WO2021077681A1 - 一种用于水光注射的透明质酸凝胶组合物及其制备方法 - Google Patents
一种用于水光注射的透明质酸凝胶组合物及其制备方法 Download PDFInfo
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- WO2021077681A1 WO2021077681A1 PCT/CN2020/082546 CN2020082546W WO2021077681A1 WO 2021077681 A1 WO2021077681 A1 WO 2021077681A1 CN 2020082546 W CN2020082546 W CN 2020082546W WO 2021077681 A1 WO2021077681 A1 WO 2021077681A1
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- hyaluronic acid
- water
- gel composition
- light injection
- acid gel
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Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
- A61K8/73—Polysaccharides
- A61K8/735—Mucopolysaccharides, e.g. hyaluronic acid; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
- A61K8/04—Dispersions; Emulsions
- A61K8/042—Gels
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J3/00—Processes of treating or compounding macromolecular substances
- C08J3/02—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
- C08J3/03—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media
- C08J3/075—Macromolecular gels
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/80—Process related aspects concerning the preparation of the cosmetic composition or the storage or application thereof
- A61K2800/91—Injection
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2305/00—Characterised by the use of polysaccharides or of their derivatives not provided for in groups C08J2301/00 or C08J2303/00
- C08J2305/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2405/00—Characterised by the use of polysaccharides or of their derivatives not provided for in groups C08J2401/00 or C08J2403/00
- C08J2405/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
Definitions
- the present invention relates to the field of biomedicine, in particular to a hyaluronic acid gel composition for water-light injection, and also relates to a preparation method of the hyaluronic acid gel composition for water-light injection.
- Water and light injection is currently one of the most extensive medical beauty projects at home and abroad. It can effectively solve the problem of skin care products that are not easily absorbed through the epidermal barrier. It can quickly and effectively replenish the skin, thereby effectively improving skin quality and delaying senescence.
- Water-light injection originated from Mesotherapy proposed by French doctor Michal Pistor in 1952. The idea is to inject a small amount of therapeutic substance into the local superficial surface. After decades of hard work, the current water-light acupuncture technology was developed.
- Water-light injection uses negative pressure technology to accurately pierce several extremely thin needles into the skin about 1 to 2 mm, and directly transport the repairing substance through the epidermal layer into the epidermis and the dermis or the dermis layer, which solves the effective ingredients in skin care products.
- Hyaluronic acid also known as hyaluronic acid, is an acidic mucopolysaccharide inherent in the human body. It is widely used in various skin care products. It is a super moisturizing agent naturally present in human skin and can maintain moisture 1,000 times its own weight. The moisture level of the skin is closely related to the content and molecular weight of hyaluronic acid. High molecular weight hyaluronic acid has stronger water retention properties. With the increase of age and the destruction of daily active oxygen free radicals, the endogenous hyaluronic acid in the skin is continuously degraded and lost, and the water retention function is gradually weakened, which leads to various skin aging symptoms, such as dryness, roughness, and dullness. , Relaxation, wrinkles, etc. (Stern et al. Clinics in Dermatology 2008, 26: 106-122; Papakonstantinou et al., Dermatoendocrinol 2012, 4: 253-258).
- Supplementing exogenous hyaluronic acid is an important measure to improve skin texture, delay aging symptoms and restore youthfulness.
- the hyaluronic acid applied on the skin surface is difficult to be effectively absorbed, especially the high molecular weight hyaluronic acid with super moisturizing ability.
- Water-light injection of hyaluronic acid can directly penetrate the epidermal barrier, and can immediately replenish hyaluronic acid in the superficial layer of the skin to achieve the effect of rapid moisturizing and moisturizing and achieve the ultimate goal of improving skin quality.
- water-light injection is mainly superficial injection to supplement exogenous hyaluronic acid, and it also contains other restorative nutrients as appropriate.
