CN110812270A - Hyaluronic acid gel composition for water light injection and preparation method thereof - Google Patents
Hyaluronic acid gel composition for water light injection and preparation method thereof Download PDFInfo
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- 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
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- 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
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- 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
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- 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
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- 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
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- 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
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- 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
Abstract
The invention discloses a hyaluronic acid gel composition for water light injection, which contains 1) disulfide bond cross-linked hyaluronic acid, wherein the content of the hyaluronic acid in the gel is not more than 10 mg/mL; and 2) non-crosslinked hyaluronic acid. The hyaluronic acid gel composition has unique advantages when being used for hydro-optic injection, is easy to inject through a micro needle head of a hydro-optic needle, can realize good uniform distribution on a subcutaneous superficial layer, and does not generate a bulge phenomenon; the moisturizing cream has quick response and long maintenance time of moisturizing effect, and can effectively improve skin quality.
Description
Technical Field
The invention relates to the field of biomedicine, in particular to a hyaluronic acid gel composition for water light injection and a preparation method of the hyaluronic acid gel composition for water light injection.
Background
In recent years, medical beauty treatment industry at home and abroad is rapidly developed, and various new beauty treatment technologies are researched and developed. The water light injection is one of the most extensive medical beauty treatment projects developed at home and abroad at present, can effectively solve the problem that skin care products used on the body surface are not easy to be absorbed through an epidermal barrier, can quickly and effectively supply water and nourishment to the skin, and can effectively improve the skin quality and delay senility. Water light injection originated from mesoderm therapy (Mesotherapy) proposed by Michal pitor in 1952 by the french physician, with the idea of injecting a trace of therapeutic substance topically and superficially; decades of efforts have been made to develop the current water laser needle technology. The water light injection precisely penetrates a plurality of extremely fine needle heads into the subcutaneous part by about 1-2 mm through a negative pressure technology, and the repairing substance is directly conveyed into the space between epidermis and dermis or dermis layer through the epidermis layer, so that the problem that effective ingredients in the skin care product cannot effectively penetrate the epidermis barrier is solved.
Hyaluronic acid, also known as hyaluronic acid, is an inherent acidic mucopolysaccharide in the human body, is commonly applied to various skin care products, is a super-strong moisturizer naturally existing in the skin of the human body, and can maintain 1000 times of the water content of the hyaluronic acid per se. The moisture level of the skin is closely related to the content and molecular weight of hyaluronic acid, and the hyaluronic acid with high molecular weight has stronger water retention performance. With the increase of age and the disruption of daily active oxygen radicals, endogenous hyaluronic acid in the skin is degraded and lost, and the water retention function is gradually weakened, so that various skin aging symptoms such as dryness, roughness, darkness, relaxation, wrinkles and the like are caused (Stern et al, Clinics in Dermatology 2008,26: 106-.
The supplement of exogenous hyaluronic acid is an important measure for improving skin quality, delaying aging symptoms and recovering young state. However, hyaluronic acid applied to the skin surface is hardly absorbed efficiently due to the epidermal barrier, and particularly high molecular weight hyaluronic acid having superior moisturizing ability. The hyaluronic acid injected by water light can directly penetrate through the epidermis barrier, and the hyaluronic acid can be immediately supplemented on the superficial layer of the skin, so that the effects of quickly supplementing water and moisturizing are realized, and the ultimate aim of improving the skin quality is fulfilled. The current water light injection mainly replenishes exogenous hyaluronic acid by superficial injection and also properly contains other repair nutrients. CN106074213A discloses a hyaluronic acid gel for water light injection, which comprises 10-30 parts of sodium hyaluronate, 0.5-3 parts of glycerol, 0.5-1.5 parts of mannitol, 1-9 parts of pH regulator and 25-45 parts of isotonic regulator. CN 105233270a discloses a pharmaceutical composition for water light therapy and its application, which comprises: 0.01-0.5 wt% of high molecular weight sodium hyaluronate, 0.01-0.3 wt% of medium molecular weight sodium hyaluronate, 0.01-1 wt% of low molecular weight sodium hyaluronate, 0.01-1 wt% of oligomeric sodium hyaluronate, 0.01-5 wt% of collagen, 0.05-1.8 wt% of an auxiliary agent, recombinant human epidermal growth factor and the balance of water, wherein the concentration of the recombinant human epidermal growth factor is 0.5-10 mu g/ml; the molecular weight of the high molecular weight sodium hyaluronate is 130-200 kilodaltons, the molecular weight of the medium molecular weight sodium hyaluronate is 50-100 kilodaltons, the molecular weight of the low molecular weight sodium hyaluronate is 5-30 kilodaltons, and the molecular weight of the oligomeric sodium hyaluronate is 3000-8000 daltons.
