阅读说明：本技术 包含甲哌卡因的透明质酸组合物 (Hyaluronic acid compositions comprising mepivacaine ) 是由 热雷米·邦贝唐 盖伊·维塔利 于 2014-12-23 设计创作，主要内容包括：本发明涉及经灭菌水性组合物,其包含至少一种透明质酸和至少甲哌卡因,以及任选地一种或更多种另外的化合物,透明质酸的浓度[HA]与甲哌卡因的浓度[MEPI]的重量比例([HA]/[MEPI])不低于0.1；[HA]/[MEPI]≥0.1。本发明还涉及甲哌卡因以等同量作为利多卡因的替代物以获得包含局部麻醉剂的透明质酸组合物的用途,在热灭菌之后所述包含局部麻醉剂的透明质酸组合物的流变性优于包含利多卡因的相同透明质酸组合物的流变性。(The present invention relates to a sterilized aqueous composition comprising at least one hyaluronic acid and at least mepivacaine, and optionally one or more additional compounds, the weight ratio ([ HA ]/[ MEPI ]) of the concentration of hyaluronic acid [ HA ] to the concentration of mepivacaine [ MEPI ] being not less than 0.1; [ HA ]/[ MEPI ] > 0.1. The invention also relates to the use of mepivacaine in equivalent amounts as a substitute for lidocaine to obtain a hyaluronic acid composition comprising a local anaesthetic which has a rheology superior to that of the same hyaluronic acid composition comprising lidocaine after heat sterilization.)

1. A sterilized aqueous composition comprising a mixture of cross-linked hyaluronic acid or a salt thereof and at least mepivacaine as a single phase mixture, characterized by a mass ratio of the concentration of hyaluronic acid [ HA ] to the concentration of mepivacaine [ MEPI ]: [ HA ]/[ MEPI ] is greater than or equal to 0.1; [ HA ]/[ MEPI ] > 0.1.

2. 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 ]: [ HA ]/[ MEPI ] is 0.1 to 50; the [ HA ]/[ MEPI ] is more than or equal to 0.1 and less than or equal to 50.

3. Sterilized aqueous composition according to any of the preceding claims, wherein the concentration of mepivacaine [ MEPI ] is from 0.01mg/g to 50 mg/g.

4. Sterilized aqueous composition according to any of the preceding claims, 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.

5. Sterilized aqueous composition according to any of the preceding claims, wherein the concentration of hyaluronic acid [ HA ] is from 2mg/g to 50mg/g of the total weight of the composition.

6. Sterilized aqueous composition according to any of the preceding claims, wherein the concentration of hyaluronic acid [ HA ] is 20mg/g of the total weight of the composition.

7. Sterilized aqueous composition according to any of the preceding claims, characterized in that the composition comprises at least one non-crosslinked hyaluronic acid or salt thereof, alone or as a mixture.

8. Sterilized aqueous composition according to any of claims 1 to 6, characterized in that the composition comprises at least one cross-linked hyaluronic acid or salt thereof, alone or as a mixture.

9. Sterilized aqueous composition according to any of the preceding claims, characterized in that the composition further comprises at least one antioxidant.

10. Sterilized aqueous composition according to any of the preceding claims, characterized in that the composition further comprises at least one additional compound.

11. Use of a sterilized aqueous composition according to any one of claims 1 to 10 for formulating a composition for filling wrinkles, for correcting skin imperfections or for plumping.

12. Use of a sterilized aqueous composition according to any one of claims 1 to 10 in the preparation of an agent to be injected into a joint as a replacement or supplement to a defective synovial fluid.

13. A kit comprising the sterilized aqueous composition of any one of claims 1 to 10 packaged in a syringe and sterilized after packaging.

14. A sterilized aqueous composition as claimed in any one of claims 1 to 10 for use as a replacement for or in addition to defective synovial fluid.

Technical Field

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.

Background

In medical applications, examples to be mentioned include injections for replacing the lacking biological fluid, for example into joints for replacement of synovial fluid, injections after surgery to avoid peritoneal adhesions, periurethral injections for treatment of incontinence and injections after surgery for correction of presbyopia (presbytie).

In cosmetic applications, examples to be mentioned include injections for filling wrinkles, fine lines and skin defects 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 they are injected using needles that must remain as thin as possible to ensure the precision of the practitioner's actions (getes) and to minimize the reactions after injection.

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

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

One of the main drawbacks of the addition of additives, whether added directly during the addition or during the sterilization phase or over time, for example during storage, is the potential deterioration of the rheology and/or the viscoelastic properties of the final gel or of its stability (d gradation).

The Michael H Gold article (Clinical Interconsiderations in Aging, 2007, 369-. The first composition developed for this purpose was based on collagen. Product(s)(approved by FDA in 1981) and(approved by the FDA in 1985) based on bovine collagen. Since then, two similar products were developed but based on human-based collagen ((ii))Andapproved by FDA at 2003).

By the end of the 80's 20 th century, Balazs developed the first hyaluronic acid-based skin augmentation compositions. Improvements have since been made to increase the stability of hyaluronic acid-based compositions.

