HK1226965B - Hyaluronic acid compositions including mepivacaine - Google Patents

Description

Hyaluronic acid composition containing mepivacaine

The present invention relates to the field of biodegradable gels and hydrogels for use as biomaterials and more particularly in the medical and cosmetic fields.

Among medical applications, examples that will be mentioned include injections for replacing deficient biological fluids, such as injections into joints for replacing synovial fluid, injections after surgery to avoid peritoneal adhesions, periurethral injections for treating incontinence and injections after surgery for correcting presbyopia.

Among cosmetic applications, examples that will be mentioned include injections for filling wrinkles, fine lines and skin imperfections or for increasing the volume of, for example, lips, cheekbones, etc.

In all these applications, the gels and hydrogels used must have optimized properties in terms of in vivo persistence, rheology and viscosity to ensure good injectability, and these hydrogels are injected using needles that must remain as thin as possible to ensure the precision of the practitioner's gestures and minimize post-injection reactions.

The gels and hydrogels used are based on polymers chosen from polysaccharides such as hyaluronic acid, keratan, heparin, cellulose and cellulose derivatives, alginic acid, xanthan gum, carrageenan, chitosan, chondroitin and biologically acceptable salts thereof.

In order to improve these gels and/or hydrogels and/or to impart particular properties thereto, a certain number of additives may be added thereto.

One major drawback of adding additives, whether added directly during addition or during the sterilization phase or over time, for example during storage, is a potential deterioration of the rheological and/or viscoelastic properties of the final gel or its stability.

Michael H. Gold's article (Clinical Interventions in Aging, 2007, 369-376) quickly traces the evolution of dermal filler products. The first compositions developed for this purpose were based on collagen. The products, Glucocorticoid (approved by the FDA in 1981) and Glucocorticoid (approved by the FDA in 1985), were based on bovine collagen. Subsequently, two similar products were developed, but based on human collagen (Glucocorticoid and Glucocorticoid, both approved by the FDA in 2003).

The first dermal filler composition based on hyaluronic acid was developed by Balazs in the late 1980s. Improvements have been made since then to increase the stability of hyaluronic acid-based compositions.

As described in the aforementioned article by Gold, the collagen-based composition contains lidocaine to reduce the pain associated with the injection technique. However, in a first phase, as described above, the hyaluronic acid-based composition does not contain any local anesthetic due to stability issues caused by the additive.

In recent years, efforts have been made to incorporate local anesthetics, particularly lidocaine, into hyaluronic acid-based gels while ensuring a certain level of stability. According to Gold's article, Puragen ^™ Plus, sold by Mentor Corporation, was the first hyaluronic acid-based filler composition to contain lidocaine. Patent application WO 2005/112 888, published on December 1, 2005, in the name of Mentor Corporation, describes a method for preparing an injectable hydrogel that can contain lidocaine.

Researchers in this field have filed numerous patent applications relating to compositions based on hyaluronic acid and comprising lidocaine.

Patent application WO 2005/067 994 published on July 28, 2005 in the name of Anika Therapeutics describes a composition based on cross-linked hyaluronic acid gel particles comprising lidocaine in Example 21. Lidocaine is merely an exemplary local anesthetic.

Patent application WO 2010/015 901 published on February 11, 2010 in the name of Allergan describes injectable dermal filler compositions based on hyaluronic acid containing lidocaine. In said document, only lidocaine-based compositions are exemplified.

Patent application WO 2010/052 430 published on 14 May 2010 in the name of Anteis describes compositions based on hyaluronic acid comprising lidocaine and one or more polyols.

Patent application WO 2012/104 419, published on August 9, 2012, in the name of Q-MED AB, also describes injectable hyaluronic acid-based dermal filler compositions containing local anesthetics. In particular, compositions containing lidocaine, bupivacaine (pKa = 8.1), and tetracaine (a = 8.5) are exemplified. The preferred local anesthetics in this specification are bupivacaine, lidocaine, and ropivacaine (pKa = 8.1). Therefore, compositions incorporating local anesthetics with a pKa less than that of lidocaine are not exemplified or individually cited. Most of the examples described in patent application WO 2012/104 419 relate to compositions containing lidocaine.

Patent application WO 2013/186 493 discloses hyaluronic acid compositions comprising sucrose octasulfate. No formulations comprising a local anesthetic are exemplified, and all examples describe compositions that are terminally sterilized by autoclaving.

Patent application FR 2 979 539 in the name of Teoxane describes preparations comprising a local anesthetic and other active agents; also in this case, only compositions comprising lidocaine are described.

Patent application CN 102805882 relates to a hyaluronic acid composition to which a local anesthetic is added just before its use, but no examples are described.

Patent application WO 2013/186 493 discloses hyaluronic acid compositions comprising a vitamin C derivative. Formulations comprising a local anesthetic are not exemplified.

Patent application KR 20140025117 describes hyaluronic acid-based compositions comprising an anesthetic agent and only describes compositions comprising lidocaine.

Other local anesthetics are mentioned in the literature, but are presented as examples only, and currently only products containing lidocaine are marketed.

Patent application EP 2 581 079 in the name of Biopolymer GmbH & Co. KG describes compositions based on hyaluronic acid and prilocaine which have a rapid prilocaine release profile.

Indeed, one of the improvements that has yet to be realized is that of obtaining the fastest possible effects of local anesthetics.

While all existing prior art relates to hyaluronic acid compositions comprising a local anesthetic, almost all prior art examples relate to lidocaine, and no prior art examples relate to mepivacaine.

Among the potential candidates are local anesthetics of the fast-acting aminoamide type, this group consisting of lidocaine, etidocaine, mepivacaine, prilocaine and articaine.

The delay of action of these local anesthetics is determined by their pKa, which is between 7.7 and 8.0. At physiological pH, the local anesthetics with the shortest delay of action are those with a pKa closest to 7.4. Due to its lipid solubility, the non-ionized alkaline form will be the local anesthetic that will penetrate the epineurium and neuronal membranes, making the molecule more readily available for blocking sodium channels. Among the possible candidates for the fast-acting aminoamide type, mepivacaine has the lowest pKa of this group, due to its pKa of 7.7; therefore, in theory, mepivacaine has the shortest delay of action of the group.

However, one of the risks associated with the incorporation of this type of molecule is its tendency to precipitate. Indeed, the basic form is lipid-soluble and therefore, during its incorporation into aqueous gels, which are generally formulated at a pH close to physiological pH (i.e. 7.4), the anesthetic will have a high tendency to precipitate.

Precipitation of local anesthetics is quite difficult to understand. Generally, the pKa is considered a good indicator of precipitation: the lower the pKa, the greater the risk of precipitation (all other things being equal). Therefore, from a pKa perspective, mepivacaine is the worst candidate for the fast-acting aminoamide group of local anesthetics (given its pKa of 7.7). This is undoubtedly the reason: mepivacaine has never been exemplified in the prior art. In fact, even in applications exploring the possibility of incorporating local anesthetics to replace lidocaine, such as patent application WO 2012/104 419 in the name of Q-MED AB, mepivacaine is cited, but only local anesthetics with higher pKa alternatives to lidocaine are exemplified: bupivacaine (pKa 8.1) and tetracaine (pKa 8.5). Finally, prilocaine (contemplated in patent application EP 2 581 079 in the name of Biopolymer GmbH & Co. KG) has a pKa of 7.9.

Indeed, it is essential that no precipitation occurs in gels injected with fine needles for wrinkle correction. Cosmetic applications dictate that injection should not be hindered, thereby avoiding poor application and resulting defective filling. Furthermore, precipitates can cause the same effects as foreign matter and thus pose a risk of inflammation. Furthermore, precipitate formation can reduce the amount of local anesthetic in solution, subsequently reducing its bioavailability and, therefore, its effectiveness.

No doubt due to the aforementioned drawbacks, although among the local anesthetics that can be incorporated into hyaluronic acid-based compositions listed, in particular in patent applications WO 2010/015 901 and WO 2012/104419, no example of a hyaluronic acid-based gel comprising mepivacaine is described.

The literature discloses an article by Cho et al., Pak. J. Pharm. Sci., 2001 Jan;24(1):87-93, which describes studies on the release of mepivacaine from hydroxypropyl methylcellulose (HPMC) gels. These compositions are formulated in gel form for direct application to the skin and transdermal administration. The article describes that increasing the concentration of mepivacaine and increasing the temperature increase the release rate of mepivacaine.

Hyaluronic acid formulations containing mepivacaine have not been described to date, undoubtedly due to the potential difficulties of their formulation at physiological pH.

Surprisingly, the Applicant has shown that the incorporation of mepivacaine into hyaluronic acid-based gels makes it possible firstly to obtain compositions without precipitates at a pH close to physiological pH and despite the unfavorable pKa of mepivacaine, and secondly these sterilized compositions have a less impaired rheology during their sterilization than compositions containing other local anesthetics of the same group.

Furthermore, this reduction in the detriment of the elastic component G' during sterilization is observed irrespective of other possible excipients or additional compounds conventionally used for the formulation of filled gels.

It is also surprising that the addition of mepivacaine makes it possible to obtain, in the presence of a polyol, a composition having systematically improved rheological properties when compared to a composition comprising neither a polyol nor an anesthetic.

Therefore, the present invention relates to a sterilized aqueous composition having a pH close to physiological pH, comprising at least one hyaluronic acid and at least mepivacaine, the mass ratio of the concentration of hyaluronic acid [HA] to the concentration of mepivacaine [MEPI] being: [HA]/[MEPI] greater than or equal to 0.1; [HA]/[MEPI] ≥ 0.1.

The term "hyaluronic acid" means cross-linked or non-cross-linked hyaluronic acid, alone or as a mixture, optionally chemically modified by substitution, alone or as a mixture, optionally in the form of its salts, alone or as a mixture.

The term "mepivacaine" means mepivacaine or a salt thereof, alone or as a mixture.

In one embodiment, the mass ratio of the concentration of hyaluronic acid [HA] to the concentration of mepivacaine [MEPI]: [HA]/[MEPI] is 0.1 to 50, and 0.1≤[HA]/[MEPI]≤50.

In one embodiment, the mass ratio of the concentration of hyaluronic acid [HA] to the concentration of mepivacaine [MEPI]: [HA]/[MEPI] is 0.5 to 40, and 0.5≤[HA]/[MEPI]≤40.

In one embodiment, the mass ratio of the concentration of hyaluronic acid [HA] to the concentration of mepivacaine [MEPI]: [HA]/[MEPI] is 1 to 30, and 1≤[HA]/[MEPI]≤30.

In one embodiment, the mass ratio of the concentration of hyaluronic acid [HA] to the concentration of mepivacaine [MEPI]: [HA]/[MEPI] is 2 to 20, and 2≤[HA]/[MEPI]≤20.

In one embodiment, the mass ratio [HA]/[MEPI] of the concentration of hyaluronic acid [HA] to the concentration of mepivacaine [MEPI] is 7/3 to 26/3, and 7/3≤[HA]/[MEPI]≤26/3.

In one embodiment, the mass ratio [HA]/[MEPI] of the concentration of hyaluronic acid [HA] to the concentration of mepivacaine [MEPI] is 2 to 20/3, and 2≤[HA]/[MEPI]≤20/3.

In one embodiment, the mass ratio [HA]/[MEPI] of the concentration of hyaluronic acid [HA] to the concentration of mepivacaine [MEPI] is 2 to 10/3, and 2≤[HA]/[MEPI]≤10/3.

In one embodiment, the mass ratio [HA]/[MEPI] of the concentration of hyaluronic acid [HA] to the concentration of mepivacaine [MEPI] is 20.

In one embodiment, the mass ratio [HA]/[MEPI] of the concentration of hyaluronic acid [HA] to the concentration of mepivacaine [MEPI] is 26/3.

In one embodiment, the mass ratio [HA]/[MEPI] of the concentration of hyaluronic acid [HA] to the concentration of mepivacaine [MEPI] is 20/3.

In one embodiment, the mass ratio [HA]/[MEPI] of the concentration of hyaluronic acid [HA] to the concentration of mepivacaine [MEPI] is 10/3.

In one embodiment, the mass ratio [HA]/[MEPI] of the concentration of hyaluronic acid [HA] to the concentration of mepivacaine [MEPI] is 7/3.

In one embodiment, the mass ratio [HA]/[MEPI] of the concentration of hyaluronic acid [HA] to the concentration of mepivacaine [MEPI] is 2.