- CN 106074213A discloses a hyaluronic acid gel for water and light injection, which consists of 10-30 parts of sodium hyaluronate, 0.5-3 parts of glycerin, 0.5-1.5 parts of mannitol, and 1-9 parts of mannitol. The pH adjuster and 25 to 45 parts of isotonic adjuster.
- CN 105233270A discloses a pharmaceutical composition for water-light therapy and its application.
- composition includes: 0.01-0.5wt% high molecular weight sodium hyaluronate, 0.01-0.3wt% medium molecular weight sodium hyaluronate, 0.01-1wt% % Low molecular weight sodium hyaluronate, 0.01-1wt% oligomeric sodium hyaluronate, 0.01-5wt% collagen, 0.05-1.8wt% adjuvant, recombinant human epidermal growth factor, the balance is water, reconstituted
- concentration of human epidermal growth factor is 0.5-10 ⁇ g/ml; the molecular weight of high molecular weight sodium hyaluronate is 1.3-2 million daltons, the molecular weight of medium molecular weight sodium hyaluronate is 500,000-1 million daltons, and the low molecular weight is transparent
- the molecular weight of sodium phosphate is 50,000 to 300,000 daltons, and the molecular weight of oligomeric sodium hyaluronate is
- hyaluronic acid is rapidly degraded into small molecular fragments and enters the body fluid circulation to be absorbed and metabolized, and loses the function of moisturizing and moisturizing in the skin; in the skin, the half-life of hyaluronic acid is less than 1 Tian (Laurent et al., Exp Physiol 1991, 76: 695-703). Therefore, although water injection can quickly replenish hyaluronic acid in the skin, it can only moisturize and moisturize in a short time, and it is difficult to achieve long-term effects such as improving skin texture, delaying aging and restoring youthfulness. For example, the research results of Amin et al.
- Cross-linking modification can delay the degradation and absorption of hyaluronic acid in the body, such as 1,4-butanediol diglycidyl ether (BDDE) cross-linked hyaluronic acid gel (such as Rui Lan Etc.)
- BDDE 1,4-butanediol diglycidyl ether
- the degradation and absorption time under the skin can be as long as 6 months, and it is widely used for wrinkle injection and filling.
- cross-linked hyaluronic acid gel products are very high (usually not less than 20mg/mL) (Edsman et al., Dermatol Surg 2012, 38:1170-1179), that is, the water content is usually not more than 98% (cross-linked The water content of hyaluronic acid is about 49 times of its own weight), and its moisturizing and moisturizing properties are poor; in addition, these cross-linked hyaluronic acid gel products also have greater gel strength and need to be crushed into particles before they can be used.
- the cross-linked hyaluronic acid gel in the prior art has a long degradation time, it is not suitable for water-light injection and has a slow onset; the technical problem that hyaluronic acid used for water-light injection has a short maintenance time in the body is prolonged The water retention time of hyaluronic acid injection by water light needle and the accelerated onset time.
- the present application provides a hyaluronic acid gel composition for water light injection, which has longer degradation and absorption time than existing hyaluronic acid, and is more effective. Long hydration and moisturizing maintenance time and faster onset time. It is also suitable for water-light injection. It has low impurity toxicity and does not cause bulging. Therefore, water-light injection can more effectively improve the skin texture.
- a hyaluronic acid gel composition for water-light injection containing:
- Disulfide bond cross-linked hyaluronic acid, and its content is not more than 10mg/mL;
- Water-light injection is usually carried out by local spot injection, supplementing the superficial layer of each injection point with nourishing substances such as hyaluronic acid.
- nourishing substances such as hyaluronic acid.
- the nourishing substance needs to have a certain fluidity, which can quickly diffuse to the non-injection point, so as to play a role of moisturizing and moisturizing on the entire skin (such as the face).
- the hyaluronic acid gel composition for water light injection includes non-crosslinked hyaluronic acid.
- Non-cross-linked hyaluronic acid has good flow and dispersibility. It has a quick effect after water injection and can play a role of rapid hydration and moisturizing. Its disadvantages are that the degradation and absorption are too fast, and the duration of moisturizing and moisturizing is short, which is difficult to satisfy water. The need for moisturizing and maintaining time in light needle application.
