JP7170232B2 - Adhesive film for living body and cosmetic method of sticking the film for living body - Google Patents

Description

TECHNICAL FIELD The present disclosure relates to a film to be attached to a living body and a cosmetic method for attaching the film to be attached to a living body.

2. Description of the Related Art Conventionally, bioadhesive films that are attached to biomedical tissues such as skin are known.

For example, Patent Document 1 describes a beauty method that is excellent in the so-called secondary adhesion-less effect, in which a large amount of a coloring material such as a pigment is blended, and a cosmetic such as a foundation does not adhere to clothes or the like. Also described are thin films for use in This thin film consists of a base film and a support, and the base film has a thickness of 10 to 500 nm. In the cosmetic method described in Patent Document 1, a base film is attached to the skin, and the attached thin film support is removed. The material of the base film is a material such as polylactic acid. Components such as hyaluronic acid are supported on the base film.

International Publication No. 2014/058060

In the technique described in Patent Literature 1, no study has been made on a bioadhesive film containing regenerated cellulose. Accordingly, the present disclosure provides a film for bioadhesion that contains regenerated cellulose and is advantageous in shortening the time required for attachment to a living tissue.

This disclosure is
Containing regenerated cellulose and an accelerator that promotes attachment of the regenerated cellulose to living tissue,
is self-supporting with a thickness of 20 to 5000 nm,
the accelerator has an HLB value of 4 to 18;
A bioadhesive film is provided.

Additional effects and advantages of the disclosed embodiments will become apparent from the specification and drawings. Benefits and/or advantages are individually provided by the various embodiments or features disclosed in the specification and drawings, and not all are required to obtain one or more of these.

The bioadhesive film described above contains regenerated cellulose and is advantageous in shortening the time required for attachment to a living tissue.

FIG. 1 is a cross-sectional view schematically showing an example of the laminate of the present disclosure. FIG. 2A is a diagram showing a method of using the bioadhesive film of the present disclosure. FIG. 2B is a diagram showing a method of using the bioadhesive film of the present disclosure. FIG. 2C is a diagram showing a method of using the bioadhesive film of the present disclosure. FIG. 3 is a cross-sectional view schematically showing another example of the laminate of the present disclosure.

(Findings on which this disclosure is based)
As described in Patent Literature 1, polylactic acid is known as a film material that is attached to living tissue such as skin. However, since polylactic acid exhibits hydrophobicity, problems such as stuffiness may occur, and it is not necessarily appropriate to attach a polylactic acid film to living tissue for a long period of time. On the other hand, a cellulose film tends to have a high water vapor permeability and easily permeates moisture such as perspiration. Therefore, when a cellulose film is applied to the skin, it is possible to reduce discomfort caused by problems such as stuffiness.

The present inventors have developed a self-supporting bioadhesive membrane with a thickness of several μm or less composed of regenerated cellulose, which has not been realized in the past. The inventors of the present invention conducted further studies on this membrane to be attached to a living body, and found that there is room for shortening the time required for attachment to a living tissue. Therefore, the present inventors repeated a great deal of trial and error in order to shorten the time required for attaching the biological adhesive film to the biological tissue. As a result, the present inventors have newly found that the time required for attachment to a living tissue can be shortened by including a predetermined component in a membrane to be applied to a living body containing regenerated cellulose. Based on this new knowledge, the present inventors devised the membrane for bioadhesion according to the present disclosure.

A summary of aspects of the disclosure follows.

(Item 1)
Containing regenerated cellulose and an accelerator that promotes attachment of the regenerated cellulose to living tissue,
is self-supporting with a thickness of 20 to 5000 nm,
the accelerator has an HLB value of 4 to 18;
A film to be attached to a living body.

(Item 2)
Item 2. The biological patch film according to item 1, wherein the regenerated cellulose has a weight average molecular weight of 30,000 or more.

(Item 3)
The biological patch film according to item 1 or 2, having a thickness of 20 to 1300 nm.

(Item 4)
The biological patch according to any one of items 1 to 3, wherein the regenerated cellulose has a weight average molecular weight of 150,000 or more.

(Item 5)
The bioadhesive membrane according to any one of items 1 to 4, wherein the accelerator is a compound having an ethylene glycol chain or a polyethylene glycol chain.

式（Ａ）、（Ｂ）、及び（Ｃ）において、ａ、ｂ、ｃ、ｄ、及びｅのそれぞれが０以上の整数であり、ａ及びｂの少なくとも１つが１以上の整数であり、ｃ、ｄ、及びｅの少なくとも１つが１以上の整数であり、ｆが１以上の整数であり、Ｒ₁及びＲ₂は、各々独立して、アルキル基、アルコキシ基、（ポリ）エチレングリコール（アルキルエーテル）基、又は（ポリ）プロピレングリコール基を意味する。(Item 6)
The accelerator is at least one selected from the group consisting of a compound represented by the following formula (A), a compound represented by the following (B), and a compound represented by the following (C), item 1 6. The film to be applied to a living body according to any one of 1 to 5.

In formulas (A), (B), and (C), each of a, b, c, d, and e is an integer of 0 or more, at least one of a and b is an integer of 1 or more, and c , d, and at least one of e is an integer of 1 or more, f is an integer of 1 or more, and R ₁ and R ₂ are each independently an alkyl group, an alkoxy group, a (poly)ethylene glycol (alkyl ether) group or (poly)propylene glycol group.

(Item 7)
The biological adhesive membrane according to any one of items 1 to 6, wherein the content of the accelerator in the biological adhesive membrane is 10 to 90% by weight.

(Item 8)
Said accelerators are bisPEG-18 methyl ether dimethylsilane, polyoxyethylene (4)(6) sorbitan monooleate, polyoxyethylene (4)(6) sorbitan monolaurate, polyoxyethylene (4)(20) ) sorbitan monolaurate, polyoxyethylene (4) (20) sorbitan monopalmitate, polyoxyethylene (4) (20) sorbitan monostearate, PEG-11 methyl ether dimethicone, PEG-9 dimethicone, PEG-9 methyl The biological patch according to any one of items 1 to 7, which is at least one selected from the group consisting of ether dimethicone and PEG/PPG-20/22 butyl ether dimethicone.

