CN111249525A

CN111249525A - Injectable facial filler composition gel for cosmetic and plastic surgery and preparation method thereof

Info

Publication number: CN111249525A
Application number: CN202010219476.XA
Authority: CN
Inventors: 冯幸福
Original assignee: Ningbo Santemuse Biotechnology Co ltd
Current assignee: Ningbo Santemuse Biotechnology Co ltd
Priority date: 2020-03-25
Filing date: 2020-03-25
Publication date: 2020-06-09

Abstract

The invention relates to an injection type face filler composition gel for beauty and plastic, which comprises a combined gel matrix and poly-L-lactic acid, wherein the combined gel matrix comprises an injection water solution, sodium hyaluronate and poly-L-lactide spheres, the poly-L-lactide spheres account for 0.5-30% of the total weight of the injection water solution, and the sodium hyaluronate accounts for 0.1-30% of the total weight of the injection water solution. The chemically cross-linked hyaluronic acid solution containing PLA microspheres or crystals of the present invention may be injected into the epidermis, middle layer or deep dermis to correct contour defects of facial skin, or such a composition may be injected into loose connective tissue around the lip muscles or into the lips to improve the appearance of the lips, and may be applied to specific parts of the face, etc.

Description

Injectable facial filler composition gel for cosmetic and plastic surgery and preparation method thereof

Technical Field

The invention relates to the technical field of hyaluronic acid and derivatives thereof, in particular to an injection type facial filler composition gel for cosmetic and plastic, and a preparation method of the injection type facial filler composition gel for cosmetic and plastic.

Background

The history of bioabsorbable materials for soft tissue augmentation of the face dates back to early 1980 when bovine collagen was introduced to treat fine lines, wrinkles and volume defects. Since then, various non-permanent, absorbable dermal fillers and facial prostheses have been approved and used worldwide (hyaluronic acid, collagen and porcine small intestine submucosa). Semi-permanent and permanent dermal fillers have also been developed. Semi-permanent materials include hydroxyapatite (Radiesse) and poly-L-lactic acid (Sculptra). Non-absorbable materials such as PMMA microspheres (Bellafill) and PTFE facial catgut have also been used to correct facial defects.

Currently, dermal fillers or products for soft tissue filling consist mainly of Hyaluronic Acid (HA). There are 110 hyaluronic acid fillers (Miinews) on the european market. These HA fillers are all cross-linked, mainly distinguished by concentration and particle size of the HA. However, none of these current HA products contain supplementary ingredients that extend the clinical persistence of the product. The invention describes the preparation and application of a hyaluronic acid composition comprising microspheres or crystals consisting of poly-1-lactic acid, polyglycolide and copolymers of poly-1-lactide with glycolipids.

Hyaluronic acid was discovered by Meyer and Palmer in 1934. Karl Meyer isolated the polysaccharides from the vitreous humor. Due to the uronic acid contained therein, Meyer names the substance hyaluronic acid according to hyalos (glassy meaning) and uronic acid. At physiological pH, all carboxyl groups on the uronic acid residue are dissociated, and when sodium is the counterion, the polysaccharide is called sodium hyaluronate. In 1986, Balazs proposed the name of hyaluronic acid. This is a currently recognized term. The abbreviation "HA" will be used in this application to denote hyaluronic acid, which includes hyaluronic acid and its metal salts.

HA is a linear polysaccharide (long-chain biopolymer) that is a disaccharide unit composed of the units D-glucuronic acid and N-acetyl-D-glucosamine, linked by the β.1-3 and β.1-4 glucosides.

HA HAs viscous flow properties, elasticity and pseudoplasticity. This attribute is unique to the HA. Other glycosaminoglycans (GAGs) form viscous solutions only at much higher concentrations than HA, and they are unable to form a viscoelastic polymer network. HA HAs been shown to be important in diverse activities such as tissue hydration, lubrication, solute transport, cell migration, cell function, cell differentiation and cell proliferation.

The prior art exists for the use of hyaluronic acid compositions in soft tissue augmentation. Still other patents and patent applications describe the potential use of polylactide, polyethylene glycol and combinations thereof in drug delivery, either for tissue repair when combined with growth factors, or for soft tissue augmentation alone (without the addition of hyaluronic acid). Still other patents and patent applications mention potential applications of bioabsorbable polymer particles containing lactic acid polymers. However, none of the methods can produce a crosslinked hyaluronic acid composition containing poly-L-lactic acid microspheres or crystals for soft tissue augmentation.