However, under the action of hyaluronidase in vivo, hyaluronic acid is rapidly degraded into small molecular fragments which enter body fluid circulation and are absorbed and metabolized, and the function of locally moisturizing skin is lost; in skin, hyaluronic acid has a half-life of less than 1 day (Laurent et al, Exp Physiol 1991,76: 695-. Therefore, although the water light injection can quickly supplement hyaluronic acid on local skin, the water injection can only supplement water and keep moisture in a short time, and the long-term effects of improving skin quality, delaying aging, recovering young state and the like are difficult to realize. For example, the results of Amin et al (Dermatol Surg 2006,32: 1467-.
Cross-linked modifications which retard the degradation and absorption of hyaluronic acid in vivo, e.g. 1, 4-butanediol diglycidyl ether (BDDE) cross-linked hyaluronic acid gels (e.g. hyaluronic acid gel
Etc.) can be degraded and absorbed for more than 6 months under the skin, and is widely used for wrinkle injection filling. However, current crosslinked hyaluronic acid gel products are high in content (generally not less than 20mg/mL) (Edsman et al, Dermatol Surg 2012,38:1170-1179), i.e., generally not more than 98% in water content (water content of about 49 times the weight of the crosslinked hyaluronic acid itself), and poor in moisturizing performance; in addition, the cross-linked hyaluronic acid gel products also have higher gel strength, can be used after being crushed into granules, have higher extrusion force, and are difficult to perform superficial layer injection through a water smooth needle with a very fine needle head; in addition, these crosslinked hyaluronic acid gel products have poor fluidity, cannot be uniformly distributed on the superficial layer of water light injection, are easy to form bulges, and cannot be degraded and eliminated in a short period of time. Therefore, there are many limitations in the use of current crosslinked hyaluronic acid gel products for water light injection.
Disclosure of Invention
Aims to solve the problems that the cross-linked hyaluronic acid gel in the prior art is not suitable for water light injection and has slow effect although the degradation time is long; the hyaluronic acid gel composition for the water light injection is longer in degradation and absorption time, longer in water replenishing and moisture retaining maintenance time and faster in onset time than the existing hyaluronic acid, is suitable for the water light injection, is low in impurity toxicity, does not generate a bulge phenomenon, and can be used for effectively improving skin quality through the water light injection.
The invention is realized by the following technical scheme:
a hyaluronic acid gel composition for aqueous light injection comprising:
1) disulfide bond cross-linked hyaluronic acid, and its content is not more than 10 mg/mL; and
2) non-crosslinked hyaluronic acid.
The water light injection is usually performed by a local point injection method, and a shallow surface layer of each injection point is supplemented with a nourishing substance such as hyaluronic acid. However, the injection points are quite spaced, so that the nourishing substance is required to have certain fluidity and to rapidly diffuse to the non-injection point part, thereby playing the role of moisturizing the whole skin (such as the face).
The hyaluronic acid gel composition for water light injection according to the present invention includes non-crosslinked hyaluronic acid. The non-crosslinked hyaluronic acid has better flowing dispersivity, takes effect quickly after water light injection, can play a role in quickly replenishing water and moisturizing, and has the defects of too quick degradation and absorption, short replenishing water and moisturizing duration and difficulty in meeting the requirement of replenishing water and moisturizing maintenance time in water light needle application.
The hyaluronic acid gel composition for water light injection according to the present invention further comprises disulfide-bond-crosslinked hyaluronic acid, and the content thereof is not more than 10 mg/ml.
Generally, after hyaluronic acid is crosslinked, the hyaluronic acid is often limited to an injection site due to large gel strength, high hyaluronic acid content and poor flow dispersivity, and cannot be used for water light injection. And the crosslinked hyaluronic acid has slow effect and even completely fails to meet the requirement of water light injection. Therefore, the crosslinked hyaluronic acid gel needs to be specially and optimally designed for water light injection.
