KR20190036227A - Preparation Method of Sodium Hyaluronate Film by Automatic Control Coater and Sodium Hyaluronate Film prepared Thereof - Google Patents

Abstract

The present invention relates to a method of producing a hyaluronate film and a hyaluronate film produced thereby and, more specifically, to a method of producing a hyaluronate film, which enables a large-batch production using an automatic applicator, and a hyaluronate film which may be used as a mask pack, a patch, a film-type adhesion barrier, and the like. In particular, the method of producing a hyaluronate film comprises the steps of: (a) dissolving hyaluronate in a solvent, thereby forming a hyaluronate solution of 0.1-30.0 wt%; (b) injecting the formed hyaluronate solution into an automatic applicator and casting a film in a thickness of 0.025-5mm; and (c) drying the cast film at 30-50°C. According to the present invention, the method of producing a hyaluronate film by using an automatic applicator enables a convenient large-batch production, and can conveniently adjust properties through controlling viscosity of the hyaluronate and thickness of the film. The hyaluronate film thus produced may be used for cosmetics, drugs, packs for medical devices, patches, artificial skin, adhesion barriers, and so forth.

Description

A method of producing a hyaluronate film by an automatic applicator and a hyaluronate film prepared therefrom (Preparation Method of Sodium Hyaluronate Film by Automatic Control Coater and Sodium Hyaluronate Film Prepared Thereof)

The present invention relates to a process for producing a hyaluronate film and a hyaluronate film produced therefrom, and more particularly to a process for producing a hyaluronate film by an automatic dispenser which is easy to mass- And a hyaluronate film usable as an anti-adhesion agent.

In order to mass-produce a film product, it is essential that the thickness of the film can be easily controlled in a uniform and reproducible manner. In particular, automation methods are recommended because of differences in skill between workers in film production in solution. Film casting using automatic control coater helps solve these problems. The automatic dispenser is advantageous in that the film is cast at a constant speed in the production of the film, and the pressure and flatness applied to the sample are provided under the same conditions. When using an automatic applicator with easy thickness control, it is possible to mass-produce reproducible and uniform film products by controlling the thickness of the film according to the use purpose of the product.

Meanwhile, Sodium Hyaluronate (Hyaluronic Acid), a biomaterial mainly present in synovial fluid and extracellular matrix, is a linear polymeric polysaccharide. Hyaluronate, which is widely distributed in human connective tissues, epithelium and nervous tissues, is a safe material with high biocompatibility. It can contain a large amount of water and has excellent viscoelasticity. Therefore, it can be used as a medicine for degenerative arthritis, eye drops, Anti-aging materials such as wrinkle-improving fillers, medical devices such as anti-adhesion agents for tissue repair, and moisturizing and wrinkle-improving materials are widely used in various fields such as cosmetics and foods.

However, due to its excellent biocompatibility, it is exposed to the air and is easily contaminated by microorganisms and the like when the water is introduced.

All hyaluronate products such as cosmetics, joint injections, fillers, etc., which are on the market, are in a state of aqueous solution, so there is a great concern about microbial contamination. Therefore, cosmetic products are used in excess of toxic preservatives or in the case of pharmaceuticals and medical devices under sterile conditions It requires great attention to the storage, distribution and use of end products as well as difficulties in production.

The present inventors have found that when a hyaluronic acid salt product is manufactured into a suture fiber or a film having a minimum moisture content, it has a high resistance to microbial contamination (Korean Patent No. 1709608, Korean Patent Application No. 2017-0029094 Hyaluronic acid products, which are solid rather than liquid, can be easily managed for production and storage, which is convenient for producers and users as well as for practitioners.

Studies on hyaluronate films have been limited by the inventors of the present invention except for a patent (Application No .: No. 2017-0029094) in which a film was manufactured by a solvent casting method of 100% hyaluronate. However, when a solvent casting method is used, there is a problem that it is difficult to mass-produce a hyaluronate film containing a hyaluronate at a high concentration and having uniform appearance and physical properties.

The present inventors have made efforts to solve the above problems. As a result, the present inventors have found that when casting a hyaluronate solution into an automatic coater and then drying it, a hyaluronate film having various thicknesses can be uniformly mass- It is confirmed that the physical properties can be controlled by controlling the viscosity and the thickness, and the present invention has been completed.

It is an object of the present invention to provide a method for producing a hyaluronate film having biocompatibility and anti-aging function and being utilized in various fields.