(Item 9)
A cosmetic method for attaching a film to be attached to a living body, comprising:
The bioadhesive membrane contains regenerated cellulose and an accelerator having an HLB value of 4 to 18 that promotes attachment of the regenerated cellulose to a living tissue, and is a self-supporting type having a thickness of 20 to 5000 nm. and
attaching an adhesive containing an oily component to a biological tissue and the biological adhesive film, and attaching the biological adhesive film to the biological tissue;
beauty method.

(Item 10)
A cosmetic method according to item 9, wherein the oily component is at least one selected from the group consisting of fatty acids, paraffins, naphthenes, cycloparaffins, and silicone oils.

(embodiment)
Hereinafter, embodiments of the present disclosure will be described with reference to the drawings. In addition, the following embodiments are merely examples, and the biological adhesive film and the method of attaching the biological adhesive film of the present disclosure are not limited to the following embodiments. Matters such as numerical values, shapes, materials, components, arrangement of components, connection forms, and steps and the order of steps shown in the following embodiments are examples and are intended to limit the present disclosure. It's not something. The following various embodiments can be combined with each other unless inconsistent. In addition, among the constituent elements in the following embodiments, constituent elements that are not described in independent claims indicating the highest concept should not be understood as essential constituent elements. In the following description, constituent elements having substantially the same functions are denoted by common reference numerals, and their description may be omitted. Also, some elements may be omitted to avoid over-complicating the drawings.

The bioadhesive film 10 shown in FIG. 1 contains regenerated cellulose and an accelerator. The accelerator facilitates attachment of regenerated cellulose to living tissue. Regenerated cellulose typically forms the skeleton (base material) of the biological patch 10 . The bioadhesive membrane 10 is a self-supporting membrane having a thickness of 20 to 5000 nm. As used herein, "self-supporting membrane" means a membrane that can maintain its morphology without a support. For example, when the self-supporting membrane is lifted by pinching a portion of the self-supporting membrane using fingers or tweezers, the self-supporting membrane can be formed without the support without damaging the self-supporting membrane. can be lifted in its entirety. Accelerators have an HLB value of 4-18. As used herein, HLB value means the value determined by the Griffin method. According to Griffin's method, HLB value is defined as 20×(sum of formula weights of hydrophilic moieties)/molecular weight.

Regenerated cellulose is rich in hydroxyl groups. In addition, the biological adhesive film 10 can be used with an adhesive containing an oil component interposed between the biological adhesive film 10 and the biological tissue. When the HLB value of the accelerator is 4 or more, a strong interaction such as hydrogen bonding may occur between the hydroxyl groups of the regenerated cellulose and the accelerator. On the other hand, when the HLB value of the accelerator is 18 or less, the accelerator exhibits moderate hydrophobicity, and moderate hydrophobic interaction or the like occurs between the accelerator and the hydrophobic group of the fatty acid or silicone oil contained in the mounting agent. interaction occurs. Therefore, having an HLB value between 4 and 18 in the accelerator will result in proper interaction between the accelerator and the regenerated cellulose and mounting agent. As a result, the accelerator promotes attachment of the regenerated cellulose to the living tissue and shortens the time required for attachment to the living tissue. It should be noted that the hydrophilic portion of this accelerator does not easily interact with highly hydrophobic membranes such as polylactic acid membranes, and it is thought that it is difficult to promote attachment of highly hydrophobic membranes to living tissue.

Accelerators are, for example, compounds with ethylene glycol or polyethylene glycol chains. In this case, the ethylene glycol or polyethylene glycol chains of the accelerator are likely to interact with the hydroxyl groups of the regenerated cellulose.

The accelerator includes a compound represented by the following formula (A), a compound represented by the following (B), and the following (
It can be at least one selected from the group consisting of compounds represented by C). In formulas (A), (B), and (C), each of a, b, c, d, and e is an integer of 0 or more, at least one of a and b is an integer of 1 or more, and c , d, and at least one of e is an integer of 1 or more, f is an integer of 1 or more, and R ₁ and R ₂ are each independently an alkyl group, an alkoxy group, a (poly)ethylene glycol (alkyl ether) group or (poly)propylene glycol group.

In formula (A), the values of a and b are not particularly limited as long as a and b are integers of 0 or more and at least one of a and b is an integer of 1 or more. Each of a and b is 18, for example. In this case, the accelerator has a high degree of safety.

In formula (B), if c, d, and e are integers of 0 or more, and at least one of c, d, and e is an integer of 1 or more, the values of c, d, and e are is not particularly limited. Each of c, d, and e can be, for example, 6-100. When each of c, d, and e is 6 or more, the hydrophilicity of the accelerator is high, and the accelerator easily flows. Therefore, the biological adhesive film 10 can be easily attached to a biological tissue. When each of c, d, and e is 100 or less, the promoter tends to exist in a liquid state at room temperature (15 to 25° C.), and the biological adhesive membrane 10 can be easily attached to a biological tissue. Each of c, d, and e may be 6-20. When each of c, d, and e is 20 or less, the HLB value of the promoter can easily be adjusted to 4-18 by appropriately adjusting the chain length of R ₁ .

In formula (B), the chain length of R ₁ is not particularly limited as long as it is an alkyl group, an alkoxy group, a (poly)ethylene glycol (alkyl ether) group, or a (poly)propylene glycol group. When R ₁ is an alkyl group or an alkoxy group, R ₁ has, for example, a molecular chain made up of 8-30 carbon atoms. Such molecular chains often exist as substances such as sebum in living organisms. Therefore, even if R ₁ is eliminated from the promoter by hydrolysis, the fatty acid formed by the elimination of R ₁ is likely to have biocompatibility and is less likely to cause harm to living organisms. Further, when R ₁ is a (poly)ethylene glycol (alkyl ether) group or (poly)propylene glycol group, R ₁ is, for example, a molecular chain made up of 1 to 1000 ethylene glycol or propylene glycol repeating units. have. Such molecular chains are safe because they are often used as cosmetic ingredients, for example. Therefore, even if R ₁ is eliminated from the accelerator by hydrolysis, the (poly)ethylene glycol (alkyl ether) group or (poly)propylene glycol group formed by the elimination of R ₁ is biocompatible. and is less likely to cause harm to living organisms.

