• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    COMPOSITION OF HYALURONIC ACID.It is a composition of injectable hyaluronic acid that comprises a hyaluronic acid; a local anesthetic selected from the group consisting of amide and ester local anesthetics or a combination thereof; and an ascorbic acid derivative in an amount that prevents or reduces the effect on viscosity and elastic modulus G 'of the composition caused by the local anesthetic by heat sterilization. The present invention also relates to medical and non-medical use, as a cosmetic of this composition, and to a method of manufacturing that composition.
    公开号:BR112013019500A2
    申请号:R112013019500-2
    申请日:2012-02-03
    公开日:2020-11-10
    发明作者:Katarina Edsman；Asa Wiebensjö
    申请人:Q-Med Ab；
    IPC主号:
    专利说明:

    "HYALURONIC ACID COMPOSITION" Field of the invention The present invention relates to the field of injectable hyaluronic acid compositions and the use of such compositions in cosmetic or medical applications. 5 Background One of the most widely used biocompatible polymers for medical use is hyaluronic acid.
    This is a naturally occurring polysaccharide that belongs to the group of glycosaminoglycans (GAGs). Hyaluronic acid and the other GAGs consist of negatively charged heteropolysaccharide chains that have the capacity to absorb 10 large amounts of water.
    Hyaluronic acid and products derived from hyaluronic acid are widely used in the biomedical and cosmetic fields, for example, during viscosurgery and as a skin filler.
    Water-absorbing gels, or hydrogels, are widely used in the bio-medical field.
    These are generally repaired by chemical crosslinking of polymers in infinite networks.
    Although native hyaluronic acid and some cross-linked hyaluronic acid products absorb water until they are completely dissolved, cross-linked hyaluronic acid gels typically absorb a certain amount of water until they are saturated, that is, they have a capacity finite liquid retention, or degree of expansion. 20 Since hyaluronic acid is present with an identical chemical structure except for its molecular mass in most living organisms, it provides minimal reactions and allows for advanced medical uses.
    Cross-linking and other modifications of the hyaluronic acid molecule are necessary to increase its in vivo duration.
    Furthermore, these modifications affect the liquid retention capacity of the hyaluronic acid molecule.
    As a consequence of this, hyaluronic acid has been the subject of many modification attempts.
    Hyaluronic acid products for injection are usually combined with a suitable anesthetic, for example, lidocaine, to reduce the pain or discomfort experienced by the patient due to the injection procedure. Description of the invention An object of the present invention is to provide an improved injectable hyaluronic acid composition for medical and non-medical applications.
    Hyaluronic acid compositions for use in injection need to be sterilized before use.
    Sterilization is usually performed by heat treatment, such as autoclave. The heat treatment generally results in a reduction in the stiffness or viscosity of the hyaluronic acid composition.
    As mentioned above, hyaluronic acid products for injection are generally combined with a suitable anesthetic, for example,
    caína, to reduce the pain or discomfort felt by the patient due to the injection procedure.
    It has been observed that the addition of some commonly used anesthetics, for example, lidocaine, neutralize the effect of heat treatment on the rheology of a hyaluronic acid composition in such a way that the resulting composition becomes more rigid or viscous than a gel without lidocaine. .
    This change in rheology can be disadvantageous in some applications, for example, in applications where superficial injection of the gel is required or desired, or when a very fine gauge needle is required or desired.
    Examples of such applications include revitalizing the skin and increasing soft tissue, for example, filling in wrinkles or contouring the face or body, by injections of hyaluronic acid gel. 10 It has been revealed that the addition of a relatively small amount of an ascorbic acid derivative to a hyaluronic acid composition comprising a local anesthetic selected from the group consisting of amide and ester local anesthetics can effectively reduce the "increase of viscosity "of the hyaluronic acid composition caused by the local anesthetic by sterilizing the composition by autoclave.
    Thus, the addition of a relatively small amount of an ascorbic acid derivative to a hyaluronic acid composition comprising a local anesthetic can facilitate the use of thinner needles for injection without increasing the force required to expel the composition and without making changes in the hyaluronic acid component.
    Also, the reduction in viscosity and the elastic modulus G 'of the solution is advantageous in applications where the composition is injected close to the skin surface, for example, in revitalizing the skin or increasing soft tissue, for example, filling in wrinkles. or contour of the face or body, by injecting hyaluronic acid gel.
    The effect of the ascorbic acid derivative on viscosity and elastic modulus G 'in the composition was shown for unmodified and modified hyaluronic acids, for example, cross-linked hyaluronic acids, this indicates that it is common to all compositions that comprise hyaluronic acid.
    In addition to the advantageous effect on viscosity and elastic modulus G 'in the composition, the addition of an ascorbic acid derivative to the composition also provides additional benefits.
    Ascorbic acid (also known as vitamin C) and its derivatives 30 can act as reducing agents and purge aggressive oxidizing agents and radicals.
    Since ascorbic acid and its derivatives can increase collagen formation, they can increase skin morphology.
    These can also increase the formation of an epidermal barrier, reduce the loss of transepidermal water, improve wound healing, and thus play an important role in preventing skin aging and associated dry skin conditions.
    Ascorbic acid and its derivatives are known for their anti-inflammatory and photoprotective properties as well as their action on improving skin damage induced by UV.
    It has also been shown that ascorbic acid and its derivatives can clinically improve dermatological conditions that have inflammation as a component of the disease process, such as psoriasis and asteatotic eczema.
    Since ascorbic acid and its derivatives can suppress the formation of melanin, they can also have a skin lightening effect, and these have demonstrated the clinical improvement of melasma and 5 senile freckles.
    These can also promote hair growth.
    It has been suggested that ascorbic acid and its derivatives also have anti-cancer properties.
    The addition of an ascorbic acid derivative to the hyaluronic acid composition generally has no effect, or little effect, on the stability of the composition.
    Notably, it has been observed that the addition of an ascorbic acid derivative does not increase the stability of the hyaluronic acid composition.
    Studies by the inventors have shown that the addition of the ascorbic acid derivative can sometimes result in a slight reduction in the stability of the hyaluronic acid composition.
    However, the inventors have found that the advantages associated with adding the ascorbic acid derivative outweigh the slight reduction in stability caused by the addition in some cases.
    To avoid unnecessary reduction in the stability of the hyaluronic acid composition, the concentration of the ascorbic acid derivative should be kept below the maximum concentrations as shown below.
    In accordance with the aspects illustrated here, an injectable hyaluronic acid composition is provided which comprises: a hyaluronic acid, 20 a local anesthetic selected from the group consisting of amide and ester local anesthetics or a combination thereof, and a derived from ascorbic acid in an amount that prevents or reduces the effect on viscosity and elastic modulus G 'of the composition caused by the local anesthetic by heat sterilization. The term "injectable" means that the hyaluronic acid composition is provided in a form that is suitable for parenteral injection, for example, into soft tissue, such as the skin, of an individual or patient.
    An injectable composition must be sterile and free of components that can cause adverse reactions when introduced into soft tissue, such as the skin, of an individual or patient.
    This implies that there is no immune response or very mild immune response in the treated individual.
    That is, there is no undesired local or systemic or only very mild effect on the treated individual.
    The viscosity and elastic modulus G 'of the hyaluronic acid composition can be measured according to various methods well known to the skilled person.
    The viscosity can be, for example, measured as "zero shear, river viscosity" 35 by rotational viscosimetry using a VOR Bohling rheometer (Measurement system 014 or PP 30, Gap 1.00 mm). Other methods of measuring viscosity may also be applicable.
    The elastic module G 'can, for example, be measured using a VOR rheometer
    Bohling (Measurement system PP 30, Gap 1.00 mm) when performing a deformation scan was performed to find the linear viscoelastic region (LVR) and then measure the viscoelastic properties within the LVR.
    Other methods for measuring the elastic modulus G 'may also be applicable. 5 The injectable hyaluronic acid composition is preferably aqueous and the hyaluronic acid, the local anesthetic and the ascorbic acid derivative are preferably expanded, dissolved or dispersed in the aqueous phase.
    The injectable hyaluronic acid composition comprises a hyaluronic acid.
    Hyaluronic acid can be a modified hyaluronic acid, for example, branched or reticulated.
    According to some modalities, hyaluronic acid is a cross-linked hyaluronic acid.
    According to specific modalities, hyaluronic acid is a hyaluronic acid gel.
    Unless otherwise stated, the term "hyaluronic acid" encompasses all variants and combinations of variants of hyaluronic acid, hyaluronate or hyaluronan, of various chain lengths and charge states, as well as with various chemical modifications, including crosslinking.
    That is, the term also covers the various hyaluronate salts of hyaluronic acid with various counterions, such as sodium hyaluronate.
    Various modifications of hyaluronic acid are also included by the term, such as oxidation, for example, oxidation of -CHZOH groups to -CHO and / or -COOH; oxidation of vicinal hydroxyl group periodate, 20 optionally followed by reduction, for example, reduction of -CHO to -CH2OH or coupling with amines to form imines followed by reduction to secondary amines; sulfation; deamidation, optionally followed by deamidation or amide formation with new acids; esterification; crosslinking; substitutions with various compounds, for example, using cross-linking agent or carbodiimide-assisted coupling; including 25 coupling of different molecules, such as proteins, peptides and active drug components, to hyaluronic acid; and deacetylation.
    Other examples of modifications are couplings of isourea, hydrazide, bromocyanine, monopoxide and monosulfone.
    Hyaluronic acid can be obtained from several sources of animal and non-animal origin.
    Sources of non-animal origin include yeast and, preferably, bacteria.
    The molecular weight of a single hyaluronic acid molecule is typically in the range of 0.1-10 MDa, however other molecular weights are possible.
    In some modalities, the concentration of said hyaluronic acid is in the range of 1 to 100 mglml.
    In some modalities, the concentration of said hyaluronic acid is in the range of 2 to 50 mglml.
    In specific modalities, the concentration of said hyaluronic acid 35 is in the range of 5 to 30 mglml or in the range of 10 to 30 mglml.
    In some embodiments, hyaluronic acid is cross-linked.
    The cross-linked hyaluronic acid comprises cross-links between the chains of hyaluronic acid, which create a continuous network of hyaluronic acid molecules that is kept linked by covalent cross-links, physical entanglement of the hyaluronic acid chains and various interactions, such as electrostatic interactions, hydrogen bonding and van der Weals forces.
    Crosslinking of hyaluronic acid can be carried out by modification with a chemical crosslinking agent.
    The chemical cross-linking agent can, for example, be selected from the group consisting of divinyl sulfone, multiepoxides and diepoxides.
    According to the modalities, the chemical cross-linking agent is selected from the group consisting of 1,4-butanediol diglycidyl ether (BDDE), 1,2-ethanediol diglycidyl ether (EDDE) and diepoxyoctane.
    According to a preferred embodiment, the chemical cross-linking agent is 1,4-butanediol 10 diglycidyl ether (BDDE). The cross-linked hyaluronic acid product is preferably biocompatible.
    This implies that there is no immune response or only very mild in the treated individual.
    That is, there is no undesired local or systemic or only very mild effect on the treated individual.
    The cross-linked hyaluronic acid product according to the invention can be a gel, 15 or a hydrogel.
    That is, it can be referred to as a water-insoluble, but substantially diluted, system of hyaluronic acid molecules when subjected to a liquid, typically an aqueous liquid.
    The gel generally contains liquid by weight and can contain, for example, 90-99.9% water, but behaves like a solid due to a network of three-dimensional crosslinked hyaluronic acid within the liquid.
    Due to its significant liquid content, the gel is structurally flexible and similar to natural tissue, which makes it very useful as a framework in tissue engineering and for tissue augmentation.
    As mentioned, the crosslinking of hyaluronic acid to form the crosslinked hyaluronic acid gel can, for example, be carried out by modification with a chemical crosslinking agent, for example, BDDE (1,4-butandiol diglycidylether). The concentration of hyaluronic acid and the extent of cross-linking affect the mechanical properties, for example, the properties of elastic modulus G ', and stability of the gel.
