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    • 专利摘要:
    The present invention relates to injectable compositions for dermal fillers in the form of a gel, comprising hyaluronic acid (HA), carboxymethylcellulose (CMC), and, optionally, microparticles, such as calcium hydroxyapatite microparticles (CaHAP). Dermal filler injectable compositions have improved rheological properties and at the same time have low extrusion forces. The present invention further relates to a method for preparing such injectable compositions for dermal filling and their uses for therapeutic and cosmetic purposes.
    公开号:BR112017010074B1
    申请号:R112017010074-6
    申请日:2015-11-12
    公开日:2021-05-04
    发明作者:Nadine Hagedorn；Roland Stragies；Franck Villain；Lubin BELKOVI；Radia El-Banna
    申请人:Merz Pharma Gmbh & Co. Kgaa；
    IPC主号:
    专利说明:

    FIELD OF THE INVENTION
    [001] The present invention relates to injectable compositions for dermal filling in the form of a gel, comprising cross-linked hyaluronic acid (HA), carboxymethylcellulose (CMC), and, optionally, microparticles, such as calcium hydroxyapatite microparticles (CaHAP). Injectable dermal filler compositions have improved rheological properties and at the same time have low extrusion forces. The present invention further relates to a method for preparing such injectable compositions for dermal filling and their uses for therapeutic and cosmetic purposes. SUMMARY OF THE INVENTION
    [002] It is a common desire to achieve and maintain a jo appearance as a common denominator of beauty. Over time, however, the skin begins to lose its youthful appearance, especially on the face. The most common aesthetic signs of facial aging include visible skin wrinkles, deep nasolabial folds, glabellar lines, puppet lines, buccal commissures, and perioral wrinkles.
    [003] These aging changes are often treated by injecting dermal fillers to increase tissue volume. Currently, there are numerous dermal fillers available, which can be broadly classified into two categories. The first category of fillers provides a long-term effect, or create volume, and includes fillers, with cross-linked hyaluronic acid (HA) fillers. The second category of fillings provides a long-term effect by inducing neocollagenesis. The known and widely used example is Radiesse®, which comprises calcium hydroxyapatite microspheres, a carboxymethylcellulose (CMC) gel carrier and glycerin.
    [004] The ideal dermal fillers should be biocompatible, have a low adverse effect profile and provide a reasonably long-lasting persistence (longevity), an effective volumizing capacity and ease of injection. HA based fillers offer many of these desirable dermal filler properties. Since HA is found in almost all species, it has no antigenicity and has excellent tolerance. In addition, it allows the production of cross-linked HA products that have good lifting ability, and are stable for more than 12 months up to two years.
    [005] A major disadvantage of HA-based fillers is, however, that they are often difficult to inject. For this reason, non-crosslinked HA ("free" HA) is commonly added as a lubricant to facilitate injection. Unfortunately, the desired reduction in extrusion form that is caused by the addition of free HA compromises other desirable physical properties of the gel. In particular, the storage modulus parameter G' (G') is reduced, thus resulting in a reduced volumization effect, and the dynamic viscosity is reduced.
    [006] Radiesse® is a dermal filler that also provides desirable features of a dermal filler, including acceptable longevity, biocompatibility and a good capacity to create volume. When injected, the small calcium hydroxyapatite microspheres act as a scaffold that promotes the formation of new tissue, similar to its surrounding environment. However, since Radiesse® CMC vehicle is rapidly absorbed in vivo (in about 3 months), there is a transient and potential reduction in the filling effect, as neocollagenesis may not be synchronized with CMC clearance. In addition, there is no antidote (reverse agent) available for CMC that would allow for a partial correction after application of the filler.
    European Patent No. 1 080 698, filed in 1993, discloses a soft tissue augmentation material comprising finely divided ceramic particles (eg, CaHA) and covers, inter al/a, Radiesse®. Furthermore, WO 2014/056723 describes a viscoelastic gel comprising cross-linked HA in a concentration between 1% and (w/v) and hydroxyapatite particles in a concentration between 10% and 70% (w/v). PURPOSE OF THE INVENTION
    [008] In view of the above, the aim of the present invention is to provide a composition for long-lasting dermal filler having improved rheological properties and, at the same time, easily injectable. SUMMARY OF THE INVENTION
    [009] The above objective is solved by providing an injectable composition for dermal filler in the form of a gel that makes use of carboxymethylcellulose as a lubricant. A new type of dermal filler offers good longevity, is easily injectable, and has improved rheological properties (ie, a G (G') storage modulus and dynamic viscosity), resulting in an excellent capacity to generate volume.
    [0010] In a first aspect, the present invention provides an injectable composition for dermal filling in the form of a gel, comprising cross-linked hyaluronic acid (HA) (for example, cross-linked with BDDE) and carboxymethylcellulose (CMC).
    [0011] Cross-linked HA is generally present in a concentration of 0.1% to 4.0% weight/volume (eg, 0.5% to 4.0% or 1.0% to 4, 0% weight/volume) and provides a cross-linked matrix, while CMC is generally present in a concentration of 1.0% to 25% volume/volume, and is added as a lubricant/lubricant phase. In a preferred embodiment, the injectable dermal filler composition additionally comprises resorbable biocompatible microparticles, specifically, calcium hydroxyapatite microparticles.
    [0012] In a second aspect, the present invention provides a kit comprising the injectable composition for dermal filler according to the first aspect of the invention.
    [0013] In a third aspect, the present invention provides a method for preparing an injectable composition for dermal filler according to the first aspect of the invention, comprising the following steps: (a) providing a cross-linked hyaluronic acid gel, (b ) providing a carboxymethylcellulose gel, (c) mixing the cross-linked hyaluronic acid gel and the carboxymethylcellulose gel.
    [0014] In a fourth aspect, the present invention relates to the use of an injectable composition for dermal filler according to the first aspect of the invention or the kit according to the second aspect of the invention for cosmetic applications such as treatment of facial lines.
    [0015] A fifth aspect, the present invention provides an injectable composition for dermal filler according to the first aspect of the invention or a kit according to the second aspect of the invention for use in therapy, specifically, for use in the treatment of incontinence urinary tract, vesicoureteral reflux, vocal fold insufficiency and vocal fold medialization.
    [0016] In a sixth aspect, the present invention provides a method for replacing or filling a biological tissue or increasing the volume of a biological tissue, comprising administering to an individual in need thereof an effective amount of the injectable composition to dermal filler according to the first aspect of the invention.
    [0017] Specific embodiments of the present invention are presented in the appended claims.