The disulfide bond cross-linked hyaluronic acid contained in the composition has the content of not more than 10mg/mL in gel, has good biocompatibility and stability, can realize effective disulfide bond cross-linking, and delays metabolic absorption in vivo. The hyaluronic acid gel composition for the water light injection is prepared without adding a cross-linking agent, has simple preparation process and no impurities, and can avoid the complex process of the current cross-linked hyaluronic acid gel product and toxic and side effects caused by the residual cross-linking agent. The disulfide-bond cross-linked hyaluronic acid for water light injection according to the present invention can be prepared by using thiol-modified hyaluronic acid derivatives disclosed in the applicant's prior art patent document CN 102399295 a. The disulfide bond cross-linked hyaluronic acid has many advantages when being used for water light injection, such as easy water light injection, uniform distribution on a subcutaneous shallow surface layer, no bulge phenomenon, and the maintenance time of the water replenishing and moisturizing effect is obviously superior to that of the uncrosslinked hyaluronic acid.
The hyaluronic acid gel composition provided by the invention simultaneously contains the disulfide bond cross-linked hyaluronic acid gel and the non-cross-linked hyaluronic acid, has the advantages of the disulfide bond cross-linked hyaluronic acid gel and the non-cross-linked hyaluronic acid when being used for water light injection, and better solves the problems in the prior art. Not only meets the requirement of flow dispersivity, but also prolongs the water retention time and accelerates the onset speed.
In the present invention, the content of the disulfide-bond-crosslinked hyaluronic acid is expressed as the weight (mg/mL) of the disulfide-bond-crosslinked hyaluronic acid contained in a unit volume of the hyaluronic acid gel composition. The content of disulfide bond cross-linked hyaluronic acid in the hyaluronic acid gel composition for water light injection is not more than 10mg/mL, preferably 1-4 mg/mL, and particularly preferably 2-3 mg/mL.
The content of disulfide-bond-crosslinked hyaluronic acid in the hyaluronic acid gel composition for water light injection according to the present invention is low, typically only 50% or less of the current crosslinked hyaluronic acid product, compared to the content of the crosslinked hyaluronic acid product (typically not less than 20 mg/mL); therefore, the hyaluronic acid gel composition for the hydro-optic injection has lower strength and better fluidity, is easier to inject through the ultra-fine needle of the hydro-optic needle, and realizes uniform distribution on the subcutaneous superficial layer.
In the present invention, the content of the non-crosslinked hyaluronic acid is expressed as the weight (mg/mL) of the non-crosslinked hyaluronic acid contained in a unit volume of the hyaluronic acid gel composition. The content of the non-crosslinked hyaluronic acid in the hyaluronic acid gel composition for water light injection is usually not more than 10mg/mL, preferably between 1 and 5mg/mL, and particularly preferably between 2 and 4 mg/mL.
In the present invention, the molecular weight means an average molecular weight. Cross-linked hyaluronic acid does not have the concept of molecular weight due to its cross-linked structure. The molecular weight distribution of non-crosslinked hyaluronic acid is wide, and different molecular weights have different physicochemical and biological properties, for example, high molecular weight hyaluronic acid with molecular weight more than 800kDa (80 ten thousand daltons) generally has good moisturizing performance, while small molecular weight hyaluronic acid (oligosaccharide of 6-20 disaccharide repeating units, i.e. molecular weight 2.4 KDa-8 KDa) can slightly improve blood circulation (promote micro-angiogenesis), promote fibroblast growth and secretion synthesis of endogenous macromolecular hyaluronic acid (Smejkalova et al, Harry's society biology 9th Edition Vol.2.part 4.1.3, pp.605-622; publication: Chemical Publishing Company, 2015).
In one embodiment of the invention, the non-crosslinked hyaluronic acid may be of a molecular weight generally between 1kDa and 10,000kDa, preferably between 800kDa and 3,000kDa, particularly preferably between 1,000kDa and 2,800 kDa.
In another embodiment of the present invention, the non-crosslinked hyaluronic acid may also comprise two or more different molecular weights, preferably wherein at least one non-crosslinked hyaluronic acid has a molecular weight between 1.6KDa and 500KDa and wherein at least one non-crosslinked hyaluronic acid has a molecular weight between 800KDa and 3,000KDa, particularly preferably wherein at least one non-crosslinked hyaluronic acid has a molecular weight between 2.4KDa and 8KDa and wherein at least one non-crosslinked hyaluronic acid has a molecular weight between 1,000KDa and 2,800 KDa.