- the hyaluronic acid gel composition for water light injection according to the present invention also includes disulfide bond cross-linked hyaluronic acid, and its content is not more than 10 mg/ml.
- hyaluronic acid is cross-linked, due to the greater gel strength, higher hyaluronic acid content, and poor flow and dispersion, it is often limited to the injection site and cannot be used for water-light injection.
- the cross-linked hyaluronic acid has a slow onset of effect, and even completely fails to meet the requirements of water injection. Therefore, the cross-linked hyaluronic acid gel needs to be specially optimized for water-light injection.
- the disulfide bond cross-linked hyaluronic acid contained in the composition according to the present invention has a content of not more than 10 mg/mL in the gel, has good biocompatibility and stability, and can realize effective disulfide bond cross-linking Link, delay the metabolism and absorption in the body. It is used to prepare the hyaluronic acid gel composition for water and light injection without adding a cross-linking agent, the preparation process is simple, does not contain impurities, and can avoid the current complex process and cross-linking agent for cross-linking hyaluronic acid gel products Toxic side effects caused by residues.
- the hyaluronic acid sulfhydryl derivative disclosed in the applicant's prior art patent document CN 102399295A can be used to prepare the disulfide bond cross-linked hyaluronic acid for water-light injection of the present invention.
- the use of the disulfide bond cross-linked hyaluronic acid for water-light injection has many advantages, such as easy water-light injection, uniform distribution in the superficial subcutaneous layer, no bulging phenomenon, and the maintenance time of moisturizing and moisturizing effect is significantly better than that of the previous Cross-linked hyaluronic acid, etc.
- the hyaluronic acid gel composition provided by the present invention contains both the above-mentioned disulfide bond cross-linked hyaluronic acid gel and non-cross-linked hyaluronic acid, and has the advantages of both when used for water-light injection.
- the above-mentioned problems existing in the prior art are better solved. It not only meets the requirement of flow dispersion, but also prolongs the water retention time and speeds up the effect.
- the content of the disulfide cross-linked hyaluronic acid is expressed as the weight (mg/mL) of the disulfide cross-linked hyaluronic acid contained in the unit volume of the hyaluronic acid gel composition.
- the content of disulfide cross-linked hyaluronic acid in the hyaluronic acid gel composition for water-light injection of the present invention is not more than 10 mg/mL, preferably 1 to 4 mg/mL, particularly preferably 2 to 3 mg/mL .
- the content of disulfide cross-linked hyaluronic acid in the hyaluronic acid gel composition for water injection of the present invention is low .
- the hyaluronic acid gel composition for water injection of the present invention has lower strength, better fluidity, and is easier to pass
- the ultra-fine needle of the water light needle is used for injection and achieves uniform distribution in the superficial layer of the skin.
- the content of the non-crosslinked hyaluronic acid is expressed as the weight (mg/mL) of the non-crosslinked hyaluronic acid contained in the unit volume of the hyaluronic acid gel composition.
- the content of non-cross-linked hyaluronic acid in the hyaluronic acid gel composition for water-light injection of the present invention is usually not more than 10 mg/mL, preferably between 1 and 5 mg/mL, particularly preferably 2 ⁇ 4mg/mL.
- the molecular weight refers to the average molecular weight.
- Cross-linked hyaluronic acid has no concept of molecular weight due to its cross-linked structure.
- the molecular weight distribution of non-crosslinked hyaluronic acid is very wide, and different molecular weights have different physical, chemical and biological properties.
- high molecular weight hyaluronic acid with a molecular weight greater than 800kDa (800,000 daltons) usually has good moisturizing and moisturizing properties.
- the molecular hyaluronic acid (an oligosaccharide with 6-20 disaccharide repeating units, that is, the molecular weight is 2.4KDa ⁇ 8KDa) can slightly improve blood supply (promote micro-angiogenesis), promote fibroblast growth and endogenous macromolecule transparency
- the secretion and synthesis of plasmic acid (Smejkalova et al., Harry's Cosmeticology 9th Edition Vol.2.Part 4.1.3, pp.605-622; Publisher: Chemical Publishing Company, 2015).