    [0018] Additional objects, advantages and features of the present invention will become apparent to those skilled in the art in view of the following detailed description of the invention, drawings and examples. BRIEF DESCRIPTION OF THE DRAWINGS
    [0019] FIGURE 1 shows the extrusion force of an HA/CMC dermal filler composition according to the present invention (MHAG gel with 15% (v/v) CMC; gray bar) and a composition for free HA/HA dermal filler (MHAG gel free with 15% (v/v) free HA; hatched bar) compared to a HA only gel (MHAG gel; black bar).
    [0020] FIGURE 2 shows the modulus of elasticity (G') of a composition for dermal filler of HA/CMC according to the present invention (MHAG gel with 15% (v/v) of CMC; gray bar) and a free HA/HA dermal filler composition (MHAG gel with 15% (v/v) free HA; hatched bar) compared to a HA-only gel (MHAG gel; black bar).
    FIGURE 3 shows the viscosity of an HNCMC dermal filler composition according to the present invention (MHAG gel with 15% (v/v) CMC; gray bar) and a HA dermal filler composition /Free HA (MHAG gel free with 15% (v/v) HA free; hatched bar) compared to an HA-only gel (MHAG gel; black bar).
    FIGURE 4 shows the extrusion force of an HNCaHAP/CMC dermal filler composition according to the present invention (MHAI with 10% (v/v) CMC; black bar) compared to a gel of HA/CaHAP (MHAI; gray bar), a free HA/CaHAP/HA gel (MHAI with 10% free HA; hatched bar), and a dilution of the MHAI gel (MHAI with diluted HA (15 mg/ml of HA); unfilled bar).
    FIGURE 5 shows the modulus of elasticity (G') of an HNCaHAP/CMC dermal filler composition according to the present invention (MHAI with 10% (v/v) CMC; black bar) compared to one HA/CaHAP gel (MHAI; gray bar), one free HA/CaHAP/HA gel (MHAI with 10% free HA; hatched bar), and one MHAI gel dilution (MHAI with diluted HA ( 15 mg/ml HA); unfilled bar).
    FIGURE 6 shows the viscosity of an HA/CaHAP/CMC dermal filler composition according to the present invention (MHAI with 10% (v/v) CMC; black bar) compared to a gel of HA/CaHAP (MHAI; gray bar), a free HA/CaHAP/HA gel (MHAI with 10% free HA; hatched bar), and a dilution of the MHAI gel (MHAI with diluted HA (15 mg/ml of HA); unfilled bar).
    FIGURE 7 shows the influence of different concentrations of CMC on the extrusion force of an HA/CaHAP dermal filler (MHAI; black bar), an HA/CaHAP gel with 5% CMC (MHAI with 5 % CMC; gray bar), an HA/CaHAP gel with 10% CMC (MHAI with 10% CMC; hatched bar), and HA/CaHAP gel with 15% CMC (MHAI with 15% CMC; bar without filling). DETAILED DESCRIPTION OF THE INVENTION
    [0026] The injectable dermal filler of the present invention provides several advantages over known fillers, including excellent biocompatibility, improved persistence, high moisture retention, no immunogenicity, and safe absorption by the body, while maintaining desirable rheological and mechanical properties for use as a dermal filler.
    [0027] In particular, the inventors of the present invention have found that adding a small amount of carboxymethylcellulose (CMC) in a light crosslinked HA gel surprisingly to a long-lasting dermal filler composition, exhibiting a low strength of extrusion, while having improved mechanical properties (ie, high modulus of elasticity (G') and high dynamic viscosity) providing high volumizing capacity. In other words, the dermal filler in accordance with the present invention has been found to unexpectedly provide an ideal balance of longevity, liftability and ease of injection.
    [0028] Furthermore, in a preferred embodiment of the present invention, where the dermal filler composition additionally contains microparticles (e.g., calcium hydroxyapatite microparticles (CaHAP)), the advantages of Radiesse® (i.e., the neocollagenesis due to calcium hydroxyapatite particles) can be combined with the advantage of a partial reversibility/correction possibility due to the possibility of using a hyaluronidase enzyme to degrade and dissolve the cross-linked HA vehicle. Another advantage is that the crosslinked HA vehicle will last longer than the current non-crosslinked CMC vehicle used, for example, in Radiesse®. This will avoid the known performance/volumization effect gap, which is seen between the dissolution time of CMC and the induction of neocollagenesis by the microparticles.
    [0029] In a first aspect, the present invention relates to an injectable dermal filler composition in the form of a gel, comprising cross-linked hyaluronic acid and carboxymethylcellulose.
    [0030] As used herein, the term "dermal filler" broadly refers to a material or composition designed to add volume to areas of soft tissue deficiency. The term "dermal filler" as used herein has the same meaning, and is used interchangeably, with the term "soft tissue filler". That is, the term "dermal filler" should not be interpreted as imposing any limitations on the location and type of injection, and generally encompasses uses at various levels below the dermis, for example, sub-muscularly above the periosteum and on the piano subcutaneous. Within the meaning of the present invention, the term "soft tissue" generally refers to tissues that connect, support, or surround other structures and organs in the body. In the present invention, soft tissues include, for example, muscles, tendons (bands of fibers that connect muscles to bones), fibrous tissues, fat, blood vessels, nerves and synovial tissues (tissues around joints).
    [0031] According to the present invention, the injectable composition for dermal filling to a gel. The term "gel", as used herein, generally refers to a material having a fluidity at room temperature between that of a liquid and that of a solid. Furthermore, the term "gel" is intended to mean a material capable of absorbing water (ie, a "hydrogel"). Within the scope of the present invention, the injectable composition for dermal filler generally comprises a physiologically acceptable fluid carrier such as a non-pyrogenic isotonic buffer, in particular a physiological saline solution which is preferably buffered.
    [0032] Furthermore, the dermal composition of the present invention is "injectable". This means that the dermal filler composition is suitable for injection into the skin or other tissue in order to bring the dermal filler composition to the desired target site. An "injectable" composition within the meaning of the present invention can be dispensed from syringes under normal conditions, under normal pressure.
    [0033] According to the present invention, the concentration of carboxymethylcellulose is preferably between 1.0 and 25.0%, more preferably between 5.0% and 20%, and most preferably between 10% and 15% volume/volume. Within the scope of the present invention, it is generally used as a lubricant or lubrication step. A carboxymethylcellulose suitable for use in the present invention may have a molecular weight in the range of 5.0 x 10' Da (low viscosity CMC) to 1.5 x 106 Da (high viscosity CMC), for example, in the range from 9.0 x 10' to 7.0 x 105 Da, in particular in the range of 1.5 x 1 or 5 to 5.0 x 105 Da.
