WO2019220697A1 - Selectively permeable film for application to living body, percutaneous absorption kit, and aesthetic method - Google Patents

Abstract

The present invention provides: a selectively permeable film for application to the living body, the film selectively allowing water to rapidly pass therethrough; a percutaneous absorption kit; and an aesthetic method. This selectively permeable film for application to the living body comprises regenerated cellulose, has a thickness of 20-1,300 nm, and selectively allows water to pass therethrough. The selectively permeable film for application to the living body can be self-supporting.

Description

Selective permeation membrane for living body application, transdermal absorption kit and cosmetic method

The present disclosure relates to a permselective membrane for biological application, a transdermal absorption kit, and a cosmetic method.

For the purpose of cosmetic effect, a sheet pack has been proposed for holding active ingredients on the skin and transdermally absorbing, that is, absorbing the active ingredients from the skin. Patent Document 1 proposes a multilayer technical composite including a layer of a semipermeable membrane having air permeability without releasing an active ingredient to the outside. Patent Document 2 proposes a self-supporting cosmetic sheet for skin that can adhere to the skin without a 30-1000 nm adhesive containing a biocompatible hydrophobic polymer layer.

Special table 2008-538705 gazette JP 2014-227389 A

The present disclosure provides a permselective membrane for bioadhesion, a percutaneous absorption kit, and a cosmetic method that selectively permeate water quickly.

The permselective membrane for bioadhesion of the present disclosure is a self-supportable permselective membrane for bioadhesion, includes regenerated cellulose, has a thickness of 20 nm to 1300 nm, and selectively permeates water.

According to an embodiment of the present disclosure, a self-supporting cellulose membrane that selectively permeates water is provided.

FIG. 1 is a diagram showing an example of an X-ray diffraction pattern of natural cellulose. FIG. 2 is an exploded perspective view showing an example of the configuration of the electrode used in the electroporation apparatus. FIG. 3A is a diagram illustrating one step of the cosmetic method. FIG. 3B is a diagram illustrating one step of the cosmetic method. FIG. 3C is a diagram illustrating one step of the cosmetic method. FIG. 4 is a schematic perspective view showing a laminated sheet 100 </ b> B having the cellulose film 100. FIG. 5 is a schematic perspective view showing a state where a part of the protective layer 101 is peeled from one main surface of the cellulose film 100. FIG. 6 is a diagram for explaining an example in which the liquid 300 and / or the cream 302 are interposed between the cellulose film 100 and the skin 200. FIG. 7 is a view showing a state in which the laminated sheet 100B is stuck on the skin 200. FIG. FIG. 8 is a diagram showing a state in the middle of peeling off the protective layer 101 from the cellulose film 100 on the skin 200. FIG. 9 is a schematic perspective view showing a laminated sheet 100 </ b> C having the cellulose film 100, the protective layer 101, and the second protective layer 102. FIG. 10 is a schematic perspective view showing a state where a part of the protective layer 101 is peeled from the cellulose film 100 of the laminated sheet 100C. FIG. 11 is a view showing a state in which a laminated sheet of the cellulose film 100 and the second protective layer 102 is applied to the skin 200. FIG. 12 is a diagram schematically illustrating a state in which the colored cellulose film 100b is attached to the skin 200. FIG. 13 is a diagram showing the penetration of hyaluronic acid (Mw: 2000-4000) into skin in Example 1 and Comparative Example 1-6. FIG. 14 is a graph showing the penetration of hyaluronic acid (Mw: 5000-10000) into skin in Example 1 and Comparative Example 1-2. FIG. 15 is a diagram showing the penetration of vitamin C into skin in Example 1 and Comparative Example 1. FIG. 16 shows the results of Examples 1 and 3 and Comparative Examples 4 and 8 and shows the relationship between the thickness of the regenerated cellulose and the adhesion to the skin.

Conventional sheet packs for retaining active ingredients on the skin may have air permeability, that is, water vapor permeability, in order to suppress the stuffiness of the skin. However, conventional sheet packs cannot selectively permeate liquid water. The present inventor has conceived that a membrane containing regenerated cellulose is used for percutaneous absorption, and in the process of studying the structure of regenerated cellulose, the membrane containing regenerated cellulose quickly permeates liquid water. Found to get. By utilizing this feature, it is considered that an aqueous solution containing an active ingredient such as beauty can be concentrated and held on the skin, and the cosmetic ingredient can be absorbed more efficiently from the skin. Based on such knowledge, the inventor of the present application has come up with a novel permselective membrane for living body application, a transdermal absorption kit, and a cosmetic method. The outlines of the permselective membrane for living body application, the transdermal absorption kit and the cosmetic method of the present disclosure are as follows.

[Item 1]
A self-supporting permselective membrane for bioadhesion, which comprises regenerated cellulose, has a thickness of 20 nm to 1300 nm, and selectively permeates water.

[Item 2]
The permselective membrane for living body application according to item 1, wherein the permselective membrane for living body application has biocompatibility.

[Item 3]
The permselective membrane for bioadhesive according to item 1 or 2, wherein the permselective membrane for bioadhesive does not substantially permeate a compound having a molecular weight of 60 or more.

[Item 4]
4. The permselective membrane for biological application according to any one of items 1 to 3, wherein the regenerated cellulose has a crystallinity of 0 to 12%.

[Item 5]
The permselective membrane for bioadhesive according to any one of items 1 to 4, wherein the permselective membrane for bioadhesive has a water absorption rate of 50% or more.

[Item 6]
6. The permselective membrane for biological application according to any one of items 1 to 5, wherein the regenerated cellulose has a weight average molecular weight of 150,000 or more.

[Item 7]
The permselective membrane for biological application according to any one of Items 1 to 6,
At least one selected from the group consisting of an iontophoresis device, an electroporation device and an ultrasound introduction device;
A transdermal absorption kit comprising:

[Item 8]
8. The transdermal absorption kit according to item 7, wherein the electroporation device includes an electrode pad including a pair of electrodes and at least one insulating layer covering one surface of the pair of electrodes.

[Item 9]
A cosmetic method in which an aqueous solution containing an active ingredient is placed between the permselective membrane for attaching a living body according to any one of items 1 to 6 and the skin.

[Item 10]
Placing an aqueous solution containing an active ingredient on the skin;
Applying the permselective membrane for biological application according to any one of items 1 to 6 to the skin so as to cover at least a part of the aqueous solution;
A cosmetic method comprising the step of allowing the active ingredient to penetrate from the skin into the interior.

[Item 11]
Item 11. The cosmetic method according to Item 10, wherein the infiltrating step uses at least one selected from the group consisting of a perforation forming method, an ion introduction method, and an ultrasonic introduction method.

Hereinafter, embodiments of the present disclosure will be described in detail. It should be noted that each of the embodiments described below shows a comprehensive or specific example. Numerical values, shapes, materials, components, arrangement and connection forms of components, steps, order of steps, and the like shown in the following embodiments are merely examples, and are not intended to limit the present disclosure. The various aspects described herein can be combined with each other as long as no contradiction arises. In addition, among the constituent elements in the following embodiments, constituent elements that are not described in the independent claims indicating the highest concept are described as optional constituent elements. In the following description, components having substantially the same function are denoted by common reference numerals, and description thereof may be omitted. In addition, in order to avoid the drawing from becoming excessively complicated, illustration of some elements may be omitted.

(Selective permeable membrane for biological application)
The permselective membrane for biological application according to an embodiment of the present disclosure includes regenerated cellulose and has a thickness of 20 nm to 1300 nm. Moreover, the permselective membrane for biological sticking can selectively permeate | transmit water.

Regenerated cellulose is, for example, cellulose substantially represented by the following formula (I). Here, “the cellulose substantially represented by the formula (I)” means a cellulose in which 90% or more of hydroxyl groups of glucose residues in the cellulose represented by the formula (I) remain. The ratio of the hydroxyl group in glucose of cellulose can be quantified by a known method such as X-ray photoelectron spectroscopy (XPS). Moreover, said definition means that the cellulose may contain the branched structure. The artificially derivatized cellulose typically does not fall under “substantially the cellulose represented by the formula (I)”. On the other hand, “cellulose substantially represented by the formula (I)” does not exclude cellulose regenerated through derivatization. Even cellulose regenerated through derivatization may fall under “substantially represented by formula (I)”. Regenerated cellulose may be uncrosslinked.