Disclosure of Invention

The present invention addresses the above-described problems and provides an injectable facial filler composition gel for cosmetic and cosmetic use and a method for producing the same.

In order to solve the technical problems, the invention is realized by the following technical scheme:

the invention provides an injection type face filler composition gel for beauty and plastic, which comprises a combined gel matrix and poly-L-lactic acid, wherein the combined gel matrix comprises an injection water solution, sodium hyaluronate and poly-L-lactide spheres, the poly-L-lactide spheres account for 0.5-30% of the total weight of the injection water solution, and the sodium hyaluronate accounts for 0.1-30% of the total weight of the injection water solution.

The invention further provides that: also comprises one or more of anesthetic, polyalcohol, vitamins, bacteriostatic agent, antioxidant, or mineral salts.

The invention further provides that: the anesthetic is lidocaine, the anesthetic accounts for 0.05-1% of the total weight of the gel of the injection type facial filler composition for cosmetic and plastic, the polyalcohol comprises one or more of sorbitol, glycerol, mannitol, propylene glycol, erythritol, xylitol, maltitol and lactitol, the polyalcohol accounts for 0.1 to 15 percent of the total weight of the gel of the injection type facial filler composition for cosmetic and plastic, the vitamins include vitamin C, vitamin E, and vitamin B group, and account for 0.1-5.0 mg/mL of total gel weight of the injectable facial filler composition for skin care and plastic, the bacteriostatic agent comprises one or more of thimerosal, benzalkonium bromide, chlorobutanol, benzyl alcohol or benzyl esters, the bacteriostatic agent accounts for 0.01-0.5% of the total weight of the gel of the injection type facial filler composition for beauty and plastic.

The invention further provides that: the poly-L-lactide spheres account for 10-20% of the total weight of the aqueous solution for injection, and the sodium hyaluronate accounts for 10-20% of the total weight of the aqueous solution for injection.

The invention further provides that: the water solution for injection is a sodium chloride solution or a phosphate buffer solution with the mass concentration of 0.9%.

The invention further provides that: the poly-L-lactide ball accounts for 10 to 30 percent of the total weight of the gel of the injection type facial filler composition for beauty and plastic.

The invention further provides that: the average particle diameter of the poly-L-lactide sphere is 15-100 mu m.

The invention further provides that: the average particle diameter of the poly-L-lactide sphere is 25-50 mu m.

The invention further provides that: the poly-L-lactide spheres may be replaced with polyglycolide and lactide or copolymers of L-lactide and glycolide (PLGA).

The invention also provides a preparation method of the injectable facial filler composition gel for cosmetic and plastic surgery, which is characterized by comprising the following steps:

1) adding sodium hyaluronate and poly-L-lactide spheres into the water solution for injection under the condition of slow stirring, and fully wetting and swelling;

2) standing for 6h to obtain clear and transparent solution or gel;

3) adding poly-L-lactic acid crystal into clear transparent solution or gel, grinding or stirring for 10min, and pumping the mixture back and forth between two syringes to obtain uniform mixture, wherein the formation of air bubbles can be avoided.

4) -centrifuging the mixture at 3500rpm to ensure removal of air bubbles, to prepare a gel of the injectable cosmetic face-filling composition.

The chemically cross-linked hyaluronic acid solution containing PLA microspheres or crystals of the present invention may be injected into the epidermis, middle layer or deep dermis to correct contour defects of facial skin, or such a composition may be injected into loose connective tissue around the lip muscles or into the lips to improve the appearance of the lips. The hyaluronic acid/PLA composition may be injected through a 27-30 gauge needle. The material remains substantially colorless and provides a durable clinical effect. The composition may be prepackaged in a ready-to-use syringe containing materials that may exhibit varying degrees of persistence.

Drawings

FIG. 1 is a graph showing the results of an experiment according to an embodiment of the present invention.