    [0034] Furthermore, a carboxymethylcellulose suitable for use in the present invention may be selected from a low viscosity carboxymethylcellulose having a viscosity of 75 mPa.s to 750 mPa.s as measured with a Brookfield spindle viscometer (model LW) at 25°C and a rotation speed of 60 rpm with size No. 1 or No. 2 spindles using a 2% aqueous solution, a medium viscosity carboxymethylcellulose, having a viscosity of 750 mPa.s to 4,000 mPa. s, as measured with a Brookfield spindle viscometer (model LVT) at 25°C and a rotation speed of 30 rpm with size No. 2 or No. 3 spindles using a 2% aqueous solution, and a high viscosity carboxymethylcellulose, having a viscosity of 4,000 mPa.s to 25,000 mPa.s, measured with a Brookfield spindle viscometer (model LVT) at 25°C and a rotation speed of 30 rpm with size No. 3 or spindles 4, using a 1% aqueous solution.
    [0035] Furthermore, carboxymethylcellulose typically has a degree of substitution of 0.20 to 1.50, preferably 0.40 to 1.10, more preferably 0.60 to 0.95, and with most preferably, 0.70 to 0.90. As used herein, the "degree of substitution" (degree of etherification), as used herein, is defined below: [C6H7O2(OH)x(OCH2COOm)y]n, where in the degree of polymerization (eg, 450 to 4,000 ) ex + y = 3, where y and a degree of substitution. The degree of substitution can be determined as known in the theory (for example, according to the method described in the Codex Oenological International COEI-1-C MC:2009).
    [0036] The hyaluronic tissue is present in the composition in a concentration preferably from 0.1% to 5.0% or 0.2% to 4.5% or 0.3% to 4.0% or 0.4% to 4.0% or 0.5% to 4.0% or 0.7% to 4.0% or 1.0% to 4.0%, more preferably 0.5% to 3.0% or 1.0% to 3.0% or 1.5% to 3.0% or 2.0% to 3.0%, most preferably 1.0% to 2.5% or 2.0% to 2. 5% weight/volume. Within the scope of the present invention, the crosslinked HA forms a "matrix". As used herein, the term "matrix" is intended to mean a network of polysaccharides, both cross-linked and non-cross-linked, in the form of a solution or gel. In addition, the term "hyaluronic acid" or "HA", as used herein, means hyaluronic acid, hyaluronate, and any hyaluronate salt such as sodium hyaluronate.
    [0037] In the context of the present invention, cross-linked hyaluronic acid is not limited in any way, and includes cross-linked hyaluronic acid, prepared from a single hyaluronic acid or two or more hyaluronic acids that differ in their molecular weight (see , for example, US 2010/0316683 A1 or WO 2013/185934 A1 which are incorporated herein by reference). Also, within the scope of the present invention, crosslinked hyaluronic acid can form a "polydensified" gel, which is characterized by a variation in the degree of crosslinking within the gel, that is, a "polydensified" gel has (at least) two different density levels, with denser parts (greater degree of crosslinking) and less dense parts (lesser degree of crosslinking).
    [0038] Polydensified gels can be prepared, for example, by a first crosslinking reaction to crosslink the first polysaccharide(s), followed by a second crosslinking reaction to crosslink the second(s) polysaccharide(s) to form a double cross-linked gel. Said first and said second polysaccharide(s) may, for example, be independently the same hyaluronic acid or two different hyaluronic acids that differ in their average molecular weight (eg, a low molecular weight hyaluronic acid and a hyaluronic acid high molecular weight). The double-crosslinking process (dynamic crosslinking technology) is known in the art, and is described, for example, in EP 1 711 552 B1, which is hereby incorporated by reference.
    [0039] Within the scope of the present invention, the cross-linked hyaluronic acid can be prepared by the cross-linking of a single hyaluronic acid, or by the cross-linking of a first hyaluronic acid and a second hyaluronic acid and, optionally, at least one additional hyaluronic acid , in which the first, second and at least one additional hyaluronic acid differ in their average molecular weights.
    [0040] Preferably, the hyaluronic acid has an average molecular weight of 0.1 x 106 to 4.0 x 106 Da or 0.3 x 106 to 4.0 x 106 Da or 0.5 x 106 to 4.0 x 106 Da, in particular, 1.0 x 106 to 3.0 x 106 Da or 1.5 x 106 to 2.5 x 106 Da. Said first hyaluronic acid has an average molecular weight of 1.0 x 106 Da to less than 1.0 x 106 Da, more preferably 3.0 x 105 Da to 9.0 x 105 Da, and most preferably 5.0 x 105 Da to 8.0 x 105 or 5 Da. second hyaluronic acid generally has an average molecular weight greater than 1.0 x 106 Da to 5.0 x 106 Da, in particular between 1.5 x 106 Da and 4.0 x 106 Da, and preferably between 2 .0 x 106 Da and 3.0 x 106 Da. The ratio of the weight of the first HA to the weight of the second HA in the injectable dermal filler composition of the present invention is not limited in any way, and may, for example, range from 0.001:99.999 to 99.999:0.001, preferably from about 70:30 to about 99.9:0.1, and most preferably from about 90:10 to about 99.0:1.0 .
    [0041] Various methods can be applied in the present invention to determine the molecular weight of HA, such as intrinsic viscosity measurements (eg, according to Chinese Pharmacopoeia, 2nd revision, 2006), capillary electrophoresis (EO) (eg, according to Kinoshita et al, Biomed. Chromatogr., 2002, 16:141-45), high performance gel permeation chromatography (HPGPC) (eg according to Kim et al, Food Chem., 2008) , 109: 63-770), and multi-angle laser light scattering combined with size exclusion chromatography (SEC-MALLS) (for example, according to Hokputsa et al., Eur. Biophys. J. Biophys. Lett. , 2003, 32:450-456).
    [0042] Preferably, the injectable composition for dermal filler according to the present invention is cross-linked with BDDE (title 1,4-diglycidyl butanediol). Hyaluronic acid crosslinked with BDDE may have a degree of modification, expressed as the ratio of the sum of BDDE crosslinkers with single and double bonds and the sum of disaccharide units of hyaluronic acid, from 0.5% to 25%, preferably 1.0% to 15%, more preferably 2.0 to 10%, and most preferably 3.0% to 8.0% or 4.0% to 7%.
    The degree of modification can be determined by NMR, according to methods known in the art (Edsman et al., Gel Properties of Hyaluronic Acid Dermal Fillers, Dermatol. Surg. 2012, 38:1170-1179; Guarise et al., ., SEC determination of cross-link efficiency in hyaluronan fillers, Carbohydrate Polymers 2012, 88:428-434; Kenne et al., Modification and cross-linking parameters in hyaluronic acid hydrogels - Definitions and analytical methods, Carbohydrate Polymers 2013, 91:410-418).
    [0044] In summary, the dialyzed and sterilized gels are degraded before performing the measurement by NMR. Degradation can be performed by chondroitinase AC (Edsman et al., supra; Kenne et al., supra), NaOH (Guarise et al., supra), addition of hyaluronidase (e.g., 150 U sheep hyaluronidase to 1 g of gel) or by incubation at 90 °C for at least 35 h. The solutions obtained are then lyophilized, dissolved in D2O, and thoroughly homogenized.
