uncrosslinked HA added is present in a concentration of about 0.1 mg / g to about 3 mg / g. Preferably, the uncrosslinked HA may be present in a concentration of about 0.2 mg / g to about 1.5 mg / g. In other embodiments, no uncrosslinked HA is present in the gel, or at least no uncrosslinked HA is added to the gel to act as a lubricant. The compositions described herein exhibit a high level of elasticity, expressed as a modulus (G') value measured by oscillatory rheology at a strain of 0.8%, measured over a range of frequencies using a cone-plate system. In some embodiments, the elastic modulus of the composition measured at a frequency of 5 Hz is about 500 Pa to about 900 Pa. This is considered high elasticity in the context of HA-based dermal fillers, contributing to the lifting effect by increasing the implant's resistance to shear deformation.

[0017] Cohesion refers to the ability of a gel to stick to itself, e.g. resistance to cutting and the ability of the gel to be stretched or compressed without breaking into pieces. The cohesion of a gel according to the invention can be quantified as follows (see Derek Jones "Injectable Filers: Principles and Practice", Wiley, 2011, Chapter 3): A small sample of the gel (e.g. 1 mL) is placed on the flat surface of the rheometer. The sample is placed so as to form a small pile. A movable top plate is placed on top of the sample, completely covering it so that the sample is not visible, e.g. when looking at the plate perpendicular to the surface of the rheometer. To ensure this, a plate with dimensions larger than the dimensions of the sample must be selected. Ideally, the center of the plate is placed on the sample. Typically, a top plate with a diameter of 25 mm is used for 1 mL of gel material.

[0018] In the next step of the measurement, the gap between the movable plate and the surface is adjusted to 2.5 mm. The force (Fn) exerted by the sample in the normal direction on the plate is recorded while the plate is moved slowly and steadily from this initial position to a gap width of 0.9 mm within 2 min. Once the gap width reaches 0.9 mm, the system is allowed to relax for 12 minutes. During this time, measurements are continued. Five measurements are taken. To normalize the measured forces, the first five Fn values ​​measured at the beginning of the test are all averaged (arithmetic mean) and the average value obtained is subtracted from all other data points. The maximum force at the end of the compression part of the test (when the gap width between the upper plate and the flat surface reaches a minimum of 0.9 mm) is called the compression force and is a characteristic value for determining the cohesiveness of the gel.

[0019] Specifically, a force of 20 gmf (0.1962 N) or greater indicates a cohesive material within the meaning of the present invention. Gels with lower compressive force values ​​are generally not considered cohesive in the context of the present invention. The accuracy of this measurement is on the order of ±5 gmf. In the context of the present invention, the injectable formulation has a high cohesiveness of at least about 60 gmf, for example about 60 to about 200 gmf. For example, in a preferred embodiment, the cohesiveness is about 60 to about 100 gmf, which provides the implant with a high resistance to pressure and normal forces in the facial soft tissues. In the context of dermal fillers, cohesiveness as defined above, together with its elastic modulus G', contributes to the lifting capacity (clinically referred to as the volume expansion / bulkiness effect) clinically provided by the gel. Cohesive gels exhibit good volume expansion effects, whereas non-cohesive or weakly cohesive materials with similar elastic modulus have less lifting capacity because the non-cohesive gel material spreads more than the cohesive material when subjected to vertical compression. In the context of the present invention, the composition exhibits both a high level of elastic modulus and a high level of cohesiveness to maximize the lifting effect upon implantation.

[0020] In certain advantageous exemplary embodiments, the implant or filler of the present invention generally comprises a cohesive and sterile composition that can be implanted subcutaneously or epiperiosteally in a patient in need thereof, for example, in the chin area, nose or jawline of a patient desiring to improve facial contours or enhance the chin. The composition generally comprises crosslinked hyaluronic acid (HA) crosslinked with 1,4-butanediol diglycidyl ether (BDDE), and the composition has an HA concentration of greater than 20 mg / g. For example, in some embodiments, the HA concentration is about 22.5 mg / g or about 25 mg / g or about 27.5 mg / g. The HA used for crosslinking may be made from a mixture of low molecular weight hyaluronic acid and high molecular weight hyaluronic acid. In some embodiments, the composition has an elastic modulus of about 500 Pa to about 900 Pa at 5 Hz and a cohesiveness of greater than about 60 gmf. Advantageously, in some embodiments, the composition exhibits an extrusion force of about 4N to about 15N, such as about 8N to about 10N, at 13mm / min using a 1mL COC syringe and a 27G x 13mm needle.

[0021] In one aspect of the present invention, injectable HA-based implants are provided that have improved lifting capacity compared to commercially available HA-based dermal fillers.The implants of the present invention are alternatively referred to as dermal fillers and subdermal fillers in some examples of this disclosure.The implants and fillers of the present invention are based on hyaluronic acid (HA) and pharma-ceutically acceptable salts of HA, such as sodium hyaluronate (NaHA).Methods of making these compositions and methods of using these compositions are also provided.