- the non-crosslinked hyaluronic acid may have a molecular weight, and its molecular weight is usually between 1KDa and 10,000KDa, preferably between 800KDa and 3,000KDa, particularly preferably between 1,000KDa ⁇ 2,800Kda.
- the non-crosslinked hyaluronic acid may also include two or more different molecular weights, preferably at least one of the non-crosslinked hyaluronic acid has a molecular weight of 1.6KDa
- the molecular weight of at least one non-crosslinked hyaluronic acid is between 800KDa and 3,000KDa. It is particularly preferred that the molecular weight of at least one non-crosslinked hyaluronic acid is between 2.4 and 8KDa.
- a non-crosslinked hyaluronic acid has a molecular weight between 1,000KDa and 2,800KDa.
- the hyaluronic acid can be in the form of its salt (such as sodium salt, potassium salt, zinc salt, calcium salt, etc.), or it can include a non-crosslinked structure obtained by chemical modification.
- its salt such as sodium salt, potassium salt, zinc salt, calcium salt, etc.
- Derivatives such as carboxymethyl hyaluronic acid, acetylated hyaluronic acid, etc.
- a method similar to that disclosed in the prior art (CN 101721349A) of the applicant of the present invention can be used to prepare the disulfide bond cross-linked hyaluronic acid of the present invention.
- the preparation method realizes disulfide bond cross-linking by the hyaluronic acid sulfhydryl derivative aqueous solution under the oxidation of oxygen (oxygen in the air and/or dissolved oxygen in the aqueous solution), without the need to add a cross-linking agent, and the by-products are Water has many advantages such as simple production process and no impurities, which avoids the current complicated process of cross-linking hyaluronic acid gel products and the potential toxic and side effects caused by the residual cross-linking agent.
- the above-mentioned preparation method of disulfide cross-linked hyaluronic acid does not require a purification process, and is particularly suitable for preparing cross-linked gels with low strength and certain fluidity, and is suitable for water Light injection purposes.
- the hyaluronic acid sulfhydryl derivatives refer to hyaluronic acid derivatives containing sulfhydryl groups, which can be prepared by sulfhydryl modification of hyaluronic acid, and also include various hyaluronic acid derivatives further through sulfhydryl groups.
- the sulfhydryl derivative prepared by chemical modification.
- the side chain carboxyl groups, side chain hydroxyl groups, and reducing end groups of hyaluronic acid or its salts or derivatives are usually reactive functional groups that can be modified by sulfhydrylization, as disclosed in previous documents such as WO 2009/006780A1.
- hyaluronic acid sulfhydryl derivatives can be used to prepare the hyaluronic acid sulfhydryl derivatives of the present invention; these hyaluronic acid sulfhydryl derivatives better maintain the initial structure, physiological functions and biological functions of hyaluronic acid. Compatibility, and can achieve effective disulfide bond cross-linking, significantly delaying the metabolism and absorption in the body.
- sulfhydryl derivatives of hyaluronic acid with various sulfhydryl content can be used to prepare the disulfide cross-linked hyaluronic acid of the present invention.
- the sulfhydryl content is expressed as the number of micromoles of sulfhydryl groups per gram of hyaluronic acid sulfhydryl derivatives ( ⁇ mol/g).
- the sulfhydryl content of the hyaluronic acid sulfhydryl derivatives used in the present invention is usually between 10 and 100 ⁇ mol/g.
- the preferred mercapto group content is between 10-50 ⁇ mol/g, and the particularly preferred mercapto group content is between 20-40 ⁇ mol/g.
- Another object of the present invention is to provide a method for preparing the hyaluronic acid gel composition for water-light injection.
