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HYALURONIC ACID COMPOSITION

20220000752 · 2022-01-06

    Inventors

    Cpc classification

    International classification

    Abstract

    An injectable hyaluronic acid composition including a hyaluronic acid; a local anesthetic selected from the group of amide and ester type local anesthetics or a combination thereof; and an ascorbic acid derivative in an amount which prevents or reduces the effect on the viscosity and/or elastic modulus G′ of the composition caused by the local anesthetic upon sterilization by heat. Further, the medical and non-medical, such as cosmetic, use of such a composition, and to a method of manufacturing such a composition.

    Claims

    1-40. (canceled)

    41. A sterilized injectable hyaluronic acid composition for use in a dermatological treatment of a subject in need thereof, wherein the sterilized injectable hyaluronic acid composition comprises: (a) modified hyaluronic acid in a concentration from about 1 to about 100 mg/ml, (b) a local anesthetic in a concentration from about 0.1 to about 30 mg/ml, and (c) an ascorbic acid derivative in a concentration from about 0.01 mg/ml to about 5 mg/ml, wherein the composition is subjected to sterilization by autoclaving at a F0-value≥4, and wherein no or mild local or systemic effects occur after the subject is treated with the hyaluronic acid composition.

    42. The composition of claim 41, wherein the dermatological treatment is selected from the group consisting of wound healing, treatment of dry skin conditions and sun-damaged skin, treatment of hyper pigmentation disorders, treatment and prevention of hair loss, and treatment of conditions that have inflammation as a component of the disease process.

    43. The composition of claim 41, wherein the composition is used to treat psoriasis or asteototic eczema.

    44. The composition of claim 41, wherein the dermatological treatment is cosmetic or medical.

    45. The composition of claim 41, wherein the modified hyaluronic acid is crosslinked with a chemical crosslinking agent to form a crosslinked hyaluronic acid, wherein a degree of modification of the hyaluronic acid gel is less than 2 mol %.

    46. The composition of claim 45, wherein the crosslinked hyaluronic acid is biocompatible.

    47. The composition of claim 45, wherein the crosslinked hyaluronic acid is a gel or a hydrogel.

    48. The composition of claim 47, wherein the crosslinked hyaluronic acid is a gel and wherein the hyaluronic acid concentration and extent of crosslinking affect mechanical properties of the gel.

    49. The composition of claim 46, wherein no, or mild immune response occurs in the subject after treatment.

    50. The composition of claim 47, wherein the crosslinked hyaluronic acid is a gel and wherein the hyaluronic acid gel comprises a portion of hyaluronic acid which is not crosslinked.

    51. A cosmetic use of a sterilized injectable hyaluronic acid composition in a subject in need thereof, wherein the sterilized injectable hyaluronic acid composition comprises: (a) modified hyaluronic acid in a concentration from about 1 to about 100 mg/ml, (b) a local anesthetic in a concentration from about 0.1 to about 30 mg/ml, and (c) an ascorbic acid derivative in a concentration from about 0.01 mg/ml to about 5 mg/ml, wherein: the cosmetic use is to improve the appearance of skin, prevent hair loss, treat hair loss, fill wrinkles or contour the face or body of the subject.

    52. The sterilized injectable hyaluronic acid composition of claim 41, wherein the composition is subjected to sterilization by autoclaving at a F0-value≥4, and wherein no or mild local or systemic effects occur after the subject is treated with the hyaluronic acid composition.

    53. The composition of claim 52, wherein the modified hyaluronic acid is crosslinked with a chemical crosslinking agent to form a crosslinked hyaluronic acid, wherein a degree of modification of the hyaluronic acid gel is less than 2 mol %.

    54. The composition of claim 53, wherein the crosslinked hyaluronic acid is biocompatible.

    55. The composition of claim 54, wherein the crosslinked hyaluronic acid is a gel or a hydrogel.

    56. The composition of claim 55, wherein the crosslinked hyaluronic acid is a gel and wherein the hyaluronic acid concentration and extent of crosslinking affect mechanical properties of the gel.

    57. The composition of claim 55, wherein the crosslinked hyaluronic acid is a gel and wherein the hyaluronic acid gel comprises a portion of hyaluronic acid which is not crosslinked.

    58. A cosmetic method of improving the appearance of skin, preventing hair loss, treating hair loss, filling wrinkles or contouring the face or body of a subject, comprising: a) providing the sterilized injectable hyaluronic acid composition of claim 51, and b) injecting said sterilized injectable hyaluronic acid composition into the skin of the subject.

    59. The method of claim 57, wherein the sterilized injectable hyaluronic acid composition is injected into the cutis and/or subcutis.

    60. A sterilized injectable hyaluronic acid composition for use in the treatment of a joint disorder by intraarticular injection, wherein the sterilized injectable hyaluronic acid composition comprises: (a) a hyaluronic acid gel, (b) a therapeutically relevant concentration of lidocaine, and (c) an ascorbic acid derivative selected from the group consisting of ascorbyl phosphates, ascorbyl sulfates, and ascorbyl glycosides, in an amount which prevents or reduces the effect on the viscosity and/or elastic modulus G′ of the composition caused by the lidocaine upon sterilization by heat, wherein the concentration of the ascorbic acid derivative in the composition is in the range of 0.01 to 5 mg/ml, and the composition has been subjected to sterilization by autoclaving at a F0-value≥4, wherein the hyaluronic acid gel is crosslinked by modification with a chemical crosslinking agent, wherein a degree of modification of the hyaluronic acid gel is less than 2 mol %, and wherein the hyaluronic acid composition does not exhibit increased stability compared to the same composition without an ascorbic acid derivative.

    Description

    BRIEF DESCRIPTION OF THE DRAWINGS

    [0095] FIG. 1 is a graph showing the effect of MAP (Magnesium Ascorbyl Phosphate) on a hyaluronic acid gel with lidocaine.

    [0096] FIG. 2 is a graph showing the effect of MAP on a hyaluronic acid gel with lidocaine.

    [0097] FIG. 3 is a graph showing the effect of MAP on a non-crosslinked hyaluronic acid with lidocaine.

    [0098] FIG. 4 is a graph showing the effect of MAP on a non-crosslinked hyaluronic acid with lidocaine.

    [0099] FIG. 5 is a graph showing the effect of MAP on a hyaluronic acid gel with lidocaine autoclaved at various F.sub.0 values.

    [0100] FIG. 6 is a graph showing the effect of MAP on a hyaluronic acid gel with bupivacaine.

    [0101] FIG. 7 is a graph showing the effect of MAP on a hyaluronic acid gel with tetracaine.

    [0102] FIG. 8 is a graph showing the effect of SAP (Sodium Ascorbyl Phosphate) on a hyaluronic acid gel with lidocaine.