[0022] As used herein, hyaluronic acid (HA) refers to any hyaluronic acid salt, including but not limited to sodium hyaluronate (NaHA), potassium hyaluronate, magnesium hyaluronate, calcium hyaluronate, and combinations thereof. Both HA and its pharma- ceutically acceptable salts can be used in the present invention.

[0023] Further, in embodiments using an anesthetic agent, the concentration of the one or more anesthetic agents is an amount effective to reduce pain experienced upon injection of the composition. The at least one local anesthetic agent may be selected from the group consisting of ambucaine, amoranone, amylocaine, benoxinate, benzocaine, betoxycaine, biphenamine, bupivacaine, butacaine, butamben, butanilicaine, butetamine, butoxycaine, carticaine, chloroprocaine, cocaethylene, cocaine, cyclomethycaine, dibucaine, dimethisoquin, dimethocaine, diperodone, dicyclomine, ecgonidine, ecgonine, ethyl chloride, etidocaine, beta-eucaine, euprosin, phenalcomine, formocaine, hexylcaine, hydroxytetracaine, isobutyl p-aminobenzoate, The anesthetic agent may be selected from the group consisting of leucinocaine mesylate, levoxadrol, lidocaine, mepivacaine, meprylcaine, metabutoxycaine, methyl chloride, myrtecaine, naepain, octocaine, orthocaine, oxetazaine, parethoxycaine, phenacaine, phenol, piperocaine, pyridocaine, polidocanol, pramoxine, prilocaine, procaine, propanocaine, proparacaine, propipocaine, propoxycaine, pseudococaine, pyrrocaine, ropivacaine, salicyl alcohol, tetracaine, tricaine, trimecaine, zolamine, and salts thereof. In one embodiment, the at least one anesthetic agent is lidocaine, such as in the form of lidocaine HCl. The compositions described herein may have a lidocaine concentration of about 0.1% to about 5% by weight of the composition, for example about 0.2% to about 1.0% by weight of the composition. In one embodiment, the composition has a lidocaine concentration of about 0.3% (w / w) of the composition. The concentrations of lidocaine in the compositions described herein are therapeutically effective, meaning that the concentration is appropriate to provide therapeutic benefit without harming the patient.

[0024] The compositions of the present invention can be prepared by the steps of providing a purified HA material, for example in the form of NaHA fibers, having a desired molecular weight, for example a mixture of low and high molecular weight HA in a desired ratio, hydrating the HA material, and crosslinking the hydrated HA material with a suitable crosslinking agent in a desired ratio to form a crosslinked HA-based gel. The gel is then neutralized and swollen. If desired, a solution containing lidocaine, preferably an acid salt of lidocaine chlorohydrate, may be added to form a HA / lidocaine gel. The gel may be homogenized, for example by stirring or mixing with the application of shear forces. The homogenized composition may then be filled into a syringe. The syringe is then sterilized by autoclaving at an effective temperature and pressure. For example, the composition is sterilized by autoclaving, for example by exposing the composition to a temperature of at least about 120° C. to about 130° C. and / or a pressure of at least about 12 pounds per square inch (PSI) to about 20 PSI for at least about 1 minute to about 15 minutes. Sterile syringes are packaged with fine gauge needles for use by the physician.

[0025] More specifically, the initial unpurified HA material may comprise NaHA fiber or powder, e.g., bacterially derived NaHA fiber. Alternatively, the HA material may be from an animal source, e.g., from a rooster's comb. It is contemplated that the HA material may be a combination of unpurified materials that include HA and at least one other polysaccharide, e.g., another glycosaminoglycan (GAG). In one method of preparing the composition, the purified and dried NaHA fibers are hydrated in an alkaline solution to prepare an uncrosslinked NaHA gel. Any suitable alkaline solution can be used to hydrate NaHA in this step, including but not limited to aqueous solutions containing sodium hydroxide (NaOH), potassium hydroxide (KOH), sodium bicarbonate (NaHCO3), lithium hydroxide (LiOH), and the like. The resulting alkaline gel will have a pH greater than 7.5. The resulting alkaline gel may have a pH greater than 9, or a pH greater than 10, or a pH greater than 12, or a pH greater than 13.

[0026] The next step in the manufacturing process may include cross-linking the hydrated alkaline NaHA gel with a suitable cross-linking agent. The cross-linking agent may be any agent known to be suitable for cross-linking polysaccharides and their derivatives through their hydroxyl groups. One particularly suitable cross-linking agent is 1,4-butanediol diglycidyl ether (BDDE). In another embodiment, cross-linking of the HA is achieved during hydration of the HA fibers by hydrating a combination of high and low molecular weight fibers in an alkaline solution containing a cross-linking agent, such as BDDE. The degree of cross-linking in the HA component of the compositions of the invention is at least about 4% and up to about 12% (w / w) BDDE / HA, such as about 10%, such as about 8%, such as about 6%, such as about 4%. In certain embodiments, the degree of cross-linking is about 6.5%. In some embodiments, the HA has a degree of cross-linking of about 6.5%. In other embodiments, the HA has a degree of cross-linking of about 7.5%, or about 8.5%, or about 9.5%, or about 10.5%.