In one embodiment, the concentration of mepivacaine [MEPI] is from 0.01 mg/g to 50 mg/g of the total weight of the composition.

In one embodiment, the concentration of mepivacaine [MEPI] is from 0.05 mg/g to 45 mg/g of the total weight of the composition.

In one embodiment, the concentration of mepivacaine [MEPI] is from 0.1 mg/g to 40 mg/g of the total weight of the composition.

In one embodiment, the concentration of mepivacaine [MEPI] is from 0.2 mg/g to 30 mg/g of the total weight of the composition.

In one embodiment, the concentration of mepivacaine [MEPI] is from 0.5 mg/g to 20 mg/g of the total weight of the composition.

In one embodiment, the concentration of mepivacaine [MEPI] is from 1 mg/g to 15 mg/g of the total weight of the composition.

In one embodiment, the concentration of mepivacaine [MEPI] is from 1 mg/g to 10 mg/g of the total weight of the composition.

In one embodiment, the concentration of mepivacaine [MEPI] is from 1 mg/g to 6 mg/g of the total weight of the composition.

In one embodiment, the concentration of mepivacaine [MEPI] is from 1 mg/g to 5 mg/g of the total weight of the composition.

In one embodiment, the concentration of mepivacaine [MEPI] is from 2 mg/g to 5 mg/g of the total weight of the composition.

In one embodiment, the concentration of mepivacaine [MEPI] is from 6 mg/g to 10 mg/g of the total weight of the composition.

In one embodiment, the concentration of mepivacaine [MEPI] is 1 mg/g total weight of the composition.

In one embodiment, the concentration of mepivacaine [MEPI] is 3 mg/g total weight of the composition.

In one embodiment, the concentration of mepivacaine [MEPI] is 4 mg/g total weight of the composition.

In one embodiment, the concentration of mepivacaine [MEPI] is 5 mg/g total weight of the composition.

In one embodiment, the concentration of mepivacaine [MEPI] is 6 mg/g total weight of the composition.

In one embodiment, the concentration of mepivacaine [MEPI] is 10 mg/g total weight of the composition.

In one embodiment, mepivacaine is selected from the group comprising mepivacaine or a pharmaceutically acceptable salt thereof.

In one embodiment, mepivacaine is selected from the group consisting of racemic mepivacaine hydrochloride, racemic mepivacaine, (R)-mepivacaine hydrochloride, (S)-mepivacaine hydrochloride, (R)-mepivacaine, and (S)-mepivacaine, or pharmaceutically acceptable salts thereof.

In one embodiment, the mepivacaine is racemic mepivacaine hydrochloride.

In one embodiment, the mepivacaine is (R)-mepivacaine hydrochloride.

In one embodiment, the mepivacaine is (S)-mepivacaine hydrochloride.

In one embodiment, the mepivacaine is racemic mepivacaine.

In one embodiment, the mepivacaine is (R)-mepivacaine.

In one embodiment, the mepivacaine is (S)-mepivacaine.

In one embodiment, the concentration of hyaluronic acid [HA] is from 2 mg/g to 50 mg/g of the total weight of the composition.

In one embodiment, the concentration of hyaluronic acid [HA] is from 4 mg/g to 40 mg/g of the total weight of the composition.

In one embodiment, the concentration of hyaluronic acid [HA] is from 5 mg/g to 30 mg/g of the total weight of the composition.

In one embodiment, the concentration of hyaluronic acid [HA] is from 10 mg/g to 30 mg/g of the total weight of the composition.

In one embodiment, the concentration of hyaluronic acid [HA] is 20 mg/g of the total weight of the composition.

In one embodiment, the sterilized aqueous composition according to the invention is characterized in that the total content of hyaluronic acid is between 0.2% and 5% by weight relative to the total weight of the composition.

In one embodiment, the sterilized aqueous composition according to the invention is characterized in that the total content of hyaluronic acid is greater than or equal to 1% by weight relative to the total weight of said composition.

In one embodiment, the sterilized aqueous composition according to the invention comprises at least one non-cross-linked hyaluronic acid or a salt thereof, alone or as a mixture.

In one embodiment, the sterilized aqueous composition according to the invention comprises at least one cross-linked hyaluronic acid or a salt thereof, alone or as a mixture.

In one embodiment, the sterilized aqueous composition according to the invention comprises at least one co-cross-linked hyaluronic acid or a salt thereof, alone or as a mixture.

In one embodiment, the sterilized aqueous composition according to the invention comprises, alone or as a mixture, at least one cross-linked or non-cross-linked hyaluronic acid or a salt thereof that is chemically modified by substitution.

In one embodiment, the hyaluronic acid is doubly cross-linked as described in patent application WO 2000/046 253 in the name of Fermentech Medical Limited.

In one embodiment, the sterilized aqueous composition according to the invention comprises a mixture of cross-linked and non-cross-linked hyaluronic acid or a salt thereof.

In one embodiment, the sterilized aqueous composition according to the invention comprises a mixture of cross-linked hyaluronic acid or a salt thereof.

In one embodiment, the mixture of cross-linked hyaluronic acid or salts thereof is a single-phase mixture, such as described in patent application WO 2009/071 697 in the name of the Applicant.

In one embodiment, the mixture of cross-linked hyaluronic acids or salts thereof is a mixture obtained by mixing several hyaluronic acids or salts thereof of different molecular weight before their cross-linking, as described in patent application WO 2004/092 222 in the name of Cornéal Industrie.

In one embodiment, the sterilized aqueous composition according to the invention comprises at least one hyaluronic acid or salt thereof substituted with groups imparting lipophilicity or hydration, such as the substituted hyaluronic acids described in patent application FR 2 983 483 in the name of the Applicant.

In one embodiment, the hyaluronic acid is in the form of a sodium or potassium salt.

The term Mw or "molecular weight" means the weight average molecular weight of a polymer measured in Daltons.

In one embodiment, the composition according to the invention is characterized in that the molecular weight Mw of said at least one hyaluronic acid is within the range of 0.01 MDa to 5 MDa.

In one embodiment, the composition according to the invention is characterized in that the molecular weight Mw of said at least one hyaluronic acid is within the range of 0.1 MDa to 3.5 MDa.

In one embodiment, the composition according to the invention is characterized in that the molecular weight Mw of said at least one hyaluronic acid is within the range of 1 MDa to 3 MDa.

In one embodiment, the composition according to the invention is characterized in that the molecular weight Mw of said at least one hyaluronic acid is 1 MDa.

In one embodiment, the composition according to the invention is characterized in that the molecular weight Mw of said at least one hyaluronic acid is 3 MDa.

In the present invention, the degree of crosslinking X is defined as being equal to the following ratio:

In one embodiment, the cross-linking degree X of the cross-linked hyaluronic acid is from 0.001 to 0.5.

In one embodiment, the cross-linking degree X of the cross-linked hyaluronic acid is from 0.01 to 0.4.

In one embodiment, the cross-linking degree X of the cross-linked hyaluronic acid is from 0.1 to 0.3.

In one embodiment, the cross-linking degree X of the cross-linked hyaluronic acid is 0.06.

In one embodiment, the cross-linking degree X of the cross-linked hyaluronic acid is 0.07.

In one embodiment, the cross-linking degree X of the cross-linked hyaluronic acid is 0.12.

In one embodiment, the sterilized aqueous composition according to the invention further comprises other polysaccharides.

In one embodiment, this other polysaccharide is selected from cellulose and its derivatives and/or alginic acid or its salts.

The aqueous composition is sterilized, ie after its preparation, it is subjected to a sterilization step performed with heat, moist heat, gamma radiation or a beam of accelerated electrons (e-beam).

In one embodiment, the sterilization step is performed by high pressure steam sterilization.

In one embodiment, sterilization by autoclaving is carried out at a temperature of 121°C to 134°C for a time appropriate to said temperature.

For example, sterilization by high pressure steam sterilization is performed at a temperature of 127° C. to 130° C. for a time of 1 minute to 20 minutes.

In one embodiment, the sterilization step is performed by irradiation with gamma radiation.

In one embodiment, the sterilized aqueous composition according to the invention further comprises at least one antioxidant.

Therefore, the present invention also relates to a sterilized aqueous composition comprising at least one hyaluronic acid, at least mepivacaine and at least one antioxidant, wherein the mass ratio of the concentration of hyaluronic acid [HA] to the concentration of mepivacaine [MEPI] is: [HA]/[MEPI] greater than 0.1; 0.1≤[HA]/[MEPI].

In one embodiment, the sterilized aqueous composition according to the invention is characterized in that the at least one antioxidant is chosen from polyols.

In one embodiment, the sterilized aqueous composition according to the invention is characterized in that the polyol is chosen from glycerol, sorbitol, propylene glycol, xylitol, mannitol, erythritol, maltitol and lactitol, alone or as a mixture.

In one embodiment, the sterilized aqueous composition according to the invention is characterized in that the polyol is chosen from mannitol, sorbitol, maltitol and glycerol, alone or as a mixture.

In one embodiment, the sterilized aqueous composition according to the invention is characterized in that the polyol is chosen from mannitol and sorbitol, alone or as a mixture.

In one embodiment, the sterilized aqueous composition according to the invention is characterized in that the polyol is mannitol.

In one embodiment, the sterilized aqueous composition according to the invention is characterized in that the polyol is sorbitol.

In one embodiment, the sterilized aqueous composition according to the invention is characterized in that the polyol is maltitol.

In one embodiment, the sterilized aqueous composition according to the invention is characterized in that the polyol is glycerol.

In one embodiment, the sterilized aqueous composition according to the invention is characterized in that the antioxidant is a mixture of mannitol and sorbitol.

In general, mannitol and similarly sorbitol, alone or as a mixture:

- Provides good resistance to deterioration by steam sterilization;

-Has high antioxidant capacity;

- Dissolves easily in hyaluronic acid compositions.

In one embodiment, the sterilized aqueous composition according to the invention is characterized in that the polyol content is between 10 mg/g and 40 mg/g relative to the total weight of the composition.

In one embodiment, the sterilized aqueous composition according to the invention is characterized in that the polyol content is between 15 mg/g and 30 mg/g relative to the total weight of the composition.

In one embodiment, the sterilized aqueous composition according to the invention is characterized in that the content of said polyol is between 15 mg/g and 25 mg/g relative to the total weight of said composition.

In one embodiment, the sterilized aqueous composition according to the invention is characterized in that the polyol content is between 20 mg/g and 40 mg/g relative to the total weight of the composition.

In one embodiment, the sterilized aqueous composition according to the invention is characterized in that the polyol content is between 20 mg/g and 30 mg/g relative to the total weight of the composition.

In one embodiment, the sterilized aqueous composition according to the invention is characterized in that the polyol content is between 25 mg/g and 35 mg/g relative to the total weight of the composition.

In one embodiment, the sterilized aqueous composition according to the invention is characterized in that the polyol content is 35 mg/g relative to the total weight of the composition.

In one embodiment, the sterilized aqueous composition according to the invention is characterized in that the polyol is mannitol and its content is from 10 mg/g to 40 mg/g relative to the total weight of the composition.

In one embodiment, the sterilized aqueous composition according to the invention is characterized in that the polyol is mannitol and its content is from 15 mg/g to 30 mg/g relative to the total weight of the composition.

In one embodiment, the sterilized aqueous composition according to the invention is characterized in that the polyol is mannitol and its content is from 15 mg/g to 25 mg/g relative to the total weight of the composition.

In one embodiment, the sterilized aqueous composition according to the invention is characterized in that the polyol is mannitol and its content is from 20 mg/g to 40 mg/g relative to the total weight of the composition.

In one embodiment, the sterilized aqueous composition according to the invention is characterized in that the polyol is mannitol and its content is from 25 mg/g to 35 mg/g relative to the total weight of the composition.

In one embodiment, the sterilized aqueous composition according to the invention is characterized in that the polyol is mannitol and its content is 35 mg/g based on the total weight of the composition.

In one embodiment, the sterilized aqueous composition according to the invention is characterized in that the polyol is sorbitol and its content is from 10 mg/g to 40 mg/g relative to the total weight of the composition.

In one embodiment, the sterilized aqueous composition according to the invention is characterized in that the polyol is sorbitol and its content is from 15 mg/g to 30 mg/g relative to the total weight of the composition.