- a technical solution of the preparation method is: the sulfhydryl derivative of hyaluronic acid is dissolved to obtain an aqueous solution, and the disulfide bond cross-linked hyaluronic acid gel is obtained through an oxidation process, and then it is physically mixed with the aqueous solution of hyaluronic acid, namely The hyaluronic acid gel composition for water-light injection of the present invention can be obtained.
- the above-mentioned oxidation process can usually be carried out under the action of oxygen, such as oxygen in the air and/or dissolved oxygen in an aqueous solution.
- oxygen such as oxygen in the air and/or dissolved oxygen in an aqueous solution.
- physical mixing process can adopt methods well known to those skilled in the art, such as mechanical stirring and mixing.
- the preparation method realizes the disulfide bond cross-linked gel under the oxidation of the hyaluronic acid sulfhydryl derivative aqueous solution under oxygen (oxygen in the air and/or dissolved oxygen in the aqueous solution), and does not require the addition of a cross-linking agent.
- the product is water, the production process is simple, and it does not contain impurities. It avoids the current complicated process of cross-linking hyaluronic acid gel products and the potential toxic side effects caused by cross-linking agent residues.
- the water injection treatment is obtained by simple mixing. Hyaluronic acid gel composition.
- the aqueous solution of hyaluronic acid thiolated derivative and the aqueous solution of hyaluronic acid can be filtered and sterilized, and then the hyaluronic acid gel for water-light injection of the present invention can be prepared under aseptic conditions.
- the glue composition can also adopt terminal sterilization and other methods, and the terminal sterilization method can adopt methods such as moist heat sterilization well known to those skilled in the art.
- Another technical solution of the preparation method is: the aqueous solution of hyaluronic acid thiolated derivative and the aqueous solution of hyaluronic acid are physically mixed to obtain a mixed solution, and then the disulfide bond cross-linking is formed through the oxidation process, that is, the method of the present invention is obtained.
- Hyaluronic acid gel composition for water injection The oxidation process can also be carried out under the action of oxygen, such as oxygen in the air and/or dissolved oxygen in an aqueous solution.
- the preparation method obtains a mixture of hyaluronic acid by simple mixing, and the aqueous solution of hyaluronic acid sulfhydryl derivative realizes disulfide bond cross-linking under the oxidation of oxygen (oxygen in the air and/or dissolved oxygen in the aqueous solution).
- the by-product is water, the production process is simple and contains no impurities, etc., which avoids the current complex process of cross-linking hyaluronic acid gel products and the potential toxic side effects caused by cross-linking agent residues, and obtains hyaluronic acid Acid gel composition.
- the preparation process can also adopt an aseptic process, or terminally sterilize the prepared hyaluronic acid gel composition.
- the non-cross-linked hyaluronic acid or its derivatives are physically embedded in the disulfide cross-linked hyaluronic acid, forming a semi-interconnected hyaluronic acid well known to those skilled in the art. Wear the structure of the network.
- the hyaluronic acid gel composition for water-light injection may also contain a variety of nutritionally active substances, such as various vitamins, amino acids, growth factors, etc., to achieve synergistic water-light injection replenishment Moisturizing and other effects.
- the nutrient active substance can be dissolved in an aqueous solution of hyaluronic acid thiolated derivative and/or an aqueous solution of hyaluronic acid, and then a hyaluronic acid gel composition containing nutrients can be prepared according to the above two preparation methods.
- the dendritic acid gel composition for water-light injection of the present invention contains both disulfide bond cross-linked hyaluronic acid and non-cross-linked hyaluronic acid, has good fluidity, and is easy to pass through the water-light needle. Injection with a fine needle can achieve a good uniform distribution in the superficial subcutaneous layer without bulging, and the advantages of fast moisturizing and long-lasting effect after water-light injection can effectively improve the skin texture.
- the hyaluronic acid gel composition for water-light injection has the advantages of disulfide cross-linked hyaluronic acid and non-cross-linked hyaluronic acid when used for water-light injection, and effectively solves the problem of non-cross-linked hyaluronic acid.