[0027] The hydrated crosslinked HA gel can be swelled to obtain the desired HA concentration. This step can be accomplished by neutralizing the crosslinked hydrated HA gel with an aqueous solution containing an acid, such as HCl. The gel is then allowed to swell in phosphate buffered saline (PBS) at low temperature for a sufficient period of time. The gel can then be purified by conventional means, such as dialysis against phosphate buffer or precipitation with alcohol, to recover the crosslinked material, stabilize the pH of the material, and remove any unreacted crosslinker. Additional water or a slightly alkaline aqueous solution can be added to achieve the desired concentration of HA in the composition. In some embodiments, the HA concentration of the composition is adjusted to greater than 20 mg / g, for example, about 25 mg / g. In other embodiments, the HA concentration is adjusted to obtain an HA concentration of about 21 mg / g, about 22 mg / g, about 23 mg / g, about 24 mg / g, about 26 mg / g, about 27 mg / g, about 28 mg / g, about 29 mg / g, or about 30 mg / g.

[0028] In embodiments where the final composition is to include an anesthetic such as lidocaine, the pH of the purified crosslinked HA gel may be adjusted to make it slightly alkaline such that the gel has a pH greater than about 7.2, for example, about 7.5 to about 8.0. This step may be accomplished by any suitable means, such as by adding to the gel an appropriate amount of dilute NaOH, KOH, NaHCO3 or LiOH, or any other alkaline molecule, solution and / or buffer composition.

[0029] An effective amount of an anesthetic, such as lidocaine, such as lidocaine HCl, is then added to the purified cross-linked NaHA gel. For example, in some embodiments, lidocaine HCl is provided in a powder form and solubilized using water for injection (WFI). The gel is kept neutral by buffering or by adjustment with dilute NaOH so that the final HA / lidocaine composition has a desired substantially neutral pH. The final composition containing lidocaine may have a lidocaine concentration of at least about 0.1% to about 5% by weight of the composition, such as about 2% by weight, or in another example, about 0.3% by weight. After addition of the lidocaine HCl or during addition of the lidocaine HCl, the HA / lidocaine gel or composition is homogenized to form a highly homogenous HA / lidocaine gel having the desired consistency and stability. Preferably, the homogenization step includes mixing, stirring, or agitating the gel with controlled shear forces to obtain a substantially homogenous mixture.

[0030] After the HA composition is homogenized, an amount of uncrosslinked HA solution or gel may be added to the composition to increase lubricity. In some embodiments, a solution of uncrosslinked HA is not added to the composition after homogenization. The composition may then be introduced into a syringe and sterilized. Syringes useful according to the present specification include any syringe known in the art capable of delivering a viscous dermal filler composition. The syringe generally has an internal volume of about 0.4 mL to about 3 mL, more preferably about 0.5 mL to about 1.5 mL, or about 0.8 mL to about 2.5 mL. This internal volume is related to the internal diameter of the syringe, which plays an important role in the extrusion force required to inject a highly viscous dermal filler composition. The internal diameter is generally about 4 mm to about 9 mm, more preferably about 4.5 mm to about 6.5 mm, or about 4.5 mm to about 8.8 mm. Furthermore, the extrusion force required to deliver the HA composition from the syringe depends on the gauge of the needle. The gauge of the needle used generally includes a gauge of about 18 G to about 40 G, more preferably about 25 G to about 33 G, or about 25 G to about 30 G. For example, in some embodiments, the composition is packaged in a 1 mL syringe and injected using a 27G needle.

[0031] One preferred method of sterilizing the filled syringe is by autoclaving. Autoclaving can be accomplished by applying a combination of heat, pressure and moisture to the sample that needs to be sterilized. Many different sterilization temperatures, pressures and cycle times can be used for this step. For example, the filled syringe can be sterilized at a temperature of at least about 120° C. to about 130° C. or higher. Moisture may or may not be used. The pressure applied depends in some embodiments on the temperature used in the sterilization process. The sterilization cycle can be at least about 1 minute to about 20 minutes or more. Another method of sterilization involves the use of gas species known to kill or eliminate infectious agents, preferably ethylene oxide is used as the sterilizing gas, which is known in the art to be useful for sterilizing medical devices and products.

[0032] Further sterilization methods include the use of radiation sources known in the art to kill or remove infectious materials. A beam of radiation is directed at a syringe containing the HA composition, with the wavelength of energy killing or removing the undesirable infectious materials. Preferred energies of use include, but are not limited to, ultraviolet (UV) light, gamma radiation, visible light, microwaves, or any other wavelength or range of wavelengths that kill or remove the undesirable infectious materials, preferably without substantially altering or degrading the HA composition. Preferably, the compositions of the invention remain stable when stored for extended periods of time. For example, many of the compositions of the invention have a shelf life of about 6 months, about 12 months, about 18 months, or about 24 months or more when stored at a temperature of about 2-25° C. In certain embodiments, the compositions are stable at a temperature of 2-25° C. for at least 18 months. In other specific embodiments, the compositions are stable at a temperature of 2-25° C. for at least 24 months.