    [0045] The measurement by NMR can be performed at, for example, 500 MHz, in a pulse of 20 degrees with several repetitions at room temperature to receive a spectrum with adequate resolution. According to the literature, the degree of modification (MoD) is evaluated by calculating the ratio between the N-acetyl signals from HA and the methylene signals from BDDE. For N-acetyl from HA, the critical signals are located at about 2.0 ppm, and at about 1.6 ppm for BDDE when solubilized in D2O. To calculate the degree of modification, integer values were identified and the proton ratio of 3H N-acetyl (CH3) to 4H methylene (CH2CH2) needs to be taken into account, according to the literature (Edsman et al., supra, and Kenne et al., supra).
    [0046] According to a preferred embodiment) of the present invention, the injectable composition for dermal filling additionally comprises biocompatible resorbable microparticles. The term "microparticles" as used herein generally refers to substantially rounded or spherical particles. Furthermore, the microparticles preferably have an average diameter of 5 pm to 500 pm, more preferably 10 pm to 200 pm, particularly preferably 15 pm to 100 pm or 20 pm to 75 pm, and most preferably preferably 25 pm to 45 pm. In the context of the present invention, the term "resorbable" generally refers to a material that can be broken down and absorbed into tissue and/or bodily fluid.
    [0047] The microparticles are preferably present in the composition in a concentration of 0.5% to 50%, or 1.0% to 50%, more preferably 1.0% to 40%, particularly preferably 5 0.0% to 35%, in particular 15.0% to 30% or 20% to 25%, and most preferably 25.0% to 35% volume/volume.
    [0048] Within the context of the present invention, the resorbable biocompatible microparticles may consist of calcium phosphate-based materials, alumina-based materials, a natural biodegradable polysaccharide or a derivative thereof, or a biodegradable polyester , polyorthoester or polyanhydride synthetic polymer.
    [0049] The term "natural polysaccharide" as used herein generally refers to a polysaccharide that occurs in nature. As used herein, a "derivative of", when used in relation to a natural polysaccharide, refers to a polysaccharide that is derived from the natural polysaccharide or chemical modification such as carboxylation, etherification, methylation, sulfonation and the like. . The term "biodegradable", as used herein, refers broadly to materials that are capable of being decomposed in vivo or living human beings and should not be interpreted to be restricted to a specific decomposition time or duration. .
    Calcium phosphate-based materials can be selected from calcium apatite, tetracalcium phosphate, calcium pyrophosphate, tricalcium phosphate, and octacalcium phosphate. Preferably, the calcium phosphate based material is calcium hydroxyapatite.
    [0051] The synthetic polymer of polyester, polyorthoester or polyanhydride can be a homopolymer or copolymer of glycolide, lactide, caprolactone and p-dioxanone, or a polymer of trimethylene carbonate, or a poly(hydroxybutyrate) or poly (hydroxyvalerate). Preferably, the synthetic polymer of biodegradable polyester, polyorthoester or polyanhydride is selected from poly-E-caprolactone, polyglycolides, polylactides, polydioxanone, poly(lactic-co-glycolic acid), poly(glycolide-co-caprolactone) and poly (trimethylene glycolide-co-carbonate), and the most preferred is poly-E-caprolactone or polydioxanone.
    [0052] According to the present invention, the injectable composition for dermal filler may additionally comprise one or more compounds selected from the group consisting of polyols, vitamins, amino acids, metals, antioxidants and mineral salts. Suitable polyols for use in the present invention include, but are not limited to, glycerin, mannitol, sorbitol, propylene glycol, erythritol, xylitol, maltitol, and lactitol. Particularly suitable for use in the present invention are mannitol and glycerin. Furthermore, polyol) and, preferably, glycol, optionally in combination with one or more of the aforementioned polyol compounds, specifically, mannitol. The polyol(ols) can, for example, be included in the injectable composition for dermal filler in a concentration of 1% to 25% or 2% to 17% or 3% to 13% volume/volume , specifically, at a concentration of 5% to 11% or 7% to 10% volume/volume.
    Suitable vitamins include vitamin C, vitamin E and group B vitamins, i.e. one or more of vitamins B1, B2, B3, B5, B6, B7, B9 and B12. The concentration of vitamin C or vitamin E, and preferably from about 0.01 mg/ml to about 10.0 mg/ml, more preferably from about 0.1 mg/ml to about 5, 0 mg/ml, the total concentration of the group B vitamins, and preferably from about 0.01 mg/ml to about 10.0 mg/ml, more preferably from about 0.1 mg/ml to about 5.0 mg/ml. Vitamins may be present to stimulate and maintain cell metabolism and therefore to promote collagen production. Particularly preferably for use in the present invention are vitamin C, vitamin E and vitamin B6.
    [0054] In addition, the injectable composition for dermal filler according to the present invention may additionally comprise an anesthetic, specifically, a local anesthetic, preferably lidocaine, in a concentration of, for example, 0.05% by weight to 5.0% by weight, 0.1% by weight to 4.0% by weight, 0.2% by weight to 3.0% by weight, 0.3% by weight to 2.0%/ 0 by weight, or 0.4% by weight to 1.0% by weight.
    [0055] It is further contemplated in the present invention that the injectable composition for dermal filler may include cross-linked and non-cross-linked polymers in addition to cross-linked HA and CMC. Specifically, the injectable dermal filler composition may additionally comprise 0.001% to 15%, specifically, 1% to 10% volume/volume of non-crosslinked hyaluronic acid. The molecular weight of the hyaluronic acid of said non-crosslinked hyaluronic acid is 6, preferably between 3.0 x 105 Da and 4.0 x 106 Da, specifically between 1.0 x 106 Da and 3.0 x 106 Da.
    [0056] Other cross-linked or non-cross-linked polymers, such as chondroitin sulfate, keratan, keratan sulfate, heparin, heparin sulfate, cellulose and its derivatives, chitosan, carrageenan, xanthan gum and alginate or one of its salts, may also be included in the injectable dermal filler composition of the present invention in small amounts (e.g. less than 10%, generally less than 5% or less than 1% volume/volume). However, it is also contemplated in the present invention that the injectable dermal filler composition does not contain cross-linked polymers in addition to the cross-linked HA described herein, and/or does not contain the non-cross-linked polymers in addition to the CMC described herein. In this context, the term "polymer", as used herein, refers to any natural or synthetic polymeric compound with repetitive structural units, including polysaccharides such as HA.