In formula (C), f is not particularly limited as long as it is an integer of 1 or more. f can be, for example, 1-100. When f is 1 or more, the accelerator is relatively hydrophobic, so that the accelerator and the mounting agent are likely to interact with each other. Therefore, the biological adhesive film 10 can be easily attached to a biological tissue. When f is 100 or less, the promoter tends to exist in a liquid state at room temperature (15 to 25° C.), and the biological adhesive membrane 10 can be easily attached to a biological tissue.

In formula (C), if R ₂ is an alkyl group, alkoxy group, (poly)ethylene glycol (alkyl ether) group, or (poly)propylene glycol group, the chain length is not particularly limited. When R ₂ is an alkyl group or an alkoxy group, R ₂ has, for example, a chain of 8 to 30 carbon atoms. Such molecular chains often exist as substances such as sebum in living organisms. Therefore, even if R ₂ is eliminated from the accelerator by hydrolysis, the fatty acid formed by the elimination of R ₂ is likely to have biocompatibility and is less likely to cause harm to living organisms. Further, when R ₂ is a (poly)ethylene glycol (alkyl ether) group or (poly)propylene glycol group, R ₂ has a molecular chain made up of, for example, 1 to 1000 ethylene glycol or propylene glycol repeating units. . Such molecular chains are safe because they are often used as cosmetic ingredients, for example. Therefore, even if R ₂ is eliminated from the accelerator by hydrolysis, the (poly)ethylene glycol (alkyl ether) or (poly)propylene glycol formed by the elimination of R ₂ is biocompatible. It is easy to use and does not cause harm to living organisms.

Accelerators include, for example, bisPEG-18 methyl ether dimethylsilane, polyoxyethylene (4)(6) sorbitan monooleate, polyoxyethylene (4)(6) sorbitan monolaurate, polyoxyethylene (4) ( 20) Sorbitan Monolaurate, Polyoxyethylene (4) (20) Sorbitan Monopalmitate, Polyoxyethylene (4) (20) Sorbitan Monostearate, PEG-11 Methyl Ether Dimethicone, PEG-9 Dimethicone, PEG-9 At least one selected from the group consisting of methyl ether dimethicone and PEG/PPG-20/22 butyl ether dimethicone. In this case, the interaction between the accelerator, the regenerated cellulose, and the adhesive becomes favorable, and the biological adhesive membrane 10 can be easily attached to the biological tissue in a short period of time.

The content of the promoter in the biological patch 10 is, for example, 10 to 90% by weight. If the content of the accelerator in the biological adhesive film 10 is 10% by weight or more, it is advantageous from the viewpoint of promoting attachment of the biological adhesive film 10 to living tissue. If the content of the promoter in the biological adhesive film 10 is 90% by weight or less, the adhesiveness of the biological adhesive film 10 is suppressed, which is advantageous from the viewpoint of ease of handling of the biological adhesive film 10 . The content of the promoter in the bioadhesive film 10 may be 15 to 50% by weight. If the content of the promoter in the biological adhesive film 10 is 15% by weight or more, it is more advantageous from the viewpoint of promoting attachment of the biological adhesive film 10 to living tissue. If the content of the accelerator in the biological adhesive film 10 is 50% by weight or less, the stickiness of the biological adhesive film 10 is further suppressed, which is more advantageous from the viewpoint of ease of handling of the biological adhesive film 10 .

The accelerator in the membrane 10 for biological application may be uniformly distributed in the thickness direction of the membrane 10 for biological application. The accelerator may be concentrated in a specific location on the biological adhesive film 10 . For example, in the biological adhesive membrane 10, a plurality of regions in which the accelerator exists at a high concentration may exist at predetermined intervals. The accelerator may be present in a layered form on the surface of the biological adhesive membrane 10 . In this case, the accelerator layer may cover the entire substrate made of regenerated cellulose, or may cover a portion of the substrate. In the biological adhesive film 10, the promoter may exist on the surface of the biological adhesive film 10, or may exist on a surface other than the surface of the biological adhesive film 10 in the thickness direction. For example, at least part of the promoter in the biological adhesive film 10 exists continuously between the surface of the biological adhesive film 10 and the regenerated cellulose in the thickness direction of the biological adhesive film 10 . In this case, as described above, the accelerator is more likely to interact with both the regenerated cellulose and the adhesive, and attachment of the biological adhesive membrane 10 to the biological tissue is more reliably promoted. .

Regenerated cellulose tends to form intramolecular and/or intermolecular hydrogen bonds, and the biological patch 10 tends to have a dense structure. Therefore, the biological patch 10 has high strength, moderate flexibility, and resistance to tearing, as will be described later. Since cellulose exhibits amphiphilicity, it can appropriately support a hydrophilic active ingredient and a hydrophobic active ingredient, and the biological patch 10 has high versatility.

The raw material for regenerated cellulose is not particularly limited. For example, the raw material of the regenerated cellulose may be plant-derived natural cellulose, biological-derived natural cellulose, regenerated cellulose such as cellophane, or processed cellulose such as cellulose nanofiber. Advantageously, the concentration of impurities in the raw material of regenerated cellulose is 10% by weight or less.

Regenerated cellulose is, for example, cellulose substantially represented by the following formula (I). Here, "cellulose substantially represented by formula (I)" means cellulose in which 90% or more of hydroxyl groups of glucose residues in cellulose represented by formula (I) remain. The ratio of the number of hydroxyl groups of glucose residues in the cellulose contained in the biological patch 10 to the number of hydroxyl groups of glucose residues in the cellulose represented by formula (I) is, for example, X-ray photoelectron spectroscopy (XPS ) can be quantified by a known method such as In some cases, the regenerated cellulose contained in the biological patch 10 may contain a branched structure. Artificially derivatized cellulose typically does not fall under "cellulose substantially represented by formula (I)". On the other hand, "cellulose substantially represented by formula (I)" does not exclude cellulose regenerated through derivatization. Even cellulose regenerated through derivatization may correspond to "cellulose substantially represented by formula (I)".