- Cross-linked hyaluronic acid has a fast onset of action but has a short duration of moisturizing and moisturizing
- disulfide cross-linked hyaluronic acid has a long time of moisturizing and moisturizing but the onset time is delayed.
- the dendritic acid gel composition for water and light injection of the present invention can be conveniently prepared by hyaluronic acid sulfhydryl derivative aqueous solution and non-crosslinked hyaluronic acid aqueous solution.
- Many advantages such as simple process, no impurities, easy addition of other nutritional active substances, etc., avoid the current complicated process of cross-linking hyaluronic acid gel products and the toxic side effects caused by the residual cross-linking agent.
- the disulfide bond crosslinking is realized by the hyaluronic acid sulfhydryl derivative aqueous solution under the oxidation of oxygen (oxygen in the air and/or dissolved oxygen in the aqueous solution), and there is no need to add a crosslinking agent,
- the by-product is water, the production process is simple, and there are many advantages such as no impurities, which avoids the current complicated process of cross-linking hyaluronic acid gel products and the potential toxic side effects caused by cross-linking agent residue; the hyaluronic acid of the present invention is obtained by simple mixing Acid gel mixture.
- Figure 2 The effect of sodium hyaluronate gel composition on skin elasticity after water injection.
- Figure 3 The effect of sodium hyaluronate gel composition on the depth of skin wrinkles after water and light injection.
- Hyaluronic acid sulfhydryl derivatives are prepared from sodium hyaluronate with a molecular weight of 180KDa as a raw material and prepared by the method reported by Shu et al. (Shu et al., Biomacromolecules 2002, 3:1304-1311). The sulfhydryl content is 24 ⁇ mol/g and 38 ⁇ mol, respectively. /g and 57 ⁇ mol/g.
- Sodium hyaluronate (50KDa) was dissolved to obtain an aqueous solution with a content of 12 mg/mL, the pH of the solution was adjusted to 7.4, and the solution was sterilized and filtered for later use.
- Example 3 Evaluation of the injectable properties of the hyaluronic acid gel composition
- Adopt Derma (Demasha) 2nd generation water-light injection device test the injectability of the hyaluronic acid gel composition prepared in Example 2 through conventional water-light injection needles (nine needles).
- the content of disulfide cross-linked hyaluronic acid in the hyaluronic acid gel composition is 1mg/mL, 2mg/mL, 3mg/mL and 4mg/mL, it has good injectability; and when the content is ⁇ 5mg/mL When it is mL, it is difficult to inject through the water light injection instrument.
- Example 4 Evaluation of the injectable properties of the diluted hyaluronic acid gel composition
- the hyaluronic acid gel composition prepared in Example 2 (disulfide cross-linked hyaluronic acid content is: 5mg/mL, 8mg/mL, 9mg/mL, 10mg/mL and 11mg/mL) and physiological saline According to the volume ratio of 1:2 for physical mixing and dilution.
- the dilution process is carried out in a syringe connected by a two-way connector.
- One syringe contains the hyaluronic acid gel composition (1 mL) prepared in Example 2, and the other syringe contains 2 mL of normal saline.
- Perform physical dilution and mixing 80 times. Two-way joints with a smaller diameter (such as less than 1mm) can be used to achieve better dilution and mixing effects.
- Adopt Derma (Demasha) 2nd generation water-light injection instrument test the injectability of the diluted hyaluronic acid gel composition through conventional water-light injection needles (nine needles). The test results show that each diluted hyaluronic acid gel composition has good injectability.
- Sodium hyaluronate is dissolved to obtain an aqueous solution with a content of 2mg/mL, 4mg/mL, 6mg/mL, 8mg/mL or 10mg/mL, the pH of the solution is adjusted to 7.4, and it is ready for use after sterilization and filtration.
- the molecular weight of the sodium hyaluronate used is 1.6KDa, 3KDa, 8KDa, 50KDa, 180KDa, 500KDa, 800KDa, 1,500KDa or 2,700KDa. It can be any of these molecular weights, or any two or more of them. The molecular weight is combined in any weight ratio.