In the present invention, the hyaluronic acid may be in the form of a salt thereof (e.g., sodium salt, potassium salt, zinc salt, calcium salt, etc.), or may be a derivative including a non-crosslinked structure obtained by chemical modification thereof, such as carboxymethyl hyaluronic acid, acetylated hyaluronic acid, etc.
In the present invention, the disulfide-bond cross-linked hyaluronic acid of the present invention can be prepared by a method similar to that disclosed in the prior art (CN 101721349A) of the present applicant. The preparation method realizes disulfide bond crosslinking through the oxidation of the hyaluronic acid sulfhydrylation derivative aqueous solution under the oxidation action of oxygen (oxygen in air and/or dissolved oxygen in the aqueous solution), has the advantages of no need of adding a crosslinking agent, water as a byproduct, simple production process, no impurity and the like, and avoids the complex process of the current crosslinked hyaluronic acid gel product and potential toxic and side effects caused by the residual crosslinking agent.
As well known to those skilled in the art, in the current preparation process of crosslinked hyaluronic acid gel products, soaking dialysis is conventionally used for purification, that is, the gel after crosslinking reaction is soaked in a large amount of water or buffered saline solution to remove impurities such as residual crosslinking agent in the crosslinked gel by dialysis; the purification process requires the cross-linked gel to have higher strength, so the current cross-linked hyaluronic acid gel products all have higher strength and are not suitable for water light injection application. In contrast, in the present invention, the above-mentioned method for preparing disulfide-bond-crosslinked hyaluronic acid does not require a purification process, and is particularly suitable for preparing a crosslinked gel having a low strength and a certain fluidity, and is suitable for water light injection.
In the present invention, the thiol-modified hyaluronic acid derivative refers to a thiol-containing hyaluronic acid derivative, which can be prepared by thiol-modification of hyaluronic acid, and also includes thiol-modified derivatives prepared by further thiol-modification of various hyaluronic acid derivatives. The side chain carboxyl, side chain hydroxyl, reducing end group and the like of hyaluronic acid or a salt or a derivative thereof are active functional groups which can be subjected to sulfhydrylation modification, and various hyaluronic acid sulfhydrylation derivative preparation methods disclosed in prior documents such as WO 2009/006780A1 can be used for preparing the hyaluronic acid sulfhydrylation derivative; the thiol-modified derivatives of hyaluronic acid well maintain the initial structure, physiological function and biocompatibility of hyaluronic acid, can realize effective disulfide bond crosslinking, and remarkably delay metabolic absorption in vivo.
In the present invention, thiol-modified derivatives of hyaluronic acid with various thiol contents can be used to prepare the disulfide-bond cross-linked hyaluronic acid of the present invention. The content of sulfydryl is expressed as micromole (mu mol/g) of sulfydryl contained in each gram of thiol-modified derivative of hyaluronic acid, the content of sulfydryl of the thiol-modified derivative of hyaluronic acid adopted by the invention is usually between 10 and 100 mu mol/g, the preferable content of sulfydryl is between 10 and 50 mu mol/g, and the particularly preferable content of sulfydryl is between 20 and 40 mu mol/g.
Still another object of the present invention is to provide a method for preparing the hyaluronic acid gel composition for water light injection.
One technical scheme of the preparation method is as follows: the sulfhydryl derivatives of hyaluronic acid are dissolved to obtain aqueous solution, disulfide bond cross-linked hyaluronic acid gel is obtained through an oxidation process, and then the hyaluronic acid gel composition for water light injection can be obtained through physical mixing with the aqueous solution of hyaluronic acid.
The oxidation process described above can generally be carried out under the action of oxygen, such as oxygen in air and/or dissolved oxygen in aqueous solution. The physical mixing process described above can be carried out by means well known to those skilled in the art, such as mechanical stirring and mixing.
The preparation method realizes disulfide bond crosslinking gel under the oxidation action of oxygen (oxygen in air and/or dissolved oxygen in an aqueous solution) through a hyaluronic acid sulfhydrylation derivative aqueous solution, has the advantages of no need of adding a crosslinking agent, water as a byproduct, simple production process, no impurity and the like, avoids the complex process of the current crosslinking hyaluronic acid gel product and potential toxic and side effects caused by the residue of the crosslinking agent, and obtains the hyaluronic acid gel composition for the hydro-acupuncture treatment through simple mixing.
