I 1111111111111111 11111 1111111111 111111111111111 IIIII IIIII lll111111111111111
`US008455465B2
`
`(12) United States Patent
`Gavard Molliard
`
`(IO) Patent No.:
`(45) Date of Patent:
`
`US 8,455,465 B2
`*Jun.4,2013
`
`(54) HEAT STERILISED INJECTABLE
`COMPOSITION OF HYALURONIC ACID OR
`ONE OF THE SALTS THEREOF, POLYOLS
`AND LIDOCAINE
`
`(75)
`
`Inventor: Samuel Gavard Molliard, Bogeve (FR)
`
`(73) Assignee: Anteis S.A., Plan-les-Ouates, Geneva
`(CH)
`
`( * ) Notice:
`
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 224 days.
`
`This patent is subject to a terminal dis(cid:173)
`claimer.
`
`(21)
`
`Appl. No.:
`
`13/119,787
`
`(22)
`
`PCT Filed:
`
`Nov. 4, 2009
`
`(86)
`
`PCT/FR2009/052134
`
`PCT No.:
`§ 371 (c)(l),
`(2), ( 4) Date: Mar. 18, 2011
`
`(87)
`
`PCT Pub. No.: WO2010/052430
`
`PCT Pub. Date: May 14, 2010
`
`(65)
`
`Prior Publication Data
`
`US 2011/0201571 Al
`
`Aug. 18, 2011
`
`(30)
`
`Foreign Application Priority Data
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`2002/0019339 Al *
`2/2002 Naughton ......................... 514/2
`2006/0122147 Al
`6/2006 Wohlrab
`11/2006 Hermitte et al.
`2006/0246137 Al
`2007/0077292 Al*
`4/2007 Pinsky
`8/2007 Hermitte et al.
`2007/0196426 Al
`9/2010 Lebreton
`2010/0226988 Al
`12/2010 Piron et al.
`2010/0316683 Al
`2011/0230438 Al *
`9/2011 Bos ................................. 514/54
`
`..... 424/450
`
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`
`FOREIGN PATENT DOCUMENTS
`98/41171 Al
`9/1998
`0046252 Al
`8/2000
`4/2004
`2004/032943 Al
`2004/092222 A2
`10/2004
`2005/012364 A2
`2/2005
`2005/085329 Al
`9/2005
`7/2007
`2007 /077399 A2
`6/2008
`2008/068297 Al
`
`OTHER PUBLICATIONS
`
`Wahl, G. "European evaluation of a new hyaluronic acid filler incor(cid:173)
`porating lidocaine", Journal of Cosmetic Dermatology, vol. 7, Nov. 6,
`2008, pp. 298-303.
`International Search Report, dated Aug. 26, 2010, from correspond(cid:173)
`ing PCT application.
`
`* cited by examiner
`
`Primary Examiner - Scarlett Goon
`(74) Attorney, Agent, or Firm - Young & Thompson
`
`Nov. 7, 2008
`
`(FR) ...................................... 08 57575
`
`(57)
`
`ABSTRACT
`
`(51)
`
`(52)
`
`(58)
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`Int. Cl.
`A0lN 43/04
`A61K 31/70
`A61K 31/715
`A61K9/14
`U.S.Cl.
`USPC ................................ 514/62; 514/54; 424/488
`Field of Classification Search
`USPC ....................................... 514/62, 54; 424/488
`See application file for complete search history.
`
`An injectable aqueous composition ofhyaluronic acid or one
`of the salts thereof, one or more polyol(s) and lidocaine is
`used for cosmetic purposes or for therapeutic purposes. It has
`improved viscoelastic rheological properties and long in vivo
`persistence. The polyol is chosen, for example, from glycerol,
`sorbitol, propylene glycol, mannitol, erythritol, xylitol, malti(cid:173)
`tol and lactitol. The particular properties are obtained by heat
`sterilizing the mixture.
`
`13 Claims, No Drawings
`
`ALL 2067
`PROLLENIUM V. ALLERGAN
`IPR2019-01505 et al.