In the embodiment of the present disclosure, the biological adhesive membrane 10 is composed of regenerated cellulose. The strength of a film formed from a suspension of natural cellulose fibers in water or the like is due to hydrogen bonding between nanofibers that make up the cellulose fibers. Therefore, only brittle cellulose membranes are obtained. In contrast, in membranes made of regenerated cellulose, the nanofibers are loosened to the molecular chain level, so the strength of the membrane made of regenerated cellulose is due to the hydrogen bonds between the cellulose molecular chains. . That is, in a membrane composed of regenerated cellulose, hydrogen bonds are uniformly formed between units smaller than nanofibers. Therefore, compared with the case where a film is formed from a suspension in which natural cellulose fibers are dispersed in water or the like, it has high strength, suppresses brittleness, and has moderate flexibility. Moreover, it is possible to provide a cellulose membrane that is difficult to tear. Here, “nanofiber” is also called “nanofibril (or microfibril)” and is the most basic unit in which cellulose molecules aggregate, and has a width of about 4 nm to about 100 nm, for example about 1 μm. or longer.

As used herein, "regenerated cellulose" means cellulose that does not have the crystalline structure I characteristic of natural cellulose. The crystal structure of cellulose can be confirmed by an XRD pattern. An example of the XRD pattern of natural cellulose (CuKα radiation (50 kV, 300 mA)) is shown. The XRD pattern shows peaks around 14-17° and 23°, which are characteristic of crystal structure I. Regenerated cellulose is often of crystalline structure II, with peaks around 12°, 20° and 22° and no peaks around 14-17° and 23°.

For example, 90% or more by mass of the regenerated cellulose contained in the biological patch 10 is regenerated cellulose that has not been chemically modified or derivatized. 98% or more by mass of the regenerated cellulose contained in the biological patch 10 may be regenerated cellulose that has not been chemically modified or derivatized. In this case, the biological patch 10 contains a large amount of cellulose that has not been chemically modified or derivatized, and it is thought that more hydroxyl groups are contained per molecular chain of cellulose. For this reason, more hydrogen bonds are formed between cellulose molecules, and the biological patch 10 is likely to have high strength. The regenerated cellulose contained in the biological patch 10 may be uncrosslinked.

The cellulose contained in the biological patch 10 has a crystallinity of 0 to 12%, for example. In this case, the amount of hydroxyl groups involved in the formation of the crystal structure is moderately small, and the adhesiveness of the film 10 for biological patch to the living body tends to be high. By performing predetermined chemical modification at sites where hydroxyl groups should exist, the membrane 10 for biological patch can exhibit various functions.

The crystallinity of the cellulose contained in the biological patch ¹⁰ is reported, for example, in Park et al. "Cellulose crystallinity index: measurement techniques and their impact on interpreting cellulase performance" Biotechnology for Biofuels 2010, 310 - can be determined by NMR-based techniques; According to this method, in the spectrum obtained by solid-state ¹³ C-NMR measurement, the peak near 87 to 93 ppm is considered to be derived from the crystal structure, and the broad peak near 80 to 87 ppm is considered to be derived from the non-crystalline structure. The crystallinity is determined by the following formula, where X is the peak area of and Y is the peak area of the latter. In the formula below, "x" represents multiplication.
(Crystallinity)% = (X/(X + Y)) x 100

As described above, the biological adhesive film 10 has a thickness of 20 to 5000 nm. If the thickness of the film 10 for sticking to a living body is 20 nm or more, the film 10 for sticking to a living body has high strength and is easy to handle. Therefore, the bioadhesive membrane 10 can function as a self-supporting membrane that can be attached to a biomedical tissue. If the thickness of the biological adhesive film 10 is 5000 nm or less, the biological adhesive film 10 is less likely to peel off when the biological adhesive film 10 is attached to a biological tissue. Further, when the thickness of the biological adhesive film 10 is within such a range, the biological adhesive film 10 can be easily peeled off from the living tissue by running water, for example. The thickness of the membrane 10 to be patched to a living body is determined by, for example, measuring the thickness of the membrane 10 to be patched to a living body at a plurality of points and averaging the measured thicknesses. The thickness at each location can be measured, for example, using a stylus profiling system DEKTAK (registered trademark) manufactured by Bruker Nano Inc.

The thickness of the biological patch 10 may be 100 nm or more. When the thickness of the film 10 for sticking to a living body is 100 nm or more, the strength of the film 10 for sticking to a living body increases, and the film 10 for sticking to a living body is easy to handle. The thickness of the biological patch 10 may be 300 nm or more. When the thickness of the membrane 10 for sticking to a living body is 300 nm or more, the strength of the membrane 10 for sticking to a living body increases, and the membrane 10 for sticking to a living body 10 is hard to break and can be used easily. The thickness of the biological patch 10 may be 500 nm or more. When the thickness of the biological patch 10 is 500 nm or more, the biological patch 10 can hold more active ingredients such as cosmetic ingredients. The thickness of the biological patch 10 may be 2000 nm or less. When the thickness of the biological adhesive film 10 is 2000 nm or less, the adhesiveness of the biological adhesive film 10 to the biological tissue is high, and the biological adhesive film 10 can be stably attached to the surface of the biological tissue such as the skin. can. The thickness of the biological patch 10 may be 1300 nm or less. When the thickness of the biological adhesive film 10 is 1300 nm or less, the adhesiveness of the biological adhesive film 10 to the biological tissue is higher, and the biological adhesive film 10 can be stably attached to the surface of the biological tissue such as the skin for a long time. can be maintained.

Regenerated cellulose, for example, has a weight average molecular weight of 30,000 or greater. In this case, a sheet having a thickness of 5000 nm or less of the membrane 10 to be applied to a living body can be produced. The weight average molecular weight of regenerated cellulose can be determined, for example, by gel permeation chromatography (GPC).

The regenerated cellulose may have a weight average molecular weight of 150,000 or greater. In this case, even if the thickness of the biological patch 10 is adjusted to 1300 nm or less, the biological patch 10 can be produced as a self-supporting film.

The shape of the biological adhesive film 10 is not particularly limited when the biological adhesive film 10 is viewed from above. The biological adhesive film 10 may be circular, elliptical, or polygonal in plan view. The biological adhesive film 10 may have an irregular shape in plan view.