Detailed Description

To make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions of the present invention will be clearly and completely described below with reference to the accompanying drawings, and it is apparent that the described embodiments are some, but not all embodiments of the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

The present invention relates to an injectable, chemically cross-linked hyaluronic acid solution comprising resorbable poly-L-lactide (PLA) or Polyglycolide (PLG) lactide or L-lactide/glycolide copolymer-PLGA (20-50 μm diameter) for soft tissue augmentation and tissue regeneration. Chemically cross-linked hyaluronic acid may be purchased from a cooperative institution or may be provided by companies producing and commercializing cross-linked hyaluronic acid for soft tissue augmentation. In addition, the cross-linked hyaluronic acid can be produced on its own using existing and published methods. Cross-linked hyaluronic acid may be produced from 1, 4-butanediol diglycidyl ether (BDDE). Poly L-lactic acid crystals or micropowder can be purchased from a number of manufacturers including Phosphorex, Carbion, Polysciences or Akina. Grinding the poly-L-lactic acid crystal, and sieving to obtain microspheres or granules with diameter of 20-50 μm. The particles are sterilized using gamma radiation, ethylene oxide or other suitable sterilization method. The cross-linked hyaluronic acid is sterilized by autoclaving. The final product is prepared by aseptically mixing sterilized poly-1-lactic acid spheres or crystals with aseptically crosslinked hyaluronic acid, and then mixing well and filling into final product syringe.

As defined herein, the term "injectable hyaluronic acid composition" refers to injectable, chemically cross-linked, biocompatible hyaluronic acid compositions, which compositions also comprise bioresorbable or absorbable microspheres, which, when injected into tissue, have the effect of filling defective tissue, such as skin lines and folds. The term "biocompatible" means that the hyaluronic acid cross-linked according to the invention is stable when implanted in the biological tissue of a subject, and more specifically does not deteriorate over time after implantation, or cause an immune response, or cause an adverse tissue reaction.

The use of hyaluronic acid compositions in soft tissue augmentation is described with reference to the prior art. Still other patent documents describe the potential use of polylactide, polyethylene glycol and combinations thereof in drug delivery, either for tissue repair when combined with growth factors, or for soft tissue augmentation alone (without the addition of hyaluronic acid). Still other patents and patent applications mention potential applications of bioabsorbable polymer particles containing lactic acid polymers. However, none of the methods can produce a crosslinked hyaluronic acid composition containing poly-L-lactic acid microspheres or crystals for soft tissue augmentation. The only soft tissue augmentation product currently containing microparticles or poly-L-lactic acid crystals is Sculptra, which consists of carboxymethylcellulose, mannitol and PLLA powder.

2) standing for 6h to obtain clear and transparent solution or gel;

Detailed preparation and testing

EXAMPLE 1 preparation of crosslinked HA/PLA compositions

For preliminary evaluation, commercial samples of cross-linked hyaluronic acid were prepared. poly-L-lactic acid crystals are added to the transparent and viscous cross-linked hyaluronic acid. The crystals added were ground and sieved to a final diameter distribution of 25-45 μm. In a clean room, the mixture was pumped slowly back and forth between two syringes to obtain a homogeneous mixture, which avoided the formation of air bubbles. The mixture was centrifuged at 3500rpm to ensure removal of air bubbles. The HA-PLA syringe is placed at 2-8 ℃ for storage.

EXAMPLE 2 evaluation of crosslinked HA/PLA blends in animals

A one month animal study was conducted to examine tissue response to HA/PLA formulations and controls, using commercially available hyaluronic acid as a control. The subjects were a healthy New Zealand white rabbit and a healthy mouse. The injection sites were the ear sites of the rabbit model and the dorsal dermis of the mouse model. After 30 days, animals were euthanized and the implantation sites were removed for fixation, sectioning and histopathological evaluation. Sections were stained with H & E, Trichrome Blue and Von Geison's (elastic fiber mesh). All stained sections were evaluated by a pathologist and image acquisition and writing of pathology reports were performed. After 1 month, histological evaluation of the HA and HA + PLA implants was clearly visible, with no obvious inflammatory phenomena; the rabbit implants and fibrous capsule around the implants had new collagen fibers formed. Staining by Van Geison did not show the generation of elastic tissue associated with the implant. Histological evaluation of HA + fibril collagen in rabbit ear models showed that collagen fibers were dispersed throughout the implant due to the fact that the HA carrier in the injection solution contained intact collagen fibers

And (4) conclusion: the inflammatory response of all implants was low. The results in the rabbit ear model showed that a small amount of early collagen fibers were interspersed in the HA and HA + PLA implants, indicating that some of the implanted tissues integrated or stimulated new collagen as shown in figure 1,

in addition, in the description of the embodiments of the present invention, unless otherwise explicitly specified or limited, the terms "mounted," "connected," and "connected" are to be construed broadly, e.g., as meaning either a fixed connection, a removable connection, or an integral connection; can be mechanically or electrically connected; they may be connected directly or indirectly through intervening media, or they may be interconnected between two elements. The specific meanings of the above terms in the present invention can be understood in specific cases to those skilled in the art.