In the present specification, “regenerated cellulose” means cellulose that does not have the crystal structure I unique to natural cellulose. The crystal structure of cellulose can be confirmed by an X-ray diffraction pattern. FIG. 1 shows an example of an X-ray diffraction pattern (CuKα ray (50 kV, 300 mA)) of natural cellulose. In the X-ray diffraction pattern shown in FIG. 1, peaks around 14-17 ° and 23 °, which are peculiar to the crystal structure I, appear. Regenerated cellulose often has a crystalline structure II and has peaks around 12 °, 20 ° and 22 °, and no peaks around 14-17 ° and 23 °.

The raw material of regenerated cellulose is not particularly limited. For example, the raw material of the regenerated cellulose can be plant-derived natural cellulose, bio-derived natural cellulose, regenerated cellulose such as cellophane, or processed cellulose such as cellulose nanofiber. It is advantageous that the concentration of impurities in the raw material of regenerated cellulose is 10% by weight or less.

Cellulose has excellent biocompatibility and is hydrophilic but not soluble in water. In particular, the regenerated cellulose can form a strong film even if it is thin because hydrogen bonds are uniformly formed in units smaller than the nanofibers of natural cellulose. In addition, it has a hydroxyl group capable of interacting with a large amount of water in the molecule, so it is considered that water can easily be selectively passed. In this specification, being excellent in biocompatibility or having biocompatibility means that it is difficult to cause reactions such as rashes and inflammations on the living body, particularly the skin.

As described above, it is preferable that the permselective membrane for bioadhesion has a thickness of 20 nm or more and 1300 nm or less. When the permselective membrane for bioadhesion has a thickness of 20 nm or more, the permselective membrane for bioadhesion can be self-supporting. In addition, since the permselective membrane for bioadhesion has a thickness of 1300 nm or less, it can follow the expansion and contraction of the skin surface and can be applied to the skin for a long time without using an adhesive or the like. Furthermore, by having a thickness of 1300 nm or less, it becomes possible to quickly permeate water quickly.

The thickness of the permselective membrane for bioadhesion may have a thickness of 50 nm to 1000 nm. When the thickness is 50 nm or more, higher strength is obtained, and handling of the permselective membrane for attaching a living body becomes easier. When the thickness of the permselective membrane for biological application is 1000 nm or less, the cellulose membrane 100 is inconspicuous when applied to the skin, which is beneficial. The permselective membrane for living body sticking may have a thickness of 500 nm or more and 1000 nm or less. When the thickness is 500 nm or more, a permselective membrane for attaching a living body that has higher strength and is difficult to break can be obtained. In addition, more effective components (for example, cosmetic components) can be retained in the cellulose film. The permselective membrane for living body sticking may have a thickness of 100 nm to 500 nm. When the thickness is 100 nm or more, it is advantageous for maintaining the shape of the thin film. By setting the thickness to 500 nm or less, the adhesiveness of the permselective membrane for biological application can be further improved. Therefore, the permselective membrane for biological application can be applied to the skin or other surface for a longer time and stably. Moreover, since the permselective membrane for bioadhesion becomes thinner, the permselective membrane for bioadhesion can be made inconspicuous on the skin.

The thickness of the permselective membrane for bioadhesion is determined by, for example, measuring the thickness of the permselective membrane for bioadhesion at a plurality of locations and averaging. The thickness at each location can be measured using, for example, a stylus profiling system DEKTAK (registered trademark) manufactured by Bruker Nano Inc.

Here, “self-supportable” means that the form as a film can be maintained without a support. For example, when a part of the film is picked up by using fingers, tweezers or the like and the film is lifted, the whole film can be lifted without a support without damaging the film.

When the permselective membrane for bioadhesion contains regenerated cellulose, the pores derived from the structure of the regenerated cellulose and the hydroxyl group of glucose, which is a repeating unit of the regenerated cellulose, are rapidly transferred to the permselective membrane for bioadhesive. And gives selective permeability. In this specification, selectively transmitting water means that liquid water is transmitted and molecules and ions larger than water are difficult to be transmitted, that is, substantially not permeated. Molecules and ions larger than water have a molecular weight of, for example, about 60 or more. As will be described in detail in the following examples, for example, after placing a selective permeation membrane for biological application on paper that changes color when water permeates, and dropping an aqueous solution containing an active ingredient on it, 30 seconds later, The paper discolors due to the permeation of water, but if the active ingredient detected from the paper is 1/10 or less of the active ingredient concentration of the dropped aqueous solution, the permselective membrane for biological application selectively permeates water. It is defined as substantially not transmitting molecules and ions having a molecular weight of 60 or more. More preferably, the concentration of the active ingredient in the permeated water is 1/20 or less, more preferably less than the detection limit. Examples of the method for detecting the active ingredient include mass spectrometry, analysis using an absorptiometer, and analysis using a fluorescence microscope when the active ingredient is a phosphor. The permeation rate of water depends on the thickness of the permselective membrane for biological application. When the permselective membrane for bioadhesion has a thickness of 20 nm or more and 1300 nm or less, discoloration of the paper disposed below can be confirmed by the above-described method within approximately 30 seconds. In other words, in the present specification, to selectively permeate water quickly confirms that liquid water has permeated from one surface of the selective permeation membrane for living body application to the other surface by visual observation within several tens of seconds. It means that water permeates as fast as possible.

It is preferable that the regenerated cellulose contained in the permselective membrane for biological application has a weight average molecular weight of 150,000 or more. By having a weight average molecular weight of 150,000 or more, more hydroxyl groups are included per molecular chain, and more hydrogen bonds between molecules are formed, so that the thickness is 20 nm or more and 1300 nm or less. A membrane capable of maintaining the shape without requiring a support can be obtained.

The permselective membrane for biological application only needs to contain a regenerated cell roll, and may contain inevitable impurities, raw materials, other additive materials, and the like. Preferably, the permselective membrane for bioadhesion contains regenerated cellulose at a ratio of 90% by mass or more.

The regenerated cellulose contained in the permselective membrane for biological application according to the embodiment of the present disclosure may have a crystallinity of 0 to 12%. According to an exemplary production method described later, it is possible to obtain a cellulose film having a crystallinity of 0%. When the degree of crystallinity is 12% or less, the adhesion of the cellulose film to the skin can be improved by appropriately reducing the proportion of hydroxyl groups involved in the formation of crystal forms. Furthermore, since the amount of hydroxyl groups involved in the formation of the crystal structure is moderately small, the number of hydroxyl groups that interact with water increases, and water can be selectively permeated more quickly. In addition, by performing a predetermined chemical modification at a site where a hydroxyl group should exist, the permselective membrane for biological application can exhibit various functions.

It is desirable that the permselective membrane for biological application has a water absorption of 50% or more. The water absorption rate is defined by the same method as described in JIS K7209. By having a water absorption rate of 50% or more, the permselective membrane for living body application can retain water and reduce the electrical resistance of the membrane itself. Thereby, it becomes possible to prevent static electricity etc., and the effect which becomes difficult to attract dust and dust (including pollen, PM2.5, etc.) in the air is shown. The water absorption is more preferably 100% or more. In addition, since the thickness of the membrane is 20 nm or more and 1300 nm or less and the electrical resistance is low, there is little voltage drop due to the resistance of the permselective membrane for living body application, and an iontophoresis device, an electroporation device, and an ultrasound introduction device are used. When an aqueous solution containing an active ingredient is disposed between the skin and the permselective membrane for attaching to a living body, the effect of introducing the active ingredient into the skin by these devices can be further enhanced.

