Hyaluronic acid film with excellent transdermal absorption rate and its manufacturing method

Abstract

The present invention relates to a hyaluronic acid film and a method for producing the same, and more particularly to a hyaluronic acid film with excellent percutaneous absorption rate and a method for producing the same. The hyaluronic acid film of the present invention is characterized by having a percutaneous absorption rate of 72 to 93%. The hyaluronic acid film of the present invention is mainly composed of ultra-low molecular weight hyaluronic acid, and has excellent percutaneous absorption rate and mechanical properties, so it can be used in a variety of applications such as cosmetic packs, edible films and patches for medical devices, and health functional foods.

Description

[Technical Field]

[0001] The present invention relates to a hyaluronic acid film and a method for producing the same, and more particularly to a hyaluronic acid film with excellent transdermal absorption rate and a method for producing the same. [Background technology]

[0002] Hyaluronic acid or hyaluronate is uniformly distributed in connective tissue, epithelium, and nervous tissue of the human body. It is a biocompatible material with various physiological activities, and can contain a large amount of water. It has excellent viscoelasticity, and its effectiveness in skin regeneration, moisturizing, maintaining elasticity, and improving wrinkles has been proven. As a result, demand for anti-aging cosmetics, foods, pharmaceuticals, fillers for medical devices, etc. containing hyaluronic acid has recently increased sharply.

[0003] Currently, most commercially available hyaluronate products are in liquid form and contain excessive amounts of water. Due to concerns about microbial contamination, they must be manufactured in sterile equipment or must use preservatives, which pose safety concerns. This makes it difficult to expand their use to industrial applications in terms of versatility and safety.

[0004] Therefore, there have been studies that attempt to solidify hyaluronic acid or hyaluronates into films, fibers, etc., rather than into a liquid phase.

[0005] Hyaluronic acid or hyaluronates are classified into ultra-low molecular weight, low molecular weight, medium molecular weight, and high molecular weight depending on the molecular weight.

[0006] JP 2014-114355 A discloses an average molecular weight of 1 × 10 5 ~4×10 6 Korean Patent Publication No. 2019-0106091 also discloses films of medium and high molecular weight hyaluronate salts with a molecular weight of 0.1 to 2.5 MDa.

[0007] Medium and high molecular weight hyaluronates have excellent skin coating effects and mechanical properties, making it easy to form films, but they have difficulty in permeating and absorbing through the skin.

[0008] In contrast, hyaluronic acid or hyaluronates with lower molecular weights are more easily permeated and absorbed through the skin, but have poor mechanical properties, making film production difficult.

[0009] Meanwhile, Korean Patent Publication No. 2019-0138907 discloses that a hyaluronic acid film with a molecular weight of 500 to 5,000,000 Da can be produced, but the molecular weight is not specified in the examples. In fact, when the molecular weight is 2,000 Da or less, a film cannot be produced, and when the molecular weight is 2,000 to 1 × 10 4 In the case of Da, a film is formed, but the surface cracks, reducing marketability. 4 It was confirmed that when the molecular weight exceeds Da, a film with a uniform surface is formed. 4 Hyaluronic acid films with a viscosity of Da or higher have the problem of low transdermal absorption.

[0010] Therefore, the present inventors have made efforts to produce a hyaluronic acid film that is easily permeable and absorbed through the skin, and as a result, 4 1 x 10 Da ultra-low molecular weight hyaluronic acid 5 ~1×10 6 We confirmed that when a medium molecular weight hyaluronate salt of Da is added, it is possible to mass-produce uniform hyaluronic acid films with excellent transdermal absorption rate, leading to the completion of the present invention. Summary of the Invention [Problem to be solved by the invention]

[0011] An object of the present invention is to provide a hyaluronic acid film with excellent transdermal absorption rate.

[0012] Another object of the present invention is to provide a method for producing a hyaluronic acid film having excellent transdermal absorption rate.