[0033] The technique of injection of the composition of the present invention may vary depending on the angle and direction of the bevel, and the amount administered. In general, to achieve optimal correction and aesthetic chin contour, the composition of the present invention is injected subcutaneously and / or supraperiosteally to increase chin projection, with treatment limited to the mandibular point, chin (underside of chin), premandibular sulcus (left and right), and underlip (chin) crease. The appropriate injection volume will be determined by the responsible physician, but generally should not exceed a maximum total volume of about 4.0 mL for the initial and additional treatments combined. Total volumes up to about 4.0 mL are permitted for repeat treatments. If the treatment area is defined as the mandibular point, chin, premandibular sulcus (left and right), and underlip (chin) crease, injection of about 2.0 mL or less is permitted for any single treatment area during any treatment period. Prior to injection of the compositions of the present invention, the treatment area must be thoroughly disinfected to ensure that the injectable filler is free of contamination by bacteria or foreign matter (eg, make-up, talc from gloves).

[0034] The supplied 27G ½″ / 27G×13mm needle is then attached to the syringe (following instructions for use). Prior to injecting the composition of the present invention, the plunger rod should be depressed until product is visibly flowing out of the needle, any excess being wiped off with sterile gauze. The compositions of the present invention are injected as follows: Inject the composition of the present invention slowly and observe for signs of skin discoloration or fading. Observe the subject for pain or discomfort. Inject the composition of the present invention smoothly and carefully. Insert the needle, taking note of the local vascularity at the injection site. Aspirate to ensure there is no backflow of blood, which would suggest the needle tip is located within a blood vessel. The mandibular point may be injected supraperiosteally with multiple small boluses. The chin may be injected supraperiosteally with multiple small boluses. The premandibular sulcus (left and right) may be injected using a deep subcutaneous fanning technique. The sublip (mental) crease may be injected using a linear, retrograde, or antegrade superficial subcutaneous stitch technique.

[0035] Once treatment is complete, gently massage the treated area to ensure the product is evenly distributed and conforms to the contours of the surrounding tissue. If overcorrection occurs, gently massage the area between fingers or against the underlying bone for optimal results. The compositions of the present invention should not be injected into blood vessels (intravascularly). Introduction of hyaluronic acid into the vascular system may cause vascular occlusion, resulting in infarction or embolism. Symptoms of vascular occlusion and embolism include pain that is not in accordance with the procedure or is distant from the injection site, and discoloration reflecting ischemic tissue, such as a white, dark, or reticular appearance immediately after injection, which may extend beyond the injection area and represent the branching distribution of blood vessels. Injecting too much product into a superficial or small area may result in visible, persistent lumps and / or discoloration.

[0036] When using a retrograde technique, the composition of the present invention is injected by applying uniform pressure to the plunger rod while slowly pulling the needle backward. It is important to stop injection just before the needle passes the subcutaneous / cutaneous interface to prevent material from leaking out or ending up on the surface of the skin. When using an antegrade technique, ensure that the needle is in the subcutaneous tissue before starting injection. If the needle becomes clogged, stop the injection without increasing pressure on the plunger rod and replace the needle. If the treated area swells immediately after injection, an ice pack may be applied to the site for a short period of time. If the subject reports an inflammatory reaction lasting more than one week, or experiences any side effects, medical personnel should take appropriate measures.

[0037] In a preferred embodiment, the composition of the invention comprises hyaluronic acid gel, preferably in an amount of about 25 mg, and lidocaine hydrochloride, preferably in an amount of about 3 mg, in a volume of phosphate buffer (pH 7.2), preferably pre-filled in a disposable syringe, e.g., 1 mL, where the hyaluronic acid gel is cross-linked with BDDE. This pre-filled disposable syringe, e.g., 1 mL, may be placed in a kit (blister pack) with two disposable needles (e.g., 27G 1 / 2" / 27G x 13 mm needles). The contents of the syringe may be sterilized by moist heat. The disposable needles may be radiation sterilized. The composition of the present invention is an injectable implant intended for the restoration and creation of facial volume, for example in the chin and jaw area. The presence of lidocaine is intended to reduce pain to the subject during the procedure. EXAMPLES

[0038] (Example 1) Manufacturing an Injectable Implant According to an Embodiment of the Invention Pre-dried fibers of sodium hyaluronate (NaHA) (0.9 g) having a molecular weight of approximately 0.9 MDa are weighed into a first container. Pre-dried fibers of NaHA (0.1 g) having a molecular weight of approximately 3.0 MDa are weighed into a second container. Two different grades of NaHA are combined and diluted in 1% sodium hydroxide solution and mixed at 20°C-50°C for 1-2 hours to obtain a substantially homogenous alkaline HA gel.