As described in the Gold article above, the collagen-based composition comprises lidocaine which attenuates pain associated with injection techniques. However, in the first stage, as mentioned above, the hyaluronic acid-based composition does not contain any local anaesthetic, considering the stability problems caused by the additives.

In recent years, efforts have been made to consider incorporating local anesthetics, particularly lidocaine, into hyaluronic acid-based gels while ensuring a certain level of stability. Puragen sold by Mentor Corporation according to the article by Gold^TMPlus is the first hyaluronic acid-based fill composition containing lidocaine. Patent application WO 2005/112888 published on 1/12/2005 in the name of Mentor Corporation describes a method for preparing injectable hydrogels that may contain lidocaine.

Researchers in the field have filed a number of patent applications relating to compositions based on hyaluronic acid and containing lidocaine.

Patent application WO 2005/067994 published in 28.7.2005 in the name of Anika Therapeutics describes in example 21 a composition based on cross-linked hyaluronic acid gel particles comprising lidocaine. Lidocaine is merely an exemplary local anesthetic.

Patent application WO 2010/015901 published on 11/2/2010 in the name of Allergan describes an injectable hyaluronic acid-based skin filler composition comprising lidocaine. In said document, only lidocaine-based compositions are illustrated.

Patent application WO 2010/052430 published on 14/5/2010 in the name of Anteis describes a hyaluronic acid-based composition comprising lidocaine and one or more polyols.

Patent application WO 2012/104419 published in the name of Q-MED AB at 8, 9, 2012 also describes injectable hyaluronic acid-based skin filling compositions comprising a local anaesthetic. In particular, compositions comprising lidocaine, bupivacaine (pKa ═ 8.1) and tetracaine (a ═ 8.5) are exemplified. Preferred local anesthetics in this specification are bupivacaine, lidocaine and ropivacaine (pKa ═ 8.1). Thus, there is no illustration or separate reference to compositions incorporating a local anesthetic with a pKa less than that of lidocaine. Most of the examples described in patent application WO 2012/104419 relate to compositions comprising lidocaine.

Patent application WO 2013/186493 discloses hyaluronic acid compositions comprising sucrose octasulfate. Formulations containing local anesthetics are not exemplified, and all examples illustrate compositions terminally sterilized by autoclaving.

Patent application FR 2979539 in the name of Teoxane describes formulations comprising a local anaesthetic and a further active agent; also in this case, only compositions comprising lidocaine are described.

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

Patent application WO 2013/186493 discloses hyaluronic acid compositions comprising vitamin C derivatives. Formulations containing a local anesthetic are not exemplified.

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

Other local anaesthetics are also mentioned in the literature, but are merely exemplary and only products containing lidocaine are currently marketed.

Patent application EP 2581079 in the name of Biopolymer GmbH & co.kg describes compositions based on hyaluronic acid and prilocaine with rapid prilocaine release characteristics.

Indeed, one of the improvements that has not been achieved is that of obtaining the fastest possible effects of local anesthetics.

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

Among the potential candidates for a fast-acting amide type of local anesthetic, this group consists of lidocaine, etidocaine, mepivacaine, prilocaine and articaine.

The delay of action of these local anesthetics depends on their pKa of 7.7 to 8.0. At physiological pH, the local anaesthetic with the shortest delay of action is the one with a pKa closest to 7.4, and due to its lipid solubility, the non-ionized basic form will be one that will penetrate the epineurium and neuronal membranes, allowing the molecule to be more rapidly available to block sodium channels thereafter. Among the potential candidates for the fast-acting aminoamide type, mepivacaine is the local anesthetic with the lowest pKa in the group due to its pKa of 7.7; thus, in theory, mepivacaine had the shortest delay in action in the group.

However, one of the risks that arises by incorporating this type of molecule is its tendency to precipitate. Indeed, the basic form is fat-soluble and therefore, during its incorporation into the aqueous gel, which is usually 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 rather difficult to understand. In general, pKa is considered a good indicator of precipitation: the lower the pKa, the greater the risk of precipitation (all other conditions being the same). Thus, from a pKa point of view, mepivacaine is (given its pKa of 7.7) the worst candidate for the local anaesthetic group of the fast acting amidoamide group. Undoubtedly for this reason: mepivacaine has never been exemplified in the prior art. Indeed, even in applications where the possibility of replacing lidocaine by a local anesthetic was studied and introduced, for example patent application WO 2012/104419 in the name of Q-MED AB, mepivacaine was cited, but only local anesthetics replacing lidocaine with higher pKa were exemplified: bupivacaine (pKa 8.1), tetracaine (pKa 8.5). Finally, prilocaine (envisaged in patent application EP 2581079 in the name of Biopolymer GmbH & co. kg) has a pKa of 7.9.