[0013] Another object of the present invention is to provide a mask pack, an edible film, and a patch for a medical device, which contain a hyaluronic acid film having excellent transdermal absorption rate. [Means for solving the problem]

[0014] In order to achieve the above object, the present invention provides a hyaluronic acid film having a transdermal absorption rate of 72 to 93%.

[0015] In the present invention, the hyaluronic acid has a molecular weight of 2,000 to 1 × 10 4 Da of hyaluronic acid 84.0-98.5% by weight and molecular weight 1 × 10 5 ~1×10 6 It is characterized by being composed of 1.5 to 16 wt % Da of hyaluronic acid.

[0016] The present invention is characterized in that the thickness of the hyaluronic acid film is 0.01 to 1.5 mm.

[0017] The present invention also provides a polymer having a molecular weight of 2,000 to 1×10 4 Da of hyaluronic acid and molecular weight 1 x 10 5 ~1×10 6 The present invention provides a method for producing a hyaluronic acid film, comprising the steps of: (a) mixing hyaluronic acid having a molecular weight of 1000 to 1000 Da with hyaluronic acid having a molecular weight of 1000 to 1000 Da and dissolving the mixture in a solvent to produce a hyaluronic acid solution; (b) filtering the hyaluronic acid solution; (c) pouring the filtered hyaluronic acid solution into an automatic applicator or mold and casting a film having a thickness of 0.02 to 3 mm; and (d) drying the cast film at a temperature of 30 to 60°C.

[0018] In the present invention, the molecular weight is 2,000 to 1 × 10 4 Da of hyaluronic acid and molecular weight 1 x 10 5 ~1×10 6The weight ratio of Da to hyaluronic acid is characterized by being 84.0 to 98.5% by weight:1.5 to 16% by weight.

[0019] In the present invention, the viscosity of the hyaluronic acid solution is characterized by being 2,000 to 25,000 cPs.

[0020] In the present invention, the pH of the hyaluronic acid solution is characterized by being 2.5 to 3.5.

[0021] In the present invention, the hyaluronic acid is characterized by being hyaluronic acid, a hyaluronate, or a mixture thereof.

[0022] The present invention also provides a cosmetic mask pack, an edible film, and a medical device patch, each containing the hyaluronic acid film. [Effects of the Invention]

[0023] The hyaluronic acid film of the present invention is mainly composed of ultra-low molecular weight hyaluronic acid, and has excellent transdermal absorption rate and mechanical properties. [Brief explanation of the drawings]

[0024] [Figure 1] This is a photograph of an ultra-low molecular weight hyaluronic acid film. [Figure 2] This is a hyaluronic acid film prepared according to an embodiment of the present invention, which is a mixture of ultra-low molecular weight (8,000 Da) hyaluronic acid and medium molecular weight (1×105 to 1×106 Da) hyaluronic acid. [Figure 3] 1 is a photograph showing the microbial stability evaluation of a hyaluronic acid film prepared according to an embodiment of the present invention. [Figure 4] 1 is a photograph of a hyaluronic acid film produced without filtering the hyaluronic acid solution. DETAILED DESCRIPTION OF THE INVENTION

[0025] Hyaluronic acid or hyaluronates with lower molecular weights are more easily permeated and absorbed through the skin, but have poor mechanical properties, making film production difficult.

[0026] Korean Patent Publication No. 2019-0138907 discloses that a hyaluronic acid film with a molecular weight of 500 to 5,000,000 Da can be produced. However, when the method described in the specification was used, a film was not produced when the molecular weight was 2,000 Da or less, and when the molecular weight was 2,000 to 10,000 Da, a film was formed but the surface cracked, reducing marketability. 4 It was confirmed that a uniform film was formed on the surface when the molecular weight was 3 × 10 Da or more. 4 Hyaluronic acid films with a viscosity of Da or higher have a low transdermal absorption rate, which means that the various physiological activities of hyaluronic acid are not properly transmitted to the skin.