`
`

`

`US 8,455,465 B2
`
`1
`HEAT STERILISED INJECTABLE
`COMPOSITION OF HYALURONIC ACID OR
`ONE OF THE SALTS THEREOF, POLYOLS
`AND LIDOCAINE
`
`BACKGROUND OF THE INVENTION
`
`2
`Lidocaine ( or lidocaine hydrochloride) is a local anesthetic
`commonly used in the cosmetic and medical fields. This
`molecule has in particular been used for many years in prod(cid:173)
`ucts for cosmetic purposes, such as products for filling
`5 wrinkles, in order to limit pain during and after injection (in
`the case of the product Zyderm® containing collagen and
`0.3% lidocaine).
`The prior art describes hyaluronic acid-based gels which
`may contain a polyol and/or lidocaine. For example,
`10 WO 2007 /077399 describes gels based on hyaluronic acid
`and on a viscous biocompatible alcohol, the sterilization
`of which increases the viscosity.
`WO 2004/032943 describes hyaluronic acid-based gels
`containing local anesthetics, including lidocaine.
`15 WO 98/41171 describes an injectable composition in the
`form of a gel based on hyaluronic acid, mannitol and
`lidocaine.
`WO 2008/068297 describes the use of a subcutaneously or
`intradermally injectable implant in the form of a hyalu(cid:173)
`ronic acid hydrogel. It also discloses the use of mannitol
`as an antioxidant.
`European evaluation of a new hyaluronic acid filler incor-
`porating lidocaine, G. WAHL, Journal a/Cosmetic Der(cid:173)
`matology, vol. 7, 6 Nov. 2008, pages 298-303, describes
`a formulation for dermatological use comprising hyalu(cid:173)
`ronic acid and lidocaine.
`
`20
`
`SUMMARY OF THE INVENTION
`
`The invention relates to an injectable aqueous composition
`in the form of a gel based on hyaluronic acid or one of the salts
`thereof, on one or more polyol(s) and on lidocaine, said
`heat-sterilized composition having improved viscoelastic
`rheological properties and long in vivo persistence, for use for
`cosmetic purposes or for therapeutic purposes.
`Hyaluronic acid-based injectable gels have been used for
`many years, for cosmetic purposes, for filling or replacing
`biological tissues (filling wrinkles, remodeling of the face,
`increasing lip volume, etc.) and also in treatment to rehydrate
`the skin by mesotherapy.
`Hyaluronic acid-based injectable gels are also used in
`many therapeutic applications. For example,
`in rheumatology, as an agent for replacement or for tem(cid:173)
`porary supplementation of synovial fluid,
`in urology/gynecology, as an agent for increasing sphincter
`volume or urethral volume,
`in ophthalmology, as an adjuvant to cataract surgery or for 25
`treating glaucoma,
`in pharmaceutics, as an agent for release of active sub(cid:173)
`stances,
`in surgery, for bone reconstrnction, increasing vocal cord
`volume or producing surgical tissues.
`A great deal of effort has been made to improve the physi(cid:173)
`cochemical stability ofhyaluronic acid-based gels in order to
`increase their in vivo persistence (i.e. the residence time of the
`gel at the injection site) and thus to increase the duration of
`treatment effectiveness.
`
`30
`
`35
`
`It has now been discovered that the addition of a polyol and
`oflidocaine to a gel based on hyaluronic acid, regardless of
`whether it is noncrosslinked or crosslinked, grafted or non(cid:173)
`grafted, or crosslinked and grafted, followed by heat-steril(cid:173)
`ization of this formulation, makes it possible to obtain (com(cid:173)
`pared with a polyol-free and lidocaine-free gel):
`a very large improvement in the rheological properties of
`the gel,
`an improvement in the persistence of the gel by countering
`the three major types of degradation of a hyaluronic
`acid-based gel in vivo ( enzymatic degradation by hyalu(cid:173)
`ronidases, free-radical degradation, thermal degradation
`at 37° C.),
`an improvement in the rheological stability of the gel over
`time and therefore a product shelf-life that may be
`extended.
`It has in fact been shown that, entirely surprisingly, the
`addition of one or more polyol(s) and oflidocaine to a hyalu(cid:173)
`ronic acid-based gel:
`does not modify the rheological properties of the gel before
`heat sterilization,
`considerably modifies the rheological properties of the gel
`after heat sterilization ( compared with a polyol-free and
`lidocaine-free gel).
`In other words, before heat sterilization, the viscoelastic
`properties of a hyaluronic acid-based gel with polyol and
`lidocaine are identical to those of a polyol-free and lidocaine(cid:173)
`free hyaluronic acid-based gel.