    Cross-linked hyaluronic acid gels are generally characterized in terms of "degree of modification". The degree of modification of hyaluronic acid gels generally varies between 0.1 and 15% per moi.
    It has been found that the effect of the ascorbic acid derivative on viscosity and elastic modulus G 'in the composition according to the present invention is particularly considerable in crosslinked hyaluronic acid gels with a low degree of modification.
    The most considerable effect is obtained in hyaluronic acid gels with a degree of modification of 2% per moi or less, such as 1.5% per moi or less, such as 1.25% per moi or less, for example, in the 0.1 to 35 2% per moi, as in the range of 0.2 to 1.5% per moi, as in the range of 0.3 to 1.25% per moi, as compared to more crosslinked hyaluronic acid gels.
    The degree of modification (% per moi) describes the amount of crosslinking agent (s) that is bound to HA, i.e., the molar amount of bound crosslinking agent (s) relative to the total molar amount of units of repeat HA disaccharide.
    The degree of modification reflects the degree to which HA has been minimally modified by the crosslinking agent.
    The reaction conditions for crosslinking and suitable analytical techniques to determine the degree of modification are well known 5 by those skilled in the art, who can easily adjust these and other relative factors and then provide adequate conditions to obtain a degree of modification in the range of 0 , 1-2% and check the resulting product characteristics in relation to the degree of modification.
    A BDDE crosslinked hyaluronic acid gel (1,4-butandiol diglycidyl ether) can, for example, be prepared according to the method described in Examples 1 and 2 of published international patent application WO 9704012. In a preferred embodiment, the acid The composition's hyaluronic acid is present in the form of a cross-linked hyaluronic acid gel that is cross-linked by a chemical cross-linking agent, in which the concentration of said hyaluronic acid is in the range of 10 to 30 mglml and the degree of change with the said chemical cross-linking agent is in the range of 0.1 to 2% 15 per moi.
    Hyaluronic acid gels can also comprise a portion of hyaluronic acid that is not cross-linked, that is, not linked to the three-dimensional cross-linked hyaluronic acid network.
    However, it is preferred that at least 50% by weight, preferably at least 60% by weight, more preferably, at least 70% by weight, and with maximum preference, at least 80% by weight, of the Hyaluronic acid in a gel composition forms part of the cross-linked hyaluronic acid network.
    The injectable hyaluronic acid composition further comprises a local anesthetic selected from the group consisting of amide and ester local anesthetics or a combination thereof.
    A local anesthetic is a drug that causes reversible local anesthesia and 25 loss of nociception.
    When it is used on specific nerve pathways (nerve block), effects such as analgesia (loss of sensation of pain) and paralysis (loss of muscle strength) can be obtained.
    The local anesthetic can be added to the hyaluronic acid composition to reduce the pain or discomfort experienced by the patient due to the injection procedure.
    The groups of amide-type local anesthetics (also commonly referred to as 30 aminoamides) and ester-type local anesthetics (also commonly referred to as aminoester) are well defined and identified by the technique.
    The amide and ester type local anesthetic molecules are constructed in a simple chemical plane, which consists of an aromatic part linked by an amide or ester bond to a basic side chain.
    The only exception is benzocaine, which has no basic group 35.
    All other anesthetics are weak bases, with pKa values generally in the range of 8-9, so that these are generally, but not completely, ionized at physiological pH.
    As a result of their similarity, they can be expected to have similar chemical and physical effects on the composition of hyaluronic acid.
    According to some modalities, the local anesthetic is selected from the group consisting of local anesthetics such as amide and ester, for example, bupivacaine, butanilicaine, carticaine, cinchocaine (dibucaine), clibucaine, ethyl parapiperidinoacetylamino-5 benzoate, etidocaine , lignocaine (lidocaine), mepivacaine, oxetazaine, prilocaine, ropivacaine, tolicaine, trimecaine, vadocaine, articaine, levobupivacaine, amylocaine, cocaine, propanocaine, chlormecaine, cyclomethecin, proximityetacaine, ametocaine (tetracaine), butane- , butoxicaine, butyl aminobenzoate, chloroprocaine, dimetocaine (larocaine), oxybuprocaine, piperocaine, paretoxicaine, procaine (novocaine), propoxicaine, tricaine or a combination thereof.
    According to some modalities, the local anesthetic is selected from the group consisting of amide-type local anesthetics, for example, bupivacaine, butanilica-ine, carticaine, cinchocaine (dibucaine), clibucaine, ethyl parapiperidinoacetylaminobenzoate, etidocaine, lignocaine (lidocaine ), mepivacaine, oxetazain, prilocaine, ropivacaine, 15 tolicaine, trimecain, vadocaine, articaine, levobupivacaine or a combination of these.
    According to some modalities, the local anesthetic is selected from the group consisting of bupivacaine, lidocaine, and ropivacaine, or a combination of these.
    According to specific modalities, the local anesthetic is lidocaine.
    Lidocaine is a well-known substance that has been used extensively as a local anesthetic in injectable formulations, such as hyaluronic acid compositions.
    The concentration of the amide or ester type local anesthetic can be selected by the skilled person within the therapeutically relevant concentration ranges of each specific local anesthetic or a combination of these.
    In some embodiments, the concentration of said local anesthetic is in the range of 25 0.1 to 30 mg / ml.
    In some modalities, the concentration of said local anesthetic is in the range of 0.5 to 10 mg / m1. When lidocaine is used as the local anesthetic, lidocaine may preferably be present in a concentration in the range of 1 to 5 mg / ml, more preferably in the range of 2 to 4 mg / ml, as in a concentration of about 3 mglml. 30 The injectable hyaluronic acid composition further comprises an ascorbic acid derivative.
    The term "ascorbic acid derivative", as used herein, means ascorbic acid or ascorbic acid derivatives that comprise the general chemical structure of asorbic acid.
    Thus, the ascorbic acid derivative can be a compound that comprises the chemical structure:
    9H
    0 0
    The ascorbic acid derivative of the composition can be ascorbic acid or a structurally related compound or derivative of ascorbic acid. Ascorbic acid itself may be useful in some applications, but due to its low stability, it may have limited use in some practical applications. The ascorbic acid derivative can be soluble in water. The solubility of the ascorbic acid derivative in water under atmospheric conditions may preferably be sufficient to allow the dissolution of a desired concentration of the ascorbic acid derivative in the composition. The water solubility of the water-soluble ascorbic acid derivative under atmospheric conditions may preferably be sufficient to allow a concentration of 0.001 mg / ml or more, and more preferably, 0.01 mglml or more, in the composition of hyaluronic acid. The ascorbic acid derivative may be able to form ascorbic acid or ascorbate in vivo, for example, through enzymatic degradation mediated by phosphatases, glucosidases, etc. Thus, according to one embodiment, the ascorbic acid derivative is capable of forming ascorbic acid or ascorbate when placed under in vivo conditions. In some embodiments, the ascorbic acid derivative is selected from the group consisting of an ascorbic acid phosphate ester, an ascorbic acid carboxylic acid ester, an ascorbic acid sulfate, an ascorbic acid sulfonate ester, an ascorbic acid carbonate and an ascorbic acid substituted by acetal or ketal, or a combination thereof. The ascorbic acid derivative can be, for example, a compound having the general formula: R4 R3 0H R2- 0 0R1 I) in which R1, R2, R3, R4 are, independently, H or an organic substituent. Compound I can be, for example, an ascorbic acid phosphate ester, where at least one of R1, R2, R3 and R4 is
    The 0, X where X is H, alkyl, alkenyl, alkynyl, aryl, an amine, an alcohol, a glycoside, or where n can be 0 to 500.
    The counterions can be, however without limiting character, Na *, K ', Ca24, A13 + Li + Zn2 + or Mg24 Compound I can be, for example, an ester of ascorbic acid carboxylic acid, in which at least one among R1 , R2, R3 and R4 is
    The `Y 5 where Y is H, alkyl, alkenyl, aikinyl, aryl, an amine, an alcohol, a glycoside, an amino acid ester or where n can be 0 to 500. Compound I can be, for example, a sulfate ascorbic acid, where at least one between RI, R2, R3 and R4 is
    O O. 10 Counterions can be, however without limiting character, Na ', K +, Ca2 +, AI3 + Li + Zn24 or Mgt +. Compound I can be, for example, an ascorbic acid sulfonate ester, where at least one between RI, R2, R3 and R4 is
    The S - z
    The 15 where Z is H, alkyl, alkenyl, alkynyl, aryl, an amine, an alcohol, a glycoside, or where n can be 0 to 500. Compound I can be, for example, an ascorbic acid carbonate, where at least one between R1, R2, R3 and R4 is
    The 20 where U is H, alkyl, alkenyl, alkynyl, aryl, an amine, an alcohol, a glycoside, or o`h'o where n can be 0 to 500. Compound 1 can be, for example, ascorbic acid replaced by acetal or ketal, where at least one between R1, R2, R3 and R4 is W wi 1 ~ where W, W ', and W "are H, alkyl, alkenyl, alkynyl, aryl, an amine, an alcohol, or 5 a carbohydrate residue, for example: o _ ooo Compound I can be, for example, an ascorbic acid substituted by acetal or ketal which has the general formula: H, Al k, Ar Aik, Ar- / p H o OHOOH, Alk, Ar Alk, Ar -) _ QH ~
    O O O O O A [k, Ary Fi, OAlk, Ar or o or Alk, Ar H. Alk, Ar where H is hydrogen, Alk is alkyl and Ar is aryl. In some embodiments, the ascorbic acid derivative is selected from the group consisting of ascorbyl phosphates, ascorbyl sulfates, and ascorbyl glycosides, or a combination thereof. In some embodiments, the ascorbic acid derivative is selected from the group consisting of ascorbyl phosphates and ascorbyl glycosides, or a combination of these. 15 In some embodiments, ascorbyl phosphate is selected from the group consisting of sodium ascorbic phosphate (SAP) and magnesium ascorbic phosphate (MAP), or a combination of these. Ascorbyl phosphates are converted to vitamin C in vivo by enzymatic hydrolysis by phosphatases. In some embodiments, the ascorbic acid derivative is an aminoalkyl phosphate of ascorbyl. In some embodiments, the ascorbic acid derivative is ascorbyl aminopropyl phosphate. In some embodiments, the ascorbic acid derivative is ascorbyl glucoside. Ascorbyl glucoside is converted into vitamin C in vivo by enzymatic hydrolysis by glucosidases. 25 In some embodiments, the ascorbic acid derivative is methylsilanol ascorbate. In some embodiments, the ascorbic acid derivative is accepted L-ascorbic acid.
    The ascorbic acid derivatives described herein can be in non-protonated or completely or partially protonated form, or in the form of a pharmaceutically acceptable salt.
    Specifically, the terms ascorbyl phosphate, ascorbyl sulfate, ascorbyl amino phosphate, ascorbyl amino propyl phosphate, ascorbyl glycoside and ascorbyl glucoside, as used herein, are intended to include the compounds in non-protonated or completely or partially protonated form , or in the form of a pharmaceutically acceptable salt.
    Examples of suitable counterions include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc.
    The concentration of the ascorbic acid derivative can be selected by the element skilled in the art depending on the specific ascorbic acid derivative used.
    In some embodiments, the concentration of said ascorbic acid derivative is in the range of 0.001 to 15 mglml.
    In some embodiments, the concentration of said ascorbic acid derivative is in the range of 0.001 to 10 mg / m1. In some embodiments, the concentration of said ascorbic acid derivative is in the range of 0.01 to 5 mglml.
    A concentration of said ascorbic acid derivative above 0.01 mg / ml is preferred since it provides a more significant reduction in viscosity and elastic modulus G 'of the hyaluronic acid composition.