    [0103] FIG. 9 is a graph showing the effect of Methylsilanol ascorbate on a hyaluronic acid gel with lidocaine.

    [0104] FIG. 10 is a graph showing the effect of Ascorbyl glucoside on a non-crosslinked hyaluronic acid with bupivacaine.

    [0105] FIG. 11 is a graph showing the effect of different concentrations of SAP on a hyaluronic acid gel with lidocaine.

    [0106] FIG. 12 is a graph showing the effect of L-Ascorbic acid acetonide on a hyaluronic acid gel with tetracaine.

    [0107] FIG. 13 is a graph showing the effect of SAP on a hyaluronic acid gel with lidocaine.

    [0108] FIG. 14 is a graph showing the effect of Aminopropyl Ascorbyl Phosphate on a non-crosslinked hyaluronic acid with lidocaine.

    [0109] FIG. 15 is a graph showing the effect of Ascorbyl glucoside on a hyaluronic acid gel with lidocaine.

    [0110] FIG. 16 is a graph showing the effect of Ascorbyl glucoside on a hyaluronic acid gel with lidocaine.

    [0111] FIG. 17 is a graph showing the effect of Ascorbyl glucoside on a hyaluronic acid gel with lidocaine.

    [0112] FIG. 18 is a graph showing the effect of MAP on a hyaluronic acid gels with lidocaine.

    [0113] FIG. 19 is a graph showing the effect of SAP on a hyaluronic acid gel with lidocaine in a stability study.

    [0114] FIG. 20 is a graph showing the effect of Ascorbyl glucoside on a hyaluronic acid gel with lidocaine in a stability study.

    [0115] FIG. 21 is a graph showing the effect of MAP or Ascorbyl glucoside on a hyaluronic acid gel with lidocaine in a stability study.

    [0116] FIG. 22 is a graph showing the effect of Ascorbyl glucoside on a hyaluronic acid gel with lidocaine in a stability study.

    ITEMIZED LISTING OF EMBODIMENTS

    [0117] 1. An injectable hyaluronic acid composition comprising [0118] a hyaluronic acid, [0119] a local anesthetic selected from the group consisting of amide and ester type local anesthetics or a combination thereof, and [0120] an ascorbic acid derivative in an amount which prevents or reduces the effect on the viscosity and/or elastic modulus G′ of the composition caused by the local anesthetic upon sterilization by heat.
    2. An injectable hyaluronic acid composition according to item 1, wherein said composition does not exhibit increased stability compared to the same composition without an ascorbic acid derivative.
    3. An injectable hyaluronic acid composition according to any one of the preceding items, wherein said hyaluronic acid is a modified hyaluronic acid.
    4. An injectable hyaluronic acid composition according to item 3, wherein said hyaluronic acid is a hyaluronic acid gel.
    5. An injectable hyaluronic acid composition according to item 4, wherein the hyaluronic acid gel is crosslinked by modification with a chemical crosslinking agent.
    6. An injectable hyaluronic acid composition according to item 5, wherein the chemical crosslinking agent is selected from the group consisting of divinyl sulfone, multiepoxides and diepoxides.
    7. An injectable hyaluronic acid composition according to item 6, wherein the chemical crosslinking agent is selected from the group consisting of 1,4-butanediol diglycidyl ether (BDDE), 1,2-ethanediol diglycidyl ether (EDDE) and diepoxyoctane.
    8. An injectable hyaluronic acid composition according to item 7, wherein the chemical crosslinking agent is 1,4-butanediol diglycidyl ether (BDDE).
    9. An injectable hyaluronic acid composition according to any one of items 5-8, wherein the hyaluronic acid gel has a degree of modification of 2 mole % or less, such as 1.5 mole % or less, such as 1.25 mole % or less.
    10. An injectable hyaluronic acid composition according to any one of items 5-8, wherein the hyaluronic acid gel has a degree of modification in the range of 0.1 to 2 mole %, such as in the range of 0.2 to 1.5 mole %, such as in the range of 0.3 to 1.25 mole %.
    11. An injectable hyaluronic acid composition according to any one of the preceding items, wherein the concentration of said hyaluronic acid is in the range of 1 to 100 mg/ml.
    12. An injectable hyaluronic acid composition according to item 11, wherein the concentration of said hyaluronic acid is in the range of 2 to 50 mg/ml.
    13. An injectable hyaluronic acid composition according to item 12, wherein the concentration of said hyaluronic acid is in the range of 10 to 30 mg/ml.
    14. An injectable hyaluronic acid composition according to any one of the preceding items, wherein said local anesthetic is selected from the group consisting of lignocaine (lidocaine), bupivacaine, butanilicaine, carticaine, cinchocaine (dibucaine), clibucaine, ethylparapiperidinoacetylaminobenzoate, etidocaine, mepivacaine, oxethazaine, prilocaine, ropivacaine, tolycaine, trimecaine, vadocaine, articaine, levobupivacaine, amylocaine, cocaine, propanocaine, clormecaine, cyclomethycaine, proxymetacaine, amethocaine (tetracaine), benzocaine, butacaine, butoxycaine, butyl aminobenzoate, chloroprocaine, dimethocaine (larocaine), oxybuprocaine, piperocaine, parethoxycaine, procaine (novocaine), propoxycaine, tricaine, or a combination thereof.
    15. An injectable hyaluronic acid composition according to any one of the preceding items, wherein said local anesthetic is selected from the group consisting of amide type local anesthetics, or a combination thereof.
    16. An injectable hyaluronic acid composition according to item 15, wherein said local anesthetic is selected from the group consisting of lignocaine (lidocaine), bupivacaine, butanilicaine, carticaine, cinchocaine (dibucaine), clibucaine, ethyl parapiperidinoacetylaminobenzoate, etidocaine, mepivacaine, oxethazaine, prilocaine, ropivacaine, tolycaine, trimecaine, vadocaine, articaine, levobupivacaine or a combination thereof.
    17. An injectable hyaluronic acid composition according to item 16, wherein said local anesthetic is selected from the group consisting of lidocaine, bupivacaine, and ropivacaine, or a combination thereof.
    18. An injectable hyaluronic acid composition according to item 17, wherein said local anesthetic is lidocaine.
    19. An injectable hyaluronic acid composition according to any one of the preceding items, wherein the concentration of said local anesthetic is in the range of 0.1 to 30 mg/ml.
    20. An injectable hyaluronic acid composition according to item 19, wherein the concentration of said local anesthetic is in the range of 0.5 to 10 mg/ml.
    21. An injectable hyaluronic acid composition according to item 20, wherein the concentration of said lidocaine is in the range of 1 to 5 mg/ml.
    22. An injectable hyaluronic acid composition according to item 21, wherein the concentration of said lidocaine is in the range of 2 to 4 mg/ml.
    23. An injectable hyaluronic acid composition according to item 22, wherein the concentration of said lidocaine is about 3 mg/ml.
    24. An injectable hyaluronic acid composition according to any one of the preceding items, wherein said ascorbic acid derivative is a compound comprising the chemical structure:

    ##STR00015##

    25. An injectable hyaluronic acid composition according to any one of the preceding items, wherein said ascorbic acid derivative is water soluble under atmospheric conditions.
    26. An injectable hyaluronic acid composition according to any one of the preceding items, wherein said ascorbic acid derivative is capable of forming ascorbic acid or ascorbate when placed in in vivo conditions.
    27. An injectable hyaluronic acid composition according to any one of the preceding items, wherein said ascorbic acid derivative is selected from the group consisting of ascorbyl phosphates, ascorbyl sulfates, and ascorbyl glycosides, or a combination thereof.
    28. An injectable hyaluronic acid composition according to any one of the preceding items, wherein said ascorbic acid derivative is selected from the group consisting of ascorbyl phosphates and ascorbyl glycosides, or a combination thereof.
    29. An injectable hyaluronic acid composition according to any one of the preceding items, wherein said ascorbic acid derivative is an ascorbyl phosphate.
    30. An injectable hyaluronic acid composition according to item 29, wherein said ascorbyl phosphate is selected from the group consisting of sodium ascorbyl phosphate (SAP) and magnesium ascorbyl phosphate (MAP).
    31. An injectable hyaluronic acid composition according to any one of items 1-28, wherein said ascorbic acid derivative is an ascorbyl glycoside.
    32. An injectable hyaluronic acid composition according to item 31, wherein said ascorbic acid derivative is ascorbyl glucoside.
    33. An injectable hyaluronic acid composition according to any one of the preceding items, wherein the concentration of said ascorbic acid derivative is in the range of 0.001 to 15 mg/ml.
    34. An injectable hyaluronic acid composition according to item 33, wherein the concentration of said ascorbic acid derivative is in the range of 0.001 to 10 mg/ml.
    35. An injectable hyaluronic acid composition according to item 34, wherein the concentration of said ascorbic acid derivative is in the range of 0.01 to 5 mg/ml.
    36. An injectable hyaluronic acid composition according to item 35, wherein the concentration of said ascorbic acid derivative is in the range of 0.01 to 0.5 mg/ml.
    37. An injectable hyaluronic acid composition according to item 30, wherein the concentration of said sodium ascorbyl phosphate (SAP) or magnesium ascorbyl phosphate (MAP) is in the range of 0.01 to 1 mg/ml.
    38. An injectable hyaluronic acid composition according to item 37, wherein the concentration of said sodium ascorbyl phosphate (SAP) or magnesium ascorbyl phosphate (MAP) is in the range of 0.01 to 0.5 mg/ml.
    39. An injectable hyaluronic acid composition according to item 31, wherein the concentration of said ascorbyl glucoside is in the range of 0.01 to 0.8 mg/ml.
    40. An injectable hyaluronic acid composition according to item 39, wherein the concentration of said ascorbyl glucoside is in the range of 0.05 to 0.4 mg/ml.
    41. An injectable hyaluronic acid composition according to item 1, comprising [0121] an aqueous hyaluronic acid gel comprising 2 to 50 mg/ml of a hyaluronic acid, [0122] 0.5 to 10 mg/ml of lidocaine, and [0123] 0.01 to 5 mg/ml of an ascorbic acid derivative selected from the group consisting of ascorbyl phosphates and ascorbyl glycosides, or a combination thereof.
    42. A sterilized injectable hyaluronic acid composition according to any one of the preceding items.
    43. A sterilized hyaluronic acid composition according to item 42, wherein the composition has been subjected to sterilization by autoclaving or similar sterilization by heat.
    44. An injectable hyaluronic acid composition as defined in any one of items 1-43 for use as a medicament.
    45. An injectable hyaluronic acid composition as defined in any one of items 1-43 for use in a dermatological treatment selected from the group consisting of wound healing, treatment of dry skin conditions and sun-damaged skin, treatment of hyper pigmentation disorders, treatment and prevention of hair loss, and treatment of conditions that have inflammation as a component of the disease process, such as psoriasis and asteototic eczema.
    46. An injectable hyaluronic acid composition as defined in any one of items 1-43 for use in the treatment of a joint disorder by intraarticular injection.
    47. Cosmetic, non-medical use of an injectable acid composition as defined in any one of items 1-43 for improving the appearance of skin, preventing and/or treating hair loss, filling wrinkles or contouring the face or body of a subject.
    48. Cosmetic, non-medical use according to item 47, for improving the appearance of the skin of a subject.
    49. Cosmetic, non-medical use according to item 47, for filling wrinkles of a subject.
    50. Cosmetic, non-medical method of improving the appearance of skin, preventing and/or treating hair loss, filling wrinkles or contouring the face or body of a subject, comprising
    a) providing an injectable hyaluronic acid composition as defined in any one of items 1-43, and
    b) injecting said injectable hyaluronic acid composition into the skin of a subject.
    51. A method according to item 50, wherein said injectable hyaluronic acid composition is injected into the cutis and/or subcutis.
    52. A method of manufacturing a hyaluronic acid composition comprising:
    a) mixing a hyaluronic acid, a local anesthetic selected from the group consisting of amide and ester type local anesthetics or a combination thereof, and an ascorbic acid derivative in an amount which prevents or reduces the effect on the viscosity and/or elastic modulus G′ of the composition caused by the local anesthetic upon sterilization by heat, and
    b) subjecting the mixture to sterilization by heat.
    53. A method according to item 52, wherein the formed hyaluronic acid composition does not exhibit increased stability compared to the same composition without an ascorbic acid derivative.
    54. A method according any one of items 52 and 53, wherein step b) comprises subjecting the mixture to a F.sub.0-value≥4.
    55. Use of an ascorbic acid derivative in an injectable hyaluronic acid composition further comprising [0124] a hyaluronic acid and [0125] a local anesthetic selected from the group consisting of amide and ester type local anesthetics or a combination thereof,
    for preventing or reducing the effect of the local anesthetic on the viscosity and/or elastic modulus G′ of the composition due to sterilization by heat.
    56. Use according to item 55, wherein the hyaluronic acid composition does not exhibit increased stability compared to the same composition without an ascorbic acid derivative.

    EXAMPLES

    [0126] Without desiring to be limited thereto, the present invention will in the following be illustrated by way of examples. Since hyaluronic acid polymer and hyaluronic acid gel may always be subject to some batch to batch variations, each example has been performed with a single batch of hyaluronic acid polymer or hyaluronic acid gel in order to obtain comparable results. Slight variations in, e.g., rheological properties or viscosity between similar compositions in different examples may be due to such batch to batch variations.