`After heat sterilization, the viscoelastic properties of a
`hyaluronic acid-based gel with polyol and lidocaine are dif-
`60 ferent than those of a polyol-free and lidocaine-free hyalu(cid:173)
`ronic acid-based gel. The gel with polyol and lidocaine has a
`very strong elasticity (higher G') and a more elastic viscoelas(cid:173)
`tic nature (lower Tan 1\) compared with a polyol-free and
`lidocaine-free gel.
`Heat sterilization profoundly modifies the strncture of the
`gel and therefore the viscoelastic properties thereof ( decrease
`in rheological parameters G' and G"/increase in the parameter
`
`DESCRIPTION OF THE PRIOR ART
`
`According to the prior art, the increasing of the persistence
`ofhyaluronic acid-based gels and therefore of their resistance 40
`to the various in vivo degradation factors is essentially carried
`out by means ofhyaluronic acid crosslinking and/or grafting
`techniques. For example,
`WO 2005/012364 describes gels based on crosslinked and
`grafted polysaccharides, including hyaluronic acid, 45
`which have better persistence than the noncrosslinked
`and/or nongrafted products.
`WO 2004/092222 describes gels based on polysaccha(cid:173)
`rides, including hyaluronic acid, containing at least one
`low-molecular-weight polysaccharide and at least one 50
`high-molecular-weight polysaccharide, said gels having
`a greater persistence than that of products which do not
`have a mixture of molecular weights.
`WO 2005/085329 describes a method of production for
`obtaining gels based on polydensified crosslinked 55
`hyaluronic acid, said gels having a long in vivo persis-
`tence.
`WO 2000/0046252 describes gels based on hyaluronic
`acid with strong "biostability" having a high degree of
`crosslinking by virtue of a process for double crosslink(cid:173)
`ing hyaluronic acid.
`Polyols belong to a family of molecules of chemical for(cid:173)
`mula CxHyOz which have at least two alcohol groups. By
`virtue of the high capacity of said pol yo ls for adjusting osmo(cid:173)
`larity, those skilled in the art know that they can introduce 65
`polyols into an injectable aqueous formulation in order to
`obtain an iso-osmolar composition.
`
`

`

`US 8,455,465 B2
`
`10
`
`4
`a) in rheumatology, as an agent for replacement or for tem(cid:173)
`porary supplementation of synovial fluid,
`b) in urology/gynecology, as an agent for increasing sphincter
`volume or urethral volume,
`c) in ophthalmology, as an adjuvant to cataract surgery or for
`treating glaucoma,
`d) in pharmaceutics, as an agent for release of active sub(cid:173)
`stances,
`e) in surgery, for bone reconstruction, increasing vocal cord
`volume or producing surgical tissues.
`According to the embodiments of the invention, the gel
`based on hyaluronic acid or one of the salts thereof is non(cid:173)
`crosslinked or crosslinked.
`According to the embodiments of the invention, the con-
`centration of hyaluronic acid or of one of the salts thereof is
`between O .01 mg/ ml and 100 mg/ ml and the molecular weight
`of the hyaluronic acid or one of the salts thereof is between
`1000 Da and 10xl06 Da.
`According to one particular embodiment of the invention,
`the crosslinking is carried out with bifunctional or polyfunc(cid:173)
`tional molecules chosen from epoxides, epihalohydrins and
`divinyl sulfone, on hyaluronic acid that is noncrosslinked or
`already crosslinked with or without one or more other
`25 polysaccharides of natural origin.
`The various types ofhyaluronic acid-based gels are known
`in the art, and crosslinked and grafted gels are described, for
`example, in WO 2005/012364.
`According to one particular embodiment of the invention,
`the gel can also contain other biocompatible polymers (such
`as polysaccharides of natural origin) and/or other active or
`nonactive substances having a positive effect on the organism
`oron the gel.
`According to the feature of the invention, these gels contain
`one or more polyol(s) chosen, for example, from glycerol,
`sorbitol, propylene glycol, xylitol, mannitol, erythritol, malti(cid:173)
`tol or lactitol.
`According to the embodiments of the invention, the polyol
`concentration in the gel is between 0.0001 and 500 mg/ml and
`more particularly between 0.0001 and 100 mg/ml.