- the disulfide cross-linked hyaluronic acid gel (6 mg/mL) prepared in Example 1 was physically stirred and mixed with the above-mentioned hyaluronic acid aqueous solution at a volume ratio of 1:1 to obtain a hyaluronic acid gel composition.
- the content of sulfur-bonded cross-linked hyaluronic acid is 3 mg/mL, and the content of hyaluronic acid is 1 mg/mL, 2 mg/mL, 3 mg/mL, 4 mg/mL, or 5 mg/mL.
- Example 6 Evaluation of the injectable properties of the hyaluronic acid gel composition
- Adopt Derma (Demasa) 2nd generation water-light injection device to test the injectability of the hyaluronic acid gel composition prepared in Example 5 through conventional water-light injection needles (nine needles). The test results show that each gel composition has good injectability.
- Hyaluronic acid sulfhydryl derivatives are prepared using sodium hyaluronate with molecular weights of 300KDa and 1,500KDa as raw materials, prepared by the method reported by Shu et al. (Shu et al., Biomacromolecules 2002, 3:1304-1311), and their sulfhydryl content is 33 ⁇ mol/ g and 40 ⁇ mol/g.
- hyaluronic acid sulfhydryl derivative and sodium hyaluronate are jointly dissolved to obtain a mixed aqueous solution, wherein the content of hyaluronic acid sulfhydryl derivative is 2.5 mg/mL or 5 mg/mL, and the content of sodium hyaluronate is 1 mg/mL, respectively.
- the molecular weight of the sodium hyaluronate used is 1.6KDa, 3KDa, 8KDa, 50KDa, 180KDa, 500KDa, 800KDa, 1,500KDa or 2,700KDa. It can be any one of these molecular weights, or any two or two of them. According to the combination of any weight ratio.
- Example 8 Evaluation of the injectable properties of the hyaluronic acid gel composition
- Adopt Derma (Demasha) 2nd generation water-light injection device test the injectability of the hyaluronic acid gel composition prepared in Example 7 through conventional water-light injection needles (nine needles). The test results show that each gel composition has good injectability.
- Example 9 Water absorption and water retention performance of hyaluronic acid gel composition
- Example 7 Using the same dilution process as in Example 4, the gel prepared in Example 7 and physiological saline were physically mixed and diluted according to a volume ratio of 1:2, and then put into a small glass bottle and left at room temperature for 1 hour. None was observed. Obvious delamination between the water phase and the gel phase indicates that the gel has good water absorption and water retention properties.
- Example 10 Evaluation of hydro-light injection effect of hyaluronic acid gel composition
- Samples used in the test group the gel composition prepared in Example 5, the content of disulfide cross-linked hyaluronic acid was 3 mg/mL (prepared with 38 ⁇ mol/g sulfhydryl derivatives), non-cross-linked sodium hyaluronate The content of 2mg/mL (1,500KDa).
- the sample used in the control group I 5 mg/mL non-crosslinked sodium hyaluronate aqueous solution (molecular weight 1.5MDa).
- the sample used in the control group II the same sample used in the test group, but does not contain non-crosslinked sodium hyaluronate.
- the relative increase in skin moisture before and after injection (%) was tested with a skin moisture meter, the relative increase in skin elasticity (%) before and after injection was tested with a skin elasticity meter, and the relative decrease in average wrinkle depth before and after injection was tested with a fast three-dimensional imaging system Evaluation.
- test results of this embodiment are shown in Figures 1-3.
- the cross-linked hyaluronic acid gel composition has a better hydro-light treatment effect, quick onset and long maintenance time; at the same time, all test subjects in the test group have no bulging phenomenon, which indicates The cross-linked hyaluronic acid gel composition has good fluidity and can be evenly distributed on the superficial layer of water injection.