    A concentration of said ascorbic acid derivative below 5 mg / ml is preferred since higher concentrations may result in an unnecessary reduction in stability of the hyaluronic acid composition without additional benefits. 20 The required concentration of the ascorbic acid derivative may vary within the ranges specified above depending on the particular ascorbic acid derivative used.
    As an example, a suitable concentration of sodium ascorbyl phosphate (SAP) or magnesium ascorbyl phosphate (MAP) can be in the range of 0.01 to 1 mglml, while an adequate concentration of ascorbyl glucoside can be in the range of 0, 1 to 5 mglml. 25 Accordingly, according to one embodiment, the ascorbic acid derivative is sodium ascorbyl phosphate (SAP) or magnesium ascorbyl phosphate (MAP) in a concentration in the range of 0.01 to 1 mgfml and, preferably, in the range of 0.01 to 0.5 mglml.
    According to another embodiment, the ascorbic acid derivative is ascorbyl glucoside in a concentration in the range of 0.01 to 1 mg / ml, preferably in the range of 0.01 to 30 0.8 mglml, and more preferably , in the range of 0.05 to 0.4 mglml.
    As mentioned, it has been observed that the addition of an ascorbic acid derivative does not increase the stability of the hyaluronic acid composition.
    In other words, the injectable hyaluronic acid composition according to the present invention does not exhibit increased stability compared to the same composition without an ascorbic acid derivative.
    The term stability, as used here, is used to denote the ability of the hyaluronic acid composition to resist degradation during storage and handling
    before use.
    It is known that the addition of constituents to a hyaluronic acid or hyaluronic acid gel can affect the stability of said hyaluronic acid or hyaluronic acid gel.
    The stability of hyaluronic acid or hyaluronic acid gel composition can be determined by a range of different methods.
    Methods for determining stability include, but are not limited to, assessing homogeneity, color, clarity, pH, gel content and rheological properties of the composition.
    The stability of a hyaluronic acid composition is generally determined by observing or measuring one or more of said parameters over time.
    Stability can, for example, be determined by measuring viscosity and elastic modulus G 'of the hyaluronic acid composition over time.
    Viscosity 10 can be measured, for example, as "zero shear viscosity, river" by rotational viscometer using a VOR Bohling rheometer (Measuring system C14 or PP 30, Gap 1.00 mm). Other methods of measuring viscosity may also be applicable.
    The elastic modulus G 'can, for example, be measured using a VOR Bohling rheometer (Measurement system PP 30, Gap 1.00 mm) when performing a deformation sweep was performed to find the linear viscoelastic region (LVR) and then measure the viscoelastic properties within the LVR.
    Other methods for measuring the elastic modulus G 'may also be applicable.
    In a more specific embodiment, an injectable hyaluronic acid composition is provided, which comprises an aqueous hyaluronic acid gel comprising 2 to 20 50 mglml of a hyaluronic acid; 0.5 to 10 mg / ml lidocaine; and 0.01 to 5 mglml of an ascorbic acid derivative selected from the group consisting of ascorbyl phosphates and ascorbyl glycosides, or a combination thereof.
    In a more specific embodiment, an injectable hyaluronic acid composition is provided, which comprises an aqueous hyaluronic acid gel comprising 2 to 25 50 mglml of a hyaluronic acid; 0.5 to 10 mglml of lidocaine; and 0.01 to 5 mg / ml of an ascorbyl phosphate, for example, sodium or magnesium ascorbyl phosphate.
    In another more specific embodiment, an injectable hyaluronic acid composition is provided, which comprises an aqueous hyaluronic acid gel that comprises 2 to 50 mglml of a hyaluronic acid; 0.5 to 10 mglml of lidocaine; and 0.01 to 5 mg / ml of an ascorbyl glycoside, for example, ascorbyl glucoside.
    In some modalities, the composition was subjected to sterilization.
    In some embodiments, the composition is sterilized, that is, the composition has undergone heat and / or steam treatment to sterilize the composition.
    In some embodiments, the composition was subjected to sterilization by autoclave or similar sterilization by heat or steam treatment.
    Can sterilization, for example, autoclave, be performed at an F9-value 4. The Fo value of a saturated steam sterilization process is the lethality expressed in terms of the equivalent time in minutes at a temperature of 121 ° C distributed by the process to the product in its final container with reference to microorganisms that have a Z value of 10. When hyaluronic acid compositions are sterilized by heat or steam treatment, viscosity and elastic modulus G 'are generally reduced.
    When a local anesthetic of the amide or ester type is added to the hyaluronic acid composition, this reduction in viscosity and elastic modulus G 'is reduced, resulting in a firmer or more viscous final product.
    The addition of the ascorbic acid derivative neutralizes this effect of the local anesthetic, thus producing a final product, which has a viscosity or elastic modulus G 'very similar to that of the composition of hyaluronic acid 10 without the local anesthetic, without making changes in the component. of hyaluronic acid.
    The cross-linked hyaluronic acid product according to the invention, or an aqueous composition thereof, can be supplied in the form of a pre-filled syringe, that is, a syringe that is pre-filled with a cross-linked hyaluronic acid composition and autoclaved. 15 The injectable hyaluronic acid compositions described here can be used in medical as well as non-medical procedures, for example, purely cosmetic, by injecting the composition into the soft tissues of a patient or individual.
    The compositions were considered useful, for example, in the increase of soft tissue, for example, filling of wrinkles, by injection of hyaluronic acid gel.
    The compositions were considered especially useful in a cosmetic treatment, referred to here as skin revitalization, with which small amounts of the hyaluronic acid composition are injected into the dermis in a number of injection sites distributed over an area of the skin that will be treated. , resulting in improved skin tone and skin elasticity.
    Skin revitalization is a simple procedure and the health risks associated with the procedure 25 are very low.
    In accordance with other aspects illustrated here, an injectable hyaluronic acid composition as described above is provided for use as a medication.
    The composition is useful, for example, in the treatment of various dermatological conditions.
    In particular, an injectable hyaluronic acid composition as described above is provided for use in a dermatological treatment selected from the group consisting of wound healing, treatment of dry skin or sun-damaged skin, treatment of disorders hyperpigmentation, treatment and prevention of hair loss, and treatment of conditions that have inflammation as a component of the disease process, such as psoriasis and asteatotic eczema.
    In other words, an injectable hyaluronic acid composition as described above is provided for use in the manufacture of a medicament for use in a dermatological treatment selected from the group consisting of wound healing, treatment of dry skin or skin conditions. sun damaged, treating hyperpigmentation disorders, treating and preventing hair loss, and treating conditions that have inflammation as a component of the disease process, such as psoriasis and asteatotic eczema.
    According to another embodiment, an injectable hyaluronic acid composition as described above is provided for use in the treatment of a joint disorder 5 by intra-articular injection.
    In accordance with other aspects illustrated here, the use of an injectable hyaluronic acid composition as described above is provided for cosmetic, non-medical treatment of an individual by injecting the composition into the individual's skin.
    A purpose of cosmetic, non-medical treatment may be to improve the appearance of the skin, prevent or treat hair loss, fill in wrinkles or contour an individual's face or body.
    Cosmetic, non-medical use does not involve the treatment of any form of illness or medical condition.
    Examples to improve the appearance of the skin include, but are not limited to, treating skin damaged or aged by the sun, revitalizing the skin, lightening the skin and treating hyperpigmentation disorders such as senile freckles, melasma and ephelides. 15 According to some modalities, the use of an injectable hyaluronic acid composition as described above is provided to improve the appearance of the skin, prevent and / or treat hair loss, fill in wrinkles or contour the face or body of an individual .
    The use preferably comprises injecting the composition into the skin or subcutis of a human individual.
    The use of the injectable hyaluronic acid composition to improve the appearance of the skin, prevent or treat hair loss, fill in wrinkles or contour an individual's face or body, can be essential or totally non-medical, for example, purely cosmetic.
    According to some modalities, the use of an injectable hyaluronic acid composition as described above is provided to improve the appearance of the skin.
    According to a preferred embodiment, the use of an injectable hyaluronic acid composition as described above is provided for the revitalization of the skin.
    According to some modalities, the use of an injectable hyaluronic acid composition as described above is provided to prevent and treat hair loss.
    According to some modalities, the use of an injectable hyaluronic acid composition as described above is provided to fill wrinkles or contour an individual's face or body.
    In accordance with other aspects illustrated here, a method is provided to improve the appearance of the skin, prevent and / or treat hair loss, fill in wrinkles or contour the face or body of an individual, comprising: a) providing a composition of injectable hyaluronic acid as described above, and b) inject said injectable hyaluronic acid composition into an individual's skin.
    In some embodiments, the injectable hyaluronic acid composition is injected into the skin or subcutis.
    According to some modalities, the method involves improving the appearance of the skin.
    According to a preferred embodiment, the method comprises revitalizing the skin. 5 According to some modalities, the method comprises preventing and treating hair loss.
    According to some modalities, the method comprises filling in wrinkles or contouring an individual's face or body.
    In accordance with other aspects illustrated here, a method of manufacturing a hyaluronic acid composition is provided which comprises: a) mixing a hyaluronic acid, a local anesthetic selected from the group consisting of local amide anesthetics and ester or a combination thereof, and an ascorbic acid derivative in an amount that prevents or reduces the effect on viscosity and the elastic modulus G 'of the composition caused by the local anesthetic by heat sterilization, and b) subject the mixture to heat sterilization.
    In the method of manufacturing the composition, said ascorbic acid derivative is operative to prevent or reduce the effect of the local anesthetic on the viscosity and / or elastic module G 'of the composition due to heat sterilization. The components of the composition, i.e., hyaluronic acid, local anesthetic and ascorbic acid derivative, can be further defined as described above for the injectable hyaluronic acid composition.
    The manufactured hyaluronic acid composition does not exhibit increased stability compared to the same composition without an ascorbic acid derivative. In some embodiments, the sterilization of step b) comprises subjecting the mixture to a heat treatment.
    In some embodiments, the sterilization of step b) comprises autoclaving the mixture at a Fo- 4. Sterilization can be further characterized as described above for the composition.
    In accordance with other aspects illustrated here, the use of an ascorbic acid derivative 30 in an injectable hyaluronic acid composition is provided, which further comprises a hyaluronic acid and a local anesthetic selected from the group consisting of local anesthetics amide and ester type or a combination of these, to prevent u reducing the effect of the local anesthetic on viscosity and the elastic modulus G 'of the composition due to heat sterilization. The components of the composition can be further defined as described above for the injectable hyaluronic acid composition.
    Sterilization can be further characterized as described above.
    The injectable hyaluronic acid composition formed using an ascorbic acid derivative does not exhibit increased stability compared to the same composition without an ascorbic acid derivative.
    Brief description of the drawings 5 Figure 1 is a graph showing the effect of MAP (Magnesium Ascorbyl Phosphate) on a hyaluronic acid gel with lidocaine.
    Figure 2 is a graph showing the effect of MAP on a hyaluronic acid gel with lidocaine.
    Figure 3 is a graph showing the effect of MAP on a non-10 hyaluronic acid cross-linked with lidocaine.
    Figure 4 is a graph showing the effect of MAP on a non-crosslinked hyaluronic acid with lidocaine.
    Figure 5 is a graph showing the effect of MAP on a hyaluronic acid gel with autoclaved lidocaine at various F0 values. 15 Figure 6 is a graph showing the effect of MAP on a hyaluronic acid gel with bupivacaine.
    Figure 7 is a graph showing the effect of MAP on a hyaluronic acid gel with tetracaine.
    Figure 8 is a graph showing the effect of SAP (Ascorbyl Sodium Phosphate) on a hyaluronic acid gel with lidocaine.
    Figure 9 is a graph showing the effect of methylsilanol ascorbate on a lidocaine hyaluronic acid gel.
    Figure 10 is a graph showing the effect of ascorbyl glucoside on a non-crosslinked hyaluronic acid with bupivacaine. 25 Figure 11 is a graph showing the effect of different concentrations of SAP on a gel of hyaluronic acid with lidocaine.