[0027] In the present invention, 2,000 to 1 × 10 4 1 x 10 Da ultra-low molecular weight hyaluronic acid 5 ~1×10 6 We aimed to confirm that adding Da medium molecular weight hyaluronate would enable the mass production of uniform hyaluronic acid films with excellent transdermal absorption.

[0028] In the present invention, ultra-low molecular weight hyaluronic acid and medium molecular weight hyaluronic acid are mixed, then dissolved in purified water to prepare a hyaluronic acid solution with a viscosity of 2,000 to 25,000 cPs (25°C), which is then poured into an automatic applicator or mold and dried at 30 to 60°C.

[0029] As a result, it was possible to mass-produce hyaluronic acid films with a uniform surface, and it was confirmed that the transdermal absorption rate of the produced hyaluronic acid films was 72-93%.

[0030] Therefore, from one aspect, the present invention relates to a hyaluronic acid film with a transdermal absorption rate of 72 to 93%.

[0031] The hyaluronic acid constituting the hyaluronic acid film has a molecular weight of 2,000 to 1×10 4 Da of hyaluronic acid 84.0-98.5% by weight and molecular weight 1 × 10 5 ~1×10 6 It is characterized by being composed of 1.5 to 16 wt % Da of hyaluronic acid.

[0032] That is, the hyaluronic acid film of the present invention is characterized by the use of hyaluronic acid having a medium molecular weight in addition to hyaluronic acid having an ultra-low molecular weight, which is not enough to form a film, in order to form the framework of the film.

[0033] In the present invention, the molecular weight of hyaluronic acid that corresponds to ultra-low molecular weight is 2,000 to 1 × 10 4 Da, and the molecular weight of hyaluronic acid, which is a low molecular weight, is 1 x 10 4 ~1×10 5 Da, and the molecular weight of hyaluronic acid, which corresponds to a medium molecule, is 1×10 5 ~1×10 6 It's Da.

[0034] Molecular weight 2,000~1×10 4 If the hyaluronic acid content of Da is less than 84.0% by weight, a film is formed, but the transdermal absorption rate is low, and if the hyaluronic acid content exceeds 98.5% by weight, no film is formed.

[0035] The hyaluronic acid film of the present invention is characterized by having a thickness of 0.01 to 1.5 mm.

[0036] In the present invention, the hyaluronic acid may be hyaluronic acid, a hyaluronate, or a mixture thereof. The hyaluronate is a salt bonded to hyaluronic acid, and examples thereof include, but are not limited to, sodium hyaluronate, calcium hyaluronate, and potassium hyaluronate.

[0037] From another viewpoint, the present invention provides: (a) a polymer having a molecular weight of 2,000 to 1×10 4 Da of hyaluronic acid and molecular weight 1 x 10 5 ~1×10 6 The present invention relates to a method for producing a hyaluronic acid film, comprising the steps of: (a) mixing hyaluronic acid having a molecular weight of 1000 to 10000 Da with hyaluronic acid having a molecular weight of 1000 to 10000 Da and dissolving the mixture in a solvent to produce a hyaluronic acid solution; (b) filtering the hyaluronic acid solution; (c) pouring the filtered hyaluronic acid solution into an automatic applicator or mold and casting a film having a thickness of 0.02 to 3 mm; and (d) drying the cast film at a temperature of 30 to 60°C.

[0038] Molecular weight 2,000~1×10 4 Da of hyaluronic acid and molecular weight 1 x 10 5 ~1×10 6 The weight ratio of Da to hyaluronic acid is preferably 84.0 to 98.5% by weight:1.5 to 16% by weight.

[0039] In the present invention, the viscosity of the hyaluronic acid solution containing a mixture of ultra-low molecular weight and medium molecular weight hyaluronic acids is preferably 2,000 to 25,000 cPs (25°C). The viscosity of the solution can vary depending on the HA molecular weight (Da), HA content, and solvent ratio, but if the viscosity is less than 2,000 cPs, it may be difficult to form a film, and if the viscosity is more than 25,000 cPs, the high viscosity may cause the film surface to become irregular when cast to a thickness of 0.02 mm to 3 mm.