In fact, it is essential that precipitation should not occur in the gel injected with a fine needle for the purpose of correcting wrinkles. The use in cosmetics requires that the injection should not be impeded, thereby avoiding poor application and therefore defective filling. Furthermore, the precipitate will cause the same effect as the foreign body and will therefore lead to a risk of inflammation. In addition, the formation of precipitates can reduce the amount of local anesthetic in solution and subsequently reduce its bioavailability and thus its effectiveness.

No doubt, due to the above drawbacks, no examples of hyaluronic acid-based gels comprising mepivacaine are described, although listed in local anaesthetics that can be incorporated into hyaluronic acid-based compositions, in particular in patent applications WO 2010/015901 and WO 2012/104419.

Articles by Cho et al, pak.j.pharm.sci., 2001 Jan; 24(1): 87-93 which describe studies on the release of mepivacaine from Hydroxypropylmethylcellulose (HPMC) gels. These compositions are formulated in gel form for direct application to the skin and transdermal application. In said article it is described that increasing the concentration of mepivacaine and increasing the temperature increases the release rate of mepivacaine.

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

Disclosure of Invention

Surprisingly, the applicant has shown that the incorporation of mepivacaine into hyaluronic acid-based gels enables firstly to obtain compositions without precipitates at pH close to physiological pH and despite the unfavourable pKa of mepivacaine, and secondly that these sterilized compositions have less impaired rheological properties during their sterilization than compositions comprising other local anesthetics of the same group.

Furthermore, this reduced impairment of the elastic component G' during sterilization is observed, irrespective of other possible excipients or additional compounds conventionally used for gel-filled formulations.

It is also surprising that the addition of mepivacaine enables to obtain compositions in the presence of polyols, which compositions systematically have improved rheology when compared to compositions not comprising polyols nor anaesthetic agents.

The present invention therefore 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 (ratio mapping) of the concentration of hyaluronic acid [ HA ] to the concentration of mepivacaine [ MEPI ]: [ HA ]/[ MEPI ] is greater than or equal to 0.1; [ HA ]/[ MEPI ] > 0.1.

Drawings

Figure 1 is a graph showing the concentration of lidocaine and mepivacaine as a function of dialysis time.

Detailed Description

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 a salt thereof, 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 ]: the [ HA ]/[ MEPI ] is 0.1 to 50, and the [ HA ]/[ MEPI ] is more than or equal to 0.1 and less than or equal to 50.

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

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

In one embodiment, the mass ratio of the concentration of hyaluronic acid [ HA ] to the concentration of mepivacaine [ MEPI ]: the [ HA ]/[ MEPI ] is 2-20, and the [ HA ]/[ MEPI ] is more than or equal to 2 and less than or equal to 20.

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

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

In one embodiment, the mass ratio of the concentration of hyaluronic acid [ HA ] to the concentration of mepivacaine [ MEPI ] [ HA ]/[ MEPI ] is from 2 to 10/3, 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 of the concentration of hyaluronic acid [ HA ] to the concentration of mepivacaine [ MEPI ] [ HA ]/[ MEPI ] is 26/3.

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

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

In one embodiment, the mass ratio of the concentration of hyaluronic acid [ HA ] to the concentration of mepivacaine [ MEPI ] [ HA ]/[ 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 0.01mg/g to 50mg/g of the total weight of the composition.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

In one embodiment, the mepivacaine is selected from: 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 2mg/g to 50mg/g of the total weight of the composition.

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

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

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

In one embodiment, the concentration of hyaluronic acid [ HA ] is 20mg/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 from 0.2% to 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 the composition.

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

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

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

In one embodiment, hyaluronic acid is double cross-linked as described in patent application WO 2000/046253 in the name of fermentatech Medical Limited.

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

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

In one embodiment, the mixture of cross-linked hyaluronic acid or salt thereof is a single-phase mixture, such as described in patent application WO 2009/071697 in the name of the applicant.

In one embodiment, the mixture of cross-linked hyaluronic acid or salts thereof is a mixture obtained by mixing several hyaluronic acids or salts thereof of different molecular weights before cross-linking thereof, as described in patent application WO 2004/092222 in the name of cornal Industrie.

In one embodiment, the sterilized aqueous composition according to the invention comprises at least one hyaluronic acid or salt thereof substituted with a group providing lipophilicity or hydratability, such as a substituted hyaluronic acid as described in patent application FR 2983483 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 the at least one hyaluronic acid is in the range of 0.01MDa to 5 MDa.

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

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

In one embodiment, the composition according to the invention is characterized in that: the molecular weight Mw of the 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 the 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 crosslinked hyaluronic acid has a degree of crosslinking X of 0.001 to 0.5.

In one embodiment, the crosslinked hyaluronic acid has a degree of crosslinking X of 0.01 to 0.4.

In one embodiment, the crosslinked hyaluronic acid has a degree of crosslinking X of 0.1 to 0.3.

In one embodiment, the crosslinked hyaluronic acid has a degree of crosslinking X of 0.06.

In one embodiment, the crosslinked hyaluronic acid has a degree of crosslinking X of 0.07.

In one embodiment, the crosslinked hyaluronic acid has a degree of crosslinking, X, of 0.12.