    Figure 12 is a graph showing the effect of L-ascorbic acid on a hyaluronic acid gel with tetracaine.
    Figure 13 is a graph showing the effect of SAP on a hyaluronic acid gel with lidocaine.
    Figure 14 is a graph showing the effect of Ascorbyl Aminopropyl Phosphate on a non-crosslinked hyaluronic acid with lidocaine.
    Figure 15 is a graph showing the effect of ascorbyl glucoside on a hyaluronic acid gel with lidocaine. 35 Figure 16 is a graph showing the effect of ascorbyl glucoside on a hyaluronic acid gel with lidocaine.
    Figure 17 is a graph showing the effect of ascorbyl glucoside on a hyaluronic acid gel with lidocaine. Figure 18 is a graph showing the effect of MAP on a hyaluronic acid gel with lidocaine. Figure 19 is a graph showing the effect of SAP on a gel of hyaluronic acid with lidocaine in a stability study. Figure 20 is a graph showing the effect of ascorbyl glucoside on a lidocaine hyaluronic acid gel in a stability study. Figure 21 is a graph showing the effect of MAP or ascorbyl glucoside on a hyaluronic acid gel with lidocaine in a stability study. 10 Figure 22 is a graph showing the effect of ascorbyl glucoside on a hyaluronic acid gel with lidocaine in a stability study. Detailed listing of modalities
    1. An injectable hyaluronic acid composition comprising -a hyaluronic acid, 15 -a local anesthetic selected from the group consisting of local anesthetics like amide and ester or a combination thereof, and -a derivative of ascorbic acid in one amount that prevents or reduces the effect on viscosity and the elastic modulus G 'of the composition caused by the local anesthetic through heat sterilization. 20 2. An injectable hyaluronic acid composition, according to item 1, in which said composition does not exhibit increased stability compared to the same composition without an ascorbic acid derivative.
    3. A composition of injectable hyaluronic acid, according to any of the previous items, in which said hyaluronic acid is a modified hyaluronic acid. 25 4. An injectable hyaluronic acid composition, according to item 3, in which said hyaluronic acid is a hyaluronic acid gel.
    5. An injectable hyaluronic acid composition, according to item 4, in which the hyaluronic acid gel is cross-linked by modification with a chemical cross-linking agent.
    6. An injectable hyaluronic acid composition, according to item 5, in which the chemical cross-linking agent is selected from the group consisting of divinyl sulfone, multiepoxides and diepoxides.
    7. An injectable hyaluronic acid composition, according to item 6, in which the chemical cross-linking agent is selected from the group consisting of 1,4-butanediol diglicidyl ether (BDDE), 1,2-ethanediol diglycidyl ether (EDDE) and diepoxyoctane. 35 8. An injectable hyaluronic acid composition, according to item 7, in which the chemical cross-linking agent is 1,4-butanediol diglycidyl ether (BDDE).
    9. An injectable hyaluronic acid composition according to any of items 5-8, in which the hyaluronic acid gel has a degree of modification of 2% per moi or less, such as 1.5% per moi or less, like 1.25% per moi or less.
    10. An injectable hyaluronic acid composition, according to any of items 5-8, in which the hyaluronic acid gel has a degree of modification in the range of 0.1 to 5 2% per moi, as in the range of 0 , 2 to 1.5% per moi, as in the range of 0.3 to 1.25% per moi.
    11. An injectable hyaluronic acid composition, according to any of the previous items, in which 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, in which 10 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, in which 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 of the previous items, in which said local anesthetic is selected from the group consisting of 15 lignocaine (lidocaine), bupivacaine, butanilicaine, carticaine, cincocaine (dibucaine), clibucaine, ethylparapiperidinoacetylaminobenzoate, etidocaine, mepivacaine, oxetazain, procaine, ropivacaine, tolicaine, trimecain, vadocaine, articaine, levobupivacaine, amiiocaine, cocaine, propanocaine, clamecake, amethycin, cyclomethacin, , butyl aminobenzoate, chloroprocaine, dimethocaine-20 (larocaine), oxybutocaine, piperocaine, paretoxicaine, procaine (novocaine), propoxycin, tricaine, or a combination thereof.
    15. An injectable hyaluronic acid composition, according to any of the previous items, in which said local anesthetic is selected from the group consisting of local amide anesthetics, or a combination of these. 16. An injectable hyaluronic acid composition, according to item 15, in which said local anesthetic is selected from the group consisting of lignocaine (lidocaine), bupivacaine, butanilicaine, carticaine, cincocaine (dibucaine), clibucaine, parapiperidinoace - ethyl tilaminobenzoate, ethidocaine, mepivacaine, oxetazaine, prilocaine, ropivacaine, tolicine, trimecaine, vadocaine, articaine, levobupivacaine or a combination of these. 17. An injectable hyaluronic acid composition, according to item 16, in which said local anesthetic is selected from the group consisting of lidocaine, bupivacaine, and ropivacaine, or a combination of these.
    18. An injectable hyaluronic acid composition, according to item 17, in which said local anesthetic is lidocaine. 35 19. An injectable hyaluronic acid composition, according to any of the previous items, in which the concentration of said local anesthetic is in the range of 0.1 to 30 mg / ml.
    20. A composition of injectable hyaluronic acid, according to item 19, in which 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, in which the concentration of said lidocaine is in the range of 1 to 5 mg / ml. 5 22. An injectable hyaluronic acid composition, according to item 21, in which the concentration of said lidocaine is in the range of 2 to 4 mg1m1.
    23. An injectable hyaluronic acid composition, according to item 22, in which the concentration of said lidocaine is about 3 mg / ml.
    24. An injectable hyaluronic acid composition, according to any of the 10 items above, in which said ascorbic acid derivative is a compound that comprises the chemical structure: 9H p 0 O O
    25. An injectable hyaluronic acid composition, according to any of the previous items, in which said ascorbic acid derivative is soluble in water under atmospheric conditions. 26. An injectable hyaluronic acid composition, according to any of the preceding items, wherein said ascorbic acid derivative is capable of forming the ascorbic acid or ascorbate when placed in in vivo conditions.
    27. An injectable hyaluronic acid composition, according to any of the previous items, wherein said ascorbic acid derivative is selected from the group 20 consisting of ascorbyl phosphate, ascorbyl sulfates, and ascorbyl glycosides, or a combination of these.
    28. An injectable hyaluronic acid composition according to any 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 of the previous 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 of the previous items, in which 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, in which the concentration of said ascorbic acid derivative is in the range of 0.001 to 10 mglml. 5 35. An injectable hyaluronic acid composition, according to item 34, in which the concentration of said ascorbic acid derivative is in the range of 0.01 to 5 mglml.
    36. An injectable hyaluronic acid composition, according to item 35, in which the concentration of said ascorbic acid derivative is in the range of 0.01 to 0.5 mglml.
    37. An injectable hyaluronic acid composition, according to item 30, in which 10 the concentration of said sodium ascorbyl phosphate (SAP) or magnesium ascorbyl phosphate (MAP) is in the range of 0.01 to 1 mglml.
    38. An injectable hyaluronic acid composition, according to item 37, in which the concentration of said sodium ascorbyl phosphate (SAP) or magnesium ascorbyl phosphate (MAP) is in the range of 0.01 to 0.5 mglml. 15 39. An injectable hyaluronic acid composition, according to item 31, in which 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, in which the concentration of said ascorbyl glucoside is in the range of 0.05 to 0.4 mglml.
    41. An injectable hyaluronic acid composition, according to item 1, comprising 20 - an aqueous hyaluronic acid gel comprising 2 to 50 mglml of a hyaluronic acid, -0.5 to 10 mglml of lidocaine, and -0.01 to 5 mglml of an ascorbic acid derivative selected from the group consisting of ascorbyl phosphates and ascorbyl glycosides, or a combination thereof.
    42. A sterile injectable hyaluronic acid composition, according to any of the previous items.
    43. A sterile hyaluronic acid composition, according to item 42, in which the composition was subjected to autoclave sterilization or similar heat sterilization.
    44. An injectable hyaluronic acid composition, as defined in any of items 1-43, for use as a medicine.
    45. An injectable hyaluronic acid composition, as defined in any of items 1-43, for use in a dermatological treatment selected from the group 35 consisting of wound healing, treatment of dry skin conditions and sun damaged skin , treatment of hyperpigmentation 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 asteatotic eczema.
    46. An injectable hyaluranic acid composition, as defined in any of items 1-43, for use in the treatment of a joint disorder by intra-articular injection. 5 47. Cosmetic, non-medical use of an injectable acid composition, as defined in any of items 1-43, to improve the appearance of the skin, prevent or treat hair loss, fill in wrinkles or contour the face or body of a person. an individual.
    48. Cosmetic, non-medical use, according to item 47, to improve the appearance of an individual's skin. 10 49. Cosmetic, non-medical use, according to item 47, to fill in an individual's wrinkles.
    50. Cosmetic, non-medical method to improve the appearance of the skin, prevent and treat hair loss, fill in wrinkles or contour the face or body of an individual, comprising 15 a) providing an injectable hyaluronic acid composition as defined in any of items 1-43, and b) inject said composition of injectable hyaluronic acid into an individual's skin.
    51. A method, according to item 50, in which the said composition of injectable hyaluronic acid is injected into the skin or subcutis. 20 52. A method of making a hyaluronic acid composition comprising: a) mixing a hyaluranic acid, a local anesthetic selected from the group consisting of local anesthetics like amide and ester or a combination thereof, and a derivative ascorbic acid in an amount that prevents or reduces the effect on viscosity and elastic modulus G 'of the composition caused by the local anesthetic through heat sterilization, and b) subject the mixture and heat sterilization.
    53. Method, according to item 52, in which the formed hyaluronic acid composition does not exhibit increased stability compared to the same composition without an ascorbic acid derivative.
    54. A method, according to any of items 52 and 53, in which step b) comprises subjecting the mixture to a value F0> _ 4.
    55. Use of an ascorbic acid derivative in an injectable hyaluronic acid composition that further comprises 35 - a hyaluronic acid, and -a local anesthetic selected from the group consisting of local amide and ester anesthetics or a combination thereof ,
    to prevent or reduce the effect of the local anesthetic on viscosity and the elastic modulus G 'of the composition due to heat sterilization.
    56. Use, according to item 55, in which the hyaluronic acid composition does not exhibit increased stability compared to the same composition without an ascorbic acid derivative. Examples Without limiting this, the present invention will be illustrated below by way of example. Since the polymer of hyaluronic acid and hyaluronic acid gel can always be subjected to some variations from batch to batch, each example was performed with a single batch of polymer of hyaluronic acid or hyaluronic acid gel to obtain comparable results. Slight variations, for example, in rheological properties or viscosity between similar compositions in different examples can occur due to these variations from batch to batch. Example 1. Hyaluronic acid gel with lidocaine and MAP 15 In this experiment, the rheological properties after autoclaving hyaluronic acid gels without additives were compared with hyaluronic acid gels with added docaine and hyaluronic acid gels with lidocaine and MAP added, respectively. The formulations having varying concentrations of lidocaine and MAP as shown in Table 1 were prepared as described below. Table 1, Formulation # HA Lidocaine MAP G 'gel [mg / mi] [mg / mi] [mg / mi] At 1.0 Hz [Pa] 1a 20 0 0 239 1b 20 3 0 437 1c 20 3 0, 07 394 1d 20 3 0.7 211 l and 20 1 0 440 1f 20 1 0.07 388 1g 20 1 0.7 206 In all formulations, a BODE crosslinked hyaluronic acid gel (1,4-butandiol diglycidylether) with a degree of modification of 1% per moi and a hyaluronic acid content of 20 mglml was used. The degree of modification (% per moi) describes the amount of crosslinking agent (s) that is bound to HA, that is, the molar amount of bound crosslinking agent (s) relative to the total molar amount of repeating HA disaccharide units. The degree of modification reflects the degree that HA has been chemically modified by the crosslinking agent.