In the above preparation process, the hyaluronic acid thiol-modified derivative aqueous solution and the hyaluronic acid aqueous solution may be subjected to filtration sterilization, and then the hyaluronic acid gel composition for water light injection according to the present invention may be prepared under aseptic conditions, or a terminal sterilization method may be adopted, and the terminal sterilization method may be a moist heat sterilization method known to those skilled in the art.
The other technical scheme of the preparation method is as follows: physically mixing the hyaluronic acid sulfhydrylation derivative water solution and the hyaluronic acid water solution to obtain a mixed solution, and then forming disulfide bond crosslinking through an oxidation process to obtain the hyaluronic acid gel composition for water light injection. The oxidation process may also be carried out by the action of oxygen, such as oxygen in air and/or dissolved oxygen in aqueous solution.
The preparation method obtains the hyaluronic acid mixture by simple mixing, and the hydrosulfide derivative aqueous solution of the hyaluronic acid realizes disulfide bond crosslinking under the oxidation action of oxygen (oxygen in the air and/or dissolved oxygen in the aqueous solution), has the advantages of no need of adding a crosslinking agent, water as a byproduct, simple production process, no impurity and the like, avoids the complex process of the current crosslinked hyaluronic acid gel product and potential toxic and side effects caused by the residual crosslinking agent, and obtains the hyaluronic acid gel composition.
The preparation process can also adopt an aseptic technique, or the prepared hyaluronic acid gel composition is subjected to terminal sterilization. In the gel composition prepared by this embodiment, the non-crosslinked hyaluronic acid or its derivative is physically embedded in the disulfide-bond crosslinked hyaluronic acid, forming a semi-interpenetrating network structure well known to those skilled in the art.
In the invention, the hyaluronic acid gel composition for water light injection can also contain various nutritional active substances, such as various vitamins, amino acids, growth factors and the like, so as to realize the synergistic effects of water light injection, moisturizing and the like. The nutrient active substance can be dissolved in the aqueous solution of the thiol-modified derivative of hyaluronic acid and/or the aqueous solution of hyaluronic acid, and then the hyaluronic acid gel composition containing the nutrient substance can be prepared according to the above two preparation methods.
The invention has the beneficial effects that:
the compact acid gel composition for water injection contains disulfide bond cross-linked hyaluronic acid and non-cross-linked hyaluronic acid, has good fluidity, is easy to inject through a superfine needle of a water injection needle, can realize good uniform distribution on a shallow subcutaneous surface layer, does not generate a bulge phenomenon, has the advantages of quick water replenishing and moisturizing effect, long maintenance time and the like after water injection, and can effectively improve skin quality.
The compact acid gel composition for water light injection has the advantages of disulfide bond cross-linked hyaluronic acid and non-cross-linked hyaluronic acid for water light injection, and effectively solves the problems of quick response but short moisturizing duration of the non-cross-linked hyaluronic acid and long moisturizing duration but delayed response time of the disulfide bond cross-linked hyaluronic acid.
The compact acid gel composition for water-light injection can be conveniently prepared from a hyaluronic acid sulfhydrylation derivative aqueous solution and a non-crosslinked hyaluronic acid aqueous solution, has the advantages of no need of adding a crosslinking agent, simple preparation process, no impurities, easiness in adding other nutritional active substances and the like, and avoids the complex process of the current crosslinked hyaluronic acid gel product and toxic and side effects caused by the residual crosslinking agent.
According to the preparation method, disulfide bond crosslinking is realized through the oxidation of the hyaluronic acid sulfhydrylation derivative aqueous solution under the oxidation action of oxygen (oxygen in the air and/or dissolved oxygen in the aqueous solution), and the preparation method has the advantages of no need of adding a crosslinking agent, water as a byproduct, simple production process, no impurity and the like, and avoids the potential toxic and side effects caused by the complex process of the current crosslinked hyaluronic acid gel product and the residual crosslinking agent; the hyaluronic acid gel mixture of the present invention is obtained by simple mixing.
Drawings
FIG. 1 Effect of sodium hyaluronate gel composition on skin Water content after Water light injection
Figure 2. effect of sodium hyaluronate gel composition on skin elasticity after aqueous light injection.
Figure 3. effect of sodium hyaluronate gel composition on skin wrinkle depth after aqueous light injection.
Detailed Description
Embodiments of the present invention will be described in detail below with reference to examples, but those skilled in the art will appreciate that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention.