In one embodiment, the sterilized aqueous composition according to the invention is characterized in that the polyol is sorbitol and its content is from 15 mg/g to 25 mg/g relative to the total weight of the composition.

In one embodiment, the sterilized aqueous composition according to the invention is characterized in that the polyol is sorbitol and its content is from 20 mg/g to 40 mg/g relative to the total weight of the composition.

In one embodiment, the sterilized aqueous composition according to the invention is characterized in that the polyol is sorbitol and its content is from 25 mg/g to 35 mg/g relative to the total weight of the composition.

In one embodiment, the sterilized aqueous composition according to the invention is characterized in that the polyol is sorbitol and its content is 35 mg/g relative to the total weight of the composition.

In one embodiment, the sterilized aqueous composition according to the invention is characterized in that the polyol is maltitol and its content is from 10 mg/g to 40 mg/g relative to the total weight of the composition.

In one embodiment, the sterilized aqueous composition according to the invention is characterized in that the polyol is maltitol and its content is from 15 mg/g to 30 mg/g relative to the total weight of the composition.

In one embodiment, the sterilized aqueous composition according to the invention is characterized in that the polyol is maltitol and its content is from 15 mg/g to 25 mg/g relative to the total weight of the composition.

In one embodiment, the sterilized aqueous composition according to the invention is characterized in that the polyol is maltitol and its content is from 20 mg/g to 40 mg/g relative to the total weight of the composition.

In one embodiment, the sterilized aqueous composition according to the invention is characterized in that the polyol is maltitol and its content is from 25 mg/g to 35 mg/g relative to the total weight of the composition.

In one embodiment, the sterilized aqueous composition according to the invention is characterized in that the polyol is maltitol and its content is 35 mg/g based on the total weight of the composition.

In one embodiment, the sterilized aqueous composition according to the invention is characterized in that the polyol is glycerol and its content is from 10 mg/g to 40 mg/g relative to the total weight of the composition.

In one embodiment, the sterilized aqueous composition according to the invention is characterized in that the polyol is glycerol and its content is from 15 mg/g to 30 mg/g relative to the total weight of the composition.

In one embodiment, the sterilized aqueous composition according to the invention is characterized in that the polyol is glycerol and its content is from 15 mg/g to 25 mg/g relative to the total weight of the composition.

In one embodiment, the sterilized aqueous composition according to the invention is characterized in that the polyol is glycerol and its content is from 20 mg/g to 40 mg/g relative to the total weight of the composition.

In one embodiment, the sterilized aqueous composition according to the invention is characterized in that the polyol is glycerol and its content is between 25 mg/g and 35 mg/g relative to the total weight of the composition.

In one embodiment, the sterilized aqueous composition according to the invention is characterized in that the polyol is maltitol.

In one embodiment, the sterilized aqueous composition according to the invention is characterized in that the polyol is glycerol and its content is 35 mg/g relative to the total weight of the composition.

In one embodiment, the sterilized aqueous composition according to the invention is characterized in that the mepivacaine is freely released in vivo.

In one embodiment, the sterilized aqueous composition according to the invention is characterized in that said composition also comprises at least one further compound.

In one embodiment, the sterilized aqueous composition according to the invention is characterized in that the content of said additional compound is between 0.1 mg/g and 100 mg/g of the total weight of said composition.

In one embodiment, the sterilized aqueous composition according to the invention is characterized in that the content of said additional compound is between 1 mg/g and 50 mg/g of total weight of said composition.

In one embodiment, the sterilized aqueous composition according to the invention is characterized in that the additional compound is dimethyl sulfone, hereinafter referred to as DMS.

In one embodiment, the sterilized aqueous composition according to the invention is characterized in that said additional compound is a water-soluble salt of sucrose octasulfate, hereinafter referred to as SOS.

In one embodiment, the sterilized aqueous composition according to the invention is characterized in that the additional compound is a vitamin C derivative.

In one embodiment, the vitamin C derivative is magnesium ascorbyl phosphate, hereinafter referred to as MAP.

In one embodiment, the sterilized aqueous composition according to the invention is characterized in that the additional compound belongs to the family of catecholamines.

In one embodiment, the sterilized aqueous composition according to the invention is characterized in that the additional compound belonging to the family of catecholamines is adrenaline.

In one embodiment, the sterilized aqueous composition according to the invention is characterized in that the content of said additional compound is between 0.01% and 10% by weight relative to the total weight of said composition.

In one embodiment, the sterilized aqueous composition according to the invention is characterized in that the content of said additional compound is between 0.1% and 5% by weight relative to the total weight of said composition.

In one embodiment, the total content of the additional compounds is from 0.01 mg/g to 40 mg/g of the total weight of the composition.

In one embodiment, the total content of the additional compounds is from 0.1 mg/g to 10 mg/g of the total weight of the composition.

In one embodiment, the total content of the additional compounds is from 0.1 mg/g to 1 mg/g of the total weight of the composition.

In one embodiment, the additional compound is dimethyl sulfone and is present in an amount of 1 mg/g to 10 mg/g based on the total weight of the composition.

In one embodiment, the additional compound is a water-soluble salt of sucrose octasulfate and is present in an amount of 1 mg/g to 10 mg/g based on the total weight of the composition.

In one embodiment, the additional compound is magnesium ascorbyl phosphate and is present in an amount of 0.3 mg/g to 10 mg/g based on the total weight of the composition.

The present invention also relates to a process for the preparation of the sterilized aqueous composition according to the invention.

In one embodiment, the method according to the invention is characterized in that it comprises at least:

- a step of hydrating at least one hyaluronic acid or a salt thereof, alone or as a mixture, in a buffer solution having a pH close to physiological pH to obtain a hydrogel,

- a step of incorporating mepivacaine as an aqueous solution into the hydrogel obtained in the previous step,

- a homogenization step, and

-Sterilization step.

In one embodiment, the hyaluronic acid is in the form of fibers.

In one embodiment, the hyaluronic acid is in the form of paillettes.

In one embodiment, the buffer solution is an aqueous phosphate buffer solution.

In one embodiment, the pH of the mepivacaine solution is adjusted to a value between 6.5 and 7 before its introduction into the gel and/or hydrogel.

In one embodiment, the mepivacaine solution is incorporated into the gel according to the method described in French patent application 13/52971 in the name of the present applicant.

In one embodiment, the pH of the gel and/or hydrogel is adjusted to a value between 7.7 and 8 prior to the introduction of the mepivacaine solution (without adjusting its pH).

In one embodiment, the mepivacaine solution is incorporated into the gel according to the method described in patent application WO 2010/015901 in the name of Allergan.

In one embodiment, the process according to the invention is characterized in that the hydration step is carried out at room temperature.

In one embodiment, the process according to the invention is characterized in that the homogenization step is carried out at room temperature.

In one embodiment, the method according to the invention is characterized in that it further comprises at least one step of packaging the homogenized mixture in syringes.

In one embodiment, the process according to the invention is characterized in that it further comprises at least one step of packaging the homogenized mixture in single-dose bottles.

In one embodiment, the process is characterized in that it comprises at least one sterilization step.

In one embodiment, the sterilization step is performed after the packaging step.

In one embodiment, the sterilization step is performed with heat, moist heat, gamma radiation, or with a beam of accelerated electrons (e-beam).

In one embodiment, the sterilization step is performed after packaging by high pressure steam sterilization.

In one embodiment, the sterilization step is performed after packaging by irradiation with gamma radiation or with a beam of accelerated electrons (e-beam).

In one embodiment, the method according to the invention is characterized in that the sterilization by autoclaving is carried out after packaging at a temperature of 121° C. to 134° C. for a time appropriate to said temperature.

For example, sterilization by high pressure steam sterilization is performed at a temperature of 127° C. to 130° C. for a time of 1 minute to 20 minutes.

In one embodiment, the process according to the invention is characterized in that it also comprises at least one cross-linking step.

In one embodiment, the process according to the invention is characterized in that said cross-linking step occurs between said hydration step and said step of incorporating mepivacaine.

In one embodiment, the process according to the invention is characterized in that the cross-linking step is carried out using at least one cross-linking agent.

In one embodiment, the process according to the invention is characterized in that the crosslinking agent is bifunctional or polyfunctional.

In one embodiment, the process according to the invention is characterized in that the bifunctional or polyfunctional crosslinking agent is selected from the group consisting of: ethylene glycol diglycidyl ether; butanediol diglycidyl ether (BDDE); polyglycerol polyglycidyl ether; polyethylene glycol diglycidyl ether; polypropylene glycol diglycidyl ether; diepoxides or polyepoxides, for example 1,2,3,4-diepoxybutane or 1,2,7,8-diepoxyoctane; dialkyl sulfones; divinyl sulfone; formaldehyde; epichlorohydrin or glutaraldehyde and carbodiimides, for example 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride (EDC).

In one embodiment, the process according to the invention is characterized in that the bifunctional crosslinker is butanediol diglycidyl ether (BDDE) or 1,2,7,8-diepoxyoctane.

In one embodiment, the preparation process according to the invention is characterized in that the cross-linking step is carried out according to techniques known to those skilled in the art.

In one embodiment, the process according to the invention is characterized in that it comprises, after the cross-linking step, at least one step of purification and washing according to techniques known to those skilled in the art.

In one embodiment, the process according to the invention is characterized in that it also comprises at least one step of incorporating at least one antioxidant.

In one embodiment, the at least one antioxidant is chosen from polyols.

In one embodiment, the polyol is selected from glycerol, sorbitol, propylene glycol, xylitol, mannitol, erythritol, maltitol and lactitol, alone or as a mixture.

In one embodiment, the process according to the invention is characterized in that it further comprises at least one step of mixing a solution of at least one additional compound with the hydrogel obtained in the hydration step.

In one embodiment, the process according to the invention is characterized in that the step of mixing a solution of at least one additional compound with the hydrogel obtained in the hydration step is carried out before the homogenization step.

In one embodiment, the process according to the invention is characterized in that the step of mixing a solution of at least one additional compound with the hydrogel obtained in the hydration step is carried out at a temperature suitable for the preparation process. In one embodiment, it is carried out at room temperature.

The present invention also relates to a method for obtaining a sterilized aqueous composition of hyaluronic acid containing a local anesthetic, said composition having, after heat sterilization, a rheological property superior to that of a composition containing lidocaine, characterized in that lidocaine is replaced by an equivalent amount of mepivacaine at the same pH.

The term "equivalent amount" means an equivalent amount by mass, molar number, or an equivalent amount with equivalent bioavailability at a pH close to physiological pH.

In said process, the composition obtained is defined as the composition according to the invention.

The present invention also relates to the use of mepivacaine in equivalent amounts in place of lidocaine to obtain a hyaluronic acid composition comprising a local anesthetic, said composition having, after heat sterilization, a rheology superior to that of the same hyaluronic acid composition comprising lidocaine.

In said use, the composition obtained is defined as the composition according to the invention.

The term "equivalent amount" means an equivalent amount by mass, molar number, or an equivalent amount of equivalent bioavailability.

The term "hyaluronic acid" means cross-linked or non-cross-linked hyaluronic acid, alone or as a mixture, optionally chemically modified by substitution, alone or as a mixture, optionally in the form of its salts, alone or as a mixture.

The term "local anesthetic" means a local anesthetic or a salt thereof, alone or as a mixture.

The term "mepivacaine" means mepivacaine or a salt thereof, alone or as a mixture.

The term "lidocaine" means lidocaine or its salts, alone or as a mixture.

The term "rheology" refers to the elastic modulus (G') and/or viscosity (η).

The term "better rheology" means higher values of elastic modulus and/or viscosity.

The term "replacement" refers to a gel formulation in which mepivacaine is incorporated instead of lidocaine.

The present invention also relates to the use of mepivacaine for improving the resistance to rheological degradation of injectable sterilized aqueous hyaluronic acid compositions during heat sterilization.

The present invention also relates to the use of mepivacaine for improving the resistance to rheological degradation of aqueous hyaluronic acid compositions containing local anesthetics during heat sterilization.

The present invention also relates to the use of mepivacaine in an aqueous hyaluronic acid composition having a rheological degradation during heat sterilization that is inferior to that of the same hyaluronic acid composition containing other local anesthetics.

The present invention also relates to a method for improving the resistance to rheological degradation of an injectable aqueous hyaluronic acid composition during heat sterilization, characterized in that the composition comprises mepivacaine.