The biological patch 10 may be a single-layer film, or may be a film having a laminated structure in which a plurality of layers are laminated. When the biological patch 10 is a film having a laminated structure, the active ingredients retained in the multiple layers may be the same or may be different for each layer. The biological patch 10 may have a laminated structure in which a layer containing regenerated cellulose and a layer made of a material other than regenerated cellulose are laminated.

In the case of cosmetic applications, the bioadhesive film 10 is used for, for example, (i) skin care such as whitening, moisturizing, and wrinkle prevention, (ii) hair care such as hair growth, hair thickening, depilation, and hair styling, or (iii) foundation, It is used for makeup such as face powder and nail art. In the case of medical use, the biological adhesive film 10 is used, for example, to administer drugs such as analgesic anti-inflammatory drugs, anti-inflammatory drugs, cardiotonic drugs, antifungal drugs, adrenocortical hormone drugs, and blood circulation promoting drugs to the living body. good too.

The biological patch 10 may contain components other than the regenerated cellulose and the accelerator. For example, the biological adhesive film 10 may contain a predetermined active ingredient. The active ingredient can be, for example, a whitening ingredient, an ultraviolet protective ingredient, a moisturizing ingredient, a hair-restoring ingredient, and a cosmetic ingredient or medicinal ingredient such as cosmetics. Cosmetic ingredients include gum arabic, tragacanth gum, galactan, guar gum, carob gum, karaya gum, carrageenan, pectin, agar, quince seed (quince), algecolloid (cassou extract), starch (rice, corn, potato, wheat), succinoglucan, Vitamin A such as casein, albumin, gelatin, mucin, chondroitin sulfate, xylitol, maltitose, sodium pyrrolidonecarboxylate, retinol, retinal, and retinoic acid, B vitamins such as thiamine, riboflavin, pyridoxine, pyridoxamine, and folic acid, ascorbic acid ( sodium), vitamin D such as ergocalciferol and cholecalciferol, vitamin E such as α-tocopherol, vitamin K such as phylloquinone and menaquinone, vitamin A derivatives such as tretinoin and retinol palmitate, fursultiamine, etc. vitamin B derivatives such as glyceryl ascorbic acid and ascorbyl tetrahexyldecanoate, vitamin D derivatives such as dihydrotachysterol, vitamin E derivatives such as α-tocopheryl acetate, α-tocopheryl quinone, and α-tocopherol succinate , hydroquinone, potassium 4-methoxysalicylate, rucinol, polyphenols such as anthocyanins, disodium 3-succinyloxyglycyrrhetinate, placenta, dioxybenzone, 2-ethylhexyl 4-methoxycinnamate, various amino acids, keratin, hydroxyapatite, phosphoric acid Ceramics such as tricalcium, calcium carbonate, alumina, zirconia, chitin, chitosan, arbutin, ellagic acid, kojic acid, tranexamic acid, glycerol, sodium lactate, hyaluronic acid, ceramide, minoxidil, finasteride, collagen, elastin, various extracts, citric acid Acid, lecithin, carbomer, xanthan gum, dextran, palmitic acid, lauric acid, petroleum jelly, titanium oxide, iron oxide, synthetic pigment, dye, phenoxyethanol, fullerene, astaxanthin, coenzyme, human oligopeptide, glycerin, diglycerin, sorbitol, pyrrolidone carboxylic acid Acid, fatty acid polyglyceryl, polyglycerin, jojoba oil, trimethylglycine, mannitol, trehalose, glycosyltrehalose, pullulan, erythritol, elastin, dipropylene glycol recall, butylene glycol, ethyl ethylhexanoate, sodium acrylate, disodium edetate, sucrose fatty acid ester, squalane, polyethylene glycol, polyoxyethylene hydrogenated castor oil, glycerin stearate, ethanol, polyvinyl alcohol, hydroxyethyl cellulose, or ectoin is. Medicinal ingredients include, for example, cepharanthine, rutin, isosorbide nitrate, indomethacin, diflucortolone valerate, acyclovir, ketoconazole, ketoprofen, diclofenac sodium, dexamethasone propionate, felbinac, clobetasol propionate, loxoprofen, methyl salicylate, or tacrolimus. is. These active ingredients can be contained in the bioadhesive film 10 in the form of solids, solutions, dispersions, or emulsions.

At least part of the membrane 10 to be applied to a living body may be colored. For example, at least a portion of the biological patch 10 may be colored in a color close to the color of the skin. In this case, stains, moles, and scars on the skin can be covered with the membrane 10 to be applied to a living body to make them inconspicuous.

The bioadhesive film 10 is used, for example, by being attached to the skin or nails on the face, arms, or the like. Therefore, the biological patch 10 typically has an area of 7 mm ² or more. Thereby, a wide area can be covered when the biological patch film 10 is attached to the skin. In addition, the biological adhesive film 10 may be attached to the surface of a biological tissue other than the skin, such as an organ. Healing of the organ can be promoted by attaching the biological adhesive film 10 to the surface of the organ. In addition, adhesion between organs can be prevented.