The permselective membrane for biological application preferably has a pore volume of 0.3 cm ³ / g or less. When the pore volume is 0.3 cm ³ / g or less, the permselective membrane for biological application can exhibit high water selective permeability. Furthermore, it is preferable to have a pore volume of 0.05 cm ³ / g or less. When the pore volume is 0.05 cm ³ / g or less, the permselective membrane for biological application can exhibit higher water permselectivity. The pore volume in the present specification means the volume of pores having a pore diameter of 100 nm or less. The pore volume can be determined by, for example, a gas adsorption method. Since the permselective membrane for biological application has high transparency, it is considered that there are almost no pores larger than 100 nm. The permselective membrane for biological application has a pore volume of, for example, 0.001 cm ³ / g or more.

According to the permselective membrane for living body application of this embodiment, having a thickness of 20 nm or more and 1300 nm or less, the membrane can be made into a living body only with skin lotion or cosmetic liquid without the adhesive that caused the rash. It can be applied for a long time. In addition, since the main component of the permselective membrane for bioadhesion is regenerated cellulose, it is excellent in biocompatibility and can be used for a long time without any burden on the living body.

In addition, since the permselective membrane for living body application can selectively permeate water, an aqueous solution containing an active ingredient for medical or cosmetic use is placed between the living body and the permselective membrane for attaching living body. A certain water selectively permeates through the permselective membrane for bioadhesion and floats on the surface of the permselective membrane for bioadhesion. For this reason, when the solvent of the aqueous solution in contact with the living body is reduced, the concentration of the active ingredient is increased, and the concentration of the active ingredient is increased due to the concentration gradient.

Regenerated cellulose can easily form hydrogen bonds within the molecule and / or between the molecules, has a high strength even if it is thin, and can obtain an appropriate flexibility and a film that is not easily broken. In addition, active ingredients such as cosmetic ingredients can be carried in the film. Since regenerated cellulose exhibits amphiphilic properties, it can appropriately carry a hydrophilic active ingredient and a hydrophobic active ingredient. The active ingredient is not limited to a cosmetic ingredient but may be a medical ingredient.

The permselective membrane for bioadhesion according to an embodiment of the present disclosure can be used by being affixed to skin such as a face or an arm. The permselective membrane for biological application according to an embodiment of the present disclosure typically has an area of 7 mm ² or more. When the area of the cellulose membrane is 7 mm ² or more, it is beneficial because it covers a larger area when applied to the skin. Moreover, the permselective membrane for bioadhesion of the present disclosure can be applied to a living body other than skin, and may be applied to the surface of an organ, for example.

The permselective membrane for biological application has a tensile strength of 23 MPa or more, for example. In this case, for example, the permselective membrane for living body application is not easily broken even if it is applied to the skin, and can be applied to the skin for a long time. In addition, the permselective membrane for bioadhesion of the present disclosure may be at least partially colored.

The permselective membrane for biological application can be produced, for example, by the following method. First, cellulose is dissolved in a solvent to prepare a cellulose solution. In order to obtain a regenerated cellulose membrane having a weight average molecular weight of 150,000 or more, a cellulose solution may be prepared using cellulose having a weight average molecular weight of at least 150,000 or more. In this case, a self-supporting permselective membrane for attaching a living body having a thickness of 1300 nm or less can be produced. In this way, by forming the weight average molecular weight of cellulose used in the preparation of the cellulose solution to be 150,000 or more, more intermolecular hydrogen bonds are formed by including more hydroxyl groups in one molecular chain. Therefore, it is possible to stably produce a permselective membrane for bioadhesion of 1300 nm or less. The cellulose used for preparing the cellulose solution is not particularly limited as long as it has a desired weight average molecular weight.

As the cellulose used for preparing the solution, any of natural cellulose and regenerated cellulose can be used. Cellulose can be, for example, cellulose derived from plants such as pulp and cotton, or cellulose produced by organisms such as bacteria. The impurity concentration in the cellulose raw material is, for example, 10% by weight or less. The weight average molecular weight of regenerated cellulose is 2,
Since it is easy to handle when it is 000,000 or less, it is useful. More desirably, the regenerated cellulose has a weight average molecular weight of 1,000,000 or less.

The solvent is, for example, a solvent (first solvent) containing at least an ionic liquid. By using the first solvent, cellulose can be dissolved in a relatively short time. An ionic liquid is a salt composed of an anion and a cation, and can exhibit a liquid state at a temperature of 150 ° C. or lower. The ionic liquid contained in the first solvent is, for example, an ionic liquid containing an amino acid or an alkyl phosphate ester. When the first solvent contains such an ionic liquid, cellulose can be dissolved while suppressing a decrease in the molecular weight of cellulose. In particular, since an amino acid is a component that exists in a living body, an ionic liquid containing the amino acid is advantageous for producing a permselective membrane for biological application that is safer for a living body.

The cellulose may be dissolved by using an ionic liquid diluted in advance with a solvent that does not precipitate the cellulose. For example, a mixture of an aprotic polar solvent and an ionic liquid may be used as the first solvent. The aprotic polar solvent hardly forms hydrogen bonds and does not easily precipitate cellulose.

The ionic liquid contained in the first solvent is, for example, an ionic liquid represented by the following formula (II). In the ionic liquid represented by the formula (II), the anion is an amino acid. As described in Formula (II), in this ionic liquid, the anion contains a terminal carboxyl group and a terminal amino group. The cation of the ionic liquid represented by the formula (II) may be a quaternary ammonium cation.

In the formula (II), R1 to R6 independently represent a hydrogen atom or a substituent. The substituent can be an alkyl group, a hydroxyalkyl group, or a phenyl group. The substituent may contain a branch in the carbon chain. The substituent may contain a functional group such as an amino group, a hydroxyl group, or a carboxyl group. n is, for example, 4 or 5.

The ionic liquid contained in the first solvent may be an ionic liquid represented by the following formula (III). In the formula (III), R1, R2, R3 and R4 independently represent a hydrogen atom or an alkyl group having 1 to 4 carbon atoms.

In the step of preparing the cellulose solution, a second solvent may be further added. For example, the second solvent may be further added to a mixture of cellulose having a predetermined weight average molecular weight and the first solvent. The second solvent is, for example, a solvent that does not precipitate cellulose. The second solvent can be, for example, an aprotic polar solvent.

The concentration of cellulose in the cellulose solution is typically 0.2 to 15% by weight. If the cellulose concentration of the cellulose solution is 0.2% by weight or more, a biopermeable selective permeable membrane having a strength necessary for maintaining the shape of the biopermeable selective permeable membrane can be obtained while reducing the thickness of the biopermeable selective permeable membrane. . Moreover, if the density | concentration of the cellulose of a cellulose solution is 15 weight% or less, precipitation of the cellulose in a cellulose solution can be suppressed. The cellulose concentration of the cellulose solution may be 1 to 10% by weight. When the concentration of cellulose in the cellulose solution is 1% by weight or more, a permselective membrane for bioadhesion having higher strength can be obtained. When the concentration of cellulose in the cellulose solution is 10% by weight or less, a stable cellulose solution in which precipitation of cellulose is further reduced can be prepared.

Next, a cellulose solution is applied to the surface of the substrate to form a liquid film on the surface of the substrate. The contact angle with respect to the water of the surface of a board | substrate is 90 degrees or less, for example. In this case, the wettability of the cellulose solution to the substrate is appropriate, and a liquid film that spreads along the surface of the substrate can be stably formed. The material of the substrate is not particularly limited. The substrate typically has a non-porous structure with a smooth surface. In this case, it is possible to prevent the cellulose solution from entering the inside of the substrate, and it is easy to separate the permselective membrane for biological application from the substrate in a subsequent process. The substrate may be chemically or physically surface modified. As the substrate, for example, a polymer material substrate that has been subjected to surface modification treatment such as ultraviolet (UV) irradiation or corona treatment may be used. The method for surface modification is not particularly limited. For example, application of a surface modifier, surface modification, plasma treatment, sputtering, etching, or blasting can be applied.