    Example 1. Hyaluronic Acid Gel with Lidocaine and MAP

    [0127] In this experiment, the rheological properties after autoclaving of hyaluronic acid gels without additives were compared to hyaluronic acid gels with added lidocaine and hyaluronic acid gels with added lidocaine and MAP respectively.

    [0128] Formulations having various concentrations lidocaine and MAP as outlined in Table 1 were prepared as described below.

    TABLE-US-00001 TABLE 1 G′ Formulation HA Gel Lidocaine MAP at 1.0 Hz # [mg/ml] [mg/ml] [mg/ml] [Pa] 1a 20 0 0 239 1b 20 3 0 437 1c 20 3 0.07 394 1d 20 3 0.7 211 1e 20 1 0 440 1f 20 1 0.07 388 1g 20 1 0.7 206

    [0129] In all formulations a BDDE (1,4-butandiol diglycidylether) crosslinked hyaluronic acid gel with a degree of modification of 1 mole % and a hyaluronic acid content of 20 mg/ml was used. The degree of modification (mole %) describes the amount of crosslinking agent(s) that is bound to HA, i.e. molar amount of bound crosslinking agent(s) relative to the total molar amount of repeating HA disaccharide units. The degree of modification reflects to what degree the HA has been chemically modified by the crosslinking agent.

    [0130] The BDDE (1,4-butandiol diglycidylether) crosslinked hyaluronic acid gel may for example be prepared according to the method described in Examples 1 and 2 of published international patent application WO 9704012.

    [0131] A stock-solution of lidocaine hydrochloride monohydrate (CAS number 6108-05-0, Sigma Aldrich, St Louis, USA) was prepared by dissolving lidocaine hydrochloride monohydrate in WFI (water for injection) and a stock-solution of Magnesium Ascorbyl Phosphate (MAP, CAS number 114040-31-2, Nikko Chemicals co, Japan), was prepared by dissolving MAP in phosphate buffered saline (8 mM, 0.9% NaCl).

    Formulation 1a:

    [0132] The hyaluronic acid gel was diluted to the same degree as 1b-1g by adding phosphate buffered saline (8 mM, 0.9% NaCl).

    Formulation 1 b:

    [0133] Stock-solution of lidocaine was added to the hyaluronic acid gel to a final concentration of 3 mg/ml gel.

    Formulation 1c:

    [0134] Stock-solution of lidocaine and stock-solution of MAP were added to the hyaluronic acid gel to the final concentrations of 3 mg lidocaine/ml and 0.07 mg MAP/ml gel.

    [0135] Formulations 1d-1g were prepared in the same manner by varying the amounts of lidocaine stock-solution and MAP stock-solution. To all formulations phosphate buffered saline (8 mM, 0.9% NaCl) was added to adjust the dilution to the same degree.

    [0136] The pH values of the formulations were adjusted to 7.5±0.2 and the formulations were filled in 1 ml glass syringes (BD Hypak SCF) and autoclaved in a Getinge GEV 6610 ERC-1 autoclave (F.sub.0-30).

    [0137] The rheological properties of the formulations were analysed using a Bohlin VOR Reometer (Measure system PP 30, Gap 1.00 mm). Initially a strain sweep was made to find the linear viscoelastic region (LVR) and then the viscoelastic properties were measured within the LVR.

    [0138] The results are presented in FIG. 1. MAP counteracts the effect on the elastic modulus G′ of the composition caused by the local anesthetic upon sterilization by heat. The higher the concentration of MAP the larger is the decrease on the elastic G′ modulus. A higher concentration of lidocaine does not affect the increase on the elastic modulus G′.

    Example 2. Hyaluronic Acid Gel with a Higher Degree of Modification with Lidocaine and MAP

    [0139] Formulations as outlined in Table 2 were prepared essentially according to the method described in Example 1, with the exception that a hyaluronic acid gel with a higher degree of modification (approximately 7%) was used. The hyaluronic acid gel may for example be prepared according to the method described in the examples of U.S. Pat. No. 6,921,819 B2.

    TABLE-US-00002 TABLE 2 G′ Formulation HA Gel Lidocaine MAP at 1.0 Hz # [mg/ml] [mg/ml] [mg/ml] [Pa] 2a 20 0 0 393 2b 20 3 0 417 2c 20 3 0.3 388

    [0140] The pH values of the formulations were adjusted to 7.5±0.2 and the formulations were filled in 1 ml glass syringes (BD Hypak SCF) and autoclaved in a Getinge GEV 6610 ERC-1 autoclave (F.sub.0˜29).

    [0141] The rheological properties of the formulations were analysed using a Bohlin VOR Reometer (Measure system PP 30, Gap 1.00 mm). Initially a strain sweep was made to find the linear viscoelastic region (LVR) and then the viscoelastic properties were measured within the LVR.

    [0142] The results are presented in FIG. 2. MAP counteracts the effect on the elastic modulus G′ of the composition caused by the local anesthetic upon sterilization by heat.

    Example 3. Non-Crosslinked Hyaluronic Acid with Lidocaine and MAP

    [0143] Formulations as outlined in Table 3 were prepared essentially according to the method described in Example 1, with the exception that a non-crosslinked hyaluronic acid with an average molecular weight of 1×10.sup.6 Da was used.

    TABLE-US-00003 TABLE 3 Zero shear Formulation HA Lidocaine MAP viscosity # [mg/ml] [mg/ml] [mg/ml] η.sub.0 [Pas] 3a 20 0 0 3.83 3b 20 3 0 4.26 3c 20 3 0.07 2.45 3d 20 3 0.3 1.98

    [0144] The pH values of the formulations were adjusted to 7.5±0.2 and the formulations were filled in 1 ml glass syringes (BD Hypak SCF) and autoclaved in a Getinge GEV 6610 ERC-1 autoclave (F.sub.0-22).

    [0145] The viscosity of the formulations was studied using rotational viscometry using a Bohlin VOR rheometer (Measure system PP 30, Gap 1.00 mm). The results are presented in FIG. 3. MAP counteracts the effect on the viscosity of the composition caused by the local anesthetic upon sterilization by heat.

    Example 4. Non-Crosslinked Hyaluronic Acid with Lidocaine and MAP at Lower Concentrations

    [0146] Formulations as outlined in Table 4 were prepared essentially according to the method described in Example 3, with the exception that lower concentrations of MAP were used.