The dressing is not particularly limited as long as it contains an oily component. In the present specification, the oily component refers to a substance that alone can dissolve in water in an amount of 0.1% by mass or less. The oily component is, for example, at least one selected from the group consisting of fatty acids, paraffins, naphthenes, cycloparaffins, and silicone oils. The dressing is, for example, at least one selected from the group consisting of lotions, milky lotions, beauty essences, creams, and oils containing oily components. The ratio of the mass of the oil component to the mass of the dressing is not particularly limited. This ratio is, for example, 1% or more. In this case, it is easy to attach the film 10 for living body patch. This ratio is desirably 10% or more. In this case, it is easier to attach the membrane 10 for living body patch. The type of oil component is not particularly limited. The oily component is, for example, at least one selected from the group consisting of fatty acids, paraffins, naphthenes, cycloparaffins, and silicone oils, as described above. The fatty acid may be a (polyhydric) unsaturated fatty acid, a saturated fatty acid, a branched fatty acid, a cyclic fatty acid, or a fatty acid ester. Alternatively, it may be an ether-type lipid. Fatty acids are, for example, caprylic acid, pelargonic acid, capric acid, lauric acid, myristic acid, pentadecyl acid, palmitic acid, palmitoleic acid, margaric acid, stearic acid, oleic acid, vaccenic acid, linoleic acid, linolenic acid, eleostearin Acid, arachidic acid, mead acid, arachidonic acid, behenic acid, lignoceric acid, nervonic acid, cerotic acid, montanic acid, melissic acid, cyclobutanecarboxylic acid, cyclopentanecarboxylic acid, cyclohexanecarboxylic acid, cycloheptanecarboxylic acid, cyclooctane carboxylic acid, glycerin fatty acid ester such as cyclononanecarboxylic acid, cyclodecanecarboxylic acid, cycloundecanecarboxylic acid, cyclobutenecarboxylic acid, cyclopentenecarboxylic acid, cyclohexenecarboxylic acid, cycloheptenecarboxylic acid, cyclooctenecarboxylic acid, cyclononene Carboxylic acid, cyclodecene carboxylic acid, methyl cocoate, methyl laurate, isopropyl myristate, isopropyl palmitate, methyl stearate, butyl stearate, isotridecyl stearate, methyl oleate, myristyl myristate, stearyl stearate, oleic acid Isobutyl, di-n-alkyl phthalate, diisononyl phthalate, didecyl phthalate, di-alkyl phthalate, tri-n-alkyl trimellitate, adipate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan monooleate , polyethylene glycol monolaurate, polyethylene glycol monostearate, polyethylene glycol distearate, ethylene glycol distearate, propylene glycol monostearate, pentaerythritol monooleate, pentaerythritol monostearate, pentaerythritol tetrapalmitate, stearin acid monoglyceride, oleic acid monoglyceride, stearic acid mono/diglyceride, caprylic acid triglyceride, and the like. The dressing may comprise naturally derived oils containing fatty acids. Oils derived from natural products include, for example, argan oil, squalane oil, jojoba oil, horse oil, olive oil, camellia oil, rosehip oil, yuzu seed oil, macadamia nut oil, rice bran oil, almond oil, marula oil, apricot kernel. Oil, arnica oil, walnut oil, olive scrawan oil, kyorot oil, kukui nut oil, grapeseed oil, coconut oil, sunflower oil, sweet almond oil, sesame oil, tamanu oil, passionflower oil, peach kernel oil, hazelnut oil. Hemp seed oil, avocado oil, aloe vera oil, evening primrose oil, wheat germ oil, castor oil, camellia oil, calendula oil, St. John's wort oil, hippophae oil, black seed oil, boradi oil, mineral oil, or rosehip oil. such as vegetable oils, animal fats, or mineral oils. Silicone oils are, for example, methylpolysiloxane, octamethyltrisiloxane, decamethylcyclopentasiloxane, octamethylcyclotetrasiloxane, methylpolysiloxane, dimethicone, dimethiconol, cyclomethicone or amodimethicone. The dressing may also contain, for example, water, fat, alcohol, or an emulsifier, and may further contain one or more active ingredients as described above.

In one example of a cosmetic method for attaching the biological adhesive film 10, a mounting agent containing an oily component such as fatty acid, paraffin, naphthene, cycloparaffin, or silicone oil is adhered to the biological tissue and the biological adhesive film 10 to adhere to the biological tissue. The membrane 10 for living body patching is stuck on. The order of the supply of the adhesive and the work of bringing the membrane 10 for biological patch closer to the biological tissue is not particularly limited. For example, while the biological adhesive film 10 is in contact with the biological tissue, the adhesive may be dripped toward the biological adhesive film 10 and the biological tissue. Alternatively, the adhesive film 10 may be brought into contact with the adhesive adhered to the biological tissue after the adhesive is dripped onto the biological tissue.

As shown in FIG. 1, the biological adhesive membrane 10 is provided, for example, in the form of a laminate 50a. The laminate 50 a includes the membrane 10 for bio-adhesion and the first protective layer 21 . The biological adhesive film 10 has a first principal surface 11 and a second principal surface 12 . The second main surface 12 is located on the opposite side of the first main surface 11 of the membrane 10 for biological application. The first protective layer 21 is arranged on the first major surface 11 . The first protective layer 21 is a layer removable from the first major surface 11 . The first protective layer 21 is in contact with the first major surface 11, for example.

The first protective layer 21 is made of, for example, (i) polyethylene, polypropylene, polyethylene terephthalate, nylon, acrylic resin, polycarbonate, polyvinyl chloride, acrylonitrile-butadiene-styrene (ABS) resin, polyurethane, synthetic rubber, cellulose, Teflon (registered (trademark), aramids, and polyimides, sheets of polymeric materials, wovens, nonwovens, or meshes, (ii) sheet metal, or (iii) sheet glass. All or part of the surface of the first protective layer 21 may be subjected to a chemical or physical surface treatment. In addition, the first protective layer 21 has a shape that is the same as or different from the shape of the membrane 10 to be adhered to a living body, and a size that is the same as or different from the size of the membrane 10 to be stuck to a living body, in plan view. For example, a plurality of bioadhesive membranes 10 may be arranged on a single first protective layer 21 . In addition, the biological adhesive film 10 can maintain its shape without the first protective layer 21 . Therefore, even if the first protective layer 21 is removed from the first main surface 11, the bioadhesive film 10 can maintain its shape.

As shown in FIG. 2A , for example, the second main surface 12 of the biological adhesive film 10 is directed toward a specific site (for example, skin) of the biological body, and the laminate 50a is brought close to the second main surface 12 of the biological adhesive film 10 . is brought into contact with a specific part of the living body. At this time, the adhesive is supplied to a specific site of the living body or the membrane 10 for attachment to the living body. Next, as shown in FIG. 2B, the first protective layer 21 is peeled off from the first main surface 11 of the membrane 10 for biological application. At this time, the biological adhesive film 10 is in close contact with the biological tissue, and the state in which the biological adhesive film 10 is attached to the biological tissue is maintained. When the first protective layer 21 is completely peeled off, the entire first major surface 11 of the biological adhesive membrane 10 is exposed as shown in FIG. 2C.

Laminate 50a may be modified as laminate 50b shown in FIG. The laminate 50b is configured in the same manner as the laminate 50a unless otherwise specified. Components of the laminate 50b that are the same as or correspond to those of the laminate 50a are denoted by the same reference numerals, and detailed description thereof is omitted. The description regarding the laminate 50a also applies to the laminate 50b unless technically contradictory.