[0039] In a separate container, dilute the crosslinker of choice, 1,4-butanediol diglycidyl ether (BDDE), in 1% sodium hydroxide solution to a final concentration of 10% (wt / wt) BDDE. Add 10% (w / w) BDDE (1 g of the previously prepared BDDE solution) to the alkaline HA gel. Mechanically homogenize the resulting mixture. The mixture is then kept at 50°C for 3-4.5 hours. The resulting cross-linked HA polymer is then immersed in a phosphate buffer solution (PB) to which hydrochloric acid has been added to stabilize the pH. The crosslinked HA polymer thus obtained is then immersed in a phosphate buffer bath to remove unreacted crosslinker and HA, yielding a purified hydrogel with a crosslinking degree of approximately 6.5%. The high molecular weight dried HA material may be hydrated with 1 liter of phosphate buffer to obtain an uncrosslinked HA gel, which can be added to the crosslinked HA composition to give a total HA concentration of 5% (w / w).

[0040] The resulting hydrogel is then mechanically homogenized to ensure final homogeneity and packed into autoclaved sterilized syringes. The resulting gel is an injectable composition that can be administered subcutaneously or epithelially through a fine gauge needle (e.g., 27 gauge). The composition is useful for repairing, contouring, or shaping facial volume, for example, in a person's chin, jaw area, or nose, as described elsewhere herein. In one aspect of the invention, a method for improving the facial contour of a patient is provided. For example, in some embodiments, a method for modifying a person's G-Sn-Pog facial angle, for example, increasing a person's G-Sn-Pog facial angle, is provided. For example, in some embodiments, a treatment method for correcting a receding chin in a patient is provided. In some embodiments of the invention, a patient undergoing treatment has a G-Sn-Pog facial angle of less than about 165° before the first treatment. After treatment, the patient's G-Sn-Pog facial angle is increased, i.e., the facial angle is greater than the facial angle before the first treatment. In one embodiment, the patient's G-Sn-Pog angle after the administration step is about 169° or greater. The G-Sn-Pog angle can be measured by conventional devices and calculations, and may be based on calculations of the facial angle derived from, for example, a digital image of the patient, using, for example, a facial image device from Canfield Scientific. FIG. 1 shows the facial contour and landmarks for calculating the G-Sn-Pog angle of a patient, which may be used to diagnose or determine the presence and / or extent of a receding chin by known methods.

[0041] The methods generally include administering to at least one treatment area of ​​a patient's face an effective amount of a composition comprising BDDE-crosslinked hyaluronic acid (HA), wherein the HA has a degree of crosslinking of about 6.5%, or about 10%, and has an HA concentration of greater than 20 mg / g. In some embodiments, a method of treatment is provided that includes administering a composition as described herein onto the periosteum of at least one treatment area of ​​a patient's face, where the patient has a G-Sn-Pog facial angle between 145° and 165°. The facial angle value may be based on a calculation of the facial angle derived from a digital image of the patient, or other techniques may be used. According to some embodiments, the administering step results in an increase in the patient's G-Sn-Pog angle compared to the patient's G-Sn-Pog facial angle prior to treatment, e.g., immediately prior to the administering step. In some embodiments, the patient's G-Sn-Pog angle increases after the administering step for at least about 3 months, or more preferably at least about 6 months, e.g., for a period ranging from about 9 months to about 24 months. For example, the patient's G-Sn-Pog angle increases after the administering step for at least about 6 months, or at least about 9 months, or at least about 12 months, or at least about 18 months, or at least about 24 months.

[0042] In some embodiments, the treatment area is an area selected from the group consisting of the mandibular point, chin, left premaxillary groove, right premaxillary groove, and sub-lip crease. Treatment may include administering the composition to two or more locations of the treatment area. Administration includes injecting the composition suprapyosteally or subcutaneously in an amount of about 0.5 mL to about 3.0 mL per treatment area. In some embodiments, the amount injected into a given treatment area is 2.0 mL or less. In some embodiments, the total amount injected in one treatment session across all treatment areas is 2.0 mL to about 6.0 mL, e.g., about 2.5 mL, about 3.0 mL, about 3.5 mL, about 4.0 mL, about 4.5 mL, about 5.0 mL, about 5.5 mL, or about 6.0 mL. In some embodiments, the amount administered in one treatment session is about 4.0 mL or less.

[0043] Restoration and creation of volume in the chin and jaw In one aspect, the invention provides a method for restoring and creating volume in the chin and jaw, for example, shaping, shaping and contouring over specific treatment areas of the face, which may include one or more of the mandibular point (the most prominent point on the front of the chin), the chin (the lowest point of the chin), the left and right premandibular sulci (the left antigonion notch and the right antigonion notch), and the sublipal (chin) crease (the crease between the lower lip and chin).

[0044] Chin shape and prominence contribute to the proportional facial balance that underlies attractiveness. A non-prominent chin is commonly classified as a "weak chin" whereas a prominent chin is classified as a "strong chin", implying strength of character. Some studies suggest that averagely proportioned faces are considered most attractive and that a childlike appearance, including a small chin, is interpreted as attractive in women, whereas a strong chin and jaw are interpreted as attractive in men. The appearance of the chin is a determining factor in perceived attractiveness and can affect an individual's psychosocial well-being. Average proportions are determined by analyzing the representation of facial contours in populations, including the distance and angle between the nose, lips, and chin. Several soft tissue landmarks have been used to measure and diagnose deviations of chin protrusion and retrusion from average facial parameters in head analyses. The intersection of upper and lower frontal facial elements and the angle formed by the glabella, subnasal, and chin (G-Sn-Pog) points have been extensively analyzed to understand the average chin protrusion that is normal in populations. For the average chin, the Burstone angle (Figure 2) has been defined as approximately 169°, with several studies confirming approximate angles (168°–169°).