In the description of the present invention, it should be noted that the terms "first", "second", and "third" are used for descriptive purposes only and are not to be construed as indicating or implying relative importance.

Finally, it should be noted that: the above-mentioned embodiments are only specific embodiments of the present invention, which are used for illustrating the technical solutions of the present invention and not for limiting the same, and the protection scope of the present invention is not limited thereto, although the present invention is described in detail with reference to the foregoing embodiments, those skilled in the art should understand that: any person skilled in the art can modify or easily conceive the technical solutions described in the foregoing embodiments or equivalent substitutes for some technical features within the technical scope of the present disclosure; such modifications, changes or substitutions do not depart from the spirit and scope of the embodiments of the present invention, and they should be construed as being included therein. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.

Claims

1. An injectable gel of a face pack composition for cosmetic and cosmetic use, characterized in that: the gel comprises a combined gel matrix and poly-L-lactic acid, wherein the combined gel matrix comprises an injection water solution, sodium hyaluronate and poly-L-lactide spheres, the weight of the poly-L-lactide spheres accounts for 0.5-30% of the total weight of the injection water solution, and the weight of the sodium hyaluronate accounts for 0.1-30% of the total weight of the injection water solution.

2. An injectable facial filler composition gel for cosmetic and cosmetic use according to claim 1, which comprises: also comprises one or more of anesthetic, polyalcohol, vitamins, bacteriostatic agent, antioxidant, or mineral salts.

3. An injectable facial filler composition gel for cosmetic and cosmetic use according to claim 2, wherein: the anesthetic is lidocaine, the anesthetic accounts for 0.05-1% of the total weight of the gel of the injection type facial filler composition for cosmetic and plastic, the polyalcohol comprises one or more of sorbitol, glycerol, mannitol, propylene glycol, erythritol, xylitol, maltitol and lactitol, the polyalcohol accounts for 0.1 to 15 percent of the total weight of the gel of the injection type facial filler composition for cosmetic and plastic, the vitamins include vitamin C, vitamin E, and vitamin B group, and account for 0.1-5.0 mg/mL of total gel weight of the injectable facial filler composition for skin care and plastic, the bacteriostatic agent comprises one or more of thimerosal, benzalkonium bromide, chlorobutanol, benzyl alcohol or benzyl esters, the bacteriostatic agent accounts for 0.01-0.5% of the total weight of the gel of the injection type facial filler composition for beauty and plastic.

4. An injectable cosmetic face pack composition gel according to claim 1, 2 or 3, characterized in that: the poly-L-lactide spheres account for 10-20% of the total weight of the aqueous solution for injection, and the sodium hyaluronate accounts for 10-20% of the total weight of the aqueous solution for injection.

5. An injectable facial filler composition gel for cosmetic and cosmetic use according to claim 4, wherein: the water solution for injection is a sodium chloride solution or a phosphate buffer solution with the mass concentration of 0.9%.

6. An injectable facial filler composition gel for cosmetic and cosmetic use according to claim 5, wherein: the poly-L-lactide ball accounts for 10 to 30 percent of the total weight of the gel of the injection type facial filler composition for beauty and plastic.

7. An injectable facial filler composition gel for cosmetic and cosmetic use according to claim 6, wherein: the average particle diameter of the poly-L-lactide sphere is 15-100 mu m.

8. An injectable facial filler composition gel for cosmetic and cosmetic use according to claim 6, wherein: the average particle diameter of the poly-L-lactide sphere is 25-50 mu m.

9. An injectable facial filler composition gel for cosmetic and cosmetic use according to claim 4, wherein: the poly-L-lactide spheres may be replaced with polyglycolide and lactide or copolymers of L-lactide and glycolide (PLGA).

10. The preparation method of the injectable facial filler composition gel for cosmetic and plastic surgery is characterized by comprising the following steps:

2) standing for 6h to obtain clear and transparent solution or gel;