Example 1: preparation of disulfide-bond crosslinked hyaluronic acid gel
The thiol-modified hyaluronic acid derivative is prepared by using sodium hyaluronate with a molecular weight of 180KDa as a raw material and adopting a method reported by Shu and the like (Shu and the like, Biomacromolecules 2002,3: 1304-plus 1311), wherein the thiol contents of the thiol-modified hyaluronic acid derivative are 24 mu mol/g, 38 mu mol/g and 57 mu mol/g respectively.
Dissolving the thiol-modified hyaluronic acid derivative to obtain an aqueous solution with the content of 6mg/mL or 12mg/mL, adjusting the pH value of the solution to 7.4, sterilizing, filtering, and transferring into a sterile glass container; keeping for 4 weeks at room temperature, sealing and standing, and allowing the solution to lose fluidity and form disulfide bond crosslinked hydrogel.
Example 2: preparation of hyaluronic acid gel composition
Dissolving sodium hyaluronate (50KDa) to obtain 12mg/mL aqueous solution, adjusting pH value of the solution to 7.4, sterilizing and filtering for later use.
The disulfide-bond crosslinked hyaluronic acid gel (12mg/mL) prepared in example 1 was physically stirred and mixed with the aqueous hyaluronic acid solution at a volume ratio of 1:11, 1:5, 1:3, 1:2, 1:1.4, 1:0.5, 1:0.3, 1:0.2, and 1:0.091, to obtain a hyaluronic acid gel composition having a composition ratio shown in the following table.
Example 3: injectable performance evaluation of hyaluronic acid gel composition
By Derma
(demanga) 2 generation water light injection instrument, the injectability of the hyaluronic acid gel composition prepared in example 2 through a conventional water light injection needle (nine needles) was tested. When the content of disulfide-bond cross-linked hyaluronic acid in the hyaluronic acid gel composition is 1mg/mL, 2mg/mL, 3mg/mL, and 4mg/mL, good injectability is achieved; when the content is more than or equal to 5mg/mL, the injection is difficult to be carried out by a water light injection instrument.
Example 4: evaluation of injectability of hyaluronic acid gel composition after dilution
The hyaluronic acid gel composition prepared in example 2 (the contents of disulfide-bond-crosslinked hyaluronic acid were 5mg/mL, 8mg/mL, 9mg/mL, 10mg/mL and 11mg/mL, respectively) was physically mixed and diluted with physiological saline in a volume ratio of 1: 2. The dilution process was performed in two syringes connected by a joint, one of which was filled with the hyaluronic acid gel composition (1mL) prepared in example 2, and the other was filled with 2mL of physiological saline, and the two syringes were physically diluted and mixed by pushing back and forth 60 to 80 times. A smaller diameter two-way connector (e.g., less than 1mm) may be used to achieve better dilution and mixing.
By Derma
(demata) 2 generation water light injection instrument, the injectability of the diluted hyaluronic acid gel composition through a conventional water light injection needle (nine needles) was tested. The test results show that each diluted hyaluronic acid gel composition has good injectability.
Example 5: preparation of hyaluronic acid gel composition
Dissolving sodium hyaluronate to obtain water solution with content of 2mg/mL, 4mg/mL, 6mg/mL, 8mg/mL or 10mg/mL, regulating pH value of the solution to 7.4, sterilizing and filtering for later use. The molecular weight of the adopted sodium hyaluronate is 1.6KDa, 3KDa, 8KDa, 50KDa, 180KDa, 500KDa, 800KDa, 1,500KDa or 2,700KDa, and the molecular weight can be any one of the molecular weights, and the molecular weights can also be the combination of any two or more of the molecular weights according to any weight ratio.
The disulfide-bond crosslinked hyaluronic acid gel (6mg/mL) prepared in example 1 was physically stirred and mixed with the above hyaluronic acid aqueous solution at a volume ratio of 1:1 to obtain a hyaluronic acid gel composition, in which the disulfide-bond crosslinked hyaluronic acid content was 3mg/mL, and the hyaluronic acid content was 1mg/mL, 2mg/mL, 3mg/mL, 4mg/mL, or 5 mg/mL.
Example 6: injectable performance evaluation of hyaluronic acid gel composition
By Derma
(demata) 2 generation water light injection instrument, the injectability of the hyaluronic acid gel composition prepared in example 5 through a conventional water light injection needle (nine needles) was tested. The test results show that each gel composition has good injectability.