[0045] Deviations from the average chin gradually result in a perceived lack of facial attractiveness. Analysis of the relationship between facial contour and perception of attractiveness indicates that chin protrusion plays a major role in this perception. To understand the relationship between the degree of chin protrusion and attractiveness, a series of contour images that varied from an idealized contour image in increments of 2 mm were presented to a group of pretreatment orthognathic patients, clinicians, and non-experts. Subjects were asked to rank each image on a 7-point Likert scale ranging from extremely unattractive to extremely attractive. The rank of perceived attractiveness decreased on average by 0.15 on the Likert scale for each 2 mm of chin setback and became clear after a 4 mm change. The degree of chin setback desired for surgery was 11 mm for patients and clinicians and 10 mm for non-experts. The most attractive images were those that showed an ideal orthognathic contour with the mandibular point of the soft tissue lying above the true vertical line.

[0046] (Example 2) Methods for increasing the G-Sn-Pog facial angle in subjects with a receding or weak chin The composition of the present invention is administered as an injectable implant by subcutaneous or epiperiosteal injection into the chin and / or jaw area of ​​a 32 year old male subject. The subject complains of having a "weak chin". A physician measures the subject's facial angle and determines the G-Sn-Pog angle to be approximately 150°, which is substantially lower than the classic Burstone angle of an average chin (approximately 169°). The measurements are based on facial angle calculations derived from digital images obtained using a Canfield imaging device and software. The physician believes that the subject's chin / chin retrusion can be corrected with a treatment goal consistent with increasing chin protrusion horizontally (in profile) rather than lengthening or widening the chin.

[0047] Physicians believe that by using the implantable compositions described herein, they can provide a subject with a more attractive facial contour and stronger jawline. Subjects will undergo three treatment periods including an initial treatment, an additional treatment, and a repeat treatment as described below. For each treatment, the treatment area includes at least one or more of the following treatment areas: mandibular point (the most prominent point on the anterior aspect of the chin), chin (the lowest point on the chin), left premandibular sulcus (left antigonion notch), right premandibular sulcus (right antigonion notch), and / or sublabial crease (crease between the lower lip and chin).

[0048] Physicians will not implant more than 2.0 mL in any single treatment area during any treatment period. The subject will undergo the initial procedure as follows: The physician will administer the anesthetic using a sterile skin preparation according to their standard procedures. Ice and a topical anesthetic can be used to reduce discomfort during injection. The injectable anesthetic will be administered while ensuring it is limited to the treatment area and does not distort the proposed treatment area. Using the needle (27 gauge x 13 mm / 27G1 / 2") provided with the kit, the physician will subcutaneously and / or supraperiosteally inject the compositions described herein, limiting treatment to the mandibular point, chin, premandibular sulcus, and (mental) crease below the lip to increase chin projection (horizontal in profile view) and to aesthetically shape, contour, and mold the area. A suitable injection technique is described above. The goal of treatment is to increase chin projection (horizontal in profile view) and achieve an aesthetic chin contour. The physician will determine the appropriate injection volume for the initial and anticipated additional treatments, up to approximately 4.0 mL.

[0049] To achieve the desired facial contour, the physician manually manipulates the overlying tissue to gently shape the treatment area. If desired by the subject or at the physician's discretion, an additional treatment is performed approximately 30 days after the initial treatment if optimal (complete) augmentation of chin protrusion and / or aesthetic contouring is not achieved during the initial treatment. If an additional treatment is performed, the total amount of composition administered (initial and additional treatment) is approximately 2.0 mL to approximately 4.0 mL. During this visit, the physician will assess the treatment area for any local reactions and discuss any reported symptoms. 3D facial digital images (frontal and contour images) are captured to objectively calculate the angle of chin retrusion. During the additional follow-up visit, if the physician determines that optimal (complete) augmentation of chin protrusion or aesthetic contouring was not achieved after the initial treatment, the subject is encouraged to undergo an additional treatment.

[0050] If a repeat treatment is warranted by the physician and / or if desired by the subject, a single repeat treatment will be performed at a scheduled visit between 18 and 24 months. The total volume of injections into the chin for the repeat treatment will not exceed 4.0 mL. While the invention has been described and illustrated in some detail, it will be understood that the disclosure is made by way of example only, and that numerous changes in the combination and arrangement of parts may be made by those skilled in the art without departing from the scope of the invention as hereinafter claimed. Unless otherwise indicated, all numbers expressing properties such as quantities of ingredients, molecular weights, reaction conditions, etc. used in the specification and claims are to be understood as being modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and appended claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should be construed at least in light of the number of reported significant digits and by applying ordinary rounding techniques.