    TABLE-US-00004 TABLE 4 Zero shear Formulation HA Lidocaine MAP viscosity # [mg/ml] [mg/ml] [mg/ml] η.sub.0 [Pas] 4a 20 0 0 5.13 4b 20 3 0 6.16 4c 20 3 0.03 5.27 4d 20 3 0.01 5.87 4e 20 3 0.005 5.91

    [0147] The pH values of the formulations were adjusted to 7.5±0.2 and the formulations were filled in 1 ml glass syringes (BD Hypak SCF) and autoclaved in a Getinge GEV 6610 ERC-1 autoclave (F.sub.0˜22).

    The viscosity of the formulations was studied using rotational viscometry using a Bohling VOR rheometer (Measure system PP 30, Gap 1.00 mm).

    [0148] The results are presented in FIG. 4. MAP counteracts the effect on the viscosity of the composition caused by the local anesthetic upon sterilization by heat.

    Example 5. Hyaluronic Acid Gel with Lidocaine and MAP Autoclaved at Different F.SUB.0.-Values

    [0149] Formulations as outlined in Table 5 were prepared essentially according to the method described in Example 1, with the exception that a different concentration of MAP was used.

    TABLE-US-00005 TABLE 5 G′ Formulation HA Lidocaine MAP Average at 1.0 Hz # [mg/ml] [mg/ml] [mg/ml] F.sub.0 [Pa] 5a 20 0 0 22 194 5b 20 3 0 22 269 5c 20 3 0.3 22 220 5d 20 0 0 6 317 5e 20 3 0 6 363 5f 20 3 0.3 6 332

    [0150] The pH values of the formulations were adjusted to 7.5±0.2 and the formulations were filled in 1 ml glass syringes (BD Hypak SCF) and autoclaved in a Getinge GEV 6610 ERC-1 autoclave at the different F.sub.0-values described in Table 5.

    [0151] The rheological properties of the formulations were analysed using a Bohlin VOR Reometer (Measure system PP 30, Gap 1.00 mm). Initially a strain sweep was made to find the linear viscoelastic region (LVR) and then the viscoelastic properties were measured within the LVR.

    [0152] The results are presented in FIG. 5. The effect on the elastic modulus G′ of the composition caused by the local anesthetic upon sterilization by heat is slightly larger for the higher F.sub.0-value. MAP counteracts the effect on the elastic modulus G′ of the composition caused by the local anesthetic upon sterilization by heat.

    Example 6. Hyaluronic Acid Gel with Bupivacaine and MAP

    [0153] Formulations as outlined in Table 6 were prepared essentially according to the method described in Example 1, with the exceptions that lidocaine was replaced by bupivacaine (CAS-number 2180-92-9, Cambrex, Karlskoga, Sweden) and that a hyaluronic acid gel with a modification degree of <1%, with a hyaluronic acid content of 12 mg/ml was used.

    TABLE-US-00006 TABLE 6 G′ Formulation HA Gel Bupivacaine MAP at 1.0 Hz # [mg/ml] [mg/ml] [mg/ml] [Pa] 6a 12 0 0 62 6b 12 1 0 90 6c 12 1 0.3 61

    [0154] The pH values of the formulations were adjusted to 7.5±0.2 and the formulations were filled in 1 ml glass syringes (BD Hypak SCF) and autoclaved in a Getinge GEV 6610 ERC-1 autoclave (F.sub.0˜22).

    [0155] The rheological properties of the formulations were analysed using a Bohlin VOR Reometer (Measure system PP 30, Gap 1.00 mm). Initially a strain sweep was made to find the linear viscoelastic region (LVR) and then the viscoelastic properties were measured within the LVR.

    [0156] The results are presented in FIG. 6. Bupivacaine has similar effect on the elastic modulus G′ of the composition as lidocaine. MAP counteracts the effect on the elastic modulus G′ of the composition caused by the local anesthetic upon sterilization by heat.

    Example 7. Hyaluronic Acid Gel with Tetracaine and MAP

    [0157] Formulations as outlined in Table 7 were prepared essentially according to the method described in Example 1 with the exception that lidocaine was replaced by tetracaine (CAS-number 136-47-0, Sigma Aldrich, St Louis, USA) and the concentration of MAP was 0.3 mg/ml.

    TABLE-US-00007 TABLE 7 G′ Formulation HA Gel Tetracaine MAP at 0.1 Hz # [mg/ml] [mg/ml] [mg/ml] [Pa] 7a 20 0 0 154 7b 20 3 0 237 7c 20 3 0.3 196

    [0158] The pH values of the formulations were adjusted to 7.5±0.2 and the formulations were filled in 1 ml glass syringes (BD Hypak SCF) and autoclaved in a Getinge GEV 6610 ERC-1 autoclave (F.sub.0˜22).

    [0159] The rheological properties of the formulations were analysed using a Bohlin VOR Reometer (Measure system PP 30, Gap 1.00 mm). Initially a strain sweep was made to find the linear viscoelastic region (LVR) and then the viscoelastic properties were measured within the LVR.

    [0160] The results are presented in FIG. 7. Tetracaine has similar effect on the elastic modulus G′ of the composition as lidocaine. MAP counteracts the effect on the elastic modulus G′ of the composition caused by the local anesthetic upon sterilization by heat.

    Example 8. Hyaluronic Acid Gel with Lidocaine and SAP

    [0161] Formulations as outlined in Table 10 were prepared essentially according to the method described in Example 1, with the exception that Magnesium Ascorbyl Phosphate (MAP) was replaced by Sodium Ascorbyl Phosphate (SAP).

    [0162] A stock-solution of SAP (CAS number 66170-10-3, Sigma Aldrich, St Louis, USA) was prepared by dissolving SAP in phosphate buffered saline (8 mM, 0.9% NaCl).

    TABLE-US-00008 TABLE 8 G′ at Formulation HA Gel Lidocaine SAP 1.0 Hz # [mg/ml] [mg/ml] [mg/ml] [Pa] 8a 20 0 0   285 8b 20 3 0   430 8c 20 3  0.07 374

    [0163] The pH values of the formulations were adjusted to 7.5±0.2 and the formulations were filled in 1 ml glass syringes (BD Hypak SCF) and autoclaved in a Getinge GEV 6610 ERC-1 autoclave (F.sub.0˜29).

    [0164] The rheological properties of the formulations were analysed using a Bohlin VOR Reometer (Measure system PP 30, Gap 1.00 mm). Initially a strain sweep was made to find the linear viscoelastic region (LVR) and then the viscoelastic properties were measured within the LVR.

    [0165] The results are presented in FIG. 8. SAP counteracts the effect on the elastic modulus G′ of the composition caused by the local anesthetic upon sterilization by heat.

    Example 9. Hyaluronic Acid Gel with Lidocaine and Methylsilanol Ascorbate

    [0166] Formulations as outlined in Table 11 were prepared essentially according to the method described in Example 1, with the exceptions that Magnesium Ascorbyl Phosphate (MAP) was replaced by Ascorbosilane C (product number 078, Exsymol, Monaco) that contains methylsilanol ascorbate (CAS number 187991-39-5).