In one embodiment, the sterilized aqueous composition according to the invention further comprises a further polysaccharide.

In one embodiment, such other polysaccharides are selected from cellulose and derivatives thereof and/or alginic acid or a salt thereof.

The aqueous composition is sterilized, i.e. after its preparation, it is subjected to a sterilization step, which is carried out with heat, moist heat, gamma radiation or accelerated electron beams (electron beams).

In one embodiment, the sterilization step is performed by autoclaving.

In one embodiment, the sterilization by autoclaving is carried out at a temperature of 121 ℃ to 134 ℃ for a time suitable for said temperature.

For example, sterilization by autoclaving is performed at a temperature of 127 ℃ to 130 ℃ 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 present invention further comprises at least one antioxidant.

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

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

In one embodiment, the sterilized aqueous composition according to the invention is characterized in that: the polyol is selected 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 polyols are selected 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 polyols are selected from mannitol and sorbitol, either 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:

-providing a good resistance to deterioration by steam sterilization;

-has a high antioxidant power;

easily dissolved in the hyaluronic acid composition.

In one embodiment, the sterilized aqueous composition according to the invention is characterized in that: the polyol content is from 10mg/g to 40mg/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 content is from 15mg/g to 30mg/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 present in an amount of from 15mg/g to 25mg/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 content is from 20mg/g to 40mg/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 content is from 20mg/g to 30mg/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 content is from 25mg/g to 35mg/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 content is 35mg/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 mannitol and is present in an amount of 10mg/g to 40mg/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 mannitol and is present in an amount of 15mg/g to 30mg/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 mannitol and is present in an amount of 15mg/g to 25mg/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 mannitol and is present in an amount of 20mg/g to 40mg/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 mannitol and is present in an amount of from 25mg/g to 35mg/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 mannitol and is present in an amount of 35mg/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 is present in an amount of from 10mg/g to 40mg/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 is present in an amount of 15mg/g to 30mg/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 is present in an amount of 15mg/g to 25mg/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 is present in an amount of 20mg/g to 40mg/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 is present in an amount of from 25mg/g to 35mg/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 is present in an amount of 35mg/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 maltitol and its content is 10mg/g to 40mg/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 maltitol and its content is 15mg/g to 30mg/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 maltitol and its content is 15mg/g to 25mg/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 maltitol and its content is 20mg/g to 40mg/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 maltitol and its content is 25mg/g to 35mg/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 maltitol and its content is 35mg/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 is present in an amount of from 10mg/g to 40mg/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 is present in an amount of from 15mg/g to 30mg/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 is present in an amount of from 15mg/g to 25mg/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 is present in an amount of from 20mg/g to 40mg/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 is present in an amount of from 25mg/g to 35mg/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 maltitol.

In one embodiment, the sterilized aqueous composition according to the invention is characterized in that: the polyol is glycerol and is present in an amount of 35mg/g based on the total weight of the composition.

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

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

In one embodiment, the sterilized aqueous composition according to the invention is characterized in that: the additional compound is present in an amount of 0.1mg/g to 100mg/g of the total weight of the composition.

In one embodiment, the sterilized aqueous composition according to the invention is characterized in that: the additional compound is present in an amount of 1mg/g to 50mg/g of the total weight of the composition.

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

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

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

In one embodiment, the sterilized aqueous composition according to the invention is characterized in that: the additional compounds belong to the catecholamine family.

In one embodiment, the sterilized aqueous composition according to the invention is characterized in that: said further compound belonging to the catecholamine family is epinephrine.

In one embodiment, the sterilized aqueous composition according to the invention is characterized in that: the content of the additional compound is from 0.01% to 10% 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 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 total amount of the additional compound is from 0.01mg/g to 40mg/g of the total weight of the composition.

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

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

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

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

The 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 salt thereof, alone or as a mixture, in a buffer solution at 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 preceding step,

-a homogenization step, and

-a 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 flakes (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 of 6.5 to 7 prior to 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 applicant.

In one embodiment, the pH of the gel and/or hydrogel is adjusted to a value of 7.7 to 8 prior to introducing 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 method according to the invention is characterized in that: the hydration step is carried out at room temperature.

In one embodiment, the method according to the invention is characterized in that: the homogenization step is performed at room temperature.

In one embodiment, the method according to the invention is characterized in that: it also comprises at least one step of packaging the homogenized mixture in a syringe.

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 a single dose bottle.

In one embodiment, the method is characterized by: which 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 accelerated electron beams (e-beams).

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

In one embodiment, the sterilization step is performed after packaging by irradiation with gamma radiation or with accelerated electron beams (e-beams).

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

For example, sterilization by autoclaving is performed at a temperature of 127 ℃ to 130 ℃ for a time of 1 minute to 20 minutes.

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

In one embodiment, the method according to the invention is characterized in that: the cross-linking step occurs between the hydrating step and the step of incorporating mepivacaine.

In one embodiment, the method according to the invention is characterized in that: the crosslinking step is carried out using at least one crosslinking agent.

In one embodiment, the method according to the invention is characterized in that: the crosslinking agent is difunctional or polyfunctional.