As shown in FIG. 3, the laminate 50b further comprises a second protective layer 22. As shown in FIG. A second protective layer 22 is arranged on the second major surface 12 . The second protective layer 22 can protect the second major surface 12 . In addition, the second protective layer 22 facilitates handling of the laminate 50b.

The material of the second protective layer 22 may be the same as the material of the first protective layer 21 or may be different from the material of the first protective layer 21 . The second protective layer 22 has a shape that is the same as or different from the shape of the membrane 10 to be adhered to a living body, and a size that is the same as or different from the size of the membrane 10 to be stuck to a living body, in plan view. The second protective layer 22 has a shape that is the same as or different from the shape of the first protective layer 21 and a size that is the same as or different from the size of the first protective layer 21 in plan view.

Second protective layer 22 is typically removable from second major surface 12 . When using the laminate 50b, for example, first, the second protective layer 22 is peeled off from the membrane 10 for sticking to a living body. Thereby, the second main surface 12 is exposed. After that, the second principal surface 12 is brought close to the specific site of the living body, and the membrane 10 for biological application is attached to the specific site of the living body in the same manner as the laminate 50a.

Conventionally, polylactic acid has been proposed as a material for sheets to be applied to the skin. However, polylactic acid is a hydrophobic material and is unsuitable for long-term use because it may cause stuffiness. Therefore, in applications where the adhesive is applied to the skin, it is necessary to consider the irritation that the adhesive gives to the skin and the water vapor transmission rate of the adhesive.

On the other hand, if the thickness of the bioadhesive membrane 10 is 1300 nm or less, for example, it can be attached to the skin without using an adhesive. The reason why it can be applied to the skin without an adhesive even if the thickness is 500 nm or more is that the biological patch 10 exhibits flexibility even when it has a thickness of 500 nm or more, and has unevenness (e.g., cheeks, arms, etc.). It is presumed that this is because the surface of the cellulose film and the van der Waals force have a greater influence on the surface of the cellulose film than the polylactic acid film, resulting in improved adhesion. Since it can be applied to the skin without an adhesive, it is possible to reduce stuffiness and use the membrane 10 for biological application for a long period of time. Furthermore, cellulose has biocompatibility, is less likely to give physical or chemical stress to the skin even when applied directly to the skin, and is amphiphilic and hydrophilic. Since it does not dissolve in water while being held, there is no concern that it will be dissolved by moisture such as sweat, and it has excellent durability.

An example of the manufacturing method of the membrane 10 for living body patch will be described. First, cellulose is dissolved in a solvent to prepare a cellulose solution. In order to obtain a regenerated cellulose membrane with a weight average molecular weight of 30,000 or more, cellulose with a weight average molecular weight of at least 30,000 or more is used. As a result, a self-supporting bioadhesive membrane having a thickness of 5000 nm or less can be produced. In order to obtain a regenerated cellulose membrane with a weight average molecular weight of 150,000 or more, cellulose having a weight average molecular weight of at least 150,000 or more may be used to prepare the cellulose solution. In this case, a self-supporting bioadhesive membrane having a thickness of 1300 nm or less can be produced. Thus, by increasing the weight average molecular weight of the cellulose used in the preparation of the cellulose solution, more hydroxyl groups are included in one molecular chain. As a result, many intermolecular hydrogen bonds can be formed, and a thinner membrane to be applied to a living body can be stably produced. The cellulose used for preparing the cellulose solution is not particularly limited as long as it has the desired weight average molecular weight. The cellulose used to prepare the cellulose solution 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. When the weight average molecular weight of the regenerated cellulose is 2,000,000 or less, it is useful because it becomes easy to handle. 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 less. The ionic liquid contained in the first solvent is, for example, an ionic liquid containing an amino acid or an alkyl phosphate. By containing such an ionic liquid in the first solvent, cellulose can be dissolved while suppressing a decrease in the molecular weight of cellulose. In particular, since amino acids are components that exist in living organisms, ionic liquids containing amino acids are advantageous in forming the bioadhesive membrane 10 that is safer for living organisms.

Cellulose may be dissolved using an ionic liquid that has been pre-diluted with a solvent that does not precipitate cellulose. For example, a mixture of an aprotic polar solvent and an ionic liquid may be used as the first solvent. Aprotic polar solvents are less likely to form hydrogen bonds and are less likely to deposit 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 Formula (II), the anion is an amino acid. In this ionic liquid, the anion contains a terminal carboxyl group and a terminal amino group, as described in formula (II). The cation of the ionic liquid represented by formula (II) may be a quaternary ammonium cation.

In formula (II), R ₁ to R ₆ independently represent a hydrogen atom or a substituent. Substituents can be alkyl groups, hydroxyalkyl groups, or phenyl groups. Substituents may contain branches in the carbon chain. Substituents may contain functional groups such as amino groups, hydroxyl groups, or carboxyl groups. n is 4 or 5, for example.

The ionic liquid contained in the first solvent may be an ionic liquid represented by the following formula (III). In formula (III), R ₁ , R ₂ , R ₃ and R ₄ independently represent a hydrogen atom or an alkyl group having 1 to 4 carbon atoms.

A second solvent may be further added in the step of preparing the cellulose solution. For example, a second solvent may be added to the 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 an aprotic polar solvent.

The concentration of cellulose in the cellulose solution is typically 0.2-15% by weight. When the concentration of cellulose in the cellulose solution is 0.2% by weight or more, the thickness of the biological adhesive patch 10 can be reduced and the biological adhesive adhesive 10 having the strength necessary to maintain its shape can be obtained. Moreover, if the concentration of cellulose in the cellulose solution is 15% by weight or less, precipitation of cellulose in the cellulose solution can be suppressed. The concentration of cellulose in the cellulose solution may be 1-10% by weight. When the concentration of cellulose in the cellulose solution is 1% by weight or more, the bioadhesive membrane 10 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 with less cellulose precipitation 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 of water on the surface of the substrate is, for example, 70° or less. 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, the cellulose solution can be prevented from entering the interior of the substrate, and the membrane 10 for biological patch can be easily separated from the substrate in a post-process.