`According to the embodiments of the invention, the
`lidocaine concentration in the gel is between 0.0001 and 500
`mg/ml and more particularly between 0.001 and 50 mg/ml.
`According to the embodiments of the invention, the steril(cid:173)
`ization is carried out with dry or wet heat, preferably with wet
`heat. Those skilled in the art will be able to select a heat(cid:173)
`sterilization cycle (temperature and duration of the steriliza(cid:173)
`tion cycle) suitable for the sterilization of their product. For
`example, the following wet-heat-sterilization cycles can be
`used: 131 ° C., 1 min/130° C., 3 min/125° C., 7 min/121 ° C.,
`20 min/121 ° C., 10 min/100° C., 2 h.
`
`3
`Tan o). It is noted that the presence ofa polyol and oflidocaine
`in a hyaluronic acid-based gel considerably modifies the
`change in the rheological parameters during heat sterilization
`(limitation of the change in rheological parameters: decrease
`in G' and in G" significantly less strong/increase in Tan o 5
`significantly less strong).
`By limiting the degradation of the hyaluronic acid-based
`gel during heat sterilization, the structure of the hyaluronic
`acid-based gel with polyol and lidocaine is different than that
`obtained with a polyol-free and lidocaine-free hyaluronic
`acid-based gel. This structure has in particular a reinforced
`elastic nature (better ability of the gel to create volume).
`This better resistance to thermal degradation confers in
`particular on the gel a better product stability at ambient 15
`temperature overtime. Thus, a product produced according to
`this invention will have a shelf-life that may be extended
`compared with a product not containing polyol and lidocaine.
`It has also been shown that a hyaluronic acid-based gel
`with polyol and lidocaine has better resistance to the three 20
`degradation factors of a hyaluronic acid-based gel in vivo
`compared with a polyol-free and lidocaine-free gel:
`better resistance to enzymatic degradation,
`better resistance to free-radical degradation,
`better resistance to thermal degradation.
`In particular, the improvement in the resistance to thennal
`and free-radical degradation is entirely noteworthy.
`Without wishing to be bound to a theoretical explanation of
`the effect of the polyol and of the lidocaine against the deg(cid:173)
`radations of a hyaluronic acid-based gel, it is assumed that the 30
`lidocaine considerably increases the ability of a polyol to
`protect a hyaluronic acid-based gel.
`Furthermore, the polyol(s) incorporated into the hyalu(cid:173)
`ronic acid-based gel can migrate out of the gel.
`Outside the gel, the polyol(s) will be able to be diffused into 35
`the tissues and play an important role, for example, in tissue
`hydration or else by intervening in cellular or biochemical
`mechanisms.
`Finally, the presence of lidocaine in the gel is of major
`interest for improving the comfort of the patient during and 40
`after injection.
`Consequently, the injectable aqueous composition based
`on hyaluronic acid or one of the salts thereof, on one or more
`polyol(s) and on lidocaine according to the invention has the
`following advantages for cosmetic purposes or for therapeu- 45
`tic purposes:
`better viscoelastic rheological properties of the gel (in par(cid:173)
`ticular better ability to create volume) since significantly
`less degraded at sterilization,
`longer in vivo persistence of the gel and therefore a more 50
`long-term effect of the treatment by virtue of the action
`of the polyol(s) and of the lidocaine against the three
`main types of degradation of the gel in vivo,
`better rheological stability of the gel during its shelf-life,
`positive action ofthepolyols on the organism (for example, 55
`tissue hydration),
`improvement of the comfort of the patient owing to the
`anesthetizing effect oflidocaine during and after injec(cid:173)
`tion.
`The invention therefore provides a heat-sterilized inject- 60
`able composition comprising a gel based on hyaluronic acid
`or one of the salts thereof, on one or more polyol(s) and on
`lidocaine.
`This composition is used:
`for cosmetic purposes for filling biological tissues or for
`rehydrating the skin by mesotherapy;
`for therapeutic purposes such as, for example:
`
`EXAMPLES
`
`Examples are proposed in order to illustrate the invention
`but they in no way limit said invention. The formulations
`prepared in the following examples are gels based on
`crosslinked sodium hyaluronate (NaHA) with or without
`polyol and lidocaine in a buffered aqueous solution at pH=7.