A method for forming a liquid film of a cellulose solution on a substrate includes, for example, gap coating, slot die coating, spin coating, coating using a bar coater (Metering) that forms a predetermined gap with the surface of the substrate by an applicator or the like. rod coating) and gravure coating. The thickness of the liquid film adjusted by the gap thickness or slot die opening size and coating speed, spin coating speed, bar coater or gravure coating groove depth and coating speed, etc., and the concentration of the cellulose solution. By adjusting, the thickness of the permselective membrane for biological application can be adjusted. The method for forming the liquid film of the cellulose solution on the substrate may be a casting method, screen printing using a squeegee, spray coating, or electrostatic spraying.

When forming a liquid film of the cellulose solution on the substrate, at least one of the cellulose solution and the substrate may be heated. This heating may be performed, for example, in a temperature range (for example, 40 to 100 ° C.) in which the cellulose solution can be kept stable.

The liquid film of the cellulose solution formed on the substrate may be heated. The liquid film is heated, for example, at a temperature lower than the decomposition temperature of the ionic liquid contained in the first solvent (for example, 50 to 200 ° C.). The heating of the liquid film may be performed at a temperature lower than the decomposition temperature of the ionic liquid and lower than the boiling point of the second solvent. By performing the heating of the liquid membrane at such a temperature, a solvent other than the ionic liquid (for example, the second solvent) can be appropriately removed, and the strength of the selective permeable membrane for biological application and the bulk density of regenerated cellulose are high. Prone. In addition, it is possible to suppress deterioration in the quality of the permselective membrane for biological application due to bumping of the solvent in the cellulose solution. The heating of the liquid film may be performed under a reduced pressure environment. In this case, a solvent other than the ionic liquid can be appropriately removed in a shorter time at a temperature lower than the boiling point of the solvent.

After the liquid film of the cellulose solution is formed on the substrate, the liquid film may be gelled. For example, by exposing the liquid film to vapor of a liquid that is soluble in an ionic liquid and does not dissolve cellulose, the liquid film can be gelled to obtain a polymer gel sheet. For example, when a liquid film is left in an environment with a relative humidity of 30 to 100% RH, the ionic liquid in the liquid film comes into contact with water, so that the solubility of cellulose in the liquid film decreases. Thereby, a part of cellulose molecule precipitates and a three-dimensional structure is formed. As a result, the liquid film is gelled. The presence or absence of a gel point can be determined by whether or not the gelled film can be lifted.

The crystallinity of the cellulose film finally obtained can be adjusted according to the conditions of the gelation process. For example, when gelation is performed in an environment where the relative humidity is 60% RH or less, the gelation gradually proceeds, so that it is easy to stably form a three-dimensional structure of cellulose molecules, and the crystallinity is stably reduced. obtain. In an environment where the relative humidity is 40% RH or less, it is possible to obtain a regenerated cellulose membrane with a further reduced crystallinity.

The heating of the liquid film may be performed before gelling of the liquid film, may be performed after gelling of the liquid film, or may be performed before or after gelling of the liquid film. .

Next, the substrate and the polymer gel sheet are immersed in a rinsing liquid that does not dissolve cellulose. In this step, the ionic liquid is removed from the polymer gel sheet. This step is understood as a step of washing the polymer gel sheet. In this step, in addition to the ionic liquid, a part of the components (for example, the second solvent) other than the cellulose and the ionic liquid may be removed from the components contained in the cellulose solution. In this step, the rinsing liquid may be replaced a plurality of times. The rinse liquid is typically a liquid that can be dissolved in an ionic liquid. Examples of such liquids are water, methanol, ethanol, propanol, butanol, octanol, toluene, xylene, acetone, acetonitrile, dimethylacetamide, dimethylformamide, and dimethyl sulfoxide.

Next, unnecessary components such as a solvent are removed from the polymer gel sheet. In other words, the polymer gel sheet is dried. At this time, the polymer gel sheet may be dried on a protective layer or the like. As a method for drying the polymer gel sheet, drying methods such as natural drying, vacuum drying, heat drying, freeze drying, and supercritical drying can be applied. The polymer gel sheet may be dried by vacuum heating. The conditions for drying the polymer gel sheet are not particularly limited. As a condition for drying the polymer gel sheet, a time and temperature sufficient for removing unnecessary components such as the second solvent and the rinse liquid are selected. By removing unnecessary components from the polymer gel sheet, a regenerated cellulose membrane is obtained. In the drying process of the polymer gel sheet, the polymer gel sheet may be pulled with a predetermined force. In this case, the pore volume and shape of the regenerated cellulose membrane, the bulk density of the regenerated cellulose, and the like can be adjusted to a desired state by adjusting the magnitude of the tensile force applied to the polymer gel sheet.

In the step of drying the polymer gel sheet, for example, when lyophilization is applied, a solvent that can be frozen and has a boiling point of about 100 to 200 ° C. is used. For example, lyophilization can be performed using a solvent such as water, tert-butyl alcohol, acetic acid, 1,1,2,2,3,3,4-heptafluorocyclopentane, or dimethyl sulfoxide. The solvent used for lyophilization is advantageously a solvent that can be dissolved in the rinse solution. However, even if the solvent used for lyophilization is a solvent that cannot be dissolved in the rinse solution, the rinse solution in the polymer gel sheet can be dissolved in the rinse solution after the step of immersing the polymer gel sheet in the rinse solution. It is possible to carry out lyophilization by substituting with a solvent and further substituting the solvent with a solvent for lyophilization.

In order to retain an active ingredient such as a cosmetic ingredient, it can be immersed in the ingredient solution before and / or after the step of drying the polymer gel sheet. At this time, the solution may contain a plurality of active ingredients. As the solvent in the solution, for example, at least one selected from the group consisting of water, methanol, ethanol, propanol, butanol, octanol, toluene, xylene, acetone, acetonitrile, dimethylacetamide, dimethylformamide, and dimethylsulfoxide can be used. Instead of immersing the polymer gel sheet in the solution, an adhesive component may be attached to the polymer gel sheet by spraying, vapor deposition, or coating.

(Beauty method)
In the cosmetic method according to the embodiment of the present disclosure, an aqueous solution containing an active ingredient is disposed between the above-described permselective membrane for biological application and the skin. The aqueous solution may be in the form of a solution, a dispersion, or an emulsion as long as it contains water.

An active ingredient is an ingredient which shows cosmetic effects such as moisturizing and whitening on the skin. For example, gum arabic, tragacanth gum, galactan, guar gum, carob gum, caraya gum, carrageenan, pectin, agar, quince seed (malmello), algae colloid (gasso extract) ), Starch (rice, corn, potato, wheat), etc., plant-derived polymers, xanthan gum, dextran, succinoglucan, bullulan and other microorganism-derived polymers, collagen, casein, albumin, gelatin and other animal-derived polymers, hyaluron Biological polymer compounds such as acid, mucin, chondroitin sulfate, soluble collagen, polyethylene glycol, sorbitol, xylitol, maltose, sodium dl-pyrrolidonecarboxylate, sodium lactate, trime Vitamin A such as luglycine, retinol, retinal, retinoic acid, vitamin B such as thiamine, riboflavin, pyridoxine, pyridoxamine, folic acid, vitamin D such as ergocalciferol, cholecalciferol, α-tocopherol (vitamin E) phylloquinone, menaquinone Vitamins represented by vitamin K and the like, tretinoin, vitamin A derivatives such as retinol palmitate, vitamin C derivatives such as glyceryl ascorbic acid and ascorbyl tetrahexyl decanoate, ascorbic acid and its salts, α-tocopherol acetate, α-tocopherylquinone Vitamin E derivatives such as α-tocopherol succinate, tranexamic acid, arbutin, hydroquinone, kojic acid, potassium 4-methoxysalicylate, tranexamic acid, lucinol, Examples thereof include polyphenols such as ellagic acid and anthocyanins, disodium 3-succinyloxyglycyrrhetinate, rutin, minoxidil, finasteride, cephalanthin and pyrrolidone carboxylic acid.

By placing an aqueous solution containing an active ingredient between the skin and the selective permeable membrane for biological application that selectively permeates water, only water quickly penetrates the selective permeable membrane for biological application and is effective on the skin. Concentrates the ingredients, showing the effect that the active ingredients can easily penetrate from the skin to the inside. That is, the transdermal absorption effect can be enhanced.