[0040] Before injecting the mixed hyaluronic acid solution into an automatic applicator or a mold, it is preferable to filter the solution to remove air bubbles and insoluble matter. The filtration can be performed by passing the solution through a sieve (mesh size: 0.1 mm).

[0041] Without the filtration step, cracks will form around the air bubbles or insoluble matter as the film dries, producing a defective film.

[0042] In the present invention, the solvent is for dissolving hyaluronic acid or a hyaluronate, and purified water or an aqueous ethanol solution can be used. The aqueous ethanol solution preferably has an ethanol content of 0.01 to 10% by volume.

[0043] Generally, the pH of hyaluronic acid salts is 5.0 to 7.0, and hyaluronic acid solutions are vulnerable to microbial contamination, so antibacterial agents such as ethanol must be added to prevent this. However, when hyaluronic acid with a pH of 2.5 to 3.5 is used, it has excellent microbial contamination prevention effects.

[0044] The filtered hyaluronic acid solution is poured into an automatic applicator or mold, and a film having a thickness of 0.02 to 3 mm is cast. The cast film is then dried at 30 to 60°C to produce a hyaluronic acid film having a thickness of 0.01 to 1.5 mm.

[0045] If the casting thickness is less than 0.02 mm, it is difficult to form a film, and if the casting thickness exceeds 3 mm, the casting thickness cannot be maintained due to the fluidity of the solution, so a hyaluronic acid film of 0.01 mm to 1.5 mm can ultimately be produced.

[0046] The cast film is preferably dried for 6 to 24 hours at a temperature of 30 to 60° C. The drying can be performed by various drying methods without particular limitation as long as the drying is performed at a temperature of 30 to 60° C.

[0047] From another aspect, the present invention relates to a cosmetic mask pack, an edible film, a medical device patch, and the like, which contain the hyaluronic acid film. [Example]

[0048] The present invention will be described in more detail below with reference to examples. It will be apparent to those skilled in the art that these examples are merely for the purpose of illustrating the present invention and are not intended to limit the scope of the present invention.

[0049] Example 1: Preparation of hyaluronic acid film by conventional technology A hyaluronic acid film was prepared using the method described in Korean Patent Publication No. 2019-0138907. That is, a glass support was heated at 60°C for 2 hours. Then, 17% by weight of hyaluronic acid based on the total weight of the hyaluronic acid solution was dissolved in distilled water to prepare a hyaluronic acid solution. The heated support (glass) was coated with the dissolved hyaluronic acid solution to a thickness of 500 μm, dried at 60°C for 2 hours, and peeled off to prepare a hyaluronic acid film with a thickness of 80 μm. The molecular weights of the hyaluronic acid used were 500 Da, 2,000 Da, and 1×10 5 It was Da.

[0050] As a result, when the molecular weight of hyaluronic acid was 500 Da, no film was formed, when the molecular weight of hyaluronic acid was 2,000 Da, a film was formed but was not smooth, and when the molecular weight of hyaluronic acid was 1 × 10 5 It was confirmed that when the film thickness was 100 μm, a film with a smooth surface was formed.

[0051] Example 2: Preparation of hyaluronic acid film Examples 2-1 to 2-6: Production of ultra-low molecular weight hyaluronic acid film Molecular weight 500~1×10 5 Da ultra-low molecular weight hyaluronate (10-50% by volume) was dissolved in 0.01-10% by volume aqueous ethanol solution to prepare a hyaluronate solution (100-20,000 cPs). The applicator of an automatic applicator was adjusted to cast a film with a thickness of 0.02-3 mm, which was then dried in a hot air dryer at 40°C for 20 minutes to 24 hours to prepare a hyaluronate film with a thickness of 0.01-1.5 mm.

[0052] [Table 1]

[0053] As a result, similar to the results of the prior art production in Example 1, when the molecular weight was 500 Da, no film was formed, and when the molecular weight was 2,000 Da, 8,000 Da, and 10,000 Da, although films were formed, the films were easily broken and destroyed, and the molecular weight was 3×10 4 It was confirmed that a film with a smooth surface was formed when the temperature was above Da.