Another object of the present invention is to provide a hyaluronate film containing a high concentration of hyaluronate and having uniform surface and a method of mass-producing the hyaluronate film.

It is still another object of the present invention to provide a mask pack, a patch, and an artificial skin and an anti-adhesion agent comprising a hyaluronate film having resistance to microorganisms and excellent mechanical properties.

In order to accomplish the above object, the present invention provides a method for producing a hyaluronate, comprising: (a) dissolving a hyaluronate in a solvent to prepare a 0.1 to 30.0 wt% hyaluronate solution; (b) casting the prepared hyaluronate solution into an automatic coater and casting the film to a thickness of 0.025 to 5 mm; And (c) drying the cast film at 30 to 50 ° C.

In the present invention, the viscosity of the hyaluronate solution is 300 to 100,000 cPs.

The present invention also provides a hyaluronate film produced by the above method.

In the present invention, the hyaluronate film has a tensile strength of 50 to 300 MPa.

The present invention also provides a mask pack, patch, artificial skin and an anti-adhesion agent comprising the hyaluronate film.

The method of producing a hyaluronate film by the automatic dispenser of the present invention is easy to mass-produce, and the physical properties can be easily controlled by controlling the viscosity of the hyaluronic acid salt and the thickness of the film. The hyaluronate film thus prepared can be used for cosmetics, It can be applied to medicines, packs for medical devices, patches, artificial skin, and anti-adhesion agents.

1 is an explanatory diagram of a conventional automatic dispenser.
2 is a photograph of a hyaluronate film prepared according to the viscosity of a hyaluronic acid salt.
3 is a photograph of a hyaluronate film produced according to the drying method.
4 is a photograph of a hyaluronate film produced according to an embodiment of the present invention.

In the present invention, when a hyaluronate solution is injected into an automatic applicator and dried, it is possible to uniformly mass-produce hyaluronate films of various thicknesses and to control the physical properties through controlling the viscosity and thickness of the hyaluronate solution Respectively.

In the present invention, a hyaluronic acid salt solution is prepared by dissolving a hyaluronic acid salt in water or an aqueous solution of ethanol to prepare a 0.1 to 30.0 wt% hyaluronate solution, casting it into an automatic coater, casting the mixture to various thicknesses, drying at 30 to 50 ° C, Acid salt film was prepared. As a result, casting of 0.1 to 30.0% by weight of hyaluronate solution (300 to 100,000 cPs) in an automatic coater and drying at a temperature of 30 to 50 ° C resulted in the production of a hyaluronate film having a uniform surface I can confirm that I can do it. In addition, the hyaluronate film produced was excellent in mechanical properties, and it was confirmed that the hyaluronate film was easily formed into a desired shape using general scissors, knives, and general molding molds.

Accordingly, in one aspect, the present invention provides a method for producing a hyaluronate, comprising: (a) dissolving a hyaluronate in a solvent to prepare a 0.1 to 30.0 wt% hyaluronate solution; (b) casting the prepared hyaluronate solution into an automatic coater and casting the film to a thickness of 0.025 to 5 mm; And (c) drying the cast film at 30 to 50 ° C.

In the present invention, the hyaluronic acid salt is a salt in which hyaluronic acid is bound, and examples thereof include sodium hyaluronate, calcium hyaluronate, and potassium hyaluronate, but are not limited thereto.

In the present invention, the molecular weight of the hyaluronic acid salt can be used without particular limitation, but it is preferably 0.1 to 3.0 MDa. The content of the hyaluronate of the hyaluronate solution is 0.1 to 30.0% by weight. That is, when the concentration of the hyaluronate solution is less than 0.1% by weight, film formation is difficult. When the concentration exceeds 30% by weight, the film surface may be irregular due to high viscosity. For reference, the viscosity of the hyaluronate solution in the above range corresponds to 300 to 100,000 cPs. In the case of low molecular weight hyaluronic acid, it is necessary to dissolve at a high concentration to meet the reference viscosity. In the case of high molecular weight hyaluronic acid, it is dissolved at a low concentration and the reference viscosity must be met to produce a uniform film.

The solvent is used to dissolve the hyaluronate, and 100% water or an aqueous ethanol solution may be used, and the ethanol aqueous solution preferably has an ethanol content of 0.01 to 30% by volume. When water alone is used to dissolve hyaluronate, a great deal of attention is needed to prevent microbial contamination. However, when the hyaluronate is dissolved in an aqueous solution of ethanol, the effect of preventing microbial contamination But the film forming time can be shortened. However, when the ethanol content exceeds 30% by volume, there is a problem that the film becomes opaque or film is not formed as the molecular weight of the hyaluronic acid salt increases.