(Cosmetics using a transdermal absorption kit)
A transcutaneous kit according to an embodiment of the present disclosure includes the permselective membrane for biological application, and at least one selected from the group consisting of an iontophoresis device, an electroporation device, and an ultrasound introduction device. By using these, an active ingredient having a molecular weight of 500 or more, which is generally considered difficult to penetrate into the skin, can be easily penetrated into the skin.

FIG. 2 shows an example of the electrode pad 10 used in the electroporation apparatus. The electrode pad 10 includes the first electrode 23 and the second electrode 24, the insulating layers 21 a and 21 b disposed on one surface of the first electrode 23 and the second electrode 24, and the first electrode 23 and the second electrode 24. Insulating layers 25a and 25b disposed on the surface. Since the electrode 10 includes the insulating layers 25a and 25b, current can be prevented from flowing into the living body, and treatment can be performed without feeling any damage.

FIG. 3A to FIG. 3C are views for explaining a cosmetic method using a transdermal absorption kit. As shown in FIG. 3A, first, an aqueous solution 40 containing an active ingredient is applied to the skin 30. Next, as shown in FIG. 3B, the selective permeable membrane 100 for attaching a living body is attached to the skin 30 so as to cover the aqueous solution 40. Furthermore, the electrode pad 10 is disposed on the permselective membrane 100 for attaching a living body.

Next, as shown in FIG. 3B, the first electrode 23 and the second electrode 24 of the electrode pad 10 are connected to the electroporation device body 60, and the electroporation device is operated. An electric pulse is applied to the skin 30 through the electrode pad 10. Thereby, a minute hole is temporarily formed on the surface of the skin 30, and the active ingredient is infiltrated into the inside through the hole. At this time, since the selective permeable membrane 100 for biological application selectively transmits water in the aqueous solution 40, the active ingredient in the aqueous solution 40 in contact with the skin 30 is concentrated. For this reason, the active ingredient which is in contact with the skin at a high concentration becomes easier to penetrate into the inside by the electroporation method.

FIG. 3C shows how to use the transdermal kit including the iontophoresis device 70. Similar to the method of using the electroporation apparatus, an aqueous solution 40 containing an active ingredient is applied to the surface of the skin 30, and the biopermeable selective permeable membrane 100 is attached to the skin 30 so as to cover the aqueous solution 40. After that, the head 70a of the iontophoresis device 70 is brought into contact with the biological attachment selective permeable membrane 100. When the iontophoresis device 70 is operated in this state, a current path is formed between the user and the iontophoresis device 70 as indicated by a broken line by the user gripping the grip 70b of the iontophoresis device 70 by hand. A weak current flows from the head 70a to the living body. The active ingredient is allowed to penetrate into the living body according to this current path. In particular, the active ingredient is an ion, and the active ingredient can efficiently penetrate into the skin 30 by appropriately selecting the charge and current direction of the active ingredient. At this time, the permselective membrane 100 for adhering to the living body selectively permeates the water in the aqueous solution 40, so that the active ingredient in the aqueous solution 40 in contact with the living body 30 is concentrated. For this reason, the active ingredient which is in contact with the skin at a high concentration is more easily penetrated into the inside by the iontophoresis method.

The iontophoresis device and the electroporation device can be used independently, but may be used in combination. In this case, for example, first, a temporary hole is formed in the skin using an electroporation device, and then an active ingredient can be more efficiently penetrated into the living body from the formed hole by using the iontophoresis device. .

The ultrasonic introduction device can be used in the same manner as the ion introduction device. An ultrasonic introduction device may also be used in combination with an ion introduction device and / or an electroporation device. In this case, as with the iontophoresis device, a temporary hole is first formed in the skin using an electroporation device, and then the active ingredient penetrates the living body more efficiently from the formed hole when the ultrasonic introduction device is used. Can be made.

In the present embodiment, the electroporation apparatus in which the electrode pad 10 is separated from the main body has been described. However, the electroporation apparatus may be a handy type in which the electrode pad 10 is provided integrally with the main body, or the main body and the main body. A connected handy type probe may be provided, and the electrode pad 10 may be provided integrally with the probe. In these cases, the active ingredient can be efficiently infiltrated into the living body similarly by using the portion where the electrode pad 10 is provided on the surface of the permselective membrane 100 for attaching a living body.

(Laminated sheet)
4 and 5 show an example of a laminated sheet according to an embodiment of the present disclosure. As shown in FIG. 4, the permselective membrane for biological application according to an embodiment of the present disclosure may be provided in the form of a laminated sheet to which a protective layer is attached. A laminated sheet 100 </ b> B illustrated in FIG. 4 includes a cellulose film 100 and a protective layer 101 disposed on one main surface of the cellulose film 100. As the cellulose membrane 100, the above-described permselective membrane 100A for biological application can be applied, and the cellulose membrane 100 can be, for example, a membrane composed of regenerated cellulose having a weight average molecular weight of 150,000 or more. Needless to say, FIGS. 4 and 5 schematically show the laminated sheet 100B to the last, and do not reflect actual dimensions. For example, the thicknesses of the cellulose film 100 and the protective layer 101 are exaggerated in FIGS. In other drawings of the present disclosure, for convenience of explanation, a cellulose film or the like may be illustrated in a size and shape different from the actual one.

In this example, the cellulose membrane 100 has a generally circular shape. The diameter of the cellulose membrane 100 shown in FIG. 4 can be about 3 mm, for example. Of course, the shape of the cellulose membrane 100 is not limited to the example shown in FIG. 4, and may be an ellipse, a polygon, or an indefinite shape. Further, the cellulose film 100 and the protective layer 101 may have different sizes.

Refer to FIG. The cellulose film 100 has main surfaces Sf and Sb, and here, a protective layer 101 is disposed on the main surface Sb side. The protective layer 101 includes, for example, polyethylene, polypropylene, polyethylene terephthalate, nylon, acrylic resin, polycarbonate, polyvinyl chloride, acrylonitrile-butadiene-styrene (ABS) resin, polyurethane, synthetic rubber, cellulose, Teflon (registered trademark), aramid, It is a sheet or non-woven fabric such as polyimide, or a sheet-like metal or glass. Moreover, the chemical or physical surface treatment may be given to the whole or a part of the surface of these sheets or nonwoven fabrics. In this example, the protective layer 101 is also circular like the cellulose film 100. However, the shapes of the cellulose film 100 and the protective layer 101 do not need to match. For example, a plurality of cellulose films 100 may be disposed on a single protective layer 101. The protective layer 101 in the laminated sheet 100B is not a support for maintaining the shape of the cellulose film 100.

As schematically shown in FIG. 5, the protective layer 101 is configured to be peelable from the main surface Sb of the cellulose film 100. The cellulose film 100 has a tensile strength of, for example, 23 MPa or more, and can maintain its shape even when the protective layer 101 is peeled off.

Here, an example of how to use the laminated sheet of the present disclosure will be described with reference to FIGS.

First, the above-mentioned laminated sheet 100B is prepared, and as shown in FIG. 6, the main surface Sf on which the protective layer 101 is not disposed among the main surfaces Sf and Sb of the cellulose film 100 is formed on the laminated sheet 1.
It is made to oppose the part which wants to stick 00B. In this example, the main surface Sf of the cellulose film 100 is opposed to the skin 200 (for example, a part of the facial skin).

At this time, the aqueous solution 300 containing the above-mentioned active ingredient is applied on the main surface Sf of the cellulose film 100 or on the skin 200. Furthermore, a cream 302 may be arranged. The cream 302 contains, for example, oils, fats, alcohols or emulsifiers, and may further contain the above-described active ingredients.

Next, the laminated sheet 100B is attached to the skin 200 as shown in FIG. 7 by bringing the laminated sheet 100B into contact with the skin 200 with the main surface Sf of the cellulose film 100 facing the skin 200. Further, as shown in FIG. 8, the protective layer 101 is peeled from the main surface Sb of the cellulose film 100. By peeling off the protective layer 101 from the cellulose film 100, the cellulose film 100 can be left on the skin 200.