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

In one embodiment, the method according to the invention is characterized in that: the bifunctional crosslinking agent 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 crosslinking step is carried out according to techniques known to those skilled in the art.

In one embodiment, the method according to the invention is characterized in that: which comprises, after said 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 method according to the invention is characterized in that: it also includes at least one step of incorporating at least one antioxidant.

In one embodiment, the at least one antioxidant is selected 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 method according to the invention is characterized in that: it also 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 method according to the invention is characterized in that: the step of mixing a solution of at least one further compound with the hydrogel obtained in the hydration step is performed before the homogenization step.

In one embodiment, the method according to the invention is characterized in that: the step of mixing a solution of at least one further 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 invention also relates to a method for obtaining a sterilized aqueous composition of hyaluronic acid comprising a local anaesthetic, said composition having a rheology after heat sterilization superior to that of a composition comprising lidocaine, characterized in that: lidocaine was replaced with an equivalent amount of mepivacaine at the same pH.

The term "equivalent amount" means an equivalent amount by mass, by mole, or equivalent bioavailability at a pH near physiological pH.

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

The invention also relates to the use of mepivacaine to replace lidocaine in equivalent amounts to obtain a hyaluronic acid composition comprising a local anaesthetic, said composition having a rheology after heat sterilization 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 in terms of mass, moles, or equivalent amount for 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, alone or as a mixture, or a salt thereof.

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

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

The term "rheology" means the modulus of elasticity (G') and/or the viscosity (η).

The term "superior rheology" means a higher elastic modulus and/or viscosity value.

The term "replacement" means a gel formulation in which mepivacaine is incorporated in place of lidocaine.

The invention also relates to the use of mepivacaine for improving the resistance to deterioration of the rheology of an injectable sterilized aqueous hyaluronic acid composition during heat sterilization.

The invention also relates to the use of mepivacaine for improving the resistance to deterioration of the rheology of an aqueous hyaluronic acid composition comprising a local anaesthetic during heat sterilization.

The invention also relates to the use of mepivacaine in an aqueous hyaluronic acid composition having a rheological deterioration during heat sterilization inferior to that of the same hyaluronic acid composition comprising other local anaesthetics.

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

The invention also relates to a method for improving the resistance to deterioration of the rheology of an injectable aqueous hyaluronic acid composition comprising a local anaesthetic during heat sterilization, characterized in that: the composition comprises mepivacaine.

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

In one embodiment, the use or the method is 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 autoclaving.

In one embodiment, the use or the method is characterized in that: the other local anesthetic is selected from lidocaine and prilocaine.

In one embodiment, the use or the method is characterized in that: the other local anesthetic is lidocaine.

In one embodiment, the use or the method is characterized in that: the composition also includes one or more polyols.

In one embodiment, the use or the method is characterized in that: the one or more polyols are selected from glycerol, sorbitol, propylene glycol, xylitol, mannitol, erythritol, maltitol and lactitol, alone or as a mixture.

In one embodiment, the use or the method is characterized in that: the one or more polyols are selected from mannitol, sorbitol, maltitol and glycerol, alone or as a mixture.

In one embodiment, the use or the method is characterized in that: the one or more polyols are selected from mannitol and sorbitol, alone or as a mixture.

In one embodiment, the use or the method is characterized in that: at least one polyol is mannitol.

In one embodiment, the use or the method is characterized in that: the polyol is mannitol.

In one embodiment, the use or the method is characterized in that: at least one polyol is sorbitol.

In one embodiment, the use or the method is characterized in that: the polyol is sorbitol.

In one embodiment, the use or the method is characterized in that: the at least one polyol is maltitol.

In one embodiment, the use or the method is characterized in that: the polyol is maltitol.

In one embodiment, the use or the method is characterized in that: at least one polyol is glycerol.

In one embodiment, the use or the method is characterized in that: the polyol is glycerol.

In one embodiment, the use or the method is characterized in that: the polyol is present in an amount of from 10mg/g to 40mg/g based on the total weight of the composition.

In one embodiment, the use or the method is characterized in that: the polyol is present in an amount of from 15mg/g to 30mg/g based on the total weight of the composition.

In one embodiment, the use or the method is characterized in that: the polyol is present in an amount of from 15mg/g to 25mg/g based on the total weight of the composition.

In one embodiment, the use or the method is characterized in that: the polyol is present in an amount of from 20mg/g to 40mg/g based on the total weight of the composition.

In one embodiment, the use or the method is characterized in that: the polyol is present in an amount of from 25mg/g to 35mg/g based on the total weight of the composition.

In one embodiment, the use or the method is characterized in that: the polyol is present in an amount of 35mg/g based on the total weight of the composition.

In one embodiment, the use or the method is characterized in that: the polyol is mannitol and is present in an amount of 10mg/g to 40mg/g based on the total weight of the composition.

In one embodiment, the use or the method is characterized in that: the polyol is mannitol and is present in an amount of 15mg/g to 30mg/g based on the total weight of the composition.