Example 7: preparation of hyaluronic acid gel composition
The thiol-modified hyaluronic acid derivative is prepared by using 300KDa and 1,500KDa molecular weight sodium hyaluronate as raw material and adopting the method reported by Shu et al (Shu et al, Biomacromolecules 2002,3:1304-1311), and the thiol contents of the thiol-modified hyaluronic acid derivative are 33 mu mol/g and 40 mu mol/g respectively.
And dissolving the thiol-modified hyaluronic acid derivative and sodium hyaluronate together to obtain a mixed aqueous solution, wherein the content of the thiol-modified hyaluronic acid derivative is 2.5mg/mL or 5mg/mL, and the content of the sodium hyaluronate is 1mg/mL, 2mg/mL, 3mg/mL, 4mg/mL or 5mg/mL respectively. Adjusting the pH value of the solution to be neutral, and transferring the solution into a sterile glass container after moist heat sterilization; keeping the hyaluronic acid gel composition for 4 weeks in a closed and static way at room temperature, and enabling the solution to lose fluidity and form the hyaluronic acid gel composition with a semi-interpenetrating network structure.
The molecular weight of the adopted sodium hyaluronate is 1.6KDa, 3KDa, 8KDa, 50KDa, 180KDa, 500KDa, 800KDa, 1,500KDa or 2,700KDa, and the molecular weight can be any one of the molecular weights, and the molecular weights can also be the combination of any two or two of the molecular weights according to any weight ratio.
Example 8: injectable performance evaluation of hyaluronic acid gel composition
By Derma
(demanga) 2 generation water light injection apparatus, the injectability of the hyaluronic acid gel composition prepared in example 7 through a conventional water light injection needle (nine needles) was tested. The test results show that each gel composition has good injectability.
Example 9: water absorption and retention properties of hyaluronic acid gel compositions
The gel prepared in example 7 and normal saline are physically mixed and diluted according to the volume ratio of 1:2 by adopting the same dilution process as example 4, then the gel is placed into a small glass bottle and stands for 1 hour at room temperature, and no obvious layering phenomenon of a water phase and a gel phase is observed, so that the gel has good water absorption and retention performance.
Example 10: evaluation of Effect of hyaluronic acid gel composition on Water light injection
12 healthy volunteers (divided into 3 groups, and 4 in each group) were selected for facial water light injection (Derma)
2 generation water light injection instrument, conventional nine-needle water light injection needle), the injection volume is 5 mL.
Samples used in the test groups: the gel composition prepared in example 5 had a disulfide-bond-crosslinked hyaluronic acid content of 3mg/mL (prepared using 38. mu. mol/g of a thiolated derivative), and a non-crosslinked sodium hyaluronate content of 2mg/mL (1,500 KDa).
Samples used for control group I: 5mg/mL of an aqueous solution of non-crosslinked sodium hyaluronate (molecular weight 1.5 MDa).
Samples used for control group II: the same samples as used in the test group, but without the non-crosslinked sodium hyaluronate.
Skin moisture content test and improvement test of wrinkles and skin elasticity were performed at the same site at different time points after facial water light injection, respectively.
The relative increase (%) of skin moisture before and after injection was measured using a skin moisture meter, the relative increase (%) of skin elasticity before and after injection was measured using a skin elasticity meter, and the relative decrease in average depth of wrinkles before and after injection was evaluated using a rapid three-dimensional imaging system.
The test results of this example are shown in FIGS. 1-3. Compared with a control group I and a control group II, the cross-linked hyaluronic acid gel composition has better water light treatment effect, quick response and long maintenance time; meanwhile, all test objects in the test group do not find the swelling phenomenon, which indicates that the cross-linked hyaluronic acid gel composition has good fluidity and can be uniformly distributed on the superficial layer injected by water light.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the embodiments, and any other changes, modifications, combinations, substitutions and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents and are included in the scope of the present invention.
Claims (21)
1. A hyaluronic acid gel composition for use in aqueous light injection, the hyaluronic acid gel composition comprising:
1) disulfide bond cross-linked hyaluronic acid, and its content is not more than 10 mg/mL; and
2) non-crosslinked hyaluronic acid.
2. The hyaluronic acid gel composition for water light injection according to claim 1, wherein the content of the disulfide-bond cross-linked hyaluronic acid is between 1 and 4 mg/mL.
3. The hyaluronic acid gel composition for water light injection according to claim 2, wherein the content of the disulfide-bond cross-linked hyaluronic acid is between 2 and 3 mg/mL.