Another protective layer may be provided on the main surface Sf of the cellulose film 100. FIG. 9 shows another example of a laminated sheet. A laminated sheet 100C shown in FIG. 9 has a second protective layer 102 on the main surface of the cellulose membrane 100 opposite to the main surface on which the protective layer 101 is disposed. The material constituting the protective layer 102 may be the same as or different from that of the protective layer 101. The size of the protective layer 102 may be different from that of the cellulose film 100 or the protective layer 101. Typically, the protective layer 102 can also be peeled from the cellulose film 100 in the same manner as the protective layer 101. The presence of the protective layer 102 makes it easier to handle the cellulose membrane 100.

When such a laminated sheet 100C is used, first, the protective layer 101 is peeled from the cellulose film 100 as shown in FIG. By removing the protective layer 101, the main surface Sb of the cellulose film 100 is exposed. Thereafter, the exposed main surface Sb is opposed to the skin 200. As in the case of the laminated sheet 100B, at this time, the aqueous solution 300 containing the active ingredient is applied on the main surface Sb of the cellulose film 100 or on the skin 200. Furthermore, cream 302 may be applied.

Next, as shown in FIG. 11, a laminated sheet of the cellulose film 100 and the second protective layer 102 is applied to the skin 200. Thereafter, the protective layer 102 is peeled from the other main surface of the cellulose film 100, that is, the main surface opposite to the main surface Sb. The cellulose film 100 can be left on the skin 200 by peeling off the protective layer 102.

As described above, at least a part of the permselective membrane for bioadhesion of the present disclosure may be colored. FIG. 12 schematically shows a state in which the colored cellulose film 100b is attached to the skin 200. The cellulose film 100b may be a film obtained by coloring the above-described cellulose film 100 with a dye, a pigment, or the like. According to the manufacturing method described above, a transparent regenerated cellulose membrane is typically obtained. By using the cellulose membrane 100b colored with a color close to the color of the skin, when the part on which the active ingredient is applied is a stain, a mole, a scar or the like of the skin 200, the permselective membrane for bioadhesion is covered and is conspicuous. It is possible to eliminate.

The permselective membrane for biological application according to an embodiment of the present disclosure can also function as a protective sheet that protects the skin from external irritation, for example, when applied to a scar. You may give a pattern and a color to the selective permeable membrane for biological sticking by printing etc.

(Example)
Hereinafter, the permselective permselective membrane for selective permeation according to the embodiment of the present disclosure will be described in more detail with reference to examples. Embodiments of the present disclosure are not limited to the forms specified by the following examples.

(Evaluation of penetration of active ingredients)
(Example 1)
(Preparation of permselective membrane for selective biopermeation)
A regenerated cellulose membrane, which is a permselective membrane for biological application, was produced by the following procedure. First, a cellulose derived from bleached pulp made of wood and having a purity of 90% or more was prepared.

A cellulose solution was prepared by dissolving cellulose derived from bleached pulp in an ionic liquid. As the ionic liquid, 1-ethyl-3-methylimidazolium diethyl phosphate (manufactured by Aldrich, purity 98%) was used. The cellulose solution was diluted with dimethyl sulfoxide. A liquid film was formed on the substrate by applying a gap coating and applying a cellulose solution to the surface of the substrate. At this time, the size of the gap was adjusted aiming at the thickness of the regenerated cellulose film being 1000 nm.

After the formation of the liquid film, the liquid film of the cellulose solution was heated at 70 ° C. for 1 hour, and then placed in an environment of 20 ° C. and 40-60% RH to obtain a polymer gel sheet. Thereafter, the ionic liquid was removed from the polymer gel sheet by washing the polymer gel sheet. Thereafter, the polymer gel sheet was dried at a tension of about 0.1 N to obtain a regenerated cellulose film having a thickness of about 930 nm that can stand by itself. The regenerated cellulose membrane had a rectangular shape of approximately 5 cm × 5 cm.

The thickness of the regenerated cellulose film was measured by averaging several points using Bruker Nano Inc.'s stylus profiling system DEKTAK (registered trademark), and averaging the thickness of the regenerated cellulose film placed on the glass plate. Confirmed by measuring.

The weight average molecular weight of the cellulose in the regenerated cellulose membrane was measured by GPC (Gel Permeation Chromatography) -MALS (Multi Angle Light Scattering) method. For the measurement, a liquid feeding unit LC-20AD manufactured by Shimadzu Corporation was used. As a detector, a differential refractometer Optilab rEX and a multi-angle light scattering detector DAWN manufactured by Wyatt Technology Corporation were used.
HELEOS was used. The column used was TSKgel α-M manufactured by Tosoh Corporation, and the solvent used was dimethylacetamide to which 0.1 M lithium chloride was added. Measurement was performed under the conditions of column temperature: 23 ° C. and flow rate: 0.8 mL / min. The weight average molecular weight of the regenerated cellulose was about 224,000.

Park et al. "Cellulose crystallinity index: measurement techniques and their impact on interpreting cellulase performance", Biotechnology for Biofuels 2010, has been reported in ^3:10, according to the method using 13 C-NMR, to determine the degree of crystallinity of regenerated cellulose. According to this method, in the spectrum obtained by solid state ¹³ C-NMR measurement, a peak in the vicinity of 87 to 93 ppm is treated as a peak derived from the crystal structure, and a broad peak in the vicinity of 80 to 87 ppm is converted into an amorphous structure. Treated as a derived peak. When the former peak area is X and the latter peak area is Y, the crystallinity is determined from the following equation (1). In Expression (1), “×” represents multiplication.
(Crystallinity) [%] = (X / (X + Y)) × 100 (1)

^{For 13} C-NMR measurement, Varian's Unity Inova-400 and Doty Scientific, Inc. were used. A CP / MAS method was used by using a 5 mm CP / MAS probe. The measurement conditions were MAS speed: 10 kHz, room temperature (25 ° C.), sample rotation speed: 10 kHz, observation width: 30.2 kHz, observation center: 96 ppm, observation frequency: 100.574 MHz, CP pulse (1H → ¹³ C) The observation nucleus 90 ° pulse: 3.9 μsec, 1H excitation pulse: 3.8 μsec, contact time: 2.0 msec, waiting time: 10 sec or more, integration number: 8,000 times. It was confirmed that the solid ¹³ C-NMR spectrum of the cellulose measured by the CP method under these conditions was in good agreement with the solid ¹³ C-NMR spectrum measured by the DD (Dipolar Decouple) method in which a sufficient relaxation time was set. Here, tetramethylsilane (TMS) was used as a reference material for solid state ¹³ C-NMR. The calculated recrystallization cellulose crystallinity was 0%.

The pore volume was measured by a gas adsorption method using nitrogen using BELSORP-mini2 (Microtrack Bell Co., Ltd.) and analyzed by the BJH method. The pore volume of 100 nm or less was 0.016 cm ³ / g. Moreover, the water absorption of the produced film was 198%.

(Evaluation of selective permeability of water and active ingredients)
Regarding the selective permeability of the regenerated cellulose membrane, the regenerated cellulose membrane prepared above is placed on the paper that changes color when infiltrated, and water (molecular weight: 18), propanol (molecular weight: 60), octanol (molecular weight) are placed on the membrane. : 130), decane (molecular weight: 142), and oleic acid (molecular weight: 282) were added dropwise. The discoloration evaluation of the base was performed while confirming that there was no wraparound of the liquid from the surroundings.

When water was dripped, the base color changed within 10 seconds, and it was confirmed that water permeated the regenerated cellulose membrane. However, when propanol, octanol, decane, and oleic acid were dripped, even after 5 minutes had passed. No discoloration of the ground was observed, and propanol, octanol, decane and oleic acid did not permeate the regenerated cellulose membrane.