The present invention also relates to a method for improving the resistance to rheological degradation of an injectable aqueous hyaluronic acid composition containing a local anesthetic during heat sterilization, characterized in that the composition contains mepivacaine.

The present invention also relates to a method for improving the resistance of an injectable aqueous hyaluronic acid composition comprising a local anesthetic to rheological degradation during sterilization by replacing lidocaine with an equivalent amount of mepivacaine.

In one embodiment, the uses or the methods are characterized in that mepivacaine is used in equivalent amounts.

In one embodiment, the use or the method is characterized in that the sterilization is performed by high pressure steam sterilization.

In one embodiment, the uses or the methods are characterized in that the further local anesthetic is chosen from lidocaine and prilocaine.

In one embodiment, the uses or the methods are characterized in that the further local anesthetic is lidocaine.

In one embodiment, the uses or the processes are characterized in that the composition further comprises one or more polyols.

In one embodiment, the uses or the processes are characterized in that the one or more polyols are chosen from glycerol, sorbitol, propylene glycol, xylitol, mannitol, erythritol, maltitol and lactitol, alone or as a mixture.

In one embodiment, the uses or the processes are characterized in that the one or more polyols are chosen from mannitol, sorbitol, maltitol and glycerol, alone or as a mixture.

In one embodiment, the uses or the processes are characterized in that the one or more polyols are chosen from mannitol and sorbitol, alone or as a mixture.

In one embodiment, the uses or the processes are characterized in that at least one polyol is mannitol.

In one embodiment, the uses or the processes are characterized in that the polyol is mannitol.

In one embodiment, the uses or the processes are characterized in that at least one polyol is sorbitol.

In one embodiment, the uses or the processes are characterized in that the polyol is sorbitol.

In one embodiment, the uses or the processes are characterized in that the at least one polyol is maltitol.

In one embodiment, the uses or the processes are characterized in that the polyol is maltitol.

In one embodiment, the uses or the processes are characterized in that at least one polyol is glycerol.

In one embodiment, the uses or the processes are characterized in that the polyol is glycerol.

In one embodiment, the uses or the processes are characterized in that the polyol is present in an amount ranging from 10 mg/g to 40 mg/g relative to the total weight of the composition.

In one embodiment, the uses or the processes are characterized in that the polyol is present in an amount ranging from 15 mg/g to 30 mg/g relative to the total weight of the composition.

In one embodiment, the uses or the processes are characterized in that the polyol is present in an amount ranging from 15 mg/g to 25 mg/g relative to the total weight of the composition.

In one embodiment, the uses or the processes are characterized in that the polyol is present in an amount ranging from 20 mg/g to 40 mg/g relative to the total weight of the composition.

In one embodiment, the uses or the processes are characterized in that the polyol is present in an amount ranging from 25 mg/g to 35 mg/g relative to the total weight of the composition.

In one embodiment, the uses or the processes are characterized in that the polyol is present in an amount of 35 mg/g relative to the total weight of the composition.

In one embodiment, the uses or the processes are characterized in that the polyol is mannitol and is present in an amount ranging from 10 mg/g to 40 mg/g relative to the total weight of the composition.

In one embodiment, the uses or the processes are characterized in that the polyol is mannitol and is present in an amount ranging from 15 mg/g to 30 mg/g relative to the total weight of the composition.

In one embodiment, the uses or the processes are characterized in that the polyol is mannitol and is present in an amount ranging from 15 mg/g to 25 mg/g relative to the total weight of the composition.

In one embodiment, the uses or the processes are characterized in that the polyol is mannitol and is present in an amount ranging from 20 mg/g to 40 mg/g relative to the total weight of the composition.

In one embodiment, the uses or the processes are characterized in that the polyol is mannitol and is present in an amount ranging from 25 mg/g to 35 mg/g relative to the total weight of the composition.

In one embodiment, the uses or the processes are characterized in that the polyol is mannitol and is present in an amount of 35 mg/g based on the total weight of the composition.

In one embodiment, the uses or the processes are characterized in that the polyol is sorbitol and is present in an amount ranging from 10 mg/g to 40 mg/g relative to the total weight of the composition.

In one embodiment, the uses or the processes are characterized in that the polyol is sorbitol and is present in an amount ranging from 15 mg/g to 30 mg/g relative to the total weight of the composition.

In one embodiment, the uses or the processes are characterized in that the polyol is sorbitol and is present in an amount ranging from 15 mg/g to 25 mg/g relative to the total weight of the composition.

In one embodiment, the uses or the processes are characterized in that the polyol is sorbitol and is present in an amount ranging from 20 mg/g to 40 mg/g relative to the total weight of the composition.

In one embodiment, the uses or the processes are characterized in that the polyol is sorbitol and is present in an amount ranging from 25 mg/g to 35 mg/g relative to the total weight of the composition.

In one embodiment, the uses or the processes are characterized in that the polyol is sorbitol and is present in an amount of 35 mg/g relative to the total weight of the composition.

In one embodiment, the uses or the processes are characterized in that the polyol is maltitol and is present in an amount of 10 to 40 mg/g relative to the total weight of the composition.

In one embodiment, the uses or the processes are characterized in that the polyol is maltitol and is present in an amount of 15 to 30 mg/g relative to the total weight of the composition.

In one embodiment, the uses or the processes are characterized in that the polyol is maltitol and is present in an amount of 10 to 25 mg/g based on the total weight of the composition.

In one embodiment, the uses or the processes are characterized in that the polyol is maltitol and is present in an amount of 20 to 40 mg/g relative to the total weight of the composition.

In one embodiment, the uses or the processes are characterized in that the polyol is maltitol and is present in an amount ranging from 25 mg/g to 35 mg/g based on the total weight of the composition.

In one embodiment, the uses or the methods are characterized in that the polyol is maltitol and is present in an amount of 35 mg/g based on the total weight of the composition.

In one embodiment, the uses or the processes are characterized in that the polyol is glycerol and is present in an amount ranging from 10 mg/g to 40 mg/g relative to the total weight of the composition.

In one embodiment, the uses or the processes are characterized in that the polyol is glycerol and is present in an amount ranging from 15 mg/g to 30 mg/g relative to the total weight of the composition.

In one embodiment, the uses or the processes are characterized in that the polyol is glycerol and is present in an amount ranging from 10 mg/g to 25 mg/g relative to the total weight of the composition.

In one embodiment, the uses or the processes are characterized in that the polyol is glycerol and is present in an amount ranging from 20 mg/g to 40 mg/g relative to the total weight of the composition.

In one embodiment, the uses or the processes are characterized in that the polyol is glycerol and is present in an amount ranging from 25 mg/g to 35 mg/g relative to the total weight of the composition.

In one embodiment, the uses or the processes are characterized in that the polyol is glycerol and is present in an amount of 35 mg/g relative to the total weight of the composition.

In one embodiment, the use or the process is characterized in that the sterilization step is carried out by high pressure steam sterilization at a temperature between 121°C and 134°C for a time suitable for said temperature.

For example, sterilization by high pressure steam sterilization is performed at a temperature of 127° C. to 130° C. for a time of 1 minute to 20 minutes.

In one embodiment, the uses or the methods are characterized in that the composition further comprises an antioxidant.

In one embodiment, the use or the method is characterized in that the mass ratio of the concentration of hyaluronic acid [HA] to the concentration of mepivacaine [MEPI] is: [HA]/[MEPI] greater than or equal to 0.1; [HA]/[MEPI]≥0.1.

In one embodiment, the use or the method is characterized in that the mass ratio of the concentration of hyaluronic acid [HA] to the concentration of mepivacaine [MEPI]: [HA]/[MEPI] is 0.1 to 50, and 0.1≤[HA]/[MEPI]≤50.

In one embodiment, the use or the method is characterized in that the mass ratio of the concentration of hyaluronic acid [HA] to the concentration of mepivacaine [MEPI]: [HA]/[MEPI] is 0.5 to 40, and 0.5≤[HA]/[MEPI]≤40.

In one embodiment, the use or the method is characterized in that the mass ratio of the concentration of hyaluronic acid [HA] to the concentration of mepivacaine [MEPI]: [HA]/[MEPI] is 1 to 30, and 1≤[HA]/[MEPI]≤30.

In one embodiment, the use or the method is characterized in that the mass ratio of the concentration of hyaluronic acid [HA] to the concentration of mepivacaine [MEPI]: [HA]/[MEPI] is 2 to 20, and 2≤[HA]/[MEPI]≤20.

In one embodiment, the use or the method is characterized in that the mass ratio [HA]/[MEPI] of the concentration of hyaluronic acid [HA] to the concentration of mepivacaine [MEPI] is 7/3 to 26/3, and 7/3≤[HA]/[MEPI]≤26/3.

In one embodiment, the use or the method is characterized in that the mass ratio [HA]/[MEPI] of the concentration of hyaluronic acid [HA] to the concentration of mepivacaine [MEPI] is 2 to 20/3, 2≤[HA]/[MEPI]≤20/3.

In one embodiment, the use or the method is characterized in that the mass ratio [HA]/[MEPI] of the concentration of hyaluronic acid [HA] to the concentration of mepivacaine [MEPI] is 2 to 10/3, and 2≤[HA]/[MEPI]≤10/3.

In one embodiment, the use or the method is characterized in that the mass ratio [HA]/[MEPI] of the concentration of hyaluronic acid [HA] to the concentration of mepivacaine [MEPI] is 20.

In one embodiment, the use or the method is characterized in that the mass ratio [HA]/[MEPI] of the concentration of hyaluronic acid [HA] to the concentration of mepivacaine [MEPI] is 26/3.

In one embodiment, the use or the method is characterized in that the mass ratio [HA]/[MEPI] of the concentration of hyaluronic acid [HA] to the concentration of mepivacaine [MEPI] is 20/3.

In one embodiment, the use or the method is characterized in that the mass ratio [HA]/[MEPI] of the concentration of hyaluronic acid [HA] to the concentration of mepivacaine [MEPI] is 10/3.

In one embodiment, the use or the method is characterized in that the mass ratio [HA]/[MEPI] of the concentration of hyaluronic acid [HA] to the concentration of mepivacaine [MEPI] is 7/3.

In one embodiment, the use or the method is characterized in that the mass ratio [HA]/[MEPI] of the concentration of hyaluronic acid [HA] to the concentration of mepivacaine [MEPI] is 2.

In one embodiment, the uses or the processes are characterized in that the concentration of mepivacaine [MEPI] is between 0.01 mg/g and 50 mg/g of the total weight of the composition.

In one embodiment, the uses or the processes are characterized in that the concentration of mepivacaine [MEPI] is between 0.01 mg/g and 50 mg/g of the total weight of the composition.

In one embodiment, the uses or the processes are characterized in that the concentration of mepivacaine [MEPI] is between 0.05 mg/g and 45 mg/g of the total weight of the composition.

In one embodiment, the uses or the processes are characterized in that the concentration of mepivacaine [MEPI] is between 0.1 mg/g and 40 mg/g of the total weight of the composition.

In one embodiment, the uses or the processes are characterized in that the concentration of mepivacaine [MEPI] is between 0.2 mg/g and 30 mg/g of the total weight of the composition.

In one embodiment, the uses or the processes are characterized in that the concentration of mepivacaine [MEPI] is between 0.5 mg/g and 20 mg/g of the total weight of the composition.

In one embodiment, the uses or the processes are characterized in that the concentration of mepivacaine [MEPI] is between 1 mg/g and 15 mg/g of the total weight of the composition.

In one embodiment, the uses or the processes are characterized in that the concentration of mepivacaine [MEPI] is between 1 mg/g and 10 mg/g of the total weight of the composition.

In one embodiment, the uses or the processes are characterized in that the concentration of mepivacaine [MEPI] is between 1 mg/g and 6 mg/g of the total weight of the composition.

In one embodiment, the uses or the processes are characterized in that the concentration of mepivacaine [MEPI] is between 1 mg/g and 5 mg/g of the total weight of the composition.

In one embodiment, the uses or the processes are characterized in that the concentration of mepivacaine [MEPI] is between 2 mg/g and 5 mg/g of the total weight of the composition.

In one embodiment, the uses or the processes are characterized in that the concentration of mepivacaine [MEPI] is between 6 mg/g and 10 mg/g of the total weight of the composition.

In one embodiment, the uses or the methods are characterized in that the concentration of mepivacaine [MEPI] is 1 mg/g total weight of the composition.