    The BDDE crosslinked hyaluronic acid gel can, for example, be prepared according to the method described in Examples 1 and 2 of published international patent application WO 9704012. 5 A stock solution of monohydrated lidocaine hydrochloride (CAS number 6108-05-0, Sigma Aldrich, St Louis, USA) was prepared by dissolving the hydrochloride of lyocain monohydrate in WFI (water for injection) and a stock solution of Ascorbyl Magnesium Phosphate (MAP, CAS number 114040-31 -2, Nikko Chemicals co, Japan), was prepared by dissolving MAP in phosphate buffered saline (8 mM, 0.9% 10 NaCI). Formulation 1 a: The hyaluronic acid gel was diluted to the same degree as 1 b-1 g by adding phosphate buffered saline (8 mM, 0.9% NaCI). Formulation 1 b: 15 A stock solution of lidocaine was added to the hyaluronic acid gel in a final concentration of 3 mglml of gel.
    Formulation 1c: A lidocaine stock solution and a MAP stock solution were added to the hyaluronic acid gel in the final concentrations of 3 mg of lidocaine / ml and 20 0.07 mg of MAP / ml of gel.
    Formulations 1d-1g were prepared in the same way by varying the amounts of lidocaine stock solution and MAP stock solution.
    To all formulations, phosphate buffered saline (8 mM, 0.9% NaCI) was added to adjust the dilution to the same degree. 25 The pH values of the formulations were adjusted to 7.5 ± 0.2 and the formulations were loaded into 1 ml glass syringes (BD Hypak SCF) and autoclaved in a Getinge GEV 6610 ERC-1 autoclave (F0--30 ). The rheological properties of the formulations were analyzed using a VOR Bohling Rheometer (Measurement system PP 30, Gap 1.00 mm). Initially a deformation scan was performed to find the linear viscoelastic region (LVR) and then the viscoelastic properties were measured within the LVR.
    The results are shown in Figure 1. MAP neutralizes the effect on the elastic modulus G 'of the composition caused by the local anesthetic through heat sterilization.
    The higher the MAP concentration, the greater the reduction in elastic modulus G '. A higher concentration of lidocaine does not affect the increase over elastic modulus G '. Example 2. Hyaluronic acid gel with a higher degree of modification with Leirin to NAAP
    The formulations shown in Table 2 were prepared essentially according to the method described in Example 1, with the exception that a hyaluronic acid gel with a greater degree of modification (approximately 7%) was used.
    The hyaluronic acid gel can, for example, be prepared according to the method described in the examples of 5 US patent 6,921,819 B2. Table 2. Formulation # HA gel Lidocaine MAP G '[mg / ml] [mg / ml] [mg / ml] at 1.0 Hz [Pa] 2a 20 0 0 393 2b 20 3 0 417 2c 20 3 0, 3 388
    The pH values of the formulations were adjusted to 7.5 ± 0.2 and the formulations were loaded into 1 ml glass syringes (BD Hypak SCF) and autoclaved in a Getinge GEV 6610 ERC-1 (Fo-29) autoclave. rheological properties of the formulations were analyzed using a Reõ- • 10 meter VOR Bohling (Measurement system PP 30, Gap 1.00 mm). Initially, a deformation sweep to find the linear viscoelastic region (LVR) and then the viscoelastic properties were measured within the LVR. The results are shown in Figure 2. MAP neutralizes the effect on the elastic module G 'of the composition caused by local anesthetic through heat sterilization. 15 Example 3. Non-cross-linked hyaluronic acid with lidocaine and MAP The formulations shown in Table 3 were prepared essentially according to the method described in Example 1, with the exception that a non-cross-linked hyaluronic acid with an average molecular weight of 1 x 10 ' 5 Da was used.
    Table 3, Formulation # HA Lidocaine MAP Viscosity of cisa- [mg / mi] [mglml] [mg / ml] Zero insulation r) o [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 The pH values of the formulations were adjusted to 7.5 ± 0.2 and the formulations 20 were loaded into 1 ml glass syringes (BD Hypak SCF) and autoclaved in an autoclave Getinge GEV 6610 ERC-1 (F0--22) The viscosity of the formulations was studied using rotational viscometry used
    using a VOR Bohling rheometer (Measurement system PP 30, Gap 1.00 mm). The results are shown in Figure 3. MAP neutralizes the effect on the composition viscosity caused by the local anesthetic through heat sterilization.
    Example 4. Hyaluronic acid not cross-linked with lidocaine and MAP in lower concentrations The formulations shown 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 4. Formulation # HA Lidocaine MAP Viscosity of cisa- [mglml] [mglml] [mg / ml] Zero insulation in [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
    The pH values of the formulations were adjusted to 7.5 ± 0.2 and the formulations 10 were loaded into 1 ml glass syringes (BD Hypak SCF) and autoclaved in a Getinge GEV 6610 ERC-1 autoclave (F0--22 ). The viscosity of the formulations was studied using rotational viscometry using a VOR Bohling rheometer (Measurement system PP 30, Gap 1.00 mm). The results are shown in Figure 4. MAP neutralizes the effect on the viscosity of the composition caused by the local anesthetic through heat sterilization.
    Example 5. Hyaluronic acid gel with lidocaine and autoclaved MAP at different Fo values The formulations shown 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 5. Formulation # HA Lidocaine MAP Fa G '[mglml] [mg / m1] [mglml] Mean at 1.0 Hz [Pa] 5a 20 0 0 22 194 5b 20 3 0 22 269 Sc 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
    The pH values of the formulations were adjusted to 7.5 ± 0.2 and the formulations were loaded into 1 ml glass syringes (BD Hypak SCF) and autoclaved in a Getinge GEV 6610 ERC-1 autoclave at the different F0 values described in Table 5. The rheological properties of the formulations were analyzed using a Ror Bohling 5 meter (Measurement system PP 30, Gap 1.00 mm). Initially, a deformation sweep was performed to find the linear viscoelastic region (LVR) and then the viscoelastic properties were measured within the LVR.
    The results are shown in Figure 5. The effect on the elastic modulus G 'of the composition caused by the local anesthetic by heat sterilization is slightly greater for the upper F0 value.
    MAP neutralizes the effect on the elastic modulus G 'of the composition caused by the local anesthetic by means of heat sterilization.
    Example 6. Hyaluronic acid gel with buaivacaine and MAP The formulations shown 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 degree of modification of <1%, with a hyaluronic acid content of 12 mglml was used.
    Table 6. Formulation # MAP G 'Bupivacaine HA Gel [mglml] [mglml] [mg / mi] at 1.0 Hz [Pa] 6a 12 0 0 62 6b 12 1 0 90 6c 12 1 0.3 61
    The pH values of the formulations were adjusted to 7.5 ± 0.2 and the formulations were loaded into 1 ml glass syringes (BD Hypak SCF) and autoclaved in an autoclave Getinge GEV 6610 ERC-1 (FO -22) . The rheological properties of the formulations were analyzed using a VOR Bohling Rheometer (Measurement system PP 30, Gap 1.00 mm). Initially, a strain scan was performed to find the linear viscoelastic region (LVR) and then the viscoelastic properties were measured within the LVR. 25 The results are shown in Figure 6. Bupivacaine has a similar effect on the elastic modulus G 'of the composition as lidocaine.
    MAP neutralizes the effect on the elastic modulus G 'of the composition caused by the local anesthetic through heat sterilization.
    Example 7. Hyaluronic acid gel with tetracaine and MAP The formulations shown in Table 7 were prepared essentially according to the method described in Example 1 with the exception that lidocaine was replaced by 5 tetracaine (CAS number 136-47-0, Sigma Aldrich, St Louis, USA) and the MAP concentration was 0.3 mg / ml.
    Table 7. Formulation # MAP G 'HA gel Tetracaine [mg / mi] [mg / mi] [mglml] at 0.1 Hz [Pal 7a 20 0 0 154 7b 20 3 0 237 7c 20 3 0.3 196
    The pH values of the formulations were adjusted to 7.5 ± 0.2 and the formulations were loaded in 1 ml glass syringes (BD Hypak SCF) and autoclaved in a Getinge GEV 6610 ERC-1 (F0-22) autoclave. • 10 The rheological properties of the formulations were analyzed using a VOR Bohling Rheometer (Measurement system PP 30, Gap 1.00 mm). Initially, a strain scan was performed to find the linear viscoelastic region (LVR) and then the viscoelastic properties were measured within the LVR.
    The results are shown in Figure 7. Tetracaine has a similar effect 15 on the elastic modulus G 'of the lidocaine composition.
    MAP neutralizes the effect on the elastic modulus G 'of the composition caused by the local anesthetic through heat sterilization.
    Example 8. Hyaluronic acid gel with lidocaine and SAP The formulations shown in Table 10 were prepared essentially according to the method described in Example 1, with the exception that Ascorbyl Magnesium Phosphate (MAP) was replaced by Ascorbyl Phosphate Sodium (SAP). A SAP stock solution (CAS number 66170-10-3, Sigma Aldrich, St Louis, USA) was prepared by dissolving SAP in phosphate buffered saline (8 mM, 0.9% NaCI). Table 8. Formulation # HA Gel Lidocaine SAP G '[mg / mi] [mg / mi] [mg / mi] at 1.0 Hz [Pa] 8a 20 0 0 285 8b 20 3 0 430 8c 20 3 0, 07 374
    The pH values of the formulations were adjusted to 7.5 ± 0.2 and the formulations were loaded into 1 ml glass syringes (BD Hypak SCF) and autoclaved in a Getinge GEV 6610 ERC-1 autoclave (F0--29) . The rheological properties of the formulations were analyzed using a Vor Bohling 5 meter (Measurement system PP 30, Gap 1.00 mm). Initially, a strain scan was performed to find the linear viscoelastic region (LVR) and then the viscoelastic properties were measured within the LVR.
    The results are shown in Figure 8. SAP neutralizes the effect on the elastic modulus G 'of the composition caused by the local anesthetic through heat sterilization. 10 Example 9. Hyaluronic acid gel with lidocaine and methylsilanol ascorbate The formulations shown in Table 11 were prepared essentially according to the method described in Example 1, with the exceptions that Ascorbyl Magnesium Phosphate (MAP) was replaced by Ascorbosilane C ( product number 078, Exsymol, Monaco) containing methylsilanol ascorbate (CAS number 187991-39-5). Table 9. Formulation # HA gel Lidocaine G 'ascorbate [mg / ml] [mg / ml] methylsilanol at 1.0 Hz [Pa] [mg / ml] 9a 20 0 0 194 9b 20 3 0 269 9c 20 3 0.3 134
    15 The pH values of the formulations were adjusted to 7.5 ± 0.2 and the formulations were loaded into 1 ml glass syringes (BD Hypak SCF) and autoclaved in a Getinge GEV 6610 ERC-1 autoclave (F0-22) . The rheological properties of the formulations were analyzed using a VOR Bohling Rheometer (Measurement system PP 30, Gap 1.00 mm). Initially a deformation scan was performed to find the linear viscoelastic region (LVR) and then the viscoelastic properties were measured within the LVR.
    The results are shown in Figure 9. Methylsilanol ascorbate effectively neutralizes the effect on the elastic modulus G 'of the composition caused by the local anesthetic by means of heat sterilization. 25 Example 10. Non-cross-linked hyaluronic acid with bupivacaine and asbestos glucoside The formulations shown 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 10. Formulation # HA Bupivacaine Glucoside of viscosity of ci- [mglml] [mglml] ascorbyl zero salt [mg / ml] rio [Pas] 10a 20 0 0 1.79 10b 20 1 0 2.34 10c 20 1 5 2 , 11
    The pH values of the formulations were adjusted to 7.5 ± 0.2 and the formulations were loaded in 1 ml glass syringes (BD Hypak SCF) and autoclaved in a Getinge GEV 6610 ERC-1 (F0-22) autoclave. 5 The viscosity of the formulations was studied using rotational viscosimetry using a VOR Bohling rheometer (Measurement system C14). The results are shown in Figure 10. Ascorbyl glucoside neutralizes the effect on the viscosity of the composition caused by the local anesthetic by means of heat sterilization. 10 Example 11. Hyaluronic acid gel with lidocaine and different concentrations of SAP The formulations shown in Table 11 were prepared essentially according to the method described in Example 8, with the exception that different concentrations of Ascorbyl Sodium Phosphate, SAP were used.