In one embodiment, the use or the method is characterized in that: the polyol is mannitol and is present in an amount of 15mg/g to 25mg/g based on the total weight of the composition.

In one embodiment, the use or the method is characterized in that: the polyol is mannitol and is present in an amount of 20mg/g to 40mg/g based on the total weight of the composition.

In one embodiment, the use or the method is characterized in that: the polyol is mannitol and is present in an amount of from 25mg/g to 35mg/g based on the total weight of the composition.

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

In one embodiment, the use or the method is characterized in that: the polyol is sorbitol and is present in an amount of from 10mg/g to 40mg/g based on the total weight of the composition.

In one embodiment, the use or the method is characterized in that: the polyol is sorbitol and is present in an amount of 15mg/g to 30mg/g based on the total weight of the composition.

In one embodiment, the use or the method is characterized in that: the polyol is sorbitol and is present in an amount of 15mg/g to 25mg/g based on the total weight of the composition.

In one embodiment, the use or the method is characterized in that: the polyol is sorbitol and is present in an amount of 20mg/g to 40mg/g based on the total weight of the composition.

In one embodiment, the use or the method is characterized in that: the polyol is sorbitol and is present in an amount of from 25mg/g to 35mg/g based on the total weight of the composition.

In one embodiment, the use or the method is characterized in that: the polyol is sorbitol and is present in an amount of 35mg/g based on the total weight of the composition.

In one embodiment, the use or the method is characterized in that: the polyol is maltitol and its content is 10mg/g to 40mg/g based on the total weight of the composition.

In one embodiment, the use or the method is characterized in that: the polyol is maltitol and its content is 15mg/g to 30mg/g based on the total weight of the composition.

In one embodiment, the use or the method is characterized in that: the polyol is maltitol and its content is 10mg/g to 25mg/g based on the total weight of the composition.

In one embodiment, the use or the method is characterized in that: the polyol is maltitol and its content is 20mg/g to 40mg/g based on the total weight of the composition.

In one embodiment, the use or the method is characterized in that: the polyol is maltitol and its content is 25mg/g to 35mg/g based on the total weight of the composition.

In one embodiment, the use or the method is characterized in that: the polyol is maltitol and its content is 35mg/g based on the total weight of the composition.

In one embodiment, the use or the method is characterized in that: the polyol is glycerol and is present in an amount of from 10mg/g to 40mg/g based on the total weight of the composition.

In one embodiment, the use or the method is characterized in that: the polyol is glycerol and is present in an amount of from 15mg/g to 30mg/g based on the total weight of the composition.

In one embodiment, the use or the method is characterized in that: the polyol is glycerol and is present in an amount of from 10mg/g to 25mg/g based on the total weight of the composition.

In one embodiment, the use or the method is characterized in that: the polyol is glycerol and is present in an amount of from 20mg/g to 40mg/g based on the total weight of the composition.

In one embodiment, the use or the method is characterized in that: the polyol is glycerol and is present in an amount of from 25mg/g to 35mg/g based on the total weight of the composition.

In one embodiment, the use or the method is characterized in that: the polyol is glycerol and is present in an amount of 35mg/g based on the total weight of the composition.

In one embodiment, the use or the method is characterized in that: the sterilization step is carried out by autoclaving at a temperature of 121 ℃ to 134 ℃ for a time suitable for said temperature.

For example, sterilization by autoclaving is performed at a temperature of 127 ℃ to 130 ℃ for a time of 1 minute to 20 minutes.

In one embodiment, the use or the method is characterized in that: the composition further comprises an antioxidant.

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

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

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

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

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

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 7/3-26/3, and [ HA ]/[ MEPI ] is more than or equal to 7/3 and less than or equal to 26/3.

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 2-20/3, and [ HA ]/[ MEPI ] is more than or equal to 2 and less than or equal to 20/3.

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 2-10/3, and [ HA ]/[ MEPI ] is more than or equal to 2 and less than or equal to 10/3.

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

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

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

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

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

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

In one embodiment, the use or the method is characterized in that: the concentration of mepivacaine [ MEPI ] is from 0.01mg/g to 50mg/g of the total weight of the composition.

In one embodiment, the use or the method is characterized in that: the concentration of mepivacaine [ MEPI ] is from 0.01mg/g to 50mg/g of the total weight of the composition.

In one embodiment, the use or the method is characterized in that: the concentration of mepivacaine [ MEPI ] is from 0.05mg/g to 45mg/g of the total weight of the composition.

In one embodiment, the use or the method is characterized in that: the concentration of mepivacaine [ MEPI ] is from 0.1mg/g to 40mg/g of the total weight of the composition.

In one embodiment, the use or the method is characterized in that: the concentration of mepivacaine [ MEPI ] is from 0.2mg/g to 30mg/g of the total weight of the composition.

In one embodiment, the use or the method is characterized in that: the concentration of mepivacaine [ MEPI ] is from 0.5mg/g to 20mg/g of the total weight of the composition.