The casting step is preferably performed at a constant speed of 5 to 20 mm / s.

In the present invention, the automatic dispenser is widely used in general film production, and includes an applicator for adjusting the thickness of the main body and the film and a thickness adjusting dial as shown in FIG.

In the present invention, the thickness of the hyaluronate film is preferably 0.025 to 5 mm. When the thickness of the hyaluronate film is less than 0.025 mm, film formation is difficult. When the thickness of the hyaluronate film is more than 5 mm, the thickness of the film becomes thicker, resulting in increased flowability and wrinkles on the surface, have.

In the present invention, drying of the cast film is preferably carried out at 30 to 50 ° C for 6 to 24 hours. The drying can be carried out by various drying methods without particular limitation, as long as the drying is carried out at 30 to 50 ° C.

For reference, when the hyaluronate film is dried by the solvent casting method, the film is formed under the constant temperature and humidity drying conditions, but the film is not formed under the circulating drying condition.

The drying time can be appropriately adjusted within the range according to the concentration of the hyaluronate solution and the adjustment of the applicator in the automatic applicator.

The present invention relates to a hyaluronate film produced by this method from a different viewpoint.

The hyaluronate film has a tensile strength of 50 to 300 MPa.

The physical properties of the hyaluronate film can be controlled depending on the molecular weight, concentration and thickness of the hyaluronic acid salt.

In another aspect, the present invention relates to a cosmetic mask pack, a patch, and an artificial skin and an anti-adhesion agent for a medical device comprising the hyaluronate film.

For reference, adhesion is usually seen during the healing process of inflammation, which means that the fibrous material that is entangled or massively precipitated when forming granulation tissue or scar is entangled. Generally, adhesion occurs at a frequency of 67 ~ 93% after laparotomy, and some of them are spontaneously decomposed. However, in most cases, after wound healing, adhesion occurs and causes various sequelae. An anti-adhesion agent is used to physically and chemically block the occurrence of adhesion with surrounding tissues such as covering or pharmacological action.

[Example]

Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are only for illustrating the present invention and that the scope of the present invention is not construed as being limited by these embodiments.

Example 1: Determination of Film Formation Ability According to Molecular Weight Change

To confirm the film-forming ability according to the molecular weight of the hyaluronate, four hyaluronate (Hi-Aqua ^TM ) (Jinwai Bio) having a molecular weight of 0.1MDa, 0.8MDa, 1.2MDa and 2.5MDa (COAD 411, UWANG MACHINERY, KOREA) was controlled to cast a film having a thickness of 0.025 to 5 mm, and then dried in a constant temperature and humidity dryer (relative humidity 50%, temperature 40 ° C) for 6 to 24 hours to prepare a hyaluronate film, and the state of the film according to the viscosity was confirmed and shown in FIG.

For reference, the viscosity of the hyaluronic acid salt for producing a film using an automatic applicator was measured under the following conditions.

Measuring instrument Brookfield RV-II viscometer (Spindle No. 7, 12 rpm, 25 캜)

As shown in FIG. 2, irrespective of the molecular weight of the hyaluronic acid salt, film formation was impossible when the viscosity of the hyaluronate solution was 300 cPs or less (low viscosity). When the viscosity was 300 to 100,000 cPs (optimal viscosity) It was confirmed that film formation was impossible because the surface was uneven and irregular in appearance despite the use of automatic dispenser due to high viscosity when the viscosity was 100,000 cPs or more (high viscosity).

Example 2: Confirmation of film forming ability according to drying conditions

In order to confirm the film-forming ability according to the drying conditions, 1.2 M Na sodium hyaluronate was dissolved in a 10% by volume ethanol aqueous solution at a concentration of 2.0 wt%, and the film was cast by adjusting the thickness of the film to 0.1 mm with an applicator in an automatic applicator, The film was dried for 6 to 24 hours in a constant temperature and humidity dryer (relative humidity of 50 to 90% and temperature of 30 to 60 ° C) and a circulating dryer (temperature of 30 to 60 ° C) to prepare a hyaluronate film, 3.

As shown in FIG. 3, it was confirmed that the film surface of the hyaluronate film produced by the automatic applicator was uniformly formed in the circulation drier as well as the constant temperature and humidity drying dryer.

In addition, when the circulation dryer was used, it was confirmed that the drying time was shortened more than 12 hours in the constant temperature and humidity dryer, and the hyaluronate film could be produced more quickly.