    Table 11. Formulation # HA Lidocaine SAP G '[mglml] [mglml] [mglml] at 1.0 Hz [Pa] 11a 20 0 0 159 11b 20 3 0 290 11c 20 3 0.005 287 lid 20 3 0.1 256 11e 20 3 0.5 175
    The pH values of the formulations were adjusted to 7.5 ± 0.2 and the formulations 15 were loaded into 1 ml glass syringes (BD Hypak SCF) and autoclaved in a Getinge GEV 6610 ERC-1 autoclave (F0-22) . The rheological properties of the formulations were analyzed using a VOR Bohling Rheometer (Measurement system PP 30, Gap 1.00 mm). Initially a strain scan was performed to find the linear viscoelastic region (LVR) and then the 20 viscoelastic properties were measured within the LVR.
    The results are shown in Figure 11. SAP neutralizes the effect on the elastic modulus G 'of the composition caused by the local anesthetic through heat sterilization.
    The higher the concentration of SAP, the greater the effect.
    Example 12. Hyaluronic acid gel with tetracaine and L-ascorbic acid acetonide 5 The formulations shown in Table 12 were prepared essentially according to the method described in Example 7 with the exceptions that MAP was replaced by L-ascorbic acid acetonide (CAS number 15042-01-0, Carbosynth, Berkshire, UK) and a higher concentration of the derivative was used.
    Table 12. Formulation # HA gel Tetracaine L-ascorbic acid G '[mglml] [mglml] acetonide [mglml] at 1.0 Hz [Pa] 12a 20 0 0 266 12b 20 3 0 345 12c 20 3 1.0 25 The pH values of the formulations were adjusted to 7.5 ± 0.2 and the formulations 10 were loaded into 1 ml glass syringes (BD Hypak SCF) and autoclaved in an autoclave Getinge GEV 6610 ERC-1 (F0-5) . The rheological properties of the formulations were analyzed using a VOR Bohling Rheometer (Measurement system PP 30, Gap 1.00 mm). Initially, a deformation sweep was performed to find the linear viscoelastic region (LVR) and then the 15 viscoelastic properties were measured within the LVR.
    The results are shown in Figure 12. L-ascorbic acid acetonide effectively neutralizes the effect on the elastic modulus G 'of the composition caused by the local anesthetic by heat sterilization.
    Example 13. Hyaluronic acid gel with a higher degree of modification with lipid-bed and SAP The formulations shown in Table 13 were prepared essentially according to the method described in Example 1, with the exceptions that a hyaluronic acid gel with a greater degree of modification (approximately 7%) was used, that Ascorbyl Phosphate Magnesium (MAP) was replaced by Ascorbyl Phosphate Sodium, SAP (CAS number 25 66170-10-3, Sigma Aldrich, St Louis, USA), and that another concentration of the derivative was used.
    Table 13. Formulation # HA Gel Lidocaine SAP G '[mg / ml] [mglml] [mg / ml] at 1.0 Hz [Pa] 13a 20 0 0 1110 13b 20 3 0 1260 13c 20 3 0.1 1150
    The pH values of the formulations were adjusted to 7.5 ± 0.2 and the formulations were loaded into 1 ml glass syringes (BD Hypak SCF) and autoclaved in a Getinge GEV 6610 ERC-1 autoclave (F0--32) . The rheological properties of the formulations were analyzed using a Vor Bohling 5 meter (Measurement system PP 30, Gap 1.00 mm). Initially, a strain scan was performed to find the linear viscoelastic region (LVR) and then the viscoelastic properties were measured within the LVR.
    The results are shown in Figure 13. SAP neutralizes the effect on the elastic module G 'of the composition caused by the local anesthetic through sterilization by 10 heat.
    Example 14. Hyaluronic acid not cross-linked with lidocaine and Ascorbyl Aminopropyl Phosphate Table 14, Formulation # HA Lidocaine Aminopropyl Viscosity of [mg / mi] [mg / mi] Zero-shear phosphate corbila [mg / ml] rio [Pas] 14a 20 0 0 2.29 14b 20 3 0 3.45 14c 20 3 1.5 1.76 The formulations shown in Table 14 were prepared essentially according to the method described in Example 3, with the exceptions that Ascorbyl Phosphate 15 Magnesium (MAP) was replaced by Ascorbyl Aminopropyl Phosphate (Macro Care, South Korea) and a higher concentration of the derivative was used.
    The pH values of the formulations were adjusted to 7.5 ± 0.2 and the formulations were loaded in 1 ml glass syringes (BD Hypak SCF) and autoclaved in a Getinge GEV 6610 ERC-1 (F0-22) autoclave. 20 The viscosity of the formulations was studied using rotational viscometry using a VOR Bohling rheometer (Measurement system PP 30, Gap 1.00 mm). The results are shown in Figure 14. Ascorbyl aminopropyl phosphate effectively neutralizes the effect on the composition viscosity caused by the local anesthetic through heat sterilization. 25 Example 15. Hyaluronic acid gel with lidocaine and Ascorbyl glucoside The formulations shown in Table 15 were prepared essentially according to the method described in Example 1 with the exceptions that Ascorbyl Magnesium Phosphate (MAP) was replaced by Ascorbyl glucoside ( CarboMer, Inc, San Diego, USA) and another concentration of the derivative was used.
    Table 15. Formulation # Lidocaine Gel Glucoside G 'HA [mg / ml] of ascor- at 1.0 Hz [mg / ml] bila [mg / mi] [Pa] 15a 20 3 0 833 15b 20 3 0.08 777
    The pH values of the formulations were adjusted to 7.5 ± 0.2 and the formulations were loaded into 1 ml glass syringes (BD Hypak SCF) and autoclaved in a Getinge GEV 6610 ERC-1 (F0-23) autoclave. The rheological properties of the formulations were analyzed using a Vor Bohling 5 meter (Measurement system PP 30, Gap 1.00 mm). Initially, a strain scan was performed to find the linear viscoelastic region (LVR) and then the viscoelastic properties were measured within the LVR.
    The results are shown in Figure 15. Ascorbyl glucoside neutralizes the effect on the elastic modulus G 'of the composition caused by the local anesthetic by means of heat sterilization.
    Example 16. Hyaluronic acid gel with lidocaine and ascorbyl glucoside The formulations shown in Table 16 were prepared essentially according to the method described in Example 15 with the exceptions that the hyaluronic acid gel with a degree of modification of <1%, with a content of hyaluronic acid of 12 mglml was used and that a higher concentration of the derivative was used.
    Table 16. Formulation # HA gel Lidocaine G 'glucoside [mg / ml] [mg / ml] ascorbyl [mg / ml] at 1.0 Hz [Pa] 16a 12 3 0 84 16b 12 3 0.17 80
    The pH values of the formulations were adjusted to 7.5 ± 0.2 and the formulations were loaded into 1 ml glass syringes (BD Hypak SCF) and autoclaved in a Getinge GEV 6610 ERC-1 (F0-23) autoclave. The rheological properties of the formulations were analyzed using a Reõ-20 meter VOR Bohling (Measurement system PP 30, Gap 1.00 mm). Initially, a strain scan was performed to find the linear viscoelastic region (LVR) and then the viscoelastic properties were measured within the LVR.
    The results are shown in Figure 16. Ascorbyl glucoside neutralizes the effect on the elastic modulus G 'of the composition caused by the local anesthetic by means of heat sterilization.
    Example 17. Hyaluronic acid gel with lidocaine and ascorbyl glucoside Formulations shown in Table 17 were prepared essentially according to the method described in Example 15 with the exceptions that another manufacturer's ascorbyl glucoside 5 (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 mglml was used.
    Table 17. Formulation # HA Gel Lidocaine G 'glucoside [mg / mi] [mg / mi] ascorbyl [mg / mi] at 1.0 Hz [Pa] 17a 16 3 0 330 17b 16 3 0.8 314 17c 16 3 8.0 301
    The pH values of the formulations were adjusted to 7.5 ± 0.2 and the formulations were loaded into 1 ml glass syringes (BD Hypak SCF) and autoclaved in a Getinge GEV 6610 ERC-1 autoclave (F0-23 ). The rheological properties of the formulations were analyzed using a VOR Bohiing Rheometer (Measurement system PP 30, Gap 1.00 mm). Initially, a strain scan was performed to find the linear viscoelastic region (LVR) and then the viscoelastic properties were measured within the LVR. 15 The results are shown in Figure 17. Ascorbyl glucoside neutralizes the effect on the elastic modulus G 'of the composition caused by the local anesthetic by means of heat sterilization.
    Example 18. Hyaluronic acid gels with different degrees of modification with lidocaine and MAP 20 The formulations shown 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 18. Lidocaine Grade Gel formulation MAP G 'Reduction # HA / Modified solution [mg / mi] [mglm1] at 1.0 Hz in G' [mg / mi] [mole%] [Pa] [%] 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
    The pH values of the formulations were adjusted to 7.5 ± 0.2 and the formulations were loaded into 1 ml glass syringes (BD Hypak SCF) and autoclaved in a Getinge GEV 6610 ERC-1 (F0-V22) autoclave. The rheological properties of the formulations were analyzed using a VOR Bohling 5 meter (Measurement system PP 30, Gap 1.00 mm). Initially, a strain scan was performed to find the linear viscoelastic region (LVR) and then the viscoelastic properties were measured within the LVR.
    The results are shown in Figure 18. MAP neutralizes the effect on the elastic module G 'of the composition caused by the local anesthetic through sterilization by 10 heat.
    The effect is more evident in formulations with a lower degree of modification.
    Example 19. Stability study for 14 days at 60 ° C Hyaluronic acid gel with a greater degree of modification with lidocaine and SAP The formulations shown in Table 19 were prepared essentially according to the method described in Example 2, with the exceptions that Ascorbyl Phosphate 15 Magnesium (MAP) was replaced by Ascorbyl Phosphate Sodium, SAP and that a lower concentration of the derivative was used.
    Table 19. Formulation # HA Gel Lidocaine SAP [mglml] [mglml] [mglml] 19a 20 0 0 19b 20 3 0 19c 20 3 0.1
    The pH values of the formulations were adjusted to 7.5 ± 0.2 and the formulations were loaded into 1 ml glass syringes (BD Hypak SCF) and autoclaved in a Getinge GEV 6610 ERC-1 autoclave (F0--32) . 20 A stability study at 60 ° C for 14 days was carried out with sampling at 0, 3, 7, 11 and 14 days.
    The rheological properties of the formulations were analyzed using a VOR Bohling Rheometer (Measurement system PP 30, Gap 1.00 mm). Initially, a deformation sweep was performed to find the linear viscoelastic region (LVR) and then the 25 viscoelastic properties were measured within the LVR.
    The results are shown in Figure 19. The stability of the composition is not increased by SAP.
    The rate of degradation of the composition with SAP corresponds to the composition without SAP.
    Example 20. Stability study for 14 days at 60 ° C Hyaluronic acid gel with lidocaine and ascorbyl glucoside 5 The formulations shown in Table 20 were prepared essentially according to the method described in Example 1, with the exceptions that Ascorbyl Phosphate Magnesium (MAP) was replaced by Ascorbyl glucoside (CarboMer, Inc, San Diego, USA) and another concentration of the derivative was used.