`The crosslinked gels are prepared according to techniques
`well known to those skilled in the art. The sodium hyaluronate
`used to produce these gels has a molecular weight equal to
`65 2.Sxl 06 Da. The crosslinking agent used is butanediol digly(cid:173)
`cidyl ether (BDDE) and the definition of the degree of
`crosslinking used is: weight (BDDE)/weight (dry NaHA).
`
`

`

`US 8,455,465 B2
`
`5
`The incorporation of the polyol into the gel is carried out by
`adding the necessary amount of polyol (% expressed by
`weight) to the gel and mixing with a spatula for 10 minutes
`(for 50 g offinal gel).
`The incorporation of the lidocaine into the gel is carried out 5
`by adding the necessary amount oflidocaine (% expressed by
`weight) to the gel and mixing with the spatula for 10 minutes
`(for 50 g offinal gel).
`In order to have strictly identical production conditions for
`the gels with and without polyol and lidocaine, the polyol-
`free and lidocaine-free crosslinked gel is also mixed with a
`spatula for 10 minutes (for 50 g offinal gel).
`The gels prepared are packed into a glass syringe and then
`heat-sterilized (121 ° C., 10 min).
`The rheometer used to carry out the rheological character(cid:173)
`izations is anAR2000 (TA instruments) with a plate geometry
`of 40 mm, a gap of 1000 µm and an analysis temperature of
`37° C.
`
`10
`
`15
`
`Example 1
`
`6
`The gels B, C and Dare packed into a 1 ml glass syringe and
`are then wet-heat-sterilized at 121 ° C. for 10 minutes.
`A rheology measurement (frequency sweep----0.01 to 100
`Hz) is carried out for each of the gels B, C and D after
`sterilization.
`A comparison of the values of G' ( =elastic modulus), G"
`(=viscous modulus) and Tan o=G"/G' is carried out at 1 Hz.
`
`Formulation
`
`Gel B (after sterilization)
`According to the invention
`Gel C (after sterilization)
`Gel D (after sterilization)
`
`G'
`(1 Hz)
`(Pa)
`
`128
`
`91
`75
`
`G"
`(1 Hz)
`(Pa)
`
`62
`
`47
`50
`
`Tan o
`(1 Hz)
`
`0.484
`
`0.516
`0.667
`
`Considerable rheological differences, and therefore con-
`20 siderable structural differences, are observed between the
`three gels B, C and D after heat sterilization.
`After heat sterilization, the gel according to the invention
`( =gel B) displays a significantly superior elasticity (higher G')
`and elastic nature (lower Tan o) than the polyol-free and
`25 lidocaine-free gel (=gel D).
`The presence of the polyols and of the lidocaine make it
`possible to greatly limit the thermal degradation of the hyalu(cid:173)
`ronic acid-based gel during heat sterilization.
`
`Demonstration by rheology of the difference in structure
`after heat sterilization between hyaluronic acid-based gels
`with and without polyol/lidocaine
`Take A, a gel based on crosslinked NaHA (NaHA molar
`mass=2.5xl 06 Da, NaHA concentration=22.5 mg/ml, degree
`of crosslinking=9% ). The gel is then purified by dialysis for
`24 hours (regenerated cellulose, separation limit: molar
`mass=60 kDa). 150 g of purified gel is mixed with a spatula 30
`for 10 minutes.
`The resulting gel is divided up into three fractions of equal
`weight (50 g).
`Take B, fraction No. 1.1 % of glycerol, 1.5% of sorbitol and
`0.3% oflidocaine are added to this fraction. The gel is mixed 35
`with a spatula for 10 minutes.
`Take C, fraction No. 2.1 % of glycerol and 1.5% of sorbitol
`are added to this fraction. The gel is mixed with a spatula for
`10 minutes.
`Take D, fraction No. 3. A solution of NaCl of appropriate 40
`concentration is added in order to have a hyaluronic acid
`concentration and an osmolarity which are equivalent to those
`of gels B and C. The gel is mixed with a spatula for 10
`minutes.
`Take B, C and D, the gels resulting from fractions B, C and 45
`D respectively.
`The resulting gels have a pH close to 7 .00, an osmolarity
`close to 300 mOsm/kg and an equivalent hyaluronic acid
`concentration.
`A rheology measurement (frequency sweep----0.01 to 100
`Hz) is carried out for each of the gels B, C and D before
`sterilization.
`A comparison of the values of G' ( =elastic modulus), G"
`(=viscous modulus) and Tan o=G"/G' is carried out at 1 Hz.