Next, a 0.1% by weight aqueous solution of fluorescently labeled hyaluronic acid having a molecular weight of 2000 to 4000 (Fluoresceinamine labeled Sodium Hyaluronate (3K2) manufactured by PG Research Co., Ltd.) was dropped from above the regenerated cellulose membrane placed on the substrate. did. 30 seconds after the dropping, the regenerated cellulose membrane was removed, and it was confirmed whether or not the fluorescent hyaluronic acid was detected with a fluorescence microscope by the presence or absence of discoloration due to permeation of water on the base. A fluorescence microscope manufactured by Keyence Corporation was used as the fluorescence microscope. The excitation wavelength was 470 nm, the absorption wavelength was 525 nm, and the exposure time was 1/200 s. Discoloration of the groundwork due to water permeation was confirmed. Hyaluronic acid by a fluorescence microscope was below the detection limit, and it was confirmed that the regenerated cellulose membrane permeated only water. In the same manner, fluorescently labeled hyaluronic acid having a molecular weight of 5000 to 10000 (Fluoresceinamine labeled Sodium Hyaluronate (U2) manufactured by PG Research Co., Ltd.) was also evaluated. It was confirmed that hyaluronic acid by a fluorescence microscope was below the detection limit and that the regenerated cellulose membrane permeated only water.

Next, an ascorbic acid aqueous solution was dropped from above the regenerated cellulose membrane placed on the base. After 30 seconds from the dropping, the selective permeable membrane was removed, the presence or absence of discoloration due to the permeation of water on the base, the base was extracted, and it was confirmed whether ascorbic acid was detected by absorption spectrometry. Absorption analysis was performed by Shimadzu UV1600, and the absorption at 266 nm was evaluated using a calibration curve. Although discoloration of the groundwork due to water permeation was confirmed, it was confirmed that ascorbic acid by absorption spectrometry was below the detection limit, and that the regenerated cellulose membrane permeated only water.

(Evaluation of penetration of active ingredients into the skin: when using the device)
The following procedure evaluated the penetration of the active ingredient into the skin when the device was used.

¡Apply fluorescently labeled hyaluronic acid aqueous solution to the skin inside the forearm. Thereafter, a regenerated cellulose film is placed on the skin, and perforation is performed for 3 seconds at 37 V, 1 kHz, Duly 50 using an electroporation electrode in which an insulator is provided on the treatment surface side of the electrode. Immediately thereafter, ion introduction is performed for 6 seconds. Three minutes after the treatment, the stratum corneum at the treatment site was sampled by a tape strip method, and the ratio of the light emission area by hyaluronic acid to the skin area in the seventh layer was evaluated by a laser microscope. The results for hyaluronic acid with a molecular weight of 2000-4000 are shown in FIG. 13, and the results for hyaluronic acid with a molecular weight of 5000-10000 are shown in FIG.

(Evaluation of penetration of active ingredients into skin: sheet only)
The following procedure evaluated the penetration of active ingredients into the skin.

Vitamin C (sodium ascorbate) aqueous solution was dropped on the skin, and then a regenerated cellulose membrane was placed and allowed to stand for 30 minutes. Thereafter, a tape for tape stripping was affixed, and two keratins were removed. The third to twelfth (a total of ten) keratins were peeled off with a tape strip at the same location, and used as a measurement sample. For the measurement sample, 4 mL of water was added and subjected to ultrasonic treatment for 3 minutes, and the extracted liquid was evaluated using an LC-Vp10 high performance liquid chromatograph manufactured by Shimadzu Corporation. The results are shown in FIG.

(Example 2)
A regenerated cellulose membrane according to Example 2 was produced in the same manner as in Example 1 except that the condition of gap coating was adjusted aiming at a thickness of 300 nm. The thickness of the regenerated cellulose film according to Example 2 was 320 nm. The pore volume of 100 nm or less was 0.047 cm ³ / g. The thickness and pore volume of the regenerated cellulose membrane according to Example 2 were measured in the same manner as in Example 1. Using the regenerated cellulose membrane according to Example 2, the regenerated cellulose membrane according to Example 2 was placed on the base, and from that, fluorescently labeled hyaluronic acid having a molecular weight of 2000-4000 and a molecular weight of 5000-10000 was used as an active ingredient. When the contained aqueous solution was dropped and allowed to stand for 30 seconds, discoloration of the foundation due to water permeation was confirmed. In the evaluation by the fluorescence microscope, it was confirmed that any hyaluronic acid was below the detection limit, and the regenerated cellulose membrane according to Example 2 permeated only water.

(Comparative Example 1)
In the evaluation of the penetration of active ingredients into the skin when using the device, a fluorescently labeled aqueous solution of hyaluronic acid (molecular weight 2000-4000 and molecular weight 5000-10000) was applied on the skin on the inner side of the upper arm, and the film was not attached. Evaluation was performed in the same manner as in Example 1 except that perforation formation was performed. The results are shown in FIG. 13 and FIG.

Further, in the evaluation of the penetration of the active ingredient of only the sheet into the skin, the evaluation was performed in the same manner as in Example 1 except that no film was attached. The results are shown in FIG. 13 and FIG.

(Comparative Example 2)
A polylactic acid solution was prepared by dissolving polylactic acid having a weight average molecular weight of 250,000 in chloroform. After a polylactic acid solution was applied by spin coating on a substrate on which a polyvinyl alcohol film having a weight average molecular weight of about 500 was previously formed, chloroform as a solvent was vaporized. Thereafter, polyvinyl alcohol was removed by immersion in water, and a polylactic acid film of Comparative Example 2 was produced. The thickness of the obtained polylactic acid film was about 960 nm.

A polylactic acid film was placed on the ground, and an aqueous solution containing fluorescently labeled hyaluronic acid (molecular weight 2000-4000, molecular weight 5000-10000) was dropped on it and placed for 30 seconds. There wasn't. Also, no hyaluronic acid was detected in the fluorescence microscope.

In the evaluation of the penetration of active ingredients into the skin, evaluation was performed in the same manner as in Example 1 except that a polylactic acid membrane was used instead of the permselective membrane. The results are shown in FIG. 13 and FIG.

(Comparative Example 3)
Using a polyethylene terephthalate (PET) sheet with a thickness of 23 μm, a PET sheet was placed on the base, and an aqueous solution containing fluorescently labeled hyaluronic acid having a molecular weight of 2000-4000 and a molecular weight of 5000-10000 was dropped from the PET sheet as an active ingredient. However, it was allowed to stand for 30 seconds, but the base material was not discolored and water penetration could not be confirmed. Also, no hyaluronic acid was detected in the fluorescence microscope. The water absorption rate of the PET sheet was 0.4%.

In the evaluation of the penetration of the active ingredient into the skin, evaluation was performed in the same manner as in Example 1 except that a PET sheet was used instead of the permselective membrane and fluorescently labeled hyaluronic acid having a molecular weight of 2000 to 4000 was used. The results are shown in FIG.

(Comparative Example 4)
A commercially available cellophane (regenerated cellulose) having a thickness of about 20 μm is used. An aqueous solution containing cellophane on a base and containing fluorescently labeled hyaluronic acid having a molecular weight of 2000-4000 and a molecular weight of 5000-10000 as an active ingredient from above. The solution was dropped and allowed to stand for 30 seconds, but there was no discoloration of the foundation and water penetration could not be confirmed. Also, no hyaluronic acid was detected in the fluorescence microscope. The crystallinity of cellophane was 21%.

In the evaluation of the permeability of the active ingredient, evaluation was carried out in the same manner as in Example 1 except that cellophane was used instead of the permselective membrane and fluorescently labeled hyaluronic acid having a molecular weight of 2000 to 4000 was used. The results are shown in FIG.

(Comparative Example 5)
Using filter paper (natural cellulose) with a thickness of about 150 μm, place the filter paper on the base, and drop an aqueous solution containing hyaluronic acid with a molecular weight of 2000-4000 and a molecular weight of 5000-10000 as the active ingredient. After standing for 30 seconds, the penetration of water and the penetration of both active ingredients were confirmed.