    Table 20. Formulation # HA Gel Lidocaine Glucoside from [mglml] [mglml] ascorbyl [mglml] 20a 20 3 0 20b 20 3 0.17
    The pH values of the formulations were adjusted to 7.5 ± 0.2 and the - 10 formulations were loaded into 1 ml glass syringes (BD Hypak SCF) and autoclaved in a Getinge GEV 6610 ERC-1 autoclave (F0-22 ). A stability study at 60 ° C for 14 days was carried out with sampling at 0, 7 and 14 days.
    The gel content was determined by adding an excess of saline to a known amount of the preparation and dispersing the gel completely to form a diluted suspension.
    The diluted gel suspension was filtered through a 0.22 mm filter and the HA concentration in the filtrate, "the extractable part", was stopped using the carbazole method.
    The gel content was calculated as the fraction of HA in the charge that does not pass through the 0.22 mm filter when the diluted product suspension is filtered. 20 The results are shown in Figure 20. There is no change in the stability of the composition with ascorbyl glucoside compared to the formulation without ascorbyl glucoside.
    Example 21. Stability study for 14 days at 60 ° C Hyaluronic acid gel with lidocaine.
    MAP or Ascorbyl Glucoside 25 The formulations shown 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) was used and that a gel of hyaluronic acid with a degree of modification of <1%, with a content of hyaluronic acid of 12 mglml was used.
    Table 21. Formulation # HA Gel Lidocaine MAP Glucoside of [mg / M I] [mg / ml] [mglml] ascorbyl [mglml] 21a 12 3 0 0 21b 12 3 0.07 0 21c 12 3 0 0.07
    The pH values of the formulations were adjusted to 7.5 ± 0.2 and the formulations were loaded into 1 ml glass syringes (BD Hypak SCF) and autoclaved in a Getinge GEV 6610 ERC-1 (F0-26) autoclave. A stability study at 60 ° C for 14 days was carried out with sampling at 50, 3, 7, 11 and 14 days.
    The rheological properties of the formulations were analyzed using a VOR Bohling Rheometer (Measurement system PP 30, Gap 1.00 mm). Initially, a deformation sweep was performed to find the linear viscoelastic region (LVR) and then the viscoelastic properties were measured within the LVR. 10 The results are shown in Figure 21. The stability of the composition is not affected by Ascorbyl glucoside.
    In the MAP composition, a slight reduction in stability is observed.
    However, the inventors have found that the stability of the compositions is still acceptable and that the advantages associated with the addition of the derivative of ascorbic acid outweigh the slight reduction in stability caused by the addition. 15 Example 22. Stability study for 16 hours at 90 ° C Hyaluronic acid gel with lidocaine and Ascorbyl glucoside The formulations shown in Table 22 were prepared essentially according to the method described in Example 1, with the exceptions that Ascorbyl Phosphate Magnesium (MAP) was replaced by Ascorbyl Glucoside (Hayashibara Biochemical La-20 boratories, 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 mglml was used.
    Table 22. Formulation # HA gel Lidocaine Ascorbyl glucoside [mg / ml] [mglml] [mg / ml] 22a 16 3 0 22b 16 3 0.17 22c 16 3 8.0
    The pH values of the formulations were adjusted to 7.5 ± 0.2 and the formulations were loaded into 1 ml glass syringes (BD Hypak SCF) and autoclaved in a Getinge GEV 6610 ERC-1 (F0-26) autoclave. A stability study at 90 ° C for 16 hours was performed with sampling 5 at 0, 8 and 16 hours.
    The rheological properties of the formulations were analyzed using a VOR Bohling Rheometer (Measurement system PP 30, Gap 1.00 mm). Initially, a deformation sweep was performed to find the linear viscoelastic region (LVR) and then the viscoelastic properties were measured within the LVR. 10 The results are shown in Figure 22. Ascorbyl glucoside in the lowest concentration does not affect the stability of the composition.
    The higher concentration of ascorbyl glucoside reduces the stability of the composition.
    From these results, it was concluded that an ascorbyl glucoside concentration below 5 mg / ml is preferred, since higher concentrations may result in an unnecessary reduction in the stability of the hyaluronic acid composition.
    权利要求:
    Claims (24)
    [1]
    1. Use of an ascorbic acid derivative selected from the group consisting of ascorbyl phosphates, ascorbyl sulfates and ascorbyl glycosides, in a composition of injectable hyaluronic acid, FEATURED for additionally comprising: - a hyaluronic acid gel and - a therapeutically relevant concentration of a local anesthetic selected from the group consisting of amide and ester local anesthetics or a combination thereof, to prevent or reduce the effect of the local anesthetic on the viscosity and / or elastic modulus G 'of the composition due to heat sterilization, in which the concentration of said ascorbic acid derivative in the composition is in the range of 0.01 to 5 mg / ml.
    [2]
    2. Use, according to claim 1, CHARACTERIZED by the fact that the hyaluronic acid composition does not exhibit increased stability compared to the same composition without an ascorbic acid derivative.
    [3]
    3. Use, according to any of the preceding claims, CHARACTERIZED by the fact that the local anesthetic is lidocaine, preferably in a concentration in the range of 1 to 5 mg / ml.
    [4]
    4. Use according to any of the preceding claims, CHARACTERIZED by the fact that the ascorbic acid derivative is selected from the group consisting of ascorbyl phosphates and ascorbyl glycosides, or a combination thereof, preferably an ascorbyl glycoside more preferably, ascorbyl glucoside.
    [5]
    5. Use, according to any of the preceding claims, CHARACTERIZED by the fact that the concentration of the ascorbic acid derivative is in the range of 0.01 to 0.5 mg / ml.
    [6]
    6. Use, according to claim 4, CHARACTERIZED by the fact that the ascorbic acid derivative is selected from the group consisting of sodium ascorbyl phosphate (SAP) and magnesium ascorbyl phosphate (MAP) and the concentration of said ascorbyl phosphate sodium (SAP) or magnesium ascorbyl phosphate (MAP) is in the range of 0.01 to 1 mg / ml, preferably in the range of 0.01 to 0.5 mg / ml.
    [7]
    7. Use, according to claim 4, CHARACTERIZED by the fact that the ascorbic acid derivative is an ascorbyl glycoside and the concentration of said ascorbyl glycoside is in the range of 0.01 to 1 mg / ml, preferably in the range from 0.01 to 0.8 mg / ml, more preferably in the range of 0.05 to 0.4 mg / ml.
    [8]
    8. Composition of sterile injectable hyaluronic acid CHARACTERIZED by comprising: -a hyaluronic acid gel, -a therapeutically relevant concentration of a local anesthetic selected from the group consisting of amide and ester local anesthetics or a combination thereof, and - a derivative of ascorbic acid selected from the group consisting of ascorbyl phosphates, ascorbyl sulfates and ascorbyl glycosides, in an amount that prevents or reduces the effect on viscosity and / or elastic modulus G 'of the composition caused by the local anesthetic heat sterilization, in which the concentration of said ascorbic acid derivative in the composition is in the range of 0.01 to 5 mg / ml, and the composition was subjected to autoclaving sterilization at an F0 ≥ 4 value.
    [9]
    9. Composition of sterile injectable hyaluronic acid, according to claim 8, CHARACTERIZED by the fact that said composition does not exhibit increased stability compared to the same composition without an ascorbic acid derivative.
    [10]
    10. Sterile injectable hyaluronic acid composition, according to either of claims 8 or 9, CHARACTERIZED by the fact that said local anesthetic is lidocaine, preferably in a concentration in the range of 1 to 5 mg / ml.
    [11]
    11. Composition of sterile injectable hyaluronic acid according to any one of claims 8 to 10, CHARACTERIZED by the fact that said derivative of ascorbic acid is selected from the group consisting of ascorbyl phosphates and ascorbyl glycosides, or a combination thereof, preferably an ascorbyl glycoside, more preferably ascorbyl glucoside.
    [12]
    12. Sterile injectable hyaluronic acid composition according to any one of claims 8 to 11, CHARACTERIZED by the fact that the ascorbic acid derivative is in the range 0.01 to 0.5 mg / ml.
    [13]
    13. Composition of sterile injectable hyaluronic acid, according to claim 11, CHARACTERIZED by the fact that the ascorbic acid derivative is selected from the group consisting of sodium ascorbyl phosphate (SAP) and magnesium ascorbyl phosphate (MAP) and 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.
    [14]
    14. Sterile injectable hyaluronic acid composition, according to claim 11, CHARACTERIZED by the fact that the ascorbic acid derivative is ascorbyl glucoside and the concentration of said ascorbyl glucoside is in the range of 0.01 to 1 mg / ml preferably in the range of 0.01 to 0.8 mg / ml, more preferably in the range of 0.05 to 0.4 mg / ml.
    [15]
    15. Sterile injectable hyaluronic acid composition according to any of claims 8-14, CHARACTERIZED for use as a medicament.
    [16]
    16. Composition of sterile injectable hyaluronic acid, according to any one of claims 8-14, CHARACTERIZED for use in a dermatological treatment selected from the group consisting of wound healing, treatment of dry skin conditions and skin damaged by the sun, treatment of hyperpigmentation 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 astatic eczema.
    [17]
    17. Sterile injectable hyaluronic acid composition according to any one of claims 8-14, CHARACTERIZED for use in the treatment of a joint disorder by intra-articular injection.
    [18]
    18. Cosmetic, non-medical use of a sterile injectable acid composition, as defined in any of claims 8-14, CHARACTERIZED to improve the appearance of the skin, prevent and / or treat hair loss, fill in wrinkles or contour the face or body of an individual.
    [19]
    19. Cosmetic, non-medical use according to claim 18, CHARACTERIZED for improving the appearance of an individual's skin.
    [20]
    20. Cosmetic, non-medical use, according to claim 18, CHARACTERIZED for filling an individual's wrinkles.
    [21]
    21. Non-medical cosmetic method to improve the appearance of the skin, prevent and / or treat hair loss, fill in wrinkles or contour the face or body of an individual, FEATURED for understanding: a) providing a sterile injectable hyaluronic acid composition as defined in any one of claims 8-14, and b) injecting said sterile injectable hyaluronic acid composition into an individual's skin.
    [22]
    22. Method, according to claim 21, CHARACTERIZED by the fact that said sterile injectable hyaluronic acid composition is injected into the skin and / or subcutis.
    [23]
    23. Method of making a sterile injectable hyaluronic acid composition, CHARACTERIZED by understanding: a) mixing a hyaluronic acid gel, a therapeutically relevant concentration of a local anesthetic selected from the group consisting of local anesthetics from amide and ester type or a combination thereof, and an ascorbic acid derivative selected from the group consisting of ascorbyl phosphates, ascorbyl sulfates and ascorbyl glycosides, in an amount that prevents or reduces the effect on viscosity and / or elastic modulus G 'of the composition caused by the local anesthetic by heat sterilization, in which the concentration of said ascorbic acid derivative in the composition is in the range of 0.01 to 5 mg / ml, and b) submit the mixture is sterilized by autoclaving at an F0 value ≥ 4.
    [24]
    24. Method, according to claim 23, CHARACTERIZED in that the formed hyaluronic acid composition does not exhibit increased stability compared to the same composition without an ascorbic acid derivative.