`
`Formulation
`
`GelB
`According to the invention
`GelC
`GelD
`
`Variation G' (1 Hz)
`before/after sterilization
`
`-59%
`
`-71%
`-76%
`
`Example 2
`
`Demonstration of the better resistance to enzymatic deg(cid:173)
`radation of a hyaluronic acid-based gel with polyol and
`lidocaine.
`The resistance to enzymatic degradation of the gel B
`according to the invention ( see example 1) is compared with
`that of the gel D (see example 1).
`The degradation test is carried out using an AR2000 rhe(cid:173)
`ometer (TA instruments) with a plate geometry of 40 mm and
`50 a gap of 1000 µm.
`The degradation test is carried out by adding a solution of
`hyaluronidases to the test gel, homogenizing with the spatula
`for 1 minute, placing the whole at a temperature of3 7° C. and
`imposing a deformation of0.3%. The value of the parameter
`55 G' at 1 Hz is measured at t=5 min and t=40 min.
`
`Formulation
`
`Gel B (before sterilization)
`Gel C (before sterilization)
`Gel D (before sterilization)
`
`G'
`(1 Hz)
`(Pa)
`
`316
`314
`318
`
`G"
`(1 Hz)
`(Pa)
`
`94
`93
`94
`
`60
`
`Tani>
`(1 Hz)
`
`0.297
`0.296
`0.296
`
`No rheological differences, and therefore no difference in
`structure, are observed between the three gels B, C and D
`before sterilization.
`
`65
`
`G'(l Hz)
`(Pa)
`Att-5
`min
`
`115
`
`60
`
`G' (1 Hz)
`(Pa)
`Att-40
`min
`
`52
`
`24
`
`~G'
`(1 Hz)
`
`-55%
`
`-60%
`
`Formulation
`
`Gel B (sterile)
`According to
`the invention
`Gel D (sterile)
`
`

`

`7
`It is noted that the gel according to the invention has better
`resistance to enzymatic degradation.
`
`8
`The value of the parameter G' (1 Hz) was measured at t=0,
`t=4 months and t=8 months.
`
`US 8,455,465 B2
`
`Example 3
`
`Demonstration of the better resistance to free-radical deg(cid:173)
`radation of a hyaluronic acid-based gel with polyol and
`lidocaine.
`The resistance to free-radical degradation of the gel B
`according to the invention (see example 1), of the gel C (see lO
`example 1) and of the gel D (see example 1) is compared.
`The degradation test is carried out using an AR2000 rhe(cid:173)
`ometer (TA instruments) with a plate geometry of 40 mm and
`a gap of 1000 µm.
`The degradation test is carried out by adding an oxidizing 15
`agent to the test gel, homogenizing with the spatula for 1
`minute, placing the whole at a temperature of 37° C. and
`imposing a deformation of0.3%. The value of the parameter
`G' at 1 Hz is measured at t=5 min and t=40 min.
`
`20
`
`Gel B (sterile)
`According to the
`invention
`
`Gel D (sterile)
`
`128
`
`126
`
`120
`
`-6%
`
`75
`
`68
`
`66
`
`-12%
`
`Formulation
`
`G' (1 Hz) (Pa)
`Att=0
`G' (1 Hz) (Pa)
`At t = 4 months
`G' (1 Hz) (Pa)
`At t = 8 months
`LlG' (1 Hz)
`(0-8 months)
`
`It is noted that the gel according to the invention has better
`rheological stability at ambient temperature over time.
`
`25
`
`G'(l Hz)
`(Pa)
`Att=5
`min
`
`G' (1 Hz)
`(Pa)
`Att=40
`min
`
`122
`
`80
`58
`
`98
`
`38
`20
`
`LlG'
`(1 Hz)
`
`-20%
`
`-53%
`-66%
`
`Formulation
`
`Gel B (sterile)
`According to
`the invention
`Gel C (sterile)
`Gel D (sterile)
`
`It is noted that the gel according to the invention has a much
`better resistance to free-radical degradation.
`
`Example 4
`
`Demonstration of the better resistance to thermal degrada(cid:173)
`tion of a hyaluronic acid-based gel with polyol and lidocaine.
`The resistance to thermal degradation of the gel B accord(cid:173)
`ing to the invention (see example 1) and of the gel D (see
`example 1) is compared.