In one embodiment, the uses or the methods are characterized in that the concentration of mepivacaine [MEPI] is 3 mg/g total weight of the composition.

In one embodiment, the uses or the methods are characterized in that the concentration of mepivacaine [MEPI] is 4 mg/g total weight of the composition.

In one embodiment, the uses or the methods are characterized in that the concentration of mepivacaine [MEPI] is 5 mg/g total weight of the composition.

In one embodiment, the uses or the methods are characterized in that the concentration of mepivacaine [MEPI] is 6 mg/g total weight of the composition.

In one embodiment, the uses or the methods are characterized in that the concentration of mepivacaine [MEPI] is 10 mg/g total weight of the composition.

In one embodiment, the uses or the methods are characterized in that mepivacaine is selected from the group comprising mepivacaine or a pharmaceutically acceptable salt thereof.

In one embodiment, the uses or the methods are characterized in that mepivacaine is selected from the group consisting of racemic mepivacaine hydrochloride, racemic mepivacaine, (R)-mepivacaine hydrochloride, (S)-mepivacaine hydrochloride, (R)-mepivacaine and (S)-mepivacaine or pharmaceutically acceptable salts thereof.

In one embodiment the uses or the processes are characterized in that mepivacaine is racemic mepivacaine hydrochloride.

In one embodiment the uses or the processes are characterized in that mepivacaine is (R)-mepivacaine hydrochloride.

In one embodiment, the uses or the processes are characterized in that mepivacaine is (S)-mepivacaine hydrochloride.

In one embodiment the uses or the processes are characterized in that mepivacaine is racemic mepivacaine.

In one embodiment the uses or the processes are characterized in that mepivacaine is (R)-mepivacaine.

In one embodiment the uses or the processes are characterized in that mepivacaine is (S)-mepivacaine.

In one embodiment, the uses or the methods are characterized in that the concentration of hyaluronic acid [HA] is between 2 mg/g and 50 mg/g of the total weight of the composition.

In one embodiment, the uses or the methods are characterized in that the concentration of hyaluronic acid [HA] is between 4 mg/g and 40 mg/g of the total weight of the composition.

In one embodiment, the uses or the methods are characterized in that the concentration of hyaluronic acid [HA] is between 5 mg/g and 30 mg/g of the total weight of the composition.

In one embodiment, the uses or the processes are characterized in that the concentration of hyaluronic acid [HA] is between 10 mg/g and 30 mg/g of the total weight of the composition.

In one embodiment, the uses or the methods are characterized in that the concentration of hyaluronic acid [HA] is 20 mg/g of the total weight of the composition.

In one embodiment, the uses or the processes are characterized in that the total content of hyaluronic acid is between 0.2% and 5% by weight relative to the total weight of the composition.

In one embodiment, the uses or the processes are characterized in that the total content of hyaluronic acid is greater than or equal to 1% by weight relative to the total weight of the composition.

In one embodiment, the uses or the processes are characterized in that the sterilized aqueous composition comprises at least one non-cross-linked hyaluronic acid or a salt thereof, alone or as a mixture.

In one embodiment, the uses or the processes are characterized in that the sterilized aqueous composition comprises at least one cross-linked hyaluronic acid or a salt thereof, alone or as a mixture.

In one embodiment, the uses or the processes are characterized in that the sterilized aqueous composition comprises at least one co-cross-linked hyaluronic acid or a salt thereof, alone or as a mixture.

In one embodiment, the uses or the processes are characterized in that the sterilized aqueous composition comprises, alone or as a mixture, at least one hyaluronic acid or a salt thereof chemically modified by substitution and crosslinking.

In one embodiment, the use or the method is characterized in that the hyaluronic acid is double cross-linked as described in patent application WO 2000/046 253 in the name of Fermentech Medical Limited.

In one embodiment, the uses or the processes are characterized in that the sterilized aqueous composition comprises a mixture of cross-linked hyaluronic acid or salts thereof.

In one embodiment, the use or the process is characterized in that the mixture of cross-linked hyaluronic acid or salts thereof is a single-phase mixture, such as described in patent application WO 2009/071 697 in the name of the Applicant.

In one embodiment, the use or the process is characterized in that the mixture of cross-linked hyaluronic acids or salts thereof is a mixture obtained by mixing several hyaluronic acids or salts thereof of different molar masses before their cross-linking, as described in patent application WO 2004/092 222 in the name of Cornéal Industrie.

In one embodiment, the uses or the processes are characterized in that the sterilized aqueous composition comprises at least one hyaluronic acid or salt thereof substituted with groups imparting lipophilicity or hydration, such as the substituted hyaluronic acids described in patent application FR 2 983 483 in the name of the Applicant.

In one embodiment, the uses or the processes are characterized in that the hyaluronic acid is in the form of the sodium or potassium salt.

In one embodiment, the uses or the processes are characterized in that the molecular weight Mw of the at least one hyaluronic acid is in the range of 0.01 MDa to 5 MDa.

In one embodiment, the uses or the processes are characterized in that the molecular weight Mw of the at least one hyaluronic acid is in the range of 0.1 MDa to 3.5 MDa.

In one embodiment, the uses or the processes are characterized in that the molecular weight Mw of the at least one hyaluronic acid is in the range from 1 MDa to 3 MDa.

In one embodiment, the uses or the processes are characterized in that the molecular weight Mw of the at least one hyaluronic acid is 1 MDa.

In one embodiment, the uses or the processes are characterized in that the molecular weight Mw of the at least one hyaluronic acid is 3 MDa.

In one embodiment, the use or the method is characterized in that the cross-linking degree X of the cross-linked hyaluronic acid is between 0.001 and 0.5.

In one embodiment, the use or the method is characterized in that the cross-linked hyaluronic acid has a degree of cross-linking X of 0.01 to 0.4.

In one embodiment, the use or the method is characterized in that the cross-linking degree X of the cross-linked hyaluronic acid is between 0.1 and 0.3.

In one embodiment, the use or the method is characterized in that the cross-linking degree X of the cross-linked hyaluronic acid is 0.08.

In one embodiment, the use or the method is characterized in that the cross-linking degree X of the cross-linked hyaluronic acid is 0.06.

In one embodiment, the use or the method is characterized in that the cross-linking degree X of the cross-linked hyaluronic acid is 0.12.

In one embodiment, the sterilized aqueous composition according to the invention further comprises other polysaccharides.

In one embodiment, this other polysaccharide is selected from cellulose and its derivatives and/or alginic acid or its salts.

In one embodiment, the uses or the methods are characterized in that the sterilized aqueous composition further comprises a further polysaccharide.

In one embodiment, the use or the method is characterized in that the sterilized aqueous composition according to the invention further comprises a further polysaccharide chosen from cellulose and its derivatives and/or alginic acid or its salts.

In one embodiment, the uses or the processes are characterized in that the sterilized aqueous composition further comprises at least one additional compound.

In one embodiment, the uses or the processes are characterized in that the content of the additional compound in the composition is between 0.1 mg/g and 100 mg/g of the total weight of the composition.

In one embodiment, the uses or the processes are characterized in that the content of the additional compound in the composition is between 1 mg/g and 50 mg/g of the total weight of the composition.

In one embodiment, the uses or the processes are characterized in that the further compound is dimethyl sulfone, hereinafter referred to as DMS.

In one embodiment, the uses or the processes are characterized in that the further compound is a water-soluble salt of sucrose octasulfate, hereinafter referred to as SOS.

In one embodiment, the uses or the processes are characterized in that the further compound is a vitamin C derivative.

In one embodiment, the uses or the processes are characterized in that the vitamin C derivative is magnesium ascorbyl phosphate, hereinafter referred to as MAP.

In one embodiment, the uses or the methods are characterized in that the further compound belongs to the family of catecholamines.

In one embodiment, the uses or the methods are characterized in that the further compound belonging to the family of catecholamines is adrenaline.

In one embodiment, the uses or the processes are characterized in that the additional compound is present in a content ranging from 0.01% to 10% by weight relative to the total weight of the composition.

In one embodiment, the uses or the processes are characterized in that the content of the additional compound is from 0.1% to 5% by weight relative to the total weight of the composition.

In one embodiment, the uses or the processes are characterized in that the total content of further compounds is between 0.01 mg/g and 40 mg/g of total weight of the composition.

In one embodiment, the uses or the processes are characterized in that the total content of further compounds is between 0.1 mg/g and 10 mg/g of total weight of the composition.

In one embodiment, the uses or the processes are characterized in that the total content of additional compounds is between 0.1 mg/g and 1 mg/g of total weight of the composition.

In one embodiment, the uses or the processes are characterized in that the additional compound is dimethyl sulfone and is present in an amount of 1 mg/g to 10 mg/g based on the total weight of the composition.

In one embodiment, the uses or the processes are characterized in that the additional compound is a water-soluble salt of sucrose octasulfate and is present in an amount ranging from 1 mg/g to 10 mg/g relative to the total weight of the composition.

In one embodiment, the uses or the processes are characterized in that the additional compound is magnesium ascorbyl phosphate and is present in an amount ranging from 0.3 mg/g to 10 mg/g relative to the total weight of the composition.

The invention also relates to the use of a sterilized aqueous composition for formulating a composition for filling wrinkles, for correcting skin imperfections or for volumatrice (cheekbones, chin, lips).

The invention also relates to a sterilized aqueous composition according to the invention for filling wrinkles and/or correcting skin imperfections.

The present invention also relates to the use of a sterile aqueous composition for preparing a composition that can be injected into a joint as a replacement or supplement for deficient synovial fluid.

The present invention also relates to a sterilized aqueous composition according to the invention for use as a replacement or supplement for deficient synovial fluid.

The invention also relates to the use of a sterilized aqueous composition according to the invention for formulating a composition for filling wrinkles.

The present invention also relates to a sterilized aqueous composition according to the invention for use in formulating a viscosupplementation composition.

The present invention also relates to a sterilized aqueous composition according to the invention for use as a medicament.

The target applications are more particularly those generally broadly within the field of injectable viscoelastic agents and polysaccharides that are used or potentially useful in the following pathological conditions or treatments:

- Cosmetic facial injections: used to fill wrinkles, skin imperfections or to add volume (cheekbones, chin, lips);

- Internal volumizing injections: breast and buttocks enlargement, G-spot enlargement, vaginal plastic surgery, labia reconstruction, penis size increase;

- Treatment of arthritis by injection into joints as a replacement or supplement for synovial fluid deficiency;

- Periurethral injections for the treatment of urinary incontinence caused by sphincter defects;

- Postoperative injection, especially for the prevention of peritoneal adhesions;

- Post-operative injections to correct presbyopia through laser scleral incisions;

-Injection into the vitreous cavity;

-Injection during cataract surgery;

-Injection into the genitals.

More specifically, in plastic surgery, the sterilized aqueous composition obtained according to the method of the invention can be used, due to its viscoelasticity and durability, for:

- used to fill fine lines, medium-sized wrinkles, or deep wrinkles and can be injected using a narrow-diameter needle (e.g., 27-gauge needle);

- as a volumizing product for injection using larger diameter needles (e.g. 22 to 26 gauge) and longer needles (e.g. 30 to 40 mm); in this case, its cohesiveness will ensure that it remains at the injection site.

The sterilized aqueous compositions according to the invention also find important applications in joint surgery and dental surgery, for example for filling periodontal pockets.

These examples of use are by no means limiting, and the sterilized aqueous compositions according to the present invention are contemplated to be more broadly useful for:

-fill volume;

- Create space in certain tissues, thereby promoting their optimal functioning;

-Replaces deficient physiological fluids.

The present invention also relates to a kit comprising the sterilized aqueous composition according to the invention packaged in a syringe and sterilized after packaging.

The present invention also relates to a kit comprising a sterilized aqueous composition according to the invention packaged in a single-dose bottle and sterilized after packaging.

Example

a) Preparation of gel

-Non-cross-linked hyaluronic acid gel

Injectable grade sodium hyaluronate (NaHA) fibers were weighed into a container. Aqueous phosphate buffer solution was added and the whole was homogenized using a spatule at room temperature and 900 mmHg atmospheric pressure for about 1 hour.

- Cross-linked hyaluronic acid gel

A gel comprising cross-linked hyaluronic acid was obtained using sodium hyaluronate (NaHA) fibers and butanediol diglycidyl ether (BDDE) according to the method described in patent application WO 2009/071 697 in the name of the present applicant.