    TABLE-US-00009 TABLE 9 Methylsilanol G′ at Formulation HA Gel Lidocaine ascorbate 1.0 Hz # [mg/ml] [mg/ml] [mg/ml] [Pa] 9a 20 0 0   194 9b 20 3 0   269 9c 20 3 0.3 134

    [0167] The pH values of the formulations were adjusted to 7.5±0.2 and the formulations were filled in 1 ml glass syringes (BD Hypak SCF) and autoclaved in a Getinge GEV 6610 ERC-1 autoclave (F.sub.0˜22).

    [0168] The rheological properties of the formulations were analysed using a Bohlin VOR Reometer (Measure system PP 30, Gap 1.00 mm). Initially a strain sweep was made to find the linear viscoelastic region (LVR) and then the viscoelastic properties were measured within the LVR.

    [0169] The results are presented in FIG. 9. Methylsilanol ascorbate effectively counteracts the effect on the elastic modulus G′ of the composition caused by the local anesthetic upon sterilization by heat.

    Example 10. Non-Crosslinked Hyaluronic Acid with Bupivacaine and Ascorbyl Glucoside

    [0170] Formulations as outlined in Table 10 were prepared essentially according to the method described in Example 3, with the exception that lidocaine was replaced by bupivacaine and MAP was replaced by ascorbyl glucoside (CAS number 129499-78-1, CarboMer, Inc, San Diego, USA).

    TABLE-US-00010 TABLE 10 Zero Ascorbyl shear Formulation HA Bupivacaine glucoside viscosity # [mg/ml] [mg/ml] [mg/ml] η.sub.0 [Pas] 10a 20 0 0 1.79 10b 20 1 0 2.34 10c 20 1 5 2.11

    [0171] The pH values of the formulations were adjusted to 7.5±0.2 and the formulations were filled in 1 ml glass syringes (BD Hypak SCF) and autoclaved in a Getinge GEV 6610 ERC-1 autoclave (F.sub.0˜22).

    [0172] The viscosity of the formulations was studied using rotational viscometry using a Bohling VOR rheometer (Measure system C14).

    [0173] The results are presented in FIG. 10. Ascorbyl glucoside counteracts the effect on the viscosity of the composition caused by the local anesthetic upon sterilization by heat.

    Example 11. Hyaluronic Acid Gel with Lidocaine and Different Concentrations of SAP

    [0174] Formulations as outlined in Table 11 were prepared essentially according to the method described in Example 8, with the exception that different concentrations of Sodium Ascorbyl Phosphate, SAP were used.

    TABLE-US-00011 TABLE 11 G′ at Formulation HA Lidocaine SAP 1.0 Hz # [mg/ml] [mg/ml] [mg/ml] [Pa] 11a 20 0 0   159 11b 20 3 0   290 11c 20 3  0.005 287 11d 20 3 0.1 256 11e 20 3 0.5 175

    [0175] The pH values of the formulations were adjusted to 7.5±0.2 and the formulations were filled in 1 ml glass syringes (BD Hypak SCF) and autoclaved in a Getinge GEV 6610 ERC-1 autoclave (F.sub.0˜22).

    [0176] The rheological properties of the formulations were analysed using a Bohlin VOR Reometer (Measure system PP 30, Gap 1.00 mm). Initially a strain sweep was made to find the linear viscoelastic region (LVR) and then the viscoelastic properties were measured within the LVR. The results are presented in FIG. 11. SAP counteracts the effect on the elastic modulus G′ of the composition caused by the local anesthetic upon sterilization by heat. The higher the concentration of SAP the greater is the effect.

    Example 12. Hyaluronic Acid Gel with Tetracaine and L-Ascorbic Acid Acetonide

    [0177] Formulations as outlined in Table 12 were prepared essentially according to the method described in Example 7 with the exceptions that MAP was replaced by L-ascorbic acetonide (CAS-number 15042-01-0, Carbosynth, Berkshire, UK) and a higher concentration of the derivative was used.

    TABLE-US-00012 TABLE 12 L-Ascorbic G′ at Formulation HA Gel Tetracaine acid acetonide 1.0 Hz # [mg/ml] [mg/ml] [mg/ml] [Pa] 12a 20 0 0   266 12b 20 3 0   345 12c 20 3 1.0  25

    [0178] The pH values of the formulations were adjusted to 7.5±0.2 and the formulations were filled in 1 ml glass syringes (BD Hypak SCF) and autoclaved in a Getinge GEV 6610 ERC-1 autoclave (F.sub.0˜5).

    [0179] The rheological properties of the formulations were analysed using a Bohlin VOR Reometer (Measure system PP 30, Gap 1.00 mm). Initially a strain sweep was made to find the linear viscoelastic region (LVR) and then the viscoelastic properties were measured within the LVR.

    [0180] The results are presented in FIG. 12. L-Ascorbic acetonide effectively counteracts the effect on the elastic modulus G′ of the composition caused by the local anesthetic upon sterilization by heat.

    Example 13. Hyaluronic Acid Gel with a Higher Degree of Modification with Lidocaine and SAP

    [0181] Formulations as outlined in Table 13 were prepared essentially according to the method described in Example 1, with the exceptions that a hyaluronic acid gel with a higher degree of modification (approximately 7%) was used, that Magnesium Ascorbyl Phosphate (MAP) was replaced by Sodium Ascorbyl Phosphate, SAP (CAS number 66170-10-3, Sigma Aldrich, St Louis, USA), and that another concentration of the derivative was used.

    TABLE-US-00013 TABLE 13 G′ at Formulation HA Gel Lidocaine SAP 1.0 Hz # [mg/ml] [mg/ml] [mg/ml] [Pa] 13a 20 0 0   1110 13b 20 3 0   1260 13c 20 3 0.1 1150

    [0182] The pH values of the formulations were adjusted to 7.5±0.2 and the formulations were filled in 1 ml glass syringes (BD Hypak SCF) and autoclaved in a Getinge GEV 6610 ERC-1 autoclave (F.sub.0˜32).

    [0183] The rheological properties of the formulations were analysed using a Bohlin VOR Reometer (Measure system PP 30, Gap 1.00 mm). Initially a strain sweep was made to find the linear viscoelastic region (LVR) and then the viscoelastic properties were measured within the LVR.

    [0184] The results are presented in FIG. 13. SAP counteracts the effect on the elastic modulus G′ of the composition caused by the local anesthetic upon sterilization by heat.