In the evaluation of the permeability of the active ingredient, evaluation was performed in the same manner as in Example 1 except that filter paper was used instead of the permselective membrane and fluorescently labeled hyaluronic acid having a molecular weight of 2000 to 4000 was used. The results are shown in FIG.

(Comparative Example 6)
Using a commercially available nanofiber sheet containing Chitosan (Magic Facial, manufactured by Ecolife Co., Ltd.), a nanofiber sheet is placed on the base, and fluorescent labels with molecular weights of 2000-4000 and 5000-10000 are used as active ingredients from above. When an aqueous solution containing the hyaluronic acid was dropped and allowed to stand for 30 seconds, penetration of water and penetration of both active ingredients were confirmed.

In the evaluation of the permeability of the active ingredient, evaluation was performed in the same manner as in Example 1 except that a nanofiber sheet was used instead of the permselective membrane and fluorescently labeled hyaluronic acid having a molecular weight of 2000 to 4000 was used. The results are shown in FIG.

(Comparative Example 7)
A cellulose derived from bleached pulp made of wood and having a purity of 90% or more was prepared. A cellulose solution was prepared by dissolving cellulose derived from bleached pulp in an ionic liquid. As the ionic liquid, 1-ethyl-3-methylimidazolium diethyl phosphate (manufactured by Aldrich, purity 98%) was used. The cellulose solution was diluted with dimethyl sulfoxide. A liquid film was formed on the substrate by applying a gap coating and applying a cellulose solution to the surface of the substrate. At this time, the size of the gap in the gap coating was adjusted aiming at the thickness of the bioadhesive film according to Comparative Example 7 being 300 nm. After the formation of the liquid film, the polymer gel sheet was obtained by placing in a 20-60 ° C. 40-60% RH environment. Thereafter, the ionic liquid was removed from the polymer gel sheet by washing the polymer gel sheet. Thereafter, the polymer gel sheet was naturally dried to obtain a regenerated cellulose membrane according to Comparative Example 7 having a thickness of about 300 nm, which can stand by itself. In the biological patch membrane according to Comparative Example 7, the pore volume of pores having a pore diameter of 100 nm or less was 0.44 cm ³ / g.

Using the regenerated cellulose membrane according to Comparative Example 7, the regenerated cellulose membrane according to Comparative Example 7 was placed on the substrate, and from that, fluorescently labeled hyaluronic acid having a molecular weight of 2000-4000 and a molecular weight of 5000-10000 was used as an active ingredient. When the contained aqueous solution was dropped and allowed to stand for 30 seconds, penetration of water and penetration of both active ingredients were confirmed.

FIG. 13 shows the results of evaluating the permeability of hyaluronic acid having a molecular weight of 2000 to 4000 in Example 1 and Comparative Example 1-6. FIG. 13 shows that Example 1 has a higher ability to penetrate hyaluronic acid into the skin as compared with Comparative Example 1-6. In particular, by comparison with Comparative Example 2, it can be seen that hyaluronic acid can be penetrated in Example 1 even if the film has the same thickness.

FIG. 14 shows the results of evaluating the permeability of hyaluronic acid having a molecular weight of 5000 to 10,000 in Example 1 and Comparative Example 1-2. FIG. 14 shows that even when the molecular weight is 5000-10000, Example 1 has a higher ability to penetrate hyaluronic acid into the skin than Comparative Example 1-2.

FIG. 15 shows the results of evaluating vitamin C permeability of Example 1 and Comparative Example 1. From FIG. 15, it can be seen that in Example 1, the permeability of vitamin C to the skin is higher than in Comparative Example 2.

(Evaluation of adhesion to skin of selective permeable membrane for biological application)
(Example 3)
By adjusting the cellulose concentration in the cellulose solution and the size of the gap, the cellulose film of Example 3 was produced in the same manner as in Example 1 with a target thickness of 100 nm, 200 nm, 500 nm, and 1300 nm. The resulting cellulose membrane thicknesses for each target thickness were about 90 nm, about 220 nm, about 510 nm, and about 1340 nm, respectively.

(Comparative Example 8)
By adjusting the cellulose concentration in the cellulose solution and the size of the gap, the target thickness was set to 3000 nm and 5000 nm, and a cellulose film of Comparative Example 7 was produced in the same manner as in Example 1. The thickness of the obtained cellulose membrane for each target thickness was about 2700 nm and about 5000 nm, respectively.

The adhesion when the cellulose film was attached to the skin was evaluated by the following method. First, a small amount of a commercially available lotion was applied to the skin on the inner side of the upper arm, and a sample (cellulose membrane) was stuck thereon. After 5 hours in that state, it was examined whether the sample had fallen off from the skin.

FIG. 16 is a graph showing the evaluation results regarding the samples of Examples 1 and 3 and Comparative Examples 4 and 8. The vertical axis | shaft of the graph shown in FIG. 16 shows the ratio of the person from whom the sample on skin fell out among the persons (total 5 persons) to whom the sample was affixed.

From FIG. 16, it can be seen that the regenerated cellulose, which is a permselective membrane for attaching to a living body, can be provided with a thin film having a good adhesion to the skin, in other words, it is difficult to drop off from the skin when the thickness is about 1300 nm or less. . Since the permselective membrane with a thickness of 1300 nm or less can be adhered to the skin for a long time without an adhesive, the cosmetic effect can be further maintained.

The permselective membrane for biological application according to an embodiment of the present disclosure can be applied to the skin without an adhesive, and further selectively permeates water in an aqueous solution containing the active ingredient, thus increasing the active ingredient concentration on the skin. Thus, it is possible to enhance the beauty effect. Furthermore, a higher cosmetic effect can be obtained by performing the perforation forming device and / or the iontophoresis device and / or the ultrasonic wave introduction together.

The permselective membrane for biological application of the present disclosure can be used as, for example, a skin care film for beauty or medical purposes.

DESCRIPTION OF SYMBOLS 10 Electrode 21a, 21b Insulating layer 23 1st electrode 24 2nd electrode 25a, 25b Insulating layer 30 Living body 40 Aqueous solution 60 Electroporation apparatus main body 70 Iontophoresis apparatus 70a Head 70b Grip 100, 100A Selective permeation membrane 100B, 100C Sheet 101 Protective layer 102 Second protective layer 200 Skin 300 Aqueous solution 302 Cream

Claims (11)

A self-supporting permselective membrane for affixing a living body, comprising regenerated cellulose, having a thickness of 20 nm to 1300 nm and selectively permeating water. The permselective membrane for bioadhesion according to claim 1, wherein the permselective membrane for bioadhesion has biocompatibility. The permselective membrane for bioadhesive according to claim 1 or 2, wherein the permselective membrane for bioadhesive does not substantially permeate a compound having a molecular weight of 60 or more. The permselective membrane for biological application according to any one of claims 1 to 3, wherein the regenerated cellulose has a crystallinity of 0 to 12%. The permselective membrane for bioadhesive according to any one of claims 1 to 4, wherein the permselective membrane for bioadhesive has a water absorption rate of 50% or more. The permselective membrane for biological application according to any one of claims 1 to 5, wherein the regenerated cellulose has a weight average molecular weight of 150,000 or more. The permselective membrane for biological application according to any one of claims 1 to 6,
At least one selected from the group consisting of an iontophoresis device, an electroporation device and an ultrasound introduction device;
A transdermal absorption kit comprising: The transdermal absorption kit according to claim 7, wherein the electroporation apparatus includes an electrode pad including a pair of electrodes and at least one insulating layer covering one surface of the pair of electrodes. A cosmetic method in which an aqueous solution containing an active ingredient is placed between the permselective membrane for attaching a living body according to any one of claims 1 to 6 and the skin. Placing an aqueous solution containing an active ingredient on the skin;
Applying the permselective membrane for biological application according to any one of claims 1 to 6 to the skin so as to cover at least a part of the aqueous solution;
A cosmetic method comprising the step of allowing the active ingredient to penetrate from the skin into the interior. The cosmetic method according to claim 10, wherein the infiltrating step uses at least one selected from the group consisting of a perforation forming method, an ion introduction method, and an ultrasonic introduction method.

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