- Cross-linked and interpenetrating hyaluronic acid gel

The gel comprising crosslinked and interpenetrating hyaluronic acid was obtained according to the method described in patent application WO 2009/071 697 in the name of the present applicant.

- Co-cross-linked hyaluronic acid gel

The gel comprising co-crosslinked hyaluronic acid was obtained according to the method described in patent application WO 86/00079 in the name of Allergan.

- Local anesthetics

The local anesthetic is dissolved in a sterile phosphate buffer solution at a pH close to physiological pH and then incorporated into a cross-linked or non-cross-linked hyaluronic acid gel.

- Antioxidants and other compounds

The antioxidant or additional compound is dissolved in a phosphate buffer solution and then incorporated into the cross-linked or non-cross-linked hyaluronic acid gel.

-Sterilization

The composition thus obtained was packaged in syringes sterilized by high-pressure steam sterilization (T=121° C., 10 minutes).

b) Rheological measurements

The elastic component G' of the composition comprising cross-linked or non-cross-linked hyaluronic acid before and after sterilization by high-pressure steam sterilization was measured using a TA Instrument AR 2000Ex rheometer at 25°C under oscillation, and the values of the elastic component G' were recorded at a frequency of 1 Hz.

The viscosity η of the compositions was measured using a TA Instrument AR 2000Ex rheometer in controlled stress mode at 25° C. The viscosity values were recorded at a stress of 0.02 s ⁻¹ .

In the following examples, the abbreviations used are as follows: LA: local anesthetic; Aox: antioxidant; AC: additional compound; LIDO: lidocaine; MEPI: mepivacaine; PRILO: prilocaine; HA: hyaluronic acid; % G': % increase in elastic component G' relative to the reference composition.

Example 1:

Example 1 illustrates the effect of various local anesthetics on the impairment of the rheological properties of non-crosslinked or crosslinked hyaluronic acid of different molar masses, different concentrations and different degrees of crosslinking during heat sterilization.

Example 1-a:

Example 1-a illustrates the effect of various local anesthetics on the impairment of the rheological properties of a gel of hyaluronic acid with a weight-average molecular weight of 3×10 ⁶ Da at a concentration of 20 mg/g and a degree of crosslinking X=0.12 during heat sterilization.

The [HA]/[MEPI] or [HA]/[LA] ratio is 6.67 to 2.

For all measurements, a reference composition was prepared by replacing the aqueous solution of the local anesthetic (retaining the additional compound) with an equal amount of aqueous phosphate buffer solution.

The percentage increase of the elastic component G′ is defined as follows:

% increase G’=100*(Y-Y’)/Y

Where Y = the percentage of elastic component G' of the reference composition lost upon sterilization

and Y' = the percentage of elastic component G' of the test composition lost upon sterilization.

The percentage Y or Y′ lost during sterilization of the portion G′ is calculated as follows:

% loss = G' before sterilization - G' after sterilization / G' before sterilization

Table 1

At equivalent concentrations, irrespective of the ratio, the rheology of a composition comprising hyaluronic acid of weight average molecular weight 3×10 ⁶ Da at a concentration of 20 mg/g and a degree of crosslinking X=0.12 is less impaired during heat sterilization in the presence of mepivacaine than in the presence of lidocaine or prilocaine.

Example 1-b:

Example 1-b illustrates the effect of various anesthetics on the rheological properties of a gel of hyaluronic acid with a weight average molecular weight of 1×10 ⁶ Da at a concentration of 20 mg/g and a degree of cross-linking X=0.07, which is compromised during heat sterilization.

The [HA]/[MEPI] or [HA]/[LA] ratios ranged from 6.67 to 3.33.

For all measurements, a reference composition was prepared by replacing the aqueous solution of the local anesthetic (retaining the additional compound) with an equal amount of aqueous phosphate buffer solution.

Table 2 below summarizes the various compositions tested and the results obtained. The abbreviations used are as follows: LA: local anesthetic; Aox: antioxidant; AC: additional compound; LIDO: lidocaine; MEPI: mepivacaine; PRILO: prilocaine; HA: hyaluronic acid; % G': % increase in elastic component G' relative to the reference composition.

The percentage increase in elastic component G′ is defined as:

% increase G’=100*(Y-Y’)/Y

Where Y = the percentage of elastic component G' of the reference composition lost upon sterilization

and Y' = the percentage of elastic component G' of the test composition lost upon sterilization.

Table 2

As in Example 1-a, but in the presence of hyaluronic acid of lower weight average molecular weight and lower degree of cross-linking, the results obtained were confirmed regardless of the ratio.

When the best results are obtained in the presence of lidocaine or mepivacaine, the study will be continued by comparing the results obtained in the presence of mepivacaine or lidocaine alone.

Example 1-c:

Example 1-c illustrates the effect of various anesthetics on the rheological properties of a gel of hyaluronic acid with a weight average molecular weight of 3×10 ⁶ Da at a concentration of 20 mg/g and a degree of crosslinking X=0.06, which is compromised during heat sterilization.

The [HA]/[MEPI] or [HA]/[LA] ratio was 6.67.

For all measurements, a reference composition was prepared by replacing the aqueous solution of the local anesthetic (retaining the additional compound) with an equal amount of aqueous phosphate buffer solution.

Table 3 below summarizes the various compositions tested and the results obtained. The abbreviations used are as follows: LA: local anesthetic; Aox: antioxidant; AC: additional compound; LIDO: lidocaine; MEPI: mepivacaine; HA: hyaluronic acid; % G': % increase in elastic component G' relative to the reference composition.

The percentage increase in elastic component G′ is defined as:

% increase G’=100*(Y-Y’)/Y

Where Y = the percentage of elastic component G' of the reference composition lost upon sterilization

and Y' = the percentage of elastic component G' of the test composition lost upon sterilization.

Table 3

The results obtained in Example 1-a were confirmed using hyaluronic acid of the same weight average molecular weight, the same concentration but with a lower degree of cross-linking. The results obtained in Example 1-b were also confirmed using hyaluronic acid of a higher weight average molecular weight, the same concentration and a comparable degree of cross-linking.

Example 1-d:

Example 1-d illustrates the effect of various local anesthetics on the rheological properties of a gel of non-cross-linked hyaluronic acid with a weight average molecular weight of 3 x ¹⁰⁶ Da at a concentration of 20 mg/g, which is compromised during heat sterilization.

The [HA]/[MEPI] or [HA]/[LA] ratio is 20 to 2.

For all measurements, a reference composition was prepared by replacing the aqueous solution of the local anesthetic (retaining the additional compound) with an equal amount of aqueous phosphate buffer solution.

Table 4 below summarizes the various compositions tested and the results obtained. The abbreviations used are as follows: LA: local anesthetic; Aox: antioxidant; AC: additional compound; LIDO: lidocaine; MEPI: mepivacaine; HA: hyaluronic acid; %η: % increase in viscosity relative to the reference composition.

The percentage increase in viscosity η is defined as:

% improvement eta=100*(Z-Z’)/Z

Where Z = the percentage of viscosity η lost during sterilization of the reference composition

and Z' = the percentage loss in viscosity η of the test composition upon sterilization.

Table 4

Regardless of the ratio, the results obtained in Examples 1-a and 1-c were confirmed using hyaluronic acid of the same weight average molecular weight and the same concentration, but not cross-linked.

Irrespective of the ratio, weight average molecular weight and degree of cross-linking, the rheology of a composition comprising hyaluronic acid at a concentration of 20 mg/g is less impaired during heat sterilization in the presence of mepivacaine than in the presence of lidocaine or prilocaine at equivalent concentrations.

Example 2:

Example 2 illustrates the effect of various local anesthetics in the presence of antioxidants on the rheological properties of gels of non-crosslinked or crosslinked hyaluronic acid of different molecular weights, concentrations and degrees of crosslinking during heat sterilization.

Example 2-a:

Example 2-a illustrates the effect of various local anesthetics in the presence of mannitol on the rheological impairment during heat sterilization of a gel of hyaluronic acid with a weight-average molecular weight of 3×10 ⁶ Da and a degree of crosslinking X=0.12 at a concentration of 20 mg/g.

The [HA]/[MEPI] or [HA]/[LA] ratio is 20 to 2.

For all measurements, a reference composition was prepared by replacing the aqueous solution of the local anesthetic (retaining the additional compound) with an equal amount of aqueous phosphate buffer solution.

Table 5 below summarizes the various compositions tested and the results obtained. The abbreviations used are as follows: LA: local anesthetic; Aox: antioxidant; MAN: mannitol; AC: additional compound; LIDO: lidocaine; MEPI: mepivacaine; PRILO: prilocaine; HA: hyaluronic acid; % G': % increase in elastic component G' relative to the reference composition.

The percentage increase in the elastic component G’ is defined as:

% increase G’=100*(Y-Y’)/Y

Where Y = the percentage of elastic component G' of the reference composition lost upon sterilization

and Y' = the percentage of elastic component G' of the test composition lost upon sterilization.

Table 5

At equivalent concentrations, in the presence of mannitol, regardless of the ratio, the rheology of a composition comprising hyaluronic acid with a weight-average molecular weight of 3×10 ⁶ Da at a concentration of 20 mg/g and a degree of crosslinking X=0.12 is less impaired during heat sterilization in the presence of mepivacaine than in the presence of lidocaine or prilocaine.

Example 2-b:

Example 2-b illustrates the effect of various local anesthetics in the presence of antioxidants on the rheological impairment during heat sterilization of a gel of hyaluronic acid with a weight average molecular weight of 1×10 ⁶ Da at a concentration of 20 mg/g and a degree of crosslinking X=0.07.

The [HA]/[MEPI] or [HA]/[LA] ratios ranged from 6.67 to 3.33.

For all measurements, a reference composition was prepared by replacing the aqueous solution of the local anesthetic (retaining the additional compound) with an equal amount of aqueous phosphate buffer solution.

Table 6 below summarizes the various compositions tested and the results obtained. The abbreviations used are as follows: LA: local anesthetic; Aox: antioxidant; MAN: mannitol; AC: additional compound; LIDO: lidocaine; MEPI: mepivacaine; PRILO: prilocaine; HA: hyaluronic acid; % G': % increase in elastic component G' relative to the reference composition.

The percentage increase in the elastic component G’ is defined as:

% increase G’=100*(Y-Y’)/Y

Where Y = the percentage of elastic component G' of the reference composition lost upon sterilization

and Y' = the percentage of elastic component G' of the test composition lost upon sterilization.

Table 6

As in Example 2-a, but in the presence of hyaluronic acid of lower weight average molecular weight and lower degree of cross-linking, the results obtained were confirmed irrespective of the ratio.

When the best results were obtained in the presence of lidocaine or mepivacaine, the remaining studies were performed by comparing the results obtained in mepivacaine or lidocaine alone.

Example 2-c:

Example 2-c illustrates the effect of various local anesthetics in the presence of antioxidants on the rheological impairment during heat sterilization of a gel of hyaluronic acid with a weight average molecular weight of 3×10 ⁶ Da at a concentration of 20 mg/g and a degree of crosslinking X=0.06.

The [HA]/[MEPI] or [HA]/[LA] ratio is 3.33.

For all measurements, a reference composition was prepared by replacing the aqueous solution of the local anesthetic (retaining the additional compound) with an equal amount of aqueous phosphate buffer solution.

Table 7 below summarizes the various compositions tested and the results obtained. The abbreviations used are as follows: LA: local anesthetic; Aox: antioxidant; MAN: mannitol; AC: additional compound; LIDO: lidocaine; MEPI: mepivacaine; HA: hyaluronic acid; % G': % increase in elastic component G' relative to the reference composition.

The percentage increase in the elastic component G’ is defined as:

% increase G’=100*(Y-Y’)/Y

Where Y = the percentage of elastic component G' of the reference composition lost upon sterilization

and Y' = the percentage of elastic component G' of the test composition lost upon sterilization.

Table 7

The results obtained in Example 2-a were confirmed using hyaluronic acid of the same weight average molecular weight, the same concentration but a lower degree of cross-linking. The results obtained in Example 2-b were also confirmed using hyaluronic acid of a higher weight average molecular weight, the same concentration and a similar degree of cross-linking.