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Abstract
Description
Claims (21)
- 一种用于水光注射的透明质酸凝胶组合物,其特征在于,该透明质酸凝胶组合物含有:1)二硫键交联透明质酸,且其含量不大于10mg/mL;和2)非交联的透明质酸。
- 根据权利要求1所述的用于水光注射的透明质酸凝胶组合物,其特征在于,所述的二硫键交联透明质酸的含量在1~4mg/mL之间。
- 根据权利要求2所述的用于水光注射的透明质酸凝胶组合物,其特征在于,所述的二硫键交联透明质酸的含量在2~3mg/mL之间。
- 根据权利要求1所述的用于水光注射的透明质酸凝胶组合物,其特征在于,所述的二硫键交联透明质酸通过透明质酸巯基化衍生物制备。
- 根据权利要求4所述的用于水光注射的透明质酸凝胶组合物,其特征在于,所述的透明质酸巯基化衍生物的巯基含量为10~50μmol/g。
- 根据权利要求5所述的用于水光注射的透明质酸凝胶组合物,其特征在于,所述透明质酸巯基化衍生物的巯基含量为20~40μmol/g。
- 根据权利要求1所述的用于水光注射的透明质酸凝胶组合物,其特征在于,所述的非交联的透明质酸的含量小于10mg/mL。
- 根据权利要求7所述的用于水光注射的透明质酸凝胶组合物,其特征在于,所述的非交联的透明质酸的含量在1~5mg/mL之间。
- 根据权利要求8所述的用于水光注射的透明质酸凝胶组合物,其特征在于,所述的非交联的透明质酸的含量在2~4mg/mL之间。
- 根据权利要求1所述的用于水光注射的透明质酸凝胶组合物,其特征在于,所述的非交联的透明质酸分子量在800KDa~3,000KDa之间。
- 根据权利要求10所述的用于水光注射的透明质酸凝胶组合物,其特征在于,所述的非交联的透明质酸分子量在1,000KDa~2,800KDa之间。
- 根据权利要求1所述的用于水光注射的透明质酸凝胶组合物,其特征在于,所述的非交联的透明质酸包括两种及两种以上不同的分子量。
- 根据权利要求12所述的用于水光注射的透明质酸凝胶组合物,其特征在于,至少一种所述的非交联的透明质酸的分子量在1.6KDa~500KDa之间且其中至少一种所述的非交联的透明质酸的分子量在800KDa~3,000KDa之间。
- 根据权利要求13所述的用于水光注射的透明质酸凝胶组合物,其特征在于,至少一种所述的非交联的透明质酸的分子量在2.4~8KDa之间且其中至少一种所述的非交联的透明质酸 的分子量在1,000KDa~2,800KDa之间。
- 根据权利要求1所述的用于水光注射的透明质酸凝胶组合物,其特征在于,所述的用于水光注射的透明质酸凝胶组合物具有半互穿网络结构。
- 根据权利要求1-15之一所述的用于水光注射的透明质酸凝胶组合物,其特征在于,所述的用于水光注射的透明质酸凝胶组合物含有营养活性物质。
- 根据权利要求16所述的用于水光注射的透明质酸凝胶组合物,其特征在于,所述的营养活性物质包括维生素、氨基酸、生长因子等。
- 一种根据权利要求1-17之一所述的用于水光注射的透明质酸凝胶组合物的制备方法,其特征在于,该制备方法包括如下过程:透明质酸巯基化衍生物溶解得到水溶液,并经氧化过程得到二硫键交联透明质酸凝胶,然后与透明质酸的水溶液进行物理混合。
- 一种根据权利要求1-17之一所述的用于水光注射的透明质酸凝胶组合物的制备方法,其特征在于,该制备方法包括如下过程:透明质酸巯基化衍生物水溶液与透明质酸水溶液进行物理混合得到混合溶液,然后经氧化过程形成二硫键交联。
- 根据权利要求18或19所述的用于水光注射的透明质酸凝胶组合物的制备方法,其特征在于,所述的氧化过程在氧气的作用下进行。
- 根据权利要求20所述的用于水光注射的透明质酸凝胶组合物的制备方法,其特征在于,所述的氧气是指空气中的氧气和/或水溶液中的溶解氧。
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