[0051] Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values ​​set forth in the specific examples are reported as precisely as possible. However, all numerical values, inherently, contain certain errors resulting from the standard deviation found in their respective measuring techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values ​​set forth in the specific examples are reported as precisely as possible. However, all numerical values, inherently, contain certain errors resulting from the standard deviation found in their respective measuring techniques.

[0052] Certain embodiments disclosed herein may be further limited in the claims using language consisting of or consisting essentially of. When used in the claims, whether as filed or added by amendment, the transitional term "consisting of" excludes any element, step, or ingredient not specified in the claim. The transitional term "consisting essentially of" limits the claim to the specified materials or steps and those materials or steps that do not materially affect the basic and novel characteristics. The embodiments of the invention so claimed are essentially or explicitly described and enabled herein.

[0053] In closing, it should be understood that the embodiments of the invention disclosed herein are illustrative of the principles of the invention. Other modifications that may be utilized are within the scope of the invention. Thus, by way of example, but not of limitation, alternative configurations of the invention may be utilized in accordance with the teachings herein. Thus, the invention is not limited to that precisely as shown and described.

Claims

1. 1. A sterile composition that can be implanted subcutaneously or epithelially in the chin area, jawline, or nose of a patient in need thereof, comprising: The composition comprises crosslinked hyaluronic acid (HA) crosslinked with 1,4-butanediol diglycidyl ether (BDDE), The composition has an HA concentration of greater than 20 mg / g; The HA used for cross-linking is made from a mixture of low molecular weight hyaluronic acid and high molecular weight hyaluronic acid. The HA used for crosslinking is a mixture containing at least 50% by mass of low molecular weight HA based on the total mass of HA; the composition has an elastic modulus of about 500 Pa to about 900 Pa at 5 Hz; the composition has a cohesiveness of greater than 60 gmf; The composition exhibits an extrusion force of about 4 N to about 15 N at 13 mm / min using a 1 mL COC syringe and a 27 G x 13 mm needle.

2. 2. The composition of claim 1, wherein the HA concentration is about 22.5 mg / g.

3. 3. The composition of claim 1 or 2, wherein the HA concentration is about 25 mg / g.

4. 4. The composition of claim 1, wherein the HA concentration is about 27.5 mg / g.

5. 5. The composition according to claim 1, wherein the HA used for crosslinking is a mixture comprising at least 70% by weight of low molecular weight HA, preferably at least 90% by weight of low molecular weight HA, based on the total weight of HA.

6. 6. The composition of claim 1, wherein the HA used for crosslinking is a mixture containing about 90% by weight of low molecular weight HA and about 10% by weight of high molecular weight HA based on the total weight of HA.

7. 7. The composition of any one of claims 1 to 6, wherein the cohesiveness is from about 60 gmf to about 200 gmf.

8. 8. The composition of any one of claims 1 to 7, having a cohesiveness of from about 60 gmf to about 100 gmf.

9. 9. The composition of any one of claims 1 to 8, wherein the extrusion force is from about 7 N to about 12 N at 13 mm / min using a 1 mL COC syringe and a 27 G x 13 mm needle.

10. 10. The composition of any one of claims 1 to 9, wherein the extrusion force is about 8N to about 10N at 13mm / min using a 1 mL COC syringe and a 27G x 13mm needle.

11. 11. The composition of claim 1 further comprising an anesthetic agent.

12. 12. The composition of claim 1, further comprising lidocaine hydrochloride.

13. 13. The composition of claim 1, further comprising about 0.3% by weight of lidocaine hydrochloride based on the total weight of the composition.

14. The composition of any one of claims 1 to 13, wherein the HA has a degree of cross-linking of about 4% to about 10%.

15. 15. The composition of claim 1, wherein the HA has a degree of cross-linking of about 4%.

16. 16. The composition of claim 1, wherein the HA has a degree of cross-linking of about 6%.

17. 17. The composition of claim 1, wherein the HA has a degree of cross-linking of about 8%.

18. 18. The composition of any one of claims 1 to 17, wherein the HA has a degree of cross-linking of about 10% or about 6.5%.

19. 19. The composition of any one of claims 1 to 18, wherein the composition comprises about 25 mg of cross-linked HA and 3 mg of lidocaine in a volume of 1 mL of phosphate buffer at pH 7.2, the cross-linked HA preferably having a degree of cross-linking of about 6.5%.

20. 1. A method of correcting chin retrusion in a patient, comprising:

1. A method comprising: administering an effective amount of a composition comprising hyaluronic acid (HA) cross-linked with BDDE onto the periosteum of at least one treatment area of ​​the patient's face, wherein the HA has a degree of cross-linking of about 6.5% and an HA concentration of greater than 20 mg / g, and the HA used for cross-linking is a mixture comprising at least 50% by weight of low molecular weight HA relative to the total weight of the HA, and the treatment area is selected from the group consisting of the mandibular point, chin, left premaxillary sulcus, right premaxillary sulcus, and sub-lip crease.

21. 21. The method of claim 20, wherein prior to the administering step, the patient has a G-Sn-Pog angle of less than about 165° based on facial angle calculations derived from a digital image of the patient.