Example 2-d:

Example 2-d illustrates the effect of various local anesthetics in the presence of mannitol on the rheological impairment of a gel of non-crosslinked hyaluronic acid with a weight average molecular weight of 3×10 ⁶ Da at a concentration of 20 mg/g during heat sterilization.

The [HA]/[MEPI] or [HA]/[LA] ratio is 20 to 2.

For all measurements, a reference composition was prepared by replacing the aqueous solution of local anesthetic with an equal amount of aqueous phosphate buffer solution.

Table 8 below summarizes the various compositions tested and the results obtained. The abbreviations used are as follows: LA: local anesthetic; Aox: antioxidant; MAN: mannitol; AC: additional compound; MEPI: mepivacaine; HA: hyaluronic acid; %η: η% increase in viscosity relative to the reference composition.

The percentage increase in viscosity η is defined as:

% improvement eta=100*(Z-Z’)/Z

Where Y = the percentage loss of viscosity η of the reference composition during sterilization

and Y' = the percentage loss of viscosity η of the test composition upon sterilization.

Table 8

Regardless of the ratio, the results obtained in Examples 2-a and 2-c were confirmed using hyaluronic acid of the same weight average molecular weight and the same concentration, but not cross-linked.

At equivalent concentrations, irrespective of ratio, weight average molecular weight and degree of cross-linking, the rheology of a composition comprising hyaluronic acid at a concentration of 20 mg/g comprising mannitol is less impaired in the presence of mepivacaine than in the presence of lidocaine during heat sterilization.

Example 3:

Example 3 illustrates the effect of various local anesthetics in the presence of magnesium ascorbyl phosphate (hereinafter referred to as MAP) on the rheological properties of hyaluronic acid gels with different degrees of cross-linking during heat sterilization.

Example 3-a:

Example 3-a illustrates the effect of various local anesthetics in the presence of MAP on the rheological impairment during heat sterilization of a hyaluronic acid gel with a weight average molecular weight of 3×10 ⁶ Da at a concentration of 20 mg/g and a degree of crosslinking X=0.12.

The [HA]/[MEPI] or [HA]/[LA] ratio was 6.67.

For all measurements, a reference composition was prepared by replacing the aqueous solution of the local anesthetic (retaining the additional compound) with an equal amount of aqueous phosphate buffer solution.

Table 9 below summarizes the various compositions tested and the results obtained. The abbreviations used are as follows: LA: local anesthetic; Aox: antioxidant; AC: additional compound; MAP: magnesium ascorbyl phosphate; LIDO: lidocaine; MEPI: mepivacaine; HA: hyaluronic acid; % G': % increase in elastic component G' relative to the reference composition.

The percentage increase in the elastic component G’ is defined as:

% increase G’=100*(Y-Y’)/Y

Where Y = the percentage of elastic component G' of the reference composition lost upon sterilization

and Y' = the percentage of elastic component G' of the test composition lost upon sterilization.

Table 9

In the presence of MAP, the rheology of a composition comprising hyaluronic acid with a weight-average molecular weight of 3×10 ⁶ Da and a degree of crosslinking X=0.06 and a concentration of 20 mg/g is less impaired during heat sterilization in the presence of mepivacaine than in the presence of lidocaine, at equivalent concentrations and a ratio [HA]/[MEPI] of 6.67.

Example 3-b:

Example 3-b illustrates the effect of various local anesthetics in the presence of MAP on the rheological impairment during heat sterilization of a gel of hyaluronic acid with a weight average molecular weight of 3×10 ⁶ Da at a concentration of 20 mg/g and a degree of crosslinking X=0.06.

The [HA]/[MEPI] or [HA]/[LA] ratio was 6.67.

For all measurements, a reference composition was prepared by replacing the aqueous solution of the local anesthetic (retaining the additional compound) with an equal amount of aqueous phosphate buffer solution.

Table 10 below summarizes the various compositions tested and the results obtained. The abbreviations used are as follows: LA: local anesthetic; Aox: antioxidant; AC: additional compound; MAP: magnesium ascorbyl phosphate; LIDO: lidocaine; MEPI: mepivacaine; HA: hyaluronic acid; % G': % increase in elastic component G' relative to the reference composition.

The percentage increase in the elastic component G’ is defined as:

% increase G’=100*(Y-Y’)/Y

Where Y = the percentage of elastic component G' of the reference composition lost upon sterilization

and Y' = the percentage of elastic component G' of the test composition lost upon sterilization.

Table 10

The results obtained in Example 3-a were confirmed using hyaluronic acid of the same weight average molecular weight, the same concentration and the same ratio [HA]/[MEPI] but with a lower degree of cross-linking.

At equivalent concentrations, irrespective of the degree of cross-linking, the rheology of a composition comprising hyaluronic acid at a concentration of 20 mg/g in the presence of MAP during heat sterilization is less impaired in the presence of mepivacaine than in the presence of lidocaine.

Example 4:

Example 4 illustrates the effect of various local anesthetics in the presence of mannitol and SOS on the rheological impairment during heat sterilization of a gel of hyaluronic acid with a weight average molecular weight of 3×10 ⁶ Da and a degree of crosslinking X=0.12 at a concentration of 20 mg/g.

The [HA]/[MEPI] or [HA]/[LA] ratio was 6.67.

For all measurements, a reference composition was prepared by replacing the aqueous solution of the local anesthetic (retaining the additional compound) with an equal amount of aqueous phosphate buffer solution.

Table 11 below summarizes the various compositions tested and the results obtained. The abbreviations used are as follows: LA: local anesthetic; Aox: antioxidant; MAN: mannitol; AC: additional compound; SOS: sucrose octasulfate; LIDO: lidocaine; MEPI: mepivacaine; HA: hyaluronic acid; % G': % increase in elastic component G' relative to the reference composition.

The percentage increase in the elastic component G’ is defined as:

% increase G’=100*(Y-Y’)/Y

Where Y = the percentage of elastic component G' of the reference composition lost upon sterilization

and Y' = the percentage of elastic component G' of the test composition lost upon sterilization.

Table 11

At equivalent concentrations, in the presence of mannitol and SOS, at a ratio of 6.67, the rheology of the composition comprising hyaluronic acid at a concentration of 20 mg/g is less impaired in the presence of mepivacaine than in the presence of lidocaine during heat sterilization.

Example 5:

Example 5 illustrates the effect of various local anesthetics in the presence of mannitol and MAP on the rheological impairment during heat sterilization of a gel of hyaluronic acid with a weight average molecular weight of 3×10 ⁶ Da and a degree of crosslinking X=0.12 at a concentration of 20 mg/g.

Example 5-a:

Example 5-a illustrates the effect of various local anesthetics on the rheological impairment during heat sterilization of a gel of hyaluronic acid with a weight average molecular weight of 3×10 ⁶ Da and a cross-linking degree X=0.12 at a concentration of 20 mg/g in the presence of MAP and mannitol at a concentration of 0.3 mg/g.

For all measurements, a reference composition was prepared by replacing the aqueous solution of the local anesthetic (retaining the additional compound) with an equal amount of aqueous phosphate buffer solution.

Table 12 below summarizes the various compositions tested and the results obtained. The abbreviations used are as follows: LA: local anesthetic; Aox: antioxidant; MAN: mannitol; AC: additional compound; MAP: magnesium ascorbyl phosphate; LIDO: lidocaine; MEPI: mepivacaine; HA: hyaluronic acid; % G': % increase in elastic component G' relative to the reference composition.

The percentage increase in the elastic component G’ is defined as:

% increase G’=100*(Y-Y’)/Y

Where Y = the percentage of elastic component G' of the reference composition lost upon sterilization

and Y' = the percentage of elastic component G' of the test composition lost upon sterilization.

Table 12

At equivalent concentrations, at a ratio of 6.67, the rheology of a composition comprising hyaluronic acid at a concentration of 20 mg/g in the presence of mannitol and MAP at a concentration of 0.3 mg/g is less impaired in the presence of mepivacaine than in the presence of lidocaine during heat sterilization.

Example 5-b:

Example 5-b illustrates the effect of various local anesthetics on the rheological impairment during heat sterilization of a gel of hyaluronic acid with a weight average molecular weight of 3×10 ⁶ Da and a cross-linking degree X=0.12 at a concentration of 20 mg/g in the presence of mannitol and MAP at a concentration of 0.7 mg/g.

For all measurements, a reference composition was prepared by replacing the aqueous solution of the local anesthetic (retaining the additional compound) with an equal amount of aqueous phosphate buffer solution.

Table 13 below summarizes the various compositions tested and the results obtained. The abbreviations used are as follows: LA: local anesthetic; Aox: antioxidant; MAN: mannitol; AC: additional compound; MAP: magnesium ascorbyl phosphate; LIDO: lidocaine; MEPI: mepivacaine; HA: hyaluronic acid; % G': % increase in elastic component G' relative to the reference composition.

The percentage increase in the elastic component G’ is defined as:

% increase G’=100*(Y-Y’)/Y

Where Y = the percentage of elastic component G' of the reference composition lost upon sterilization

and Y' = the percentage of elastic component G' of the test composition lost upon sterilization.

Table 13

Higher concentrations of MAP were used to confirm the results obtained in Example 5-a.

Example 6:

Example 6 allows comparison of the release kinetics of mepivacaine and lidocaine, each incorporated at a concentration of 20 mg/g into a gel of hyaluronic acid with a weight-average molecular weight of 3×10 ⁶ Da and a degree of crosslinking X=0.12. The initial concentration of mepivacaine or lidocaine is 3 mg/g.

The protocol used to study the release kinetics of the two local anesthetics was identical to that used in Example 5 of patent application WO 2010/015 901 in the name of Allergan. However, the release kinetics were studied in physiological saline medium at 37° C. Monitoring by UV-visible spectrophotometry was performed to determine the local anesthetic present in the gel.

In Table 13 below, the mass percentages of lidocaine or mepivacaine in the hyaluronic acid gel measured after various dialysis times are specified.

Table 14

Time (hours) Lidocaine Mepivacaine 0 0.293 0.290 1.5 0.160 0.133 5 0.109 0.100 7 0.103 0.098 twenty three 0.091 0.086 48 0.084 0.077 72 0.082 0.075

The results obtained above are illustrated by FIG1 , which is a graph showing the concentrations of lidocaine and mepivacaine as a function of dialysis time.

Figure 1 shows the mass concentration of local anesthetic (lidocaine and/or mepivacaine) as a function of dialysis time in hours, showing that lidocaine and mepivacaine release kinetics are comparable.

Therefore, the bioavailable amount of local anesthetic is equivalent whether incorporated into lidocaine or mepivacaine.

Example 7:

Example 7 illustrates the effect of various local anesthetics on the impairment of the rheological properties of interpenetrating gels of hyaluronic acid and with or without mannitol, prepared according to patent application WO 2009/071 697 in the name of Vivacy, during heat sterilization.

Example 7-a:

Example 7-a illustrates the effect of various local anesthetics on the rheological properties of interpenetrating gels of hyaluronic acid (excluding mannitol) prepared according to patent application WO 2009/071697, filed under the name Vivacy, at a final concentration of 20 mg/g during heat sterilization. The first gel was cross-linked with NaHA having a weight-average molecular weight of 1× ^10⁶Da and a degree of cross-linking of X = 0.03, and the second gel was cross-linked with NaHA having a weight-average molecular weight of 3× ^10⁶Da and a degree of cross-linking of X = 0.06. The two gels were mixed in a 50/50 ratio. The [HA]/[MEPI] or [HA]/[LA] ratio was 6.67.

For all measurements, a reference composition was prepared by replacing the aqueous solution of the local anesthetic (retaining the additional compound) with an equal amount of aqueous phosphate buffer solution.

Table 15 below summarizes the various compositions tested and the results obtained. The abbreviations used are as follows: LA: local anesthetic; Aox: antioxidant; AC: additional compound; LIDO: lidocaine; MEPI: mepivacaine; HA: hyaluronic acid; % G': % increase in elastic component G' relative to the reference composition.

The percentage increase in the elastic component G’ is defined as:

% increase G’=100*(Y-Y’)/Y

Where Y = the percentage of elastic component G' of the reference composition lost upon sterilization

and Y' = the percentage of elastic component G' of the test composition lost upon sterilization.

Table 15

At equivalent concentrations, the rheology of the composition comprising cross-linked and interpenetrating hyaluronic acid prepared according to patent application WO 2009/071 697 in the name of Vivacy is less impaired during heat sterilization in the presence of mepivacaine than in the presence of lidocaine.