    [0057] In a preferred embodiment of the present invention, the injectable composition for dermal filler according to the present invention, including the composition comprising microparticles (e.g., calcium hydroxyapatite microparticles), additionally comprises an anesthetic, of preferably, lidocaine, and/or one or more of the polyols described above. Particularly preferably, the injectable composition for dermal filler according to the present invention, including the composition comprising microparticles of CaHAP, further comprises lidocaine and glycerin.
    [0058] In addition, according to the present invention, the injectable composition for dermal filling may have one or more of the following properties: (i) an elastic modulus G' at a frequency (f) of 0.4 Hz and 25 °C from 50 Pa to 4500 Pa, preferably 100 Pa to 4000 Pa, more preferably 150 Pa to 2500 Pa; (ii) a viscosity at a frequency of 0.4 Hz and 25°C from 20 Pa.s to 1400 Pa.s, preferably from 25 Pa.s to 1000 Pa.s, more preferably 30 Pa.s to 900 Pa.s .s; and (iii) a Delta tangent (G'/G') at a frequency of 0.4 Hz and 25°C from 0.20 to 0.8, preferably 0.25 to 0.6.
    [0059] Furthermore, the extrusion force for an injectable dermal filler composition according to the present invention that does not contain any microparticles (eg calcium hydroxyapatite microparticles) is generally in the range of 10 N to 30 N, as measured through a 25G x 1.6 cm (5/8") needle (eg Neoject) at an extrusion speed of about 50 mm/min, using a standard 1 mL syringe (eg , a 1.0 mL BD syringe.) The extrusion force for an injectable dermal filler composition according to the present invention with microparticles (eg, calcium hydroxyapatite microparticles) is generally in the range of 35 N to 70 N, as measured through a 25G TW 3/4 needle (eg Terumo K pack II) at an extrusion speed of about 50 mm/min, using a standard 1.5 mL syringe (eg a 1.5 ml plastic syringe).
    [0060] Furthermore, the injectable composition for dermal filler generally comprises a buffer, for example a phosphate buffer, to adjust the pH. Since the injectable dermal filler composition of the present invention is intended for insertion into the human body, the pH is generally in the range of 6.5 to 7.5, preferably in the range of 6.8 to 7.4. Furthermore, the osmolality is preferably about 200 mOsmol/L to about 400 mOsmol/L, more preferably about 280 mOsmol/L to about 330 mOsmol/L.
    [0061] In a second aspect, the present invention relates to a kit comprising the injectable composition for dermal filler according to the first aspect of the present invention. The kit may also contain instructions for use.
    [0062] In a third aspect, the present invention relates to a method for preparing an injectable composition for dermal filler according to the first aspect of the present invention, comprising the following steps; (a) provide a cross-linked hyaluronic acid gel, (b) provide a carboxymethylcellulose gel, (c) mix the cross-linked hyaluronic acid gel and the carboxymethylcellulose gel.
    [0063] The crosslinked hyaluronic acid gel provided in step (a) and/or the carboxymethylcellulose gel provided in step (b) preferably comprises one or more of the aforementioned polyols, specifically, glycerin. Additionally or alternatively, one or more of the aforementioned polyols, specifically glycerin, may also be added in step (c) or after step (c). Furthermore, within the scope of the present invention, the microparticles can be suspended in the carboxymethylcellulose gel provided in step (b) or, alternatively, the microparticles can be mixed together with the crosslinked hyaluronic acid gel and the carboxymethylcellulose gel in step (ç). Also, microparticles can be added to the mixture obtained in step (c).
    [0064] Preferably, the crosslinked hyaluronic acid gel of step (a) and/or the carboxymethylcellulose gel of step (b) comprises an anesthetic, for example, lidocaine. More preferably, the anesthetic (eg lidocaine) is added in step (c), or after step (c), to the mixture obtained in step (c).
    [0065] In a fourth aspect, the present invention relates to the use of an injectable composition for dermal filler according to the first aspect of the present invention or a kit according to the second aspect of the present invention for cosmetic applications.
    [0066] The use according to the fourth aspect preferably includes the cosmetic treatment of wrinkles and skin lines (for example, facial lines and facial wrinkles), glabellar lines, nasolabial folds, chin folds, puppet lines , buccal commissures, perioral wrinkles, crow's feet, skin depressions, scars, temples, subdermal eyebrow support, malar and buccal fat pads, tear gutters, nose, lips, cheeks, perioral region, infraorbital region, facial asymmetries, jaw and chin lines.
    [0067] In a fifth aspect, the present invention relates to an injectable composition for dermal filler according to the first aspect of the present invention, for use in therapy. Specifically, injectable dermal filler composition according to the first aspect of the present invention can be used in the treatment of stress urinary incontinence, vesicoureteral reflux, vocal fold insufficiency, vocal fold medialization.
    [0068] In a sixth aspect, the present invention relates to a method for replacing or filling a biological tissue or increasing the volume of biological tissue, comprising administering to an individual in need thereof an effective amount of the injectable composition to dermal filler according to the first aspect of the present invention.
    Typically, the injectable composition for dermal filler is administered by injection as by subcutaneous or intradermal injection. for example, the composition can be injected intradermally or subcutaneously using the serial perforation technique. The term "effective amount" refers to that amount of injectable dermal filler composition sufficient to produce desired beneficial or cosmetic (esthetic) or therapeutic results. An "individual" within the meaning of the present invention is any individual or patient in need of treatment for a specific condition or disease. Within the scope of the present invention, the individual is generally a human being.
    [0070] The composition is preferably administered for the treatment of a cosmetic condition, such as the treatment of wrinkles and skin lines (e.g., facial lines and facial wrinkles), glabellar lines, nasolabial folds, chin folds, puppet lines, buccal commissures, perioral wrinkles, crow's feet, skin depressions, scars, temples, subdermal support of the eyebrows, malar and buccal fat toxins, tear gutters, nose, lips, cheeks, perioral region, infraorbital region, facial asymmetries, jaw and chin lines. However, the composition can also be administered to treat a therapeutic indication, such as stress urinary incontinence, vesicoureteral reflux, vocal fold insufficiency, and vocal fold medialization.
    [0071] All explanations and comments set forth above in relation to the first aspect of the invention (for example, with respect to the ingredients or substances included in the injectable composition for dermal filler, its method of manufacture and the definitions of some technical terms) are also apply to the method according to the sixth aspect of the invention.
    [0072] The present invention will now be further illustrated by the following non-limiting examples. Examples
    [0073] The following examples demonstrate that the dermal filler composition according to the present invention has a significantly reduced extrusion force, while its mechanical properties (ie modulus of elasticity (G') and viscosity) are unexpectedly , maintained or even improved. Extrusion force measurement
    [0074] The extrusion force of HA gels (with or without CMC or without lubrication phase) was determined with a 1.0 mL BD syringe and Neoject 25G x 1.6 cm (5/8") needles. For this purpose, a TA.XTPLUS texture analyzer was used.The test was conducted using a preload of 0.500 N and a test speed of 5 cm/min (2 in/min).