22. 22. The method of claim 20 or 21, wherein the administering step results in an increase in the G-Sn-Pog angle in the patient.

23. 23. The method of any one of claims 20-22, wherein the patient's G-Sn-Pog angle increases for a period ranging from about 9 months to about 24 months after the administering step.

24. 24. The method of any one of claims 20 to 23, wherein the patient's G-Sn-Pog angle increases for at least about six months after the administering step.

25. 25. The method of any one of claims 20 to 24, wherein the patient's G-Sn-Pog angle increases for at least about 9 months after the administering step.

26. 26. The method of any one of claims 20 to 25, wherein the patient's G-Sn-Pog angle increases for at least about 12 months following the administering step.

27. 27. The method of any one of claims 20 to 26, wherein the patient's G-Sn-Pog angle increases for at least about 18 months after the administering step.

28. 28. The method of any one of claims 20 to 27, wherein after the administering step, the patient has a G-Sn-Pog angle of about 169° or greater.

29. the composition has an HA concentration of about 25 mg / g; The HA used for crosslinking of the composition is made of about 90% by weight of low molecular weight hyaluronic acid and about 10% by weight of high molecular weight hyaluronic acid based on the total weight of the HA; the composition has an elastic modulus of about 500 Pa to about 800 Pa at 5 Hz; the composition has a cohesiveness of about 60 gmf to 100 gmf; 29. The method of any one of claims 20 to 28, wherein the composition has an extrusion force of about 8N to about 10N at 13mm / min using a 1 mL COC syringe and a 27G x 13mm needle.

30. 1. A method of creating or restoring volume to a patient's chin or chin, comprising: Injecting a sterile composition subcutaneously or supraperiosteally into the chin area or jawline of a patient in need thereof; The composition comprises crosslinked hyaluronic acid (HA) crosslinked with 1,4-butanediol diglycidyl ether (BDDE), The HA used for crosslinking is a mixture containing at least 50% by mass of low molecular weight HA based on the total mass of HA; the composition has an elastic modulus of about 500 Pa to about 800 Pa at 5 Hz; the composition having a cohesiveness of about 60 gmf to about 100 gmf; The method adds volume to the patient's chin or jawline for a period ranging from about 9 months to about 24 months after the composition is injected into the patient's chin or jawline.

31. 31. The method of claim 30, wherein the composition has an extrusion force of about 8 N to about 10 N at 13 mm / min using a 1 mL COC syringe and a 27 G x 13 mm needle.

32. 32. The method of claim 30 or 31, wherein the HA has a degree of cross-linking of about 4% to about 12%.

33. 33. The method of any one of claims 30 to 32, wherein the HA has a cross-linking degree of about 6%.

34. 34. The method of any one of claims 30 to 33, wherein the HA has a cross-linking degree of about 8%.

35. 35. The method of any one of claims 30 to 34, wherein the HA has a degree of cross-linking of about 10%.

36. 36. The method of any one of claims 30 to 35, wherein the HA has a cross-linking degree of about 6.5%.

37. 37. The method of any one of claims 30 to 36, wherein the HA has a cross-linking degree of about 8.5%.

38. 38. The method of any one of claims 30 to 37, wherein the HA has a cross-linking degree of about 10.5%.

39. 20. A kit comprising the composition of any one of claims 1 to 19 pre-filled in a disposable syringe, such as a 1 mL COC syringe, and at least one disposable needle, such as a 27G x 13mm needle.

40. 1. A method of facial sculpting, such as for expanding, correcting, restoring, or creating volume in the chin and jaw area of ​​a patient, comprising:

20. The method of claim 1, further comprising administering an effective amount of the composition subcutaneously and / or peritoneally to at least one treatment area of ​​the patient's face by injecting the composition of any one of claims 1 to 19, After administration is complete, the method may include massaging the treatment area on the patient's face to ensure that the product conforms to the contours of the surrounding tissue; Optionally, the method includes disinfecting the treatment area prior to administering the composition; Preferably, the treatment area is selected from the group consisting of the chin point, chin, left premaxillary sulcus, right premaxillary sulcus, and sub-lip (chin) crease.

41. 41. The method of claim 40, wherein the composition is injected using a 1 mL COC syringe and a fine gauge needle, such as a needle of about 18G to about 40G, more preferably about 25G to about 33G, or about 25G to about 30G, e.g., a 27G x 13mm needle.

42. 42. The method of claim 40 or 41, wherein the composition is injected in an injection volume of less than 4.0 mL, such as about 2.0 mL, into a single treatment area during any treatment period.

43. 43. The method of any one of claims 40 to 42, wherein the composition is injected in a maximum total volume of less than about 4.0 mL for the initial and anticipated additional treatments combined.

44. 44. The method of any one of claims 40 to 43, comprising multiple small bolus injections over the periosteum at the mandibular point, multiple small bolus injections over the periosteum at the chin, deep subcutaneous injection in a fan-shaped technique at the left and / or right premaxillary sulcus, and linear, retrograde, or antegrade superficial subcutaneous stitch injection at the (chin) crease under the lip.

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