Example 7-b:

Example 7-b illustrates the effect of various local anesthetics on the rheological properties of interpenetrating gels of hyaluronic acid containing mannitol, prepared according to patent application WO 2009/071697 under the name Vivacy, at a final concentration of 20 mg/g, during heat sterilization. The first gel was cross-linked with NaHA having a weight-average molecular weight of 1× ^10⁶Da and a degree of cross-linking of X = 0.03, and the second gel was cross-linked with NaHA having a weight-average molecular weight of 3× ^10⁶Da and a degree of cross-linking of X = 0.06. The two gels were mixed in a 50/50 ratio. The [HA]/[MEPI] or [HA]/[LA] ratio was 6.67.

For all measurements, a reference composition was prepared by replacing the aqueous solution of the local anesthetic (retaining the additional compound) with an equal amount of aqueous phosphate buffer solution.

Table 16 below summarizes the various compositions tested and the results obtained. The abbreviations used are as follows: LA: local anesthetic; Aox: antioxidant; AC: additional compound; LIDO: lidocaine; MEPI: mepivacaine; HA: hyaluronic acid; % G': % increase in elastic component G' relative to the reference composition.

The percentage increase in the elastic component G’ is defined as:

% increase G’=100*(Y-Y’)/Y

Where Y = the percentage of elastic component G' of the reference composition lost upon sterilization

and Y' = the percentage of elastic component G' of the test composition lost upon sterilization.

Table 16

At equivalent concentrations, the rheology of the composition comprising mannitol and cross-linked and interpenetrating hyaluronic acid prepared according to patent application WO 2009/071 697 in the name of Vivacy is less impaired during heat sterilization in the presence of mepivacaine than in the presence of lidocaine.

Example 8:

Example 8 illustrates the effect of various local anesthetics (with and without mannitol) on the rheological impairment during heat sterilization of a gel of co-crosslinked hyaluronic acid prepared according to patent application WO 86/00079 in the name of Allergan.

Example 8-a:

Example 8-a illustrates the effect of various local anesthetics (without mannitol) on the rheological properties of a gel of co-crosslinked hyaluronic acid at a final concentration of 20 mg/g, prepared according to patent application WO 86/00079 in the name of Allergan, during heat sterilization: During crosslinking (1% NaOH, degree of crosslinking X=0.09, 50°C for 2 hours 30 minutes), two molar masses of NaHA were mixed in a 50/50 ratio: the first having a weight-average molecular weight of 1×10 ⁶ Da and the second having a weight-average molecular weight of 3×10 ⁶ Da. The [HA]/[MEPI] or [HA]/[LA] ratio was 6.67.

For all measurements, a reference composition was prepared by replacing the aqueous solution of the local anesthetic (retaining the additional compound) with an equal amount of aqueous phosphate buffer solution.

Table 17 below summarizes the various compositions tested and the results obtained. The abbreviations used are as follows: LA: local anesthetic; Aox: antioxidant; AC: additional compound; LIDO: lidocaine; MEPI: mepivacaine; HA: hyaluronic acid; % G': % increase in elastic component G' relative to the reference composition.

The percentage increase in the elastic component G’ is defined as:

% increase G’=100*(Y-Y’)/Y

Where Y = the percentage of elastic component G' of the reference composition lost upon sterilization

and Y' = the percentage of elastic component G' of the test composition lost upon sterilization.

Table 17

At equivalent concentrations, the rheology of the composition comprising co-crosslinked hyaluronic acid prepared according to patent application WO 86/00079 in the name of Allergan is less impaired during heat sterilization in the presence of mepivacaine than in the presence of lidocaine.

Example 8-b:

Example 8-b illustrates the effect of various local anesthetics (with mannitol) on the rheological properties of a gel of co-crosslinked hyaluronic acid at a final concentration of 20 mg/g, prepared according to patent application WO 86/00079 in the name of Allergan, during heat sterilization: During crosslinking (1% NaOH, degree of crosslinking X=0.09, 50°C for 2 hours 30 minutes), two molar masses of NaHA were mixed in a 50/50 ratio: the first having a weight-average molecular weight of 1×10 ⁶ Da and the second having a weight-average molecular weight of 3×10 ⁶ Da. The [HA]/[MEPI] or [HA]/[LA] ratio was 6.67.

For all measurements, a reference composition was prepared by replacing the aqueous solution of the local anesthetic (retaining the additional compound) with an equal amount of aqueous phosphate buffer solution.

Table 18 below summarizes the various compositions tested and the results obtained. The abbreviations used are as follows: LA: local anesthetic; Aox: antioxidant; AC: additional compound; LIDO: lidocaine; MEPI: mepivacaine; HA: hyaluronic acid; % G': % increase in elastic component G' relative to the reference composition.

The percentage increase in the elastic component G’ is defined as:

% increase G’=100*(Y-Y’)/Y

Where Y = the percentage of elastic component G' of the reference composition lost upon sterilization

and Y' = the percentage of elastic component G' of the test composition lost upon sterilization.

Table 18

At equivalent concentrations, the rheology of the composition comprising mannitol and co-crosslinked hyaluronic acid prepared according to patent application WO 86/00079 in the name of Allergan is less impaired during heat sterilization in the presence of mepivacaine than in the presence of lidocaine.

Example 9:

Example 9 illustrates the effect of the addition of various anesthetics on the impairment of the rheological properties of various hyaluronic acid gels containing various polyols during heat sterilization.

Example 9-a:

Example 9-a consists of a summary of tests relating to hyaluronic acid with a weight-average molecular weight of 3×10 ⁶ Da and a degree of cross-linking X=0.06 at a concentration of 20 mg/g.

All %G' calculations are performed using as reference a composition containing neither polyol nor local anesthetic nor additional compounds.

Table 19

The rheological properties of the composition comprising hyaluronic acid with a weight average molecular weight of 3×10 ⁶ Da at a concentration of 20 mg/g and a degree of crosslinking X=0.06 are less impaired in the presence of mepivacaine during heat sterilization relative to the reference composition.

Example 9-b:

Example 9-b consists of a summary of tests relating to hyaluronic acid with a weight-average molecular weight of 3.2×10 ⁶ Da and a degree of cross-linking X=0.06 at a concentration of 20 mg/g.

All %G' calculations are performed using as reference a composition containing neither polyol nor local anesthetic nor additional compounds.

Table 20

The rheology of the composition comprising hyaluronic acid with a weight average molecular weight of 3.2×10 ⁶ Da at a concentration of 20 mg/g and a degree of crosslinking X=0.06 is less impaired in the presence of mepivacaine during heat sterilization relative to the reference composition, regardless of the polyol incorporated into the composition.

The composition with the best results was the one comprising maltitol and mepivacaine.

Example 9-c:

Example 9-c consists of a summary of tests related to hyaluronic acid with a weight-average molecular weight of 1×10 ⁶ Da and a degree of cross-linking X=0.07 at a concentration of 20 mg/g.

All %G' calculations are performed using as reference a composition containing neither polyol nor local anesthetic nor additional compounds.

Table 21

The rheological properties of the composition comprising hyaluronic acid with a weight average molecular weight of 1×10 ⁶ Da at a concentration of 20 mg/g and a degree of crosslinking X=0.07 during heat sterilization are less impaired in the presence of mepivacaine than the reference composition.

Example 9-d:

Example 9-d consists of a summary of tests relating to hyaluronic acid with a weight-average molecular weight of 3×10 ⁶ Da at a concentration of 20 mg/g and a degree of cross-linking X=0.12.

All %G' calculations are performed using as reference a composition containing neither polyol nor local anesthetic nor additional compounds.

Table 22

The rheological properties of the composition comprising hyaluronic acid with a weight average molecular weight of 3×10 ⁶ Da at a concentration of 20 mg/g and a degree of crosslinking X=0.12 during heat sterilization are less impaired in the presence of mepivacaine than the reference composition.

Example 9-e:

Example 9-e consists of a summary of the above-described tests relating to an interpenetrating hyaluronic acid prepared according to patent application WO 2009/071 697 in the name of Vivacy.

All %G' calculations are performed using as reference a composition containing neither polyol nor local anesthetic nor additional compounds.

Table 23

The rheology of the composition comprising interpenetrating hyaluronic acid prepared according to patent application WO 2009/071697 in the name of Vivacy is less impaired in the presence of mepivacaine during heat sterilization relative to the reference composition.

Example 9-f:

Example 9-f consists of a summary of the above-described tests relating to a co-cross-linked hyaluronic acid prepared according to patent application WO 86/00079 in the name of Allergan.

All %G' calculations are performed using as reference a composition containing neither polyol nor local anesthetic nor additional compounds.

Table 24

The rheological properties of the composition comprising co-crosslinked hyaluronic acid prepared according to patent application WO 86/00079 in the name of Allergan are less impaired in the presence of mepivacaine during heat sterilization relative to the reference composition.

Example 10:

Example 10 illustrates the effect of the addition of various anesthetics on the impairment of the rheological properties of hyaluronic acid gels during heat sterilization. The results were verified over a [HA]/[MEPI] ratio range of ≥ 0.1 and at least 0.4 to 2500.

Table 25

Claims (11)

1. A sterile aqueous composition comprising at least one hyaluronic acid and at least mepivacaine with a pH close to physiological pH, characterized in that the mass ratio of the concentration of hyaluronic acid [HA] to the concentration of mepivacaine [MEPI] is greater than or equal to 0.1; Furthermore, the sterilized aqueous composition is characterized by comprising at least one antioxidant selected from polyols, said polyol being selected alone or in mixtures of glycerol, sorbitol, propylene glycol, xylitol, mannitol, erythritol, maltitol, and lactitol. Furthermore, the concentration of mepivacaine [MEPI] is from 0.01 mg/g to 50 mg/g of the total weight of the composition. It is characterized in that the concentration of hyaluronic acid [HA] is from 2 mg/g to 50 mg/g of the total weight of the composition. 2. The sterilized aqueous composition according to claim 1, characterized in that the mass ratio of the concentration of hyaluronic acid [HA] to the concentration of mepivacaine [MEPI] is 0.1 to 50. 3. The sterilized aqueous composition according to claim 1 or 2, characterized in that the mepivacaine is selected from the group comprising: racemic mepivacaine hydrochloride, (R)-mepivacaine hydrochloride, (S)-mepivacaine hydrochloride, racemic mepivacaine, (R)-mepivacaine and (S)-mepivacaine or pharmaceutically acceptable salts thereof. 4. The sterilized aqueous composition according to claim 1 or 2, characterized in that the composition comprises, alone or as a mixture, at least one non-crosslinked hyaluronic acid or a salt thereof. 5. The sterilized aqueous composition according to claim 1 or 2, characterized in that the composition comprises at least one cross-linked hyaluronic acid or its salt, either alone or as a mixture. 6. A method for preparing a sterilized aqueous composition as described in any of the preceding claims, comprising at least the following steps: - The step of hydrating fibers of at least one hyaluronic acid or its salt, either alone or as a mixture, in a buffer solution with a pH close to physiological pH to obtain a hydrogel. - The step of incorporating mepivacaine as an aqueous solution into the hydrogel obtained in the preceding steps. - Homogenization step, and - Sterilization steps, The method is characterized by further comprising at least one step of incorporating at least one antioxidant selected from polyols, said polyols being selected alone or in mixtures of glycerol, sorbitol, propylene glycol, xylitol, mannitol, erythritol, maltitol, and lactitol. Furthermore, the concentration of mepivacaine [MEPI] is from 0.01 mg/g to 50 mg/g of the total weight of the composition. It is characterized in that the concentration of hyaluronic acid [HA] is from 2 mg/g to 50 mg/g of the total weight of the composition. 7. The preparation method according to claim 6, wherein the method further comprises at least one crosslinking step. 8. Use of the sterilized aqueous composition according to any one of claims 1 to 5 in the preparation of a pharmaceutical agent for filling wrinkles, correcting skin defects, or for plumping. 9. Use of the sterilized aqueous composition according to any one of claims 1 to 5 in the preparation of an agent for injection into a joint as a substitute or supplement for defective synovial fluid. 10. A medicine box comprising the sterilized aqueous composition as described in any one of claims 1 to 5, packaged in a syringe and sterilized after packaging. 11. The sterilized aqueous composition as described in claim 1 or 2, used as a substitute or supplement for defective synovial fluid.