    [0075] The extrusion force of HA/CaHAP gels (with or without CMC or without lubrication phase) was determined with a 1.5 mL plastic syringe and Terumo K pack II 27G TW 3/4 needles. For this purpose a TA.XTPLUS Texture Analyzer is used. The test was conducted using a preload of 0.500 N and a test speed of 5 cm/min (2 in/min). Measurement of modulus of elasticity (G') and dynamic viscosity
    [0076] Modulus of elasticity (G') and dynamic viscosity were measured using an Anton Paw MCR 302 rheometer equipped with a plate-plate system with a diameter of 20 mm.
    [0077] In the case of HA gels (with or without CMC or free of free HA lubrication phase), the G' and viscosity were determined using the following settings:

    [0078] In the case of HA gels (with or without CMC or free of free HA lubrication phase), the G' and viscosity were determined using the following settings:
    Example 1 Preparation of HA gels without lubrication phase, and with or without calcium hydroxyapatite particles (MHAG gel and MHAI gel) (Comparative gels) Preparation of crosslinked solutions
    An HA "pie" was prepared by dissolving 43 g of sodium hyaluronate (average molecular weight about 2.8 MDa) in 270.35 g of phosphate buffer. The HA cake obtained can be stored in a refrigerator until needed. In addition, an alkaline solution was prepared by dissolving 3.31 g of solid sodium hydroxide in 10 ml of buffer. In addition, a BDDE solution was prepared by mixing 12.5 g of 2M NaOH solution with 88.5 g of phosphate buffer and then mixing 8.21 ml of this solution and 3.395 ml of BDDE. Crosslink
    [0080] The HA pie was manually broken into small pieces, the entire alkaline solution was added to a bowl, followed by mixing for 30 to 40 minutes at 12 rpm. Then, the BDDE solution was added into the bowl and mixing was continued for 10 to 15 minutes at 25 rpm. The temperature setpoint was changed to 33.33°C, and the mixture was left for 4 hours at this temperature. Neutralization and Purification
    A neutralizing solution was prepared by adding 920.99 g of buffer to 84.62 g of 1 M HCI. The total neutralizing solution was then added to the bowl and stirred for 2 hours at 5°C. Thereafter, the gel was purified according to methods known to those skilled in the art. The resulting gel (the "MHA gel") was then used to prepare the MHAG (without CaHAP) and MHAI (with CaHAP) gel formulations described below. MHAG gel
    [0082] In order to prepare the MHAG gel, a concentrated solution of lidocaine "LS1" was prepared by adding 2 g lidocaine to 2 g phosphate buffer, followed by gentle agitation using a magnetic stirrer until complete dissolution. Then, 467 g of the MHA gel prepared in Example 1 was mixed with 2116 µl of the "LS1" solution for 15 minutes using an appropriate mixer. Then 33 g of glycerin was added and the compounds were mixed gently for 1.5 hours. After an additional degassing step, 1 ml syringes were filled and sterilized at 127°C for 4 minutes. MHAI gel
    [0083] Furthermore, a gel which corresponds to the MHAG gel but additionally contains CaHAP particles in the same amount as the gels prepared in Examples 4 to 6 were prepared according to the procedure described above for the MHAG gel. The CaHAP crosslinked HA gel was termed "MHAI" below. Example 2 Preparation of an HA gel with 15% CMC as a lubrication phase (Inventive Gel)
    [0084] A solution of "LB1" was prepared by adding 62.75 g of glycerin to 2.150 g of lidocaine HCI, and dissolving this mixture in 135.142 g of phosphate buffer. Gentle stirring using a magnetic stirrer was then carried out until complete dissolution.
    Next, 2.764 g of NaCMC were vigorously mixed for 1 hour in a bowl with 105.24 g of LB1. After degassing, 392.025 g of the MHAG gel prepared in Example 1 was added and mixed gently for 1.5 hours. After an additional degassing step, 1 ml syringes were filled and sterilized at 127°C for 4 minutes. Example 3 Preparation of an HA gel with 15% (v/v) free HA as the lubrication phase (Comparative Gel)
    [0086] A "LB2" solution was prepared by dissolving 1.131 g of lidocaine HCI in 72.743 g of phosphate buffer. Then 1.170 g of sodium hyaluronate (2.5 to 3.0 MDa) were added. After complete dissolution, 33.005 g of glycerin was added. The mixture was then stirred at a moderate speed for 1 hour and 30 minutes and held at 5°C prior to use.
    An HA gel with 15% (v/v) free HA lubricant was prepared by mixing 106.721 g of LB2 with 387.357 g of the MHAG gel prepared in Example 1. A moderate mixture was kept for 2 hours. After degassing, 1 ml syringes were filled and sterilized at 127°C for 4 minutes. Example 4 Preparation of an HA/CaHAP gel with 5% (v/v) CMC as a lubrication phase (Inventive Gel)
    [0088] A "LB3" solution was prepared in the same manner as for LB1, except that the following materials and quantities were used: 4.633 g of NaCMC, 274.16 g of glycerin and 121.3 g of phosphate buffer.
    [0089] An HA/CaHAP gel with 5% (v/v) CMC lubricant was prepared by placing 280.02 g of CaHAP (25 μm to 45 μm), 48.22 g of LB3 and 171.84 g of the MHAG gel prepared in Example 1 in a mixing bowl. Then, 2.120 ml of a lidocaine solution (2 g of lidocaine in 2 g of phosphate buffer) was added. The mixture was stirred at moderate speed for 1.5 hours. After degassing under vacuum, 1 ml syringes were filled and sterilized at 121°C for 20 minutes. Example 5 Preparation of an HA/CaHAP gel with 10% (v/v) CMC as a lubrication phase (Inventive Gel)
    [0090] A "LB4" solution was prepared in the same manner as for LB1, except that the following materials and quantities were used: 7.039 g of NaCMC, 208.527 g of glycerin and 184.46 g of phosphate buffer.
    [0091] An HA/CaHAP gel with 10% (v/v) CMC lubrication was prepared as described in Example 4, except that the following amounts were used: 280.02 g of CaHAP (25 μm to 45 μm), 63.29 g of LB4 and 156.79 g of the MHAG gel prepared in Example 1. Example 6 Preparation of an HA/CaHAP gel with 15% (v/v) CMC with the lubrication phase (Inventive Gel)
    [0092] A "LB5" solution was prepared in the same way as for
    [0093] LB1, except that the following materials and quantities were used: 8.529 g of NaCMC, 168.266 of glycerin and 223.29 of phosphate buffer.