[0054] Examples 2-7 to 2-23: Production of hyaluronic acid films using ultra-low and medium molecular weight As shown in Table 2 below, 1×10 5 ~1×10 6 A medium molecular weight hyaluronate (pH 6.0-7.0) with a molecular weight of 2,000-10,000 Da and an ultra-low molecular weight hyaluronate (pH 6.0-7.0) with a molecular weight of 2,000-10,000 Da were mixed and dissolved in purified water to prepare a hyaluronate solution with a viscosity of 2,000-25,000 cPs. The resulting solution was passed through a sieve (mesh size: 0.1 mm), and the applicator of an automatic applicator was adjusted to cast the hyaluronate solution to a thickness of 0.02-3 mm. This was then dried in a hot air dryer at 40°C for 20 minutes to 24 hours to produce a hyaluronate film with a thickness of 0.01-1.5 mm.

[0055] [Table 2]

[0056] From Figure 1, molecular weights of 2,000 to 1 × 10 4 When Da's ultra-low molecular weight hyaluronate is used alone, the surface cracks and has an uneven shape, making it impossible to form a film. However, when ultra-low molecular weight hyaluronate and medium molecular weight hyaluronate are mixed in a specific ratio, it was confirmed that mass production of a film with a uniform surface is possible (see Figure 2).

[0057] From Table 2, it was confirmed that when the viscosity of the hyaluronate solution is less than 2,000 cPs, it is difficult to form a film, and when the viscosity of the hyaluronate solution is 25,000 cPs or more, it is difficult to cast a film with a thickness of 0.02 to 3 mm using an automatic applicator due to its high viscosity.

[0058] Furthermore, when casting was performed with a casting thickness set to 3.5 mm, the thickness of the hyaluronate solution was not maintained and it spread, making casting impossible (see 2-21).

[0059] Examples 2-24 to 2-26: Preparation of hyaluronic acid films by pH Hyaluronic acid films were produced in the same manner as in Examples 2-9, 2-11, and 2-13, except that hyaluronic acid of pH 2.5 to 3.5 was used instead of hyaluronate of pH 6.0 to 7.0, and their stability against microorganisms was evaluated.

[0060] [Table 3]

[0061] The prepared hyaluronic acid and hyaluronate films were each dissolved in sterile saline at a volume of 1%, and 1 mL of each was applied to 3M Petrifilm. After incubation at 37°C for 24 hours, the presence or absence of microbial contamination was confirmed, and the results are shown in Table 4.

[0062] [Table 4]

[0063] Table 4 shows that when hyaluronic acid salts with a pH of 6.0 to 7.0 are used, there is a risk of microbial contamination during the film manufacturing process, but when hyaluronic acid with a pH of 2.5 to 3.5 is used, microbial contamination does not occur (see Figure 3).

[0064] Examples 2-27 to 2-29: Production of hyaluronic acid films with and without filtration Hyaluronic acid salt films were produced in the same manner as in Examples 2-9, 2-11, and 2-13, except that the films were cast without filtering the hyaluronic acid salt solution, and the quality of the hyaluronic acid films was confirmed.

[0065] [Table 5]

[0066] From Table 5 and Figure 4, it was found that when the hyaluronic acid solution was sieved (mesh size: 0.1 mm) before casting, no air bubbles were generated and a good film without impurities was formed, but when the hyaluronic acid solution was not sieved, air bubbles were generated in the film or impurities were contained.

[0067] Example 3: Evaluation of percutaneous absorption rate Compare the percutaneous absorption rate of high molecular weight hyaluronate film and the ultralow molecular weight hyaluronate film produced in embodiment.Except that high molecular weight hyaluronate film uses the hyaluronate of molecular weight 1.2MDa as 100% by weight, prepare hyaluronate film in the same manner as in embodiment 2-9, and measure percutaneous absorption rate.