In one embodiment, the use or the method is characterized in that: the concentration of mepivacaine [ MEPI ] is from 1mg/g to 15mg/g of the total weight of the composition.

In one embodiment, the use or the method is characterized in that: the concentration of mepivacaine [ MEPI ] is from 1mg/g to 10mg/g of the total weight of the composition.

In one embodiment, the use or the method is characterized in that: the concentration of mepivacaine [ MEPI ] is from 1mg/g to 6mg/g of the total weight of the composition.

In one embodiment, the use or the method is characterized in that: the concentration of mepivacaine [ MEPI ] is from 1mg/g to 5mg/g of the total weight of the composition.

In one embodiment, the use or the method is characterized in that: the concentration of mepivacaine [ MEPI ] is from 2mg/g to 5mg/g of the total weight of the composition.

In one embodiment, the use or the method is characterized in that: the concentration of mepivacaine [ MEPI ] is from 6mg/g to 10mg/g of the total weight of the composition.

In one embodiment, the use or the method is characterized in that: the concentration of mepivacaine [ MEPI ] was 1mg/g total weight of the composition.

In one embodiment, the use or the method is characterized in that: the concentration of mepivacaine [ MEPI ] was 3mg/g total weight of the composition.

In one embodiment, the use or the method is characterized in that: the concentration of mepivacaine [ MEPI ] was 4mg/g total weight of the composition.

In one embodiment, the use or the method is characterized in that: the concentration of mepivacaine [ MEPI ] was 5mg/g total weight of the composition.

In one embodiment, the use or the method is characterized in that: the concentration of mepivacaine [ MEPI ] was 6mg/g total weight of the composition.

In one embodiment, the use or the method is characterized in that: the concentration of mepivacaine [ MEPI ] was 10mg/g total weight of the composition.

In one embodiment, the use or the method is characterized in that: the mepivacaine is selected from the group comprising mepivacaine or a pharmaceutically acceptable salt thereof.

In one embodiment, the use or the method is characterized in that: the mepivacaine is selected from: 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 use or the method is characterized in that: the mepivacaine is racemic mepivacaine hydrochloride.

In one embodiment, the use or the method is characterized in that: the mepivacaine is (R) -mepivacaine hydrochloride.

In one embodiment, the use or the method is characterized in that: the mepivacaine is (S) -mepivacaine hydrochloride.

In one embodiment, the use or the method is characterized in that: the mepivacaine is racemic mepivacaine.

In one embodiment, the use or the method is characterized in that: the mepivacaine is (R) -mepivacaine.

In one embodiment, the use or the method is characterized in that: the mepivacaine is (S) -mepivacaine.

In one embodiment, the use or the method is characterized in that: the concentration of hyaluronic acid [ HA ] is from 2mg/g to 50mg/g of the total weight of the composition.

In one embodiment, the use or the method is characterized in that: the concentration of hyaluronic acid [ HA ] is from 4mg/g to 40mg/g of the total weight of the composition.

In one embodiment, the use or the method is characterized in that: the concentration of hyaluronic acid [ HA ] is from 5mg/g to 30mg/g of the total weight of the composition.

In one embodiment, the use or the method is characterized in that: the concentration of hyaluronic acid [ HA ] is from 10mg/g to 30mg/g of the total weight of the composition.

In one embodiment, the use or the method is characterized in that: the concentration of hyaluronic acid [ HA ] was 20mg/g of the total weight of the composition.

In one embodiment, the use or the method is characterized in that: the total content of hyaluronic acid is from 0.2% to 5% by weight relative to the total weight of the composition.

In one embodiment, the use or the method 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 the composition.

In one embodiment, the use or the method is characterized in that: the sterilized aqueous composition comprises at least one non-crosslinked hyaluronic acid or salt thereof, alone or as a mixture.

In one embodiment, the use or the method is characterized in that: the sterilized aqueous composition comprises at least one cross-linked hyaluronic acid or salt thereof, alone or as a mixture.

In one embodiment, the use or the method is characterized in that: the sterilized aqueous composition comprises at least one co-crosslinked hyaluronic acid or salt thereof, alone or as a mixture.

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

In one embodiment, the use or the method is characterized in that: hyaluronic acid was double cross-linked as described in patent application WO 2000/046253 in the name of Fermentach Medical Limited.

In one embodiment, the use or the method is characterized in that: the sterilized aqueous composition comprises a mixture of cross-linked hyaluronic acid or a salt thereof.

In one embodiment, the use or the method is characterized in that: the mixture of cross-linked hyaluronic acid or a salt thereof is a single-phase mixture, as described for example in patent application WO 2009/071697 in the name of the applicant.

In one embodiment, the use or the method is characterized in that: the mixture of cross-linked hyaluronic acid or salts thereof is a mixture obtained by mixing several hyaluronic acids or salts thereof of different molar masses before cross-linking thereof, as described in patent application WO 2004/092222 in the name of cornal Industrie.

In one embodiment, the use or the method is characterized in that: the sterilized aqueous composition comprises at least one hyaluronic acid or salt thereof substituted with groups providing lipophilicity or hydratability, for example a substituted hyaluronic acid as described in patent application FR 2983483 in the name of the applicant.