    Example 14. Non-Crosslinked Hyaluronic Acid with Lidocaine and Aminopropyl Ascorbyl Phosphate

    [0185] Formulations as outlined in Table 14 were prepared essentially according to the method described in Example 3, with the exceptions that Magnesium Ascorbyl Phosphate (MAP) was replaced by Aminopropyl Ascorbyl Phosphate (Macro Care, South Korea) and that a higher concentration of the derivative was used.

    TABLE-US-00014 TABLE 14 Aminopropyl Zero Ascorbyl shear Formulation HA Lidocaine phosphate viscosity # [mg/ml] [mg/ml] [mg/ml] η.sub.0 [Pas] 14a 20 0 0   2.29 14b 20 3 0   3.45 14c 20 3 1.5 1.76

    [0186] The pH values of the formulations were adjusted to 7.5±0.2 and the formulations were filled in 1 ml glass syringes (BD Hypak SCF) and autoclaved in a Getinge GEV 6610 ERC-1 autoclave (F.sub.0˜22).

    [0187] The viscosity of the formulations was studied using rotational viscometry using a Bohling VOR rheometer (Measure system PP 30, Gap 1.00 mm).

    [0188] The results are presented in FIG. 14. Aminopropyl Ascorbyl phosphate effectively counteracts the effect on the viscosity of the composition caused by the local anesthetic upon sterilization by heat.

    Example 15. Hyaluronic Acid Gel with Lidocaine and Ascorbyl Glucoside

    [0189] Formulations as outlined in Table 15 were prepared essentially according to the method described in Example 1 with the exceptions that Magnesium Ascorbyl Phosphate (MAP) was replaced by Ascorbyl glucoside (CarboMer, Inc, San Diego, USA) and another concentration of the derivative was used.

    TABLE-US-00015 TABLE 15 Ascorbyl G′ at Formulation HA Gel Lidocaine glucoside 1.0 Hz # [mg/ml] [mg/ml] [mg/ml] [Pa] 15a 20 3 0   833 15b 20 3  0.08 777

    [0190] The pH values of the formulations were adjusted to 7.5±0.2 and the formulations were filled in 1 ml glass syringes (BD Hypak SCF) and autoclaved in a Getinge GEV 6610 ERC-1 autoclave (F.sub.0˜23).

    [0191] The rheological properties of the formulations were analysed using a Bohlin VOR Reometer (Measure system PP 30, Gap 1.00 mm). Initially a strain sweep was made to find the linear viscoelastic region (LVR) and then the viscoelastic properties were measured within the LVR.

    [0192] The results are presented in FIG. 15. Ascorbyl glucoside counteracts the effect on the elastic modulus G′ of the composition caused by the local anesthetic upon sterilization by heat.

    Example 16. Hyaluronic Acid Gel with Lidocaine and Ascorbyl Glucoside

    [0193] Formulations as outlined in Table 16 were prepared essentially according to the method described in Example 15 with the exceptions that a hyaluronic acid gel with a modification degree of <1%, with a hyaluronic acid content of 12 mg/ml was used and that a higher concentration of the derivative was used.

    TABLE-US-00016 TABLE 16 Ascorbyl G′ at Formulation HA Gel Lidocaine glucoside 1.0 Hz # [mg/ml] [mg/ml] [mg/ml] [Pa] 16a 12 3 0   84 16b 12 3  0.17 80

    [0194] The pH values of the formulations were adjusted to 7.5±0.2 and the formulations were filled in 1 ml glass syringes (BD Hypak SCF) and autoclaved in a Getinge GEV 6610 ERC-1 autoclave (F.sub.0˜23).

    [0195] The rheological properties of the formulations were analysed using a Bohlin VOR Reometer (Measure system PP 30, Gap 1.00 mm). Initially a strain sweep was made to find the linear viscoelastic region (LVR) and then the viscoelastic properties were measured within the LVR.

    [0196] The results are presented in FIG. 16. Ascorbyl glucoside counteracts the effect on the elastic modulus G′ of the composition caused by the local anesthetic upon sterilization by heat.

    Example 17. Hyaluronic Acid Gel with Lidocaine and Ascorbyl Glucoside

    [0197] Formulations as outlined in Table 17 were prepared essentially according to the method described in Example 15 with the exceptions that Ascorbyl glucoside from another manufacturer (Hayashibara Biochemical Laboratories, Inc, Okayama, Japan) was used and that higher concentrations of the derivative were used. In this example a hyaluronic acid gel with a hyaluronic acid content of 16 mg/ml was used.

    TABLE-US-00017 TABLE 17 Ascorbyl G′ at Formulation HA Gel Lidocaine glucoside 1.0 Hz # [mg/ml] [mg/ml] [mg/ml] [Pa] 17a 16 3 0   330 17b 16 3 0.8 314 17c 16 3 8.0 301

    [0198] The pH values of the formulations were adjusted to 7.5±0.2 and the formulations were filled in 1 ml glass syringes (BD Hypak SCF) and autoclaved in a Getinge GEV 6610 ERC-1 autoclave (F.sub.0˜23).

    [0199] The rheological properties of the formulations were analysed using a Bohlin VOR Reometer (Measure system PP 30, Gap 1.00 mm). Initially a strain sweep was made to find the linear viscoelastic region (LVR) and then the viscoelastic properties were measured within the LVR.

    [0200] The results are presented in FIG. 17. Ascorbyl glucoside counteracts the effect on the elastic modulus G′ of the composition caused by the local anesthetic upon sterilization by heat.

    Example 18. Hyaluronic Acid Gels with Different Degrees of Modification with Lidocaine and MAP

    [0201] Formulations as outlined in Table 18 were prepared essentially according to the method described in Example 1 with the exception that another concentration of MAP was used. In this example hyaluronic acid gels with different degrees of modification were used.

    TABLE-US-00018 TABLE 18 HA Gel/ Degree of G′ at Formulation Solution modification Lidocaine MAP 1.0 Hz Reduction # [mg/ml] [mole %] [mg/ml] [mg/ml] [Pa] in G′ [%] 18a 20 <1  3 0    66 — 18b 20 <1  3 0.3  38 43 18c 20 1 3 0   269 — 18d 20 1 3 0.3 220 18 18e 20 7 3 0   417 — 18f 20 7 3 0.3 388  7

    [0202] The pH values of the formulations were adjusted to 7.5±0.2 and the formulations were filled in 1 ml glass syringes (BD Hypak SCF) and autoclaved in a Getinge GEV 6610 ERC-1 autoclave (F.sub.0˜22).

    [0203] The rheological properties of the formulations were analysed using a Bohlin VOR Reometer (Measure system PP 30, Gap 1.00 mm). Initially a strain sweep was made to find the linear viscoelastic region (LVR) and then the viscoelastic properties were measured within the LVR.