4. The hyaluronic acid gel composition for water light injection according to claim 1, wherein the disulfide-bond cross-linked hyaluronic acid is prepared by thiolating a derivative of hyaluronic acid.
5. The hyaluronic acid gel composition for water light injection according to claim 4, wherein the thiol group content of the thiol-modified hyaluronic acid derivative is 10-50 μmol/g.
6. The hyaluronic acid gel composition for water light injection according to claim 5, wherein the thiol group content of the thiol-modified derivative of hyaluronic acid is 20-40 μmol/g.
7. The hyaluronic acid gel composition for water light injection according to claim 1, wherein the content of the non-crosslinked hyaluronic acid is less than 10 mg/mL.
8. The hyaluronic acid gel composition for water light injection according to claim 7, wherein the content of the non-crosslinked hyaluronic acid is between 1 and 5 mg/mL.
9. The hyaluronic acid gel composition for water light injection according to claim 8, wherein the content of the non-crosslinked hyaluronic acid is between 2 and 4 mg/mL.
10. The hyaluronic acid gel composition for aqueous light injection according to claim 1, wherein the molecular weight of the non-crosslinked hyaluronic acid is between 800KDa and 3,000 KDa.
11. The hyaluronic acid gel composition for water light injection according to claim 10, wherein the non-crosslinked hyaluronic acid has a molecular weight of 1,000 KDa-2,800 KDa.
12. The hyaluronic acid gel composition for water light injection according to claim 1, wherein the non-crosslinked hyaluronic acid comprises two or more different molecular weights.
13. The hyaluronic acid gel composition for water light injection according to claim 12, wherein at least one of the non-crosslinked hyaluronic acids has a molecular weight between 1.6KDa and 500KDa and wherein at least one of the non-crosslinked hyaluronic acids has a molecular weight between 800KDa and 3,000 KDa.
14. The hyaluronic acid gel composition for water light injection according to claim 13, wherein the molecular weight of at least one of the non-crosslinked hyaluronic acids is between 2.4 and 8KDa and the molecular weight of at least one of the non-crosslinked hyaluronic acids is between 1,000 and 2,800 KDa.
15. The hyaluronic acid gel composition for water light injection according to claim 1, wherein the hyaluronic acid gel composition for water light injection has a semi-interpenetrating network structure.
16. The hyaluronic acid gel composition for water light injection according to any of claims 1-15, wherein the hyaluronic acid gel composition for water light injection contains a nutritional active.
17. The hyaluronic acid gel composition for water light injection according to claim 16, wherein said nutraceutically active substances comprise vitamins, amino acids, growth factors, etc.
18. A method for preparing the hyaluronic acid gel composition for water light injection according to any one of claims 1 to 17, comprising the steps of: the thiol-modified hyaluronic acid derivative is dissolved to obtain an aqueous solution, and the aqueous solution is subjected to an oxidation process to obtain a disulfide-bond cross-linked hyaluronic acid gel, which is then physically mixed with the aqueous solution of hyaluronic acid.
19. A method for preparing the hyaluronic acid gel composition for water light injection according to any one of claims 1 to 17, comprising the steps of: physically mixing the hyaluronic acid sulfhydrylation derivative water solution and the hyaluronic acid water solution to obtain a mixed solution, and then forming disulfide bond crosslinking through an oxidation process.
20. The method for preparing the hyaluronic acid gel composition for water light injection according to claim 18 or 19, wherein the oxidation process is performed under the action of oxygen.
21. The method for preparing the hyaluronic acid gel composition for water light injection according to claim 20, wherein the oxygen is oxygen in the air and/or dissolved oxygen in an aqueous solution.
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| WO2021077681A1 (en) * | 2019-10-23 | 2021-04-29 | 常州百瑞吉生物医药有限公司 | Hyaluronic acid gel composition for water optoinjection, and preparation method therefor |
| CN114288207A (en) * | 2021-12-31 | 2022-04-08 | 常州百瑞吉生物医药有限公司 | Composition with moisturizing and high moisturizing functions and application thereof |
| CN117298355A (en) * | 2023-11-28 | 2023-12-29 | 常州百瑞吉生物医药股份有限公司 | Coated hyaluronic acid gel composition and preparation method and application thereof |
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| CN117180494B (en) * | 2023-11-07 | 2024-01-23 | 四川大学 | Injectable polysaccharide hydrogel capable of reducing fibrotic scar generation and preparation method thereof |
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