[0068] According to the "Guidelines for Skin Absorption Tests in Living Organisms," a Franz diffusion cell (effective area: 0.64 cm) was used. 2 The skin permeation test was carried out under sink conditions using a device (Logan Instruments, New Jersey, USA) with a chamber volume of 5 ml.

[0069] The receptor phase used in the skin permeation test was phosphate-buffered saline (PBS) at pH 7.4. The epidermal layer of prepared human skin (1.5 cm x 1.5 cm) was placed on the receptor chamber with the stratum corneum facing up. The donor chamber was then covered and secured with a clamp. The receptor phase was then loaded into a Franz diffusion cell, maintained at 32 ± 1°C, and 100 μL of hyaluronic acid film solution was applied to the donor site at regular intervals. After the permeation test, 5 mL of the receptor phase was sampled and analyzed at 1, 3, 6, 9, 12, and 24 hours, and replenished with fresh phosphate-buffered saline.

[0070] [Table 6]

[0071] From Table 6, 1.2 × 10 6 When using Da high molecular weight hyaluronic acid, the percutaneous absorption rate of the film was 33.12%, but the percutaneous absorption rate of the hyaluronic acid film made by mixing ultra-low molecular weight and medium molecular weight hyaluronic acid was 71.50-93.63%, demonstrating even better percutaneous absorption. In particular, it was confirmed that the percutaneous absorption rate increased significantly as the molecular weight decreased, and that the percutaneous absorption rate increased as the thickness of the hyaluronic acid film became thinner.

[0072] Although the specific parts of the present invention have been described in detail above, it is obvious to those skilled in the art that these specific techniques are merely preferred embodiments and do not limit the scope of the present invention. Therefore, the true scope of the present invention should be defined by the appended claims and their equivalents. [Industrial Applicability]

[0073] The hyaluronic acid film of the present invention is mainly composed of ultra-low molecular weight hyaluronic acid, and has excellent percutaneous absorption rate and mechanical properties, making it applicable to a variety of uses such as cosmetic packs, patches for medical devices, and health functional foods.

Claims

1. A hyaluronic acid film comprising 84 to 98.5% by weight of hyaluronic acid having a molecular weight of 2,000 to 1 x 10 4 Da and 1.5 to 16% by weight of hyaluronic acid having a molecular weight of 1 x 10 5 to 1 x 10 6 Da, and having a transdermal absorption rate of 72 to 93%.

2. The hyaluronic acid film according to claim 1, characterized in that the thickness of the hyaluronic acid film is 0.01 to 1.5 mm.

3. The hyaluronic acid film according to claim 1 or 2, wherein the hyaluronic acid is hyaluronic acid, a hyaluronate, or a mixture thereof.

4. (a) Molecular weight 2,000 to 1×10 ４ 84.0 to 98.5% by weight of hyaluronic acid with a molecular weight of 1 × 10 ５ ~1 x 10 ６ and 1.5 to 16 wt. % of hyaluronic acid of Da, and dissolving it in a solvent to prepare a hyaluronic acid solution; (b) filtering the hyaluronic acid solution; (c) pouring the filtered hyaluronic acid solution into an automatic applicator or mold to cast a film to a thickness of 0.02-3 mm; (d) drying the cast film at 30 to 60°C.

5. The method for producing a hyaluronic acid film according to claim 4, wherein the viscosity of the hyaluronic acid solution is 2,000 to 25,000 cPs.

6. The method for producing a hyaluronic acid film according to claim 4, wherein the pH of the hyaluronic acid solution is 2.5 to 3.

5.

7. The method for producing a hyaluronic acid film according to any one of claims 4 to 6, wherein the hyaluronic acid is hyaluronic acid, a hyaluronate, or a mixture thereof.

8. A cosmetic mask pack comprising the hyaluronic acid film of claim 1.

9. An edible film comprising the hyaluronic acid film according to claim 1.

10. A patch for a medical device comprising the hyaluronic acid film of claim 1.

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