    [0204] The results are presented in FIG. 18. MAP counteracts the effect on the elastic modulus G′ of the composition caused by the local anesthetic upon sterilization by heat. The effect is more pronounced in the formulations with a lower degree of modification.

    Example 19. Stability Study for 14 Days in 60° C.

    [0205] Hyaluronic Acid Gel with a Higher Degree of Modification with Lidocaine and SAP

    [0206] Formulations as outlined in Table 19 were prepared essentially according to the method described in Example 2, with the exceptions that Magnesium Ascorbyl Phosphate (MAP) was replaced by Sodium Ascorbyl Phosphate, SAP and that a lower concentration of the derivative was used.

    TABLE-US-00019 TABLE 19 Formulation HA Gel Lidocaine SAP # [mg/ml] [mg/ml] [mg/ml] 19a 20 0 0   19b 20 3 0   19c 20 3 0.1

    [0207] The pH values of the formulations were adjusted to 7.5±0.2 and the formulations were filled in 1 ml glass syringes (BD Hypak SCF) and autoclaved in a Getinge GEV 6610 ERC-1 autoclave (F.sub.0˜32).

    [0208] A stability study in 60° C. for 14 days was performed with sampling at 0, 3, 7, 11 and 14 days.

    [0209] The rheological properties of the formulations were analysed using a Bohlin VOR Reometer (Measure system PP 30, Gap 1.00 mm). Initially a strain sweep was made to find the linear viscoelastic region (LVR) and then the viscoelastic properties were measured within the LVR.

    [0210] The results are presented in FIG. 19. The stability of the composition is not increased by SAP. The degradation rate of the composition with SAP corresponds to the composition without SAP.

    Example 20. Stability Study for 14 Days in 60° C.

    [0211] Hyaluronic Acid Gel with Lidocaine and Ascorbyl Glucoside

    [0212] Formulations as outlined in Table 20 were prepared essentially according to the method described in Example 1, with the exceptions that Magnesium Ascorbyl Phosphate (MAP) was replaced by Ascorbyl glucoside (CarboMer, Inc, San Diego, USA) and that another concentration of the derivative was used.

    TABLE-US-00020 TABLE 20 Ascorbyl Formulation HA Gel Lidocaine glucoside # [mg/ml] [mg/ml] [mg/ml] 20a 20 3 0   20b 20 3  0.17

    [0213] The pH values of the formulations were adjusted to 7.5±0.2 and the formulations were filled in 1 ml glass syringes (BD Hypak SCF) and autoclaved in a Getinge GEV 6610 ERC-1 autoclave (F.sub.0˜22).

    [0214] A stability study in 60° C. for 14 days was performed with sampling at 0, 7 and 14 days.

    [0215] The gel content was determined by adding an excess of saline to a known amount of the preparation and dispersing the gel thoroughly to form a dilute suspension. The diluted suspension of the gel was filtered through a 0.22 mm filter and the concentration of HA in the filtrate, “the extractable part”, was determined using the carbazol method. The gel content was calculated as the fraction of HA in the filler that cannot pass through the 0.22 mm filter when filtering the diluted suspension of the product.

    [0216] The results are presented in FIG. 20. There is no change in stability for the composition with Ascorbyl glucoside compared to the formulation without Ascorbyl glucoside.

    Example 21. Stability Study for 14 Days in 60° C.

    [0217] Hyaluronic Acid Gel with Lidocaine, MAP or Ascorbyl Glucoside

    [0218] Formulations as outlined in Table 21 were prepared essentially according to the method described in Example 1, with the exceptions that MAP or Ascorbyl glucoside (CarboMer, Inc, San Diego, USA) were used and that a hyaluronic acid gel with a modification degree of <1%, with a hyaluronic acid content of 12 mg/ml was used.

    TABLE-US-00021 TABLE 21 Ascorbyl Formulation HA Gel Lidocaine MAP glucoside # [mg/ml] [mg/ml] [mg/ml] [mg/ml] 21a 12 3 0   0   21b 12 3  0.07 0   21c 12 3 0    0.07

    [0219] The pH values of the formulations were adjusted to 7.5±0.2 and the formulations were filled in 1 ml glass syringes (BD Hypak SCF) and autoclaved in a Getinge GEV 6610 ERC-1 autoclave (F.sub.0˜26).

    [0220] A stability study in 60° C. for 14 days was performed with sampling at 0, 3, 7, 11 and 14 days.

    [0221] The rheological properties of the formulations were analysed using a Bohlin VOR Reometer (Measure system PP 30, Gap 1.00 mm). Initially a strain sweep was made to find the linear viscoelastic region (LVR) and then the viscoelastic properties were measured within the LVR.

    [0222] The results are presented in FIG. 21. The stability of the composition is unaffected by Ascorbyl glucoside. In the composition with MAP a slight decrease in the stability is seen. However, the inventors have found that the stability of the compositions is still acceptable and that advantages associated with adding the ascorbic acid derivative outweigh the slight decrease in stability caused by the addition.

    Example 22. Stability Study for 16 Hours in 90° C.

    [0223] Hyaluronic Acid Gel with Lidocaine and Ascorbyl Glucoside

    [0224] Formulations as outlined in Table 22 were prepared essentially according to the method described in Example 1, with the exceptions that Magnesium Ascorbyl Phosphate (MAP) was replaced by Ascorbyl glucoside (Hayashibara Biochemical Laboratories, Inc, Okayama, Japan) and that other concentrations of the derivative were used. In this example a hyaluronic acid gel with a hyaluronic acid content of 16 mg/ml was used.

    TABLE-US-00022 TABLE 22 Ascorbyl Formulation HA Gel Lidocaine glucoside # [mg/ml] [mg/ml] [mg/ml] 22a 16 3 0   22b 16 3  0.17 22c 16 3 8.0

    [0225] The pH values of the formulations were adjusted to 7.5±0.2 and the formulations were filled in 1 ml glass syringes (BD Hypak SCF) and autoclaved in a Getinge GEV 6610 ERC-1 autoclave (F.sub.0˜26).

    [0226] A stability study in 90° C. for 16 hours was performed with sampling at 0, 8 and 16 hours.

    [0227] The rheological properties of the formulations were analysed using a Bohlin VOR Reometer (Measure system PP 30, Gap 1.00 mm). Initially a strain sweep was made to find the linear viscoelastic region (LVR) and then the viscoelastic properties were measured within the LVR.

    [0228] The results are presented in FIG. 22. Ascorbyl glucoside in the lower concentration does not affect the stability of the composition. The higher concentration of Ascorbyl glucoside decreases the stability of the composition. From these results it was concluded a concentration of Ascorbyl glucoside of below 5 mg/ml is preferred, since higher concentrations may result in unnecessary decrease of stability of the hyaluronic acid composition.