In one embodiment, the use or the method is characterized in that: hyaluronic acid is in the form of sodium or potassium salt.

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

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

In one embodiment, the use or the method is characterized in that: the molecular weight Mw of the at least one hyaluronic acid is in the range of 1MDa to 3 MDa.

In one embodiment, the use or the method is characterized in that: the molecular weight Mw of the at least one hyaluronic acid is 1 MDa.

In one embodiment, the use or the method is 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 crosslinked hyaluronic acid has a degree of crosslinking X of 0.001 to 0.5.

In one embodiment, the use or the method is characterized in that: the crosslinked hyaluronic acid has a degree of crosslinking X of 0.01 to 0.4.

In one embodiment, the use or the method is characterized in that: the crosslinked hyaluronic acid has a degree of crosslinking X of 0.1 to 0.3.

In one embodiment, the use or the method is characterized in that: the crosslinked hyaluronic acid has a degree of crosslinking X of 0.08.

In one embodiment, the use or the method is characterized in that: the crosslinked hyaluronic acid has a degree of crosslinking X of 0.06.

In one embodiment, the use or the method is characterized in that: the crosslinked hyaluronic acid has a degree of crosslinking X of 0.12.

In one embodiment, the sterilized aqueous composition according to the invention further comprises a further polysaccharide.

In one embodiment, such other polysaccharides are selected from cellulose and derivatives thereof and/or alginic acid or a salt thereof.

In one embodiment, the use or the method is characterized in that: the sterilized aqueous composition further comprises other polysaccharides.

In one embodiment, the use or the method is characterized in that: the sterilized aqueous composition according to the present invention further comprises other polysaccharides selected from the group consisting of cellulose and derivatives thereof and/or alginic acid or a salt thereof.

In one embodiment, the use or the method is characterized in that: the sterilized aqueous composition further comprises at least one additional compound.

In one embodiment, the use or the method is characterized in that: the content of the further compound in the composition is from 0.1mg/g to 100mg/g of the total weight of the composition.

In one embodiment, the use or the method is characterized in that: the content of the additional compound in the composition is from 1mg/g to 50mg/g of the total weight of the composition.

In one embodiment, the use or the method is characterized in that: the further compound is dimethyl sulfone, hereinafter referred to as DMS.

In one embodiment, the use or the method is characterized in that: the additional compound is a water-soluble salt of sucrose octasulfate, hereinafter referred to as SOS.

In one embodiment, the use or the method is characterized in that: the further compound is a vitamin C derivative.

In one embodiment, the use or the method is characterized in that: the vitamin C derivative is magnesium ascorbyl phosphate, hereinafter referred to as MAP.

In one embodiment, the use or the method is characterized in that: the additional compounds belong to the catecholamine family.

In one embodiment, the use or the method is characterized in that: said further compound belonging to the catecholamine family is epinephrine.

In one embodiment, the use or the method is characterized in that: the content of the additional compound is from 0.01% to 10% by weight relative to the total weight of the composition.

In one embodiment, the use or the method is 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 use or the method is characterized in that: the total content of additional compounds is from 0.01mg/g to 40mg/g of the total weight of the composition.

In one embodiment, the use or the method is characterized in that: the total content of additional compounds is from 0.1mg/g to 10mg/g of the total weight of the composition.

In one embodiment, the use or the method is characterized in that: the total content of additional compounds is from 0.1mg/g to 1mg/g of the total weight of the composition.

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

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

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

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

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

The invention also relates to the use of the sterilized aqueous composition for formulating a composition that can be injected into a joint as a replacement or supplement to a defective synovial fluid.

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

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

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

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

The targeted applications are more particularly the applications generally widespread in the field of injectable viscoelastic agents and polysaccharides, which are used or potentially useful in the following pathological conditions or treatments:

-cosmetic facial injection: for filling wrinkles, skin imperfections or plumpness (cheekbones, chin, lips);

-bulk injection in vivo: breast and hip enlargement, G-spot enlargement, vaginal reshaping surgery, labial reconstruction, penis enlargement;

-treating arthrosis, injected into the joint as a replacement or supplement to the defective synovial fluid;

periurethral injection for the treatment of urinary incontinence caused by sphincter deficiency;

post-operative injection, in particular for preventing peritoneal adhesions;

post-operative injection to correct presbyopia through laser scleral incisions;

-injection into a vitreous cavity;

-injection during cataract surgery;

injection into the genitalia.

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

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

-as voluminous product (volumateur) for injection using needles with larger diameter (e.g. 22 to 26 gauge) and longer needles (e.g. 30 to 40 mm); in this case, its adhesiveness (caractere coh sif) will ensure that it is held at the injection site.

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

Examples of these uses are in no way limiting and the sterilized aqueous compositions according to the invention are considered to be more broadly used for:

-a fill volume;

-creating space in certain tissues, thereby promoting optimal functioning thereof;

-replacing the absent physiological fluid.

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

The 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.