Comparative Example 1: Determination of film forming ability according to viscosity of hyaluronate solution

In order to confirm the film forming ability by film casting according to the solution viscosity of the hyaluronic acid salt, hyaluronic acid sodium salt (Hi-Aqua ^TM ) having a molecular weight of 0.1 to 2.5 MDa (Jinwoo Bio) was added to a 10 volume% %, The film was adjusted to a thickness of 0.1 mm with an applicator of an automatic applicator, casted and dried in a constant-temperature and constant-humidity dryer (relative humidity 50% and a temperature of 50 ° C) for 24 hours or more to prepare a hyaluronate film , And the state of the film according to the viscosity was confirmed and shown in Fig.

The viscosity of the hyaluronate for producing a film using an automatic applicator was measured under the following conditions in the same manner as in Example 1. [

Measuring instrument Brookfield RV-II viscometer (Spindle No. 7, 12 rpm, 25 캜)

Regardless of the molecular weight of the hyaluronate, film formation is not possible when the viscosity of the hyaluronate solution is less than 300 cPs (low viscosity). When the viscosity is higher than 100,000 cPs (high viscosity), it is impossible to form a uniform film on the surface due to excessive viscosity. And it was confirmed that the film was uniformly formed on the surface as shown in FIG. 4 when dried at the optimum viscosity.

Comparative Example 2: Determination of film formability according to film thickness

In order to confirm the film forming ability of the hyaluronate according to the thickness of the applicator of the automatic applicator, the sodium molecular weight of 1.2MDa hyaluronate was dissolved in a 10% by volume aqueous ethanol solution at a concentration of 2.0% by weight and the thickness of the film was adjusted to 0.024 to 5.001 Mm and dried for 24 hours or longer in a constant-temperature and constant-humidity dryer (relative humidity of 50% and temperature of 50 ° C) to prepare a hyaluronate film, and the state of the film according to the drying condition is shown in FIG.

As shown in FIG. 5, when the thickness of the film is less than 0.025 mm, the surface of the film is extremely curved and difficult to use. When the thickness exceeds 5 mm, the film is cast in a state in which molding is impossible. It was found that the film was not uniform and not suitable for film production because the film was deformed due to excessive time for drying.

Experimental Example 1: Measurement of mechanical properties of a hyaluronate film

In order to measure the mechanical properties of the hyaluronate film prepared in Example 1, the film prepared using the TA-XT2i Texture Analyzer (Stable Micro System, UK) was cut into 3 cm x 5 cm, and the tensile grips And tensile strength and elongation were measured. The results are shown in Table 1. [Table 1]

The molecular weight of the hyaluronate solution (MDa) 0.1 0.8 1.2 1.5 2.5 The tensile strength
(Tensile Strength) 30 to 35 120 ~ 130 151-170 210-240 300 to 321 Elongation (%) 12 to 15 25 to 33 45 to 50 55 to 58 65 ~ 68

The mechanical properties of the hyaluronate film were found to be affected by the molecular weight without being influenced by the concentration of the hyaluronate or the viscosity of the solution of the hyaluronic acid at the time of film production.

From Table 1, it can be seen that as the molecular weight of the hyaluronic acid salt increases, the tensile strength increases to 30 ~ 321 MPa and the tensile strength increases to 12 ~ 68%.

While the present invention has been particularly shown and described with reference to specific embodiments thereof, those skilled in the art will appreciate that such specific embodiments are merely preferred embodiments and that the scope of the present invention is not limited thereto will be. It is therefore intended that the scope of the invention be defined by the claims appended hereto and their equivalents.

Claims (8)

(a) dissolving hyaluronate as a solvent to prepare 0.1 to 30.0% by weight of a hyaluronate solution;
(b) casting the prepared hyaluronate solution into an automatic coater and casting the film to a thickness of 0.025 to 5 mm; And
(c) drying the cast film at 30 to 50 ° C.
The method for preparing a hyaluronate film according to claim 1, wherein the viscosity of the hyaluronate solution is 300 to 100,000 cPs.
A hyaluronate film produced by the method of claim 1 or 2.
The hyaluronate film according to claim 3, wherein the hyaluronate film has a tensile strength of 50 to 300 MPa.
A mask pack comprising the hyaluronate film of claim 3.
A patch comprising the hyaluronate film of claim 3.
An artificial skin comprising the hyaluronate film of claim 3.
An anti-adhesion agent comprising the hyaluronate film of claim 3.

Images