    [0094] A HA/CaHAP gel with 15% (v/v) CMC lubricant was prepared as described in Example 4, except that the following amounts were used: 280.02 g of CaHAP (25 μm to 45 μm) , 78.46 of LB5 141.562 g of the MHAG gel prepared in Example 1. Example 7 Preparation of an HA/CaHAP gel with 10% (v/v) free HA as lubrication phase (Comparative Gel)
    [0095] A "LB6" solution was prepared in the same manner as for LB2, except that the following materials and quantities were used: 208,548 glycerin, 3.108 g sodium hyaluronate and 188,581 g phosphate buffer.
    [0096] An HA/CaHAP gel with 10% (v/v) free HA lubricant was prepared by mixing 156.781 g of the MHAG gel prepared in Example 1 with 63.32 g of LB6 and 2120 µL of lipid solution - caine (2 g lidocaine in 2 g phosphate buffer). Then 280.02 g of CaHAP (25 µm to 45 µm) was added and mixed gently for 1.5 hours. After degassing, 1 mL syringes were filled and sterilized at 121°C for 20 minutes. Example 8 Effect of CMC lubricant or free HA lubricant on the extrusion strength of a crosslinked HA gel
    In this example, the effect of adding CMC or free HA as a lubricant on the extrusion strength of an HA gel was examined. For this purpose, the extrusion force of the following gels was measured: MHAG gel (Example 1), MHAG gel with 15% CMC (Example 2) and MHAG gel with 15% free HA (Example 3).
    [0098] It was found that the use of CMC as a lubricant significantly reduced the extrusion force. The reduction was similar to that seen with free HA (see FIGURE 1). Example 9 Impact of CMC lubricant or free HA lubricant on the modulus of elasticity (G') of a crosslinked HA gel
    [0099] In this example, the impact of CMC and free HA lubricant on the elastic modulus (G') of a gel was examined. For this purpose, the G' (at 1 Hz, 25°C) of the same gels as in Example 8 was measured.
    [00100] It was found that the addition of CMC discretely increased the G', while the addition of free HA reduced the G' (see FIGURE 2). Preservation of G' is important as this parameter influences the lifting capacity of a fill. Thus, since an even slight increase was observed with CMC, it is expected that the MHAG gel with CMC at 15% (v/v) is less likely to shift once it is under the skin, thus resulting. , in more "elevation". Example 10 Influence of CMC Lubricant or Free HA Lubricant on Viscosity of a Cross-linked HA Gel
    In this example, the influence of CMC lubricant and free HA lubricant on viscosity was examined. For this purpose, the viscosity (at 0.4 Hz, 25°C) was determined for the same gels as in Example 8.
    [00102] The addition of CMC was found to increase the viscosity, while the addition of free HA discretely reduced the viscosity (see FIGURE 3). Viscosity is also an important parameter of a filler composition, as an increased viscosity will limit the spread of the gel into soft tissue, and will also contribute to the volumizing effect. Example 11 Effect of CMC lubricant or free HA lubricant on the extrusion strength of a crosslinked HA/CaHAP gel
    [00103] In order to study whether the addition of calcium hydroxyapatite (CaHAP) particles alters the results obtained above for the addition of CMC or free HA to a cross-linked HA gel, the following gels were prepared: MHAI (comprises HA crosslinked and CaHAP and HA particles, see Example 1), MHAI with 10% CMC (Example 5) and MHAI with 10% free HA (Example 7). In addition, a "diluted MHAI" gel was prepared, which corresponds to the MHAI gel, except that the diluted MHAI gel has a HA concentration of 15 mg/g. The extrusion force of the aforementioned gels was then measured.
    [00104] It was found that the addition of 10% CMC lubricant significantly reduced the extrusion force. The reduction was slightly greater than that seen with free HA. In addition, it should be noted that the use of CMC or free HA lubricant provides a decrease in extrusion force similar to that seen with the "diluted MHAI gel" having a less concentrated HA matrix (see FIGURE 4).
    Thus, the incorporation of CaHAP particles in a cross-linked HA gel does not change the basic results observed for a cross-linked HA gel without CaHAP particles; however, the decrease in extrusion force was even more pronounced in the case of an HA gel with CaHAP particles. Example 12 Impact of CMC lubricant or free HA lubricant on the modulus of elasticity (G') of a crosslinked HA/CaHAP gel
    [00106] In this example, the impact of the CMC lubricant or the free HA lubricant on the elastic modulus (G') of a cross-linked HA/CaHAP gel was examined. For this purpose, the G' (at 1 Hz, 25°C) was determined for the same gels as in Example 11.
    [00107] It has been found that the addition of 10% CMC lubricant results in an extraordinary increase in G'. In contrast, the addition of 10% free HA is accompanied by a slight reduction in G', and the dilution of the HA matrix leads to a sharp drop in the elastic modulus, which drastically alters gel properties and clinical results ( see FIGURE 5).
    [00108] As mentioned earlier, a gel like G' will result in a better volumizing effect. Consequently, this example shows that the addition of a CMC lubricant to a cross-linked HA/CaHAP gel results in superior lifting capacity. Example 13 Influence of CMC lubricant or free HA lubricant on the viscosity of a crosslinked HA/CaHAP gel
    [00109] In this example, the influence of CMC lubricant or free HA lubricant on the viscosity of a cross-linked HA/CaHAP gel was examined. For this purpose, the viscosity (at 0.4 Hz, 25°C) was determined for the same gels as in Example 11.
    [00110] It has been found that the addition of 10% CMC lubricant results in a strong increase in viscosity, while the addition of HA has only a minimal impact. As expected, diluting the HA matrix results in a loss of viscosity that is not less than about 75%.
    [00111] In this regard, it should be noted that the concentration of the added CMC lubricant can be adjusted depending on the required extrusion force, as shown in Example 14 below. Example 14 Influence of varying CMC lubricant concentrations on the extrusion force of a cross-linked HA/CaHAP gel
    [00112] In this example, the correlation between varying concentrations of added CMC lubricant and extrusion force was examined. For this purpose, the extrusion force was measured for the following gels. MHAI (cross-linked HA/CaHAP gel; Example 1); MHAI with 5% CMC (Example 4), MHA1 with 10% CMC (Example 5), and MHAI with 15% CMC (Example 6).
    [00113] It has been found that adding only 5% CMC leads to a significant reduction in extrusion force, which can be further reduced by adding 10% CMC, and further by adding 15% CMC (see Figure 7).
    [00114] In general, Examples 1 to 14 above show that the dilution of an HA gel leads to a reduction in the extrusion force, but it is also associated with a strong reduction in the modulus of elasticity (G') and the viscosity that it will drastically impair the clinical results of the filling. Experiments further show that if free HA is added as a Lubricant, the extrusion force is reduced, but unfortunately there is also a slight to moderate reduction in G’ and viscosity.