    类似技术:
    公开号 | 公开日 | 专利标题
    US11154481B2|2021-10-26|Hyaluronic acid composition
    US8455465B2|2013-06-04|Heat sterilised injectable composition of hyaluronic acid or one of the salts thereof, polyols and lidocaine
    US10322212B2|2019-06-18|Composition comprising hyaluronic acid and mepivacaine
    ES2735376T3|2019-12-18|Injectable hyaluronic acid gel for the treatment of joint degeneration
    BR112015007772B1|2020-05-05|sterile injectable aqueous formulation containing cross-linked hyaluronic acid and hydroxyapatite for aesthetic use
    KR20180004256A|2018-01-10|A composition comprising at least one polyol and at least one anesthetic agent
    US10898613B2|2021-01-26|Hyaluronic acid gel with a divalent zinc cation
    KR102348467B1|2022-01-07|A method for manufacturing a filler containing dna fraction and the filler prepared therefrom
    WO2019002371A1|2019-01-03|Glycosaminoglycan gel with bis-tris buffer
    WO2019001784A1|2019-01-03|Hyaluronic acid gel with a divalent cation
    同族专利:
    公开号 | 公开日
    US20200261343A1|2020-08-20|
    MX340148B|2016-06-28|
    KR102030508B1|2019-10-10|
    JP2014504623A|2014-02-24|
    RU2605298C2|2016-12-20|
    US20190000740A1|2019-01-03|
    US20140039061A1|2014-02-06|
    ES2548187T3|2015-10-14|
    WO2012104419A1|2012-08-09|
    CA2825352A1|2012-08-09|
    US11154481B2|2021-10-26|
    JP6023086B2|2016-11-09|
    RU2013140182A|2015-03-10|
    MX2013008883A|2014-03-12|
    EP2670447B9|2017-12-27|
    EP2484387A1|2012-08-08|
    CN103415307B|2015-11-25|
    US20220000752A1|2022-01-06|
    EP2670447B1|2015-07-01|
    KR20140049967A|2014-04-28|
    CN103415307A|2013-11-27|
    AR085128A1|2013-09-11|
    EP2954907A1|2015-12-16|
    US10098961B2|2018-10-16|
    EP2670447A1|2013-12-11|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    JPH0753426B2|1988-12-28|1995-06-07|日立化成工業株式会社|Continuous molding method of fiber reinforced plastic with embossed pattern|
    JPH0552808B2|1989-02-15|1993-08-06|Chisso Corp|
    US5827937A|1995-07-17|1998-10-27|Q Med Ab|Polysaccharide gel composition|
    FR2737971B1|1995-08-25|1997-11-14|Lvmh Rech|USE OF VITAMIN C OR DERIVATIVES OR THE LIKE TO STIMULATE SKIN ELASTINE SYNTHESIS|
    US6063061A|1996-08-27|2000-05-16|Fusion Medical Technologies, Inc.|Fragmented polymeric compositions and methods for their use|
    TW581680B|1998-03-31|2004-04-01|Mary Kay Cosmetics Inc|A whitening cosmetic composition and a pharmaceutical composition for treating hyperpigmentation|
    FR2811996B1|2000-07-19|2003-08-08|Corneal Ind|CROSS-LINKING OF POLYSACCHARIDE , PREPARATION OF HYDROGEL ; POLYSACCHARIDE AND HYDROGEL OBTAINED, THEIR USES|
    DE10246340A1|2002-10-04|2004-04-29|Wohlrab, David, Dr.|Combination preparation of hyaluronic acid and at least one local anesthetic and its use|
    US20070129430A1|2003-10-07|2007-06-07|Satomi Miyata|Agent for enhancing the production of collagen, their preparation and use|
    US8124120B2|2003-12-22|2012-02-28|Anika Therapeutics, Inc.|Crosslinked hyaluronic acid compositions for tissue augmentation|
    US20060040895A1|2004-08-19|2006-02-23|Kipling Thacker|Aesthetic use of hyaluronan|
    WO2007041627A1|2005-10-03|2007-04-12|Pinsky Mark A|Compositions and methods for improved skin care|
    EP1884231A1|2006-08-01|2008-02-06|Auriga International S.A.|Cosmetic or pharmaceutical composition containing hyaluronic acid|
    FR2909560B1|2006-12-06|2012-12-28|Fabre Pierre Dermo Cosmetique|HYALURONIC ACID GEL FOR INTRADERMAL INJECTION|
    US9011894B2|2007-06-29|2015-04-21|Carbylan Therapeutics, Inc.|Sterile hyaluronic acid polymer compositions and related methods|
    EP2033689A1|2007-08-22|2009-03-11|Italfarmacia S.r.l.|Injectable dermatological composition for treatment of the wrinkles|
    US9481856B2|2008-06-09|2016-11-01|Bausch & Lomb Incorporated|Pharmaceutical formulations comprising stabilized polysaccharides and source of hydrogen peroxide|
    US8357795B2|2008-08-04|2013-01-22|Allergan, Inc.|Hyaluronic acid-based gels including lidocaine|
    FR2938187B1|2008-11-07|2012-08-17|Anteis Sa|INJECTABLE COMPOSITION BASED ON HYALURONIC ACID OR ONE OF ITS HEAT-STERILIZED SALTS, POLYOLS AND LIDOCAINE|
    CN101890182B|2009-09-16|2013-10-30|上海其胜生物制剂有限公司|Preparation method of medical hyaluronic acid gel preparation for sterilizing high-pressure steam|
    US20110171310A1|2010-01-13|2011-07-14|Allergan Industrie, Sas|Hydrogel compositions comprising vasoconstricting and anti-hemorrhagic agents for dermatological use|
    US20110171311A1|2010-01-13|2011-07-14|Allergan Industrie, Sas|Stable hydrogel compositions including additives|
    US20110172180A1|2010-01-13|2011-07-14|Allergan Industrie. Sas|Heat stable hyaluronic acid compositions for dermatological use|
    KR102111170B1|2011-01-13|2020-05-15|알러간, 인코포레이티드|Stable Hydrogel Compositions Including Additives|
    EP2484387A1|2011-02-03|2012-08-08|Q-Med AB|Hyaluronic acid composition|
    ES2777176T3|2011-08-25|2020-08-04|Allergan Industrie Sas|Dermal filler compositions that include antioxidants|
    CN104105474B|2011-09-14|2018-04-06|阿勒根公司|Dermal augmentation agent composition for microgroove treatment|
    FR2994846B1|2012-08-29|2014-12-26|Vivacy Lab|COMPOSITION, STERILIZED, COMPRISING AT LEAST ONE HYALURONIC ACID AND MAGNESIUM ASCORBYL PHOSPHATE|TWI328457B|2003-03-18|2010-08-11|Suntory Holdings Ltd|Angiotensin-converting enzyme inhibitory peptides|
    US20110171310A1|2010-01-13|2011-07-14|Allergan Industrie, Sas|Hydrogel compositions comprising vasoconstricting and anti-hemorrhagic agents for dermatological use|
    US20110172180A1|2010-01-13|2011-07-14|Allergan Industrie. Sas|Heat stable hyaluronic acid compositions for dermatological use|
    US9114188B2|2010-01-13|2015-08-25|Allergan, Industrie, S.A.S.|Stable hydrogel compositions including additives|
    EP2484387A1|2011-02-03|2012-08-08|Q-Med AB|Hyaluronic acid composition|
    US9408797B2|2011-06-03|2016-08-09|Allergan, Inc.|Dermal filler compositions for fine line treatment|
    US9393263B2|2011-06-03|2016-07-19|Allergan, Inc.|Dermal filler compositions including antioxidants|
    US20130096081A1|2011-06-03|2013-04-18|Allergan, Inc.|Dermal filler compositions|
    KR102015676B1|2011-06-03|2019-10-21|알러간, 인코포레이티드|Dermal filler compositions including antioxidants|
    FR2994846B1|2012-08-29|2014-12-26|Vivacy Lab|COMPOSITION, STERILIZED, COMPRISING AT LEAST ONE HYALURONIC ACID AND MAGNESIUM ASCORBYL PHOSPHATE|
    CA2896646A1|2012-12-27|2014-07-03|Hayashibara Co., Ltd.|Skin-exterior anti-ageing composition and production method therefor|
    US9421198B2|2013-07-30|2016-08-23|Teoxane|Composition comprising hyaluronic acid and mepivacaine|
    JP2017506208A|2013-10-07|2017-03-02|ボストン サイエンティフィック サイムド，インコーポレイテッドＢｏｓｔｏｎ Ｓｃｉｅｎｔｉｆｉｃ Ｓｃｉｍｅｄ，Ｉｎｃ．|Injectable composition|
    FR3015290B1|2013-12-23|2017-01-13|Lab Vivacy|HYALURONIC ACID COMPOSITIONS COMPRISING MEPIVACAINE|
    FR3036035B1|2015-05-11|2018-10-05|Laboratoires Vivacy|COMPOSITIONS COMPRISING AT LEAST ONE POLYOL AND AT LEAST ONE ANESTHETIC|
    US10004824B2|2015-05-11|2018-06-26|Laboratoires Vivacy|Compositions comprising at least one polyol and at least one anesthetic|
    CN105131348B|2015-08-19|2018-01-16|李媚|A kind of sterile injectable material|
    CN105107018B|2015-08-19|2018-08-24|李媚|A kind of preparation method of sterile injection material|
    KR101866310B1|2016-05-31|2018-06-11|주식회사 글랜젠|Skin filling material having improved durability and antioxidative activity and the maufacturing method thereof|
    EP3364942A4|2016-06-27|2019-07-17|Advanced Aesthetic Technologies, Inc.|Kits and methods of using ascorbates to modify polysaccharide fillers and delivery systems|
    KR101926751B1|2016-10-07|2019-03-07|김동진|Coated Thread For Dermal Filling And Its Coating Method|
    FR3058064B1|2016-10-28|2020-08-07|Lab Vivacy|COMPOSITION BASED ON HYALURONIC ACID INCLUDING MEPIVACAINE|
    US11058623B2|2016-12-01|2021-07-13|Daniel Dal' Asta Coimbra|Non-therapeutic method, uses of a substance that stimulates or generates an increase in volume|
    EP3562469A1|2016-12-29|2019-11-06|Nestlé Skin Health SA|Micro- or nanoparticular vesicles comprising crosslinked hyaluronic acid, compositions comprising the same and method for their use in skin care|
    EP3562470A1|2016-12-29|2019-11-06|Nestlé Skin Health SA|Composition comprising a crosslinked hyaluronic acidin combination with a low-molecular ha and/or an agent stimulating endogenous ha synthesis|
    US20210283172A1|2017-04-12|2021-09-16|Urigen Pharmaceuticals, Inc.|Article of manufacture comprising local anesthetic, buffer, and glycosaminoglycan in syringe with improved stability|
    WO2018220283A1|2017-05-29|2018-12-06|Kh Medtech Sarl|Sterile injectable composition containing cross-linked hyaluronic acid and articaine|
    WO2019001784A1|2017-06-28|2019-01-03|Nestlé Skin Health Sa|Hyaluronic acid gel with a divalent cation|
    KR102091452B1|2017-12-19|2020-03-20|대화제약 주식회사|Method for preparing prefilled syringe comprising local anesthetics and hyaluronic acid hydrogel|
    WO2019121694A1|2017-12-22|2019-06-27|Nestlé Skin Health Sa|Injectable compositions of cross-linked hyaluronic acid and bupivacaine, and uses thereof|
    WO2021173749A1|2020-02-25|2021-09-02|Amplifica, Inc.|Compositions and methods for stimulating hair growth|
    FR3111903A1|2020-06-24|2021-12-31|Laboratoires Vivacy|PROCESS FOR INCORPORATION OF ORGANIC COMPOUNDS IN SOLUTION WITHIN A HYDROGEL|
    法律状态:
    2020-11-17| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|
    2020-12-08| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2021-02-23| B08F| Application dismissed because of non-payment of annual fees [chapter 8.6 patent gazette]|Free format text: REFERENTE A 9A ANUIDADE. |
    2021-03-02| B11B| Dismissal acc. art. 36, par 1 of ipl - no reply within 90 days to fullfil the necessary requirements|
    2021-12-07| B350| Update of information on the portal [chapter 15.35 patent gazette]|
    优先权:
    申请号 | 申请日 | 专利标题
    EP11153232A|EP2484387A1|2011-02-03|2011-02-03|Hyaluronic acid composition|
    EP11153232.1|2011-02-03|
    PCT/EP2012/051875|WO2012104419A1|2011-02-03|2012-02-03|Hyaluronic acid composition|
    [返回顶部]