`The thermal degradation test is carried out by introducing
`the test gel into an incubator at 80° C. for 8 hours and mea(cid:173)
`suring the value of the parameter G' (1 Hz) at t=0 and at t=8
`days.
`
`Formulation
`
`Gel B (sterile)
`According to
`the invention
`Gel D (sterile)
`
`G' (l Hz)
`(Pa)
`Att=0
`
`G' (l Hz)
`(Pa)
`Att = 8 days
`
`128
`
`75
`
`66
`
`29
`
`LlG'
`(1 Hz)
`
`-48%
`
`- 61%
`
`It is noted that the gel according to the invention has better
`resistance to thermal degradation.
`
`Example 5
`
`Demonstration of the Better Rheological stability at ambi(cid:173)
`ent temperature over time of a hyaluronic acid-based gel with
`polyol and lidocaine.
`The gel B according to the invention (see example 1) and
`the gel D (see example D) were stored at ambient temperature
`(25° C.) for 8 months.
`
`The invention claimed is:
`l. An injectable aqueous composition in the form of a gel,
`used for cosmetic purposes or for therapeutic purposes, com(cid:173)
`prising cross-linked hyaluronic acid or one of the salts
`thereof, one or more polyol(s) selected from the group con-
`sisting of glycerol, sorbitol, mannitol, propylene glycol,
`erythritol, xylitol, maltitol and lactitol, and lidocaine, which
`has undergone heat sterilization, the effects of which are
`improved viscoelastic rheological properties and improved in
`30 vivo persistence compared to gels without said polyols and
`lidocaine.
`2. The injectable aqueous composition as claimed in claim
`1, wherein the sterilization is carried out with humid heat.
`3. The injectable aqueous composition as claimed in claim
`35 1, wherein the hyaluronic acid or one of the salts thereof is
`crosslinked with or without one or more other polysaccha(cid:173)
`rides of natural origin.
`4. The injectable aqueous composition as claimed in claim
`1, wherein the hyaluronic acid or one of the salts thereof is
`40 crosslinked with bifunctional or polyfunctional molecules
`selected from the group consisting of epoxides, epihalohy(cid:173)
`drins and divinyl sulfone.
`5. The injectable aqueous composition as claimed in claim
`1, wherein the concentration of hyaluronic acid or of one of
`45 the salts thereof is between 0.01 mg/ml and 100 mg/ml, and
`the molecular weight of the hyaluronic acid or one of the salts
`thereof is between 1000 Da and 10xl06 Da.
`6. The injectable aqueous composition as claimed in claim
`1, wherein the polyol concentration is between 0.0001 and
`50 100 mg/ml.
`7. The injectable aqueous composition as claimed in claim
`1, wherein the lidocaine concentration is between 0.0001 and
`50mg/ml.
`8. A method for filling or replacing biological tissues in a
`55 patient in need thereof, comprising injecting the injectable
`aqueous composition of claim 1 into said patient.
`9. A method for filling wrinkles, remodeling of the face or
`increasing lip volume in a patient in need thereof, comprising
`injecting the injectable aqueous composition of claim 1 into
`60 wrinkles, face or lips of said patient.
`10. A method for treating rehydration of the skin of a
`patient by mesotherapy, comprising injecting the injectable
`aqueous composition of claim 1 into the skin of said patient.
`11. A method for separating, replacing or filling a biologi-
`65 cal tissue or increasing the volume of said tissue in a patient in
`need thereof, comprising injecting the injectable aqueous
`composition of claim 1 into said patient.
`
`

`

`10
`
`US 8,455,465 B2
`
`9
`12. A method for replacement or for temporary supplemen(cid:173)
`tation of synovial fluid in a patient in need thereof, compris(cid:173)
`ing injecting the injectable aqueous composition as claimed
`in claim 1 into said patient.
`13. The injectable aqueous composition as claimed in
`claim 1, used in a field selected from the group consisting of:
`urology/gynecology, as an agent for increasing sphincter
`volume or urethral volume;
`ophthalmology, as an adjuvant to cataract surgery or for
`treating glaucoma;
`pharmaceutics, as an agent for release of active substances;
`and
`surgery, for bone reconstruction, increasing vocal cord vol(cid:173)
`ume or producing surgical tissues.
`* * * * *
`
`10
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`15
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