    [00115] In contrast, if CMC is used as a lubricant in accordance with the present invention, it has surprisingly been found that this not only leads to a strongly reduced extrusion force, but also to an increase in G' and in viscosity, especially in the case of a cross-linked HA gel with dispersed particles (CaHAP particles). Both the increase in G' and the increase in viscosity result in an improved lifting effect of the dermal filler composition after injection. Furthermore, due to the crosslinking nature of the HA gel, a long-lasting persistence in the human body will be obtained.
    [00116] Thus, the experiments presented above provide evidence that the composition for dermal filler according to the present invention provides an optimal balance of longevity, lifting capacity and ease of injection.
    权利要求:
    Claims (14)
    [0001]
    1. Injectable composition for dermal filling in the form of a gel, characterized by the fact that it comprises cross-linked hyaluronic acid and carboxymethylcellulose, in which the carboxymethylcellulose is present in a concentration of 1.0% to 25.0% volume/volume .
    [0002]
    2. Injectable composition for dermal filler according to claim 1, characterized in that the crosslinked hyaluronic acid is present in a concentration of 1.0% to 4.0% weight/volume.
    [0003]
    3. Injectable composition for dermal filler according to claim 1 or 2, characterized in that the hyaluronic acid is cross-linked with BDDE (1,4-butanediol diglycidyl ether), and preferably has a degree of modification, expressed as the ratio of the sum of BDDE crosslinkers with single and double bonds and the sum of disaccharide units of hyaluronic acid, from 0.5% to 25%.
    [0004]
    4. Injectable composition for dermal filler according to any one of claims 1 to 3, characterized in that the composition additionally comprises resorbable biocompatible microparticles in a concentration of 1% to 50% volume/volume.
    [0005]
    5. Injectable composition for dermal filler according to claim 4, characterized in that the resorbable biocompatible microparticles consist of materials based on calcium phosphate, materials based on aluminum oxide, a natural biodegradable polysaccharide or a derivative of the same, or a biodegradable polyester, a synthetic polymer of polyorthoester or polyanhydride, the calcium phosphate based materials including calcium hydroxyapatite, calcium fluorapatite, calcium chloroapatite, calcium carbonate apatite, tetracalcium phosphate, calcium pyrophosphate, tricalcium phosphate, and octacalcium phosphate.
    [0006]
    6. Injectable composition for dermal filler according to any one of claims 1 to 5, characterized in that it additionally comprises one or more compounds selected from the group consisting of anesthetics, polyols, vitamins, amino acids, metals, antioxidants and salts minerals.
    [0007]
    7. Injectable composition for dermal filler according to any one of claims 1 to 6, characterized in that the composition comprises a polyol, for example, glycerin, and/or an anesthetic, for example, lidocaine.
    [0008]
    8. Injectable composition for dermal filler according to any one of claims 1 to 7, characterized in that the composition has one or more of the following properties: (i) an elastic modulus G' at a frequency (f) of 0, 4 Hz and 25°C from 100 Pa to 4000 Pa; (ii) a viscosity at a frequency of 0.4 Hz and 25°C from 20 Pa.s to 1000 Pa.s; (iii) a Delta tangent (G"/G') at a frequency of 0.4 Hz and 25°C from 0.25 to 0.6; and (iv) a pH of 6.5 and 7.5.
    [0009]
    9. Kit, characterized in that it comprises the injectable composition for dermal filler as defined in any one of claims 1 to 8.
    [0010]
    10. Injectable composition for dermal filler according to any one of claims 1 to 8, or kit according to claim 9, characterized in that it is for use in therapy.
    [0011]
    11. Injectable composition for dermal filler according to any one of claims 1 to 8, or kit according to claim 9, characterized in that it is for use in the treatment of urinary incontinence or stress, vesicourethral reflux , vocal fold insufficiency, and oral fold medialization.
    [0012]
    12. Use of an injectable composition for dermal filler as defined in any one of claims 1 to 8, or a kit as defined in claim 9, characterized in that it is for cosmetic applications, including cosmetic treatment of wrinkles and skin lines , glabellar lines, nasolabial folds, chin folds, puppet lines, jaw lines, buccal commissures, perioral wrinkles, crow's feet, skin depressions, scars, temples, subdermal eyebrow support, malar and buccal fat pads, tear ducts, nose, lips, cheeks, chin, perioral region, infraorbital region and facial asymmetries.
    [0013]
    13. Use of injectable composition for dermal filling as defined in any one of claims 1 to 8, characterized in that it is to prepare a kit as defined in claim 9 for treating urinary incontinence or stress, vesicourethral reflux, fold insufficiency vocal cord, and medialization of the oral fold.
    [0014]
    14. Method for preparing an injectable composition for dermal filler as defined in any one of claims 1 to 8, characterized in that it comprises the following steps: (a) providing a cross-linked hyaluronic acid gel, (b) providing a gel of carboxymethylcellulose, (c) mixing the cross-linked hyaluronic acid gel and the carboxymethylcellulose gel.
    类似技术:
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    同族专利:
    公开号 | 公开日
    RU2712641C2|2020-01-30|
    SG11201703952QA|2017-06-29|
    RU2017119805A|2018-12-14|
    EP3218023B1|2018-09-05|
    KR20170117368A|2017-10-23|
    EP3218023A1|2017-09-20|
    AU2015345523A1|2017-06-08|
    CN106999625B|2020-06-16|
    ES2688731T3|2018-11-06|
    WO2016074794A1|2016-05-19|
    BR112017010074A2|2018-01-02|
    IL252265A|2021-02-28|
    US20170333596A1|2017-11-23|
    TWI716365B|2021-01-21|
    CA2967699A1|2016-05-19|
    AU2015345523B2|2019-05-16|
    LT3218023T|2018-10-25|
    ZA201703351B|2019-01-30|
    JP6721584B2|2020-07-15|
    TW201625276A|2016-07-16|
    US10335512B2|2019-07-02|
    MX2017006232A|2018-01-23|
    IL252265D0|2017-07-31|
    RU2017119805A3|2019-06-14|
    JP2017533785A|2017-11-16|
    CN106999625A|2017-08-01|
    PL3218023T3|2019-03-29|
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    法律状态:
    2019-09-03| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|
    2020-11-17| B07A| Technical examination (opinion): publication of technical examination (opinion) [chapter 7.1 patent gazette]|
    2021-03-16| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2021-05-04| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 12/11/2015, OBSERVADAS AS CONDICOES LEGAIS. |
    优先权:
    申请号 | 申请日 | 专利标题
    EP14003829.0|2014-11-13|
    EP14003829|2014-11-13|
    EP15000338.2|2015-02-05|
    EP15000338|2015-02-05|
    PCT/EP2015/002270|WO2016074794A1|2014-11-13|2015-11-12|Dermal filler based on crosslinked hyaluronic acid and carboxymethyl cellulose lubricant|
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