The substrate may have undergone chemical or physical surface modification. As the substrate, for example, a polymer material substrate that has undergone surface modification treatment such as ultraviolet (UV) irradiation or corona treatment may be used. The surface modification method is not particularly limited. For example, application of surface modifiers, surface modification, plasma treatment, sputtering, etching, or blasting can be applied.

Methods for forming a liquid film of a cellulose solution on a substrate include, for example, gap coating, slot die coating, spin coating, and coating using a bar coater (metering), in which a predetermined gap is formed between the surface of the substrate and the substrate using an applicator. rod coating) and gravure coating. The thickness of the liquid film adjusted by the thickness of the gap or the size of the opening of the slot die and the coating speed, the rotation speed of the spin coat, the depth of the groove of the bar coater or gravure coat, the coating speed, etc., and the concentration of the cellulose solution. By adjusting the thickness, the thickness of the membrane to be applied to a living body can be adjusted. The method of 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.

At least one of the cellulose solution and the substrate may be heated when forming the liquid film of the cellulose solution on the substrate. This heating may be carried out, for example, in a temperature range (eg, 40-100° C.) capable of keeping the cellulose solution stable.

The liquid film of the cellulose solution formed on the substrate may be heated. The liquid film may be heated, for example, at a temperature (eg, 50 to 200° C.) lower than the decomposition temperature of the ionic liquid contained in the first solvent. By heating the liquid film at such a temperature, the solvent other than the ionic liquid (for example, the second solvent) can be appropriately removed, and the strength of the biological patch 10 tends to increase. Heating of the liquid film may be performed in a reduced pressure environment. In this case, the 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 forming the liquid film of the cellulose solution on the substrate, the liquid film may be gelled. For example, by exposing the liquid film to the vapor of a liquid that is soluble in the ionic liquid and does not dissolve cellulose, the liquid film is gelled and a polymer gel sheet can be obtained. For example, when the 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, thereby lowering the solubility of cellulose in the liquid film. As a result, some of the cellulose molecules are precipitated to form a three-dimensional structure. As a result, the liquid film gels. The presence or absence of a gelation point can be determined by whether or not the gelled film can be lifted.

The heating of the liquid film may be performed before gelation of the liquid film, may be performed after gelation of the liquid film, or may be performed before or after gelation 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 can be understood as a step of washing the polymer gel sheet. In this step, in addition to the ionic liquid, some of the components contained in the cellulose solution other than the cellulose and the ionic liquid (for example, the second solvent) may be removed. The rinse liquid is typically a liquid that can be dissolved in the ionic liquid. Examples of such liquids are water, methanol, ethanol, propanol, butanol, octanol, toluene, xylene, acetone, acetonitrile, dimethylacetamide, dimethylformamide, and dimethylsulfoxide.

Next, the polymer gel sheet is immersed in the promoter solution. At this time, the accelerator solution may further contain the above active ingredients. Solvents in solutions of accelerators are, for example, the group consisting of water, ethanol, propanol, butanol, acetone, glycerin, propanediol, 1,3-butanediol, 1,4-butanediol, diglycerin, polyethylene glycol, and dimethicone. is at least one selected from Instead of immersing the polymer gel sheet in the accelerator solution, the accelerator may be adhered to the polymer gel sheet by spraying, vapor deposition, or coating. The polymer gel sheet may be immersed in a solution, dispersion, or emulsion containing the above-described active ingredient, separately from the immersion in the accelerator solution.

Next, unnecessary components such as solvent are removed from the polymer gel sheet. In other words, the polymer gel sheet is dried. 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. A method for drying the polymer gel sheet may be vacuum heating. Conditions for drying the polymer gel sheet are not particularly limited. As conditions for drying the polymer gel sheet, a time and temperature sufficient for removing the second solvent and the rinsing liquid are selected. The bioadhesive film 10 is obtained by removing the solvent from the polymer gel sheet.

In the step of drying the polymer gel sheet, for example, when freeze-drying is applied, a solvent that can be frozen and has a boiling point of around 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 dimethylsulfoxide.

In the above method, the polymer gel sheet is immersed in the promoter solution prior to drying the polymer gel sheet. good. For example, a polymer sheet obtained by drying a polymer gel sheet may be immersed in an accelerator solution. At this time, the accelerator solution may further contain the above active ingredients. After that, the immersed polymer sheet is further dried. Also in this case, the accelerator may be adhered to the polymer gel sheet by spraying, vapor deposition, or coating.

The bioadhesive film of the present disclosure will be described in more detail by way of examples. It should be noted that the bioadhesive film of the present disclosure is not limited to the following examples. First, the evaluation test of the membranes to be applied to a living body according to each example and each comparative example will be described.

<Wearing test>
Various dressings were applied to the skin on the inside of the forearm. A summary of the dressings used is given in Tables 1 and 2. Immediately after the adhesive was dropped, the membrane for bioadhesive application of the laminate of each example and each comparative example was brought into contact with the dropped adhesive, and timing was started. It was checked whether or not the biological adhesive film was attached to the skin every predetermined time after the start of timing, and the time required for the biological adhesive film to be attached to the skin (wearing time) was measured. . In addition, in the state in which the biological adhesive film was attached to the skin, the nonwoven fabric of the laminate could be peeled off while the biological adhesive film was stuck to the skin.

(Example 1A)
A cellulose solution having a purity of 90% or more and derived from bleached wood pulp was dissolved in an ionic liquid to prepare a cellulose solution. As the ionic liquid, an ionic liquid in which R ₁ is a methyl group and R ₂ , R ₃ and R ₄ are ethyl groups in the formula (III) was used. A coating film was formed by coating the cellulose solution on the substrate. The thickness of the coating film was adjusted so that the thickness of the film for sticking to a living body was 400 nm. After that, the coated film of the cellulose solution was gelled to form a polymer gel sheet. After that, the substrate and the polymer gel sheet were washed with a prescribed rinse liquid. Next, the washed polymer gel sheet was immersed in an aqueous solution of polyoxyethylene (4) (6) sorbitan monooleate (HLB value: 10.0), and then the polymer gel sheet was dried to obtain a polymer gel sheet according to Example 1A. A film to be applied to a living body was obtained. The biological adhesive film was removed from the substrate and layered on the nonwoven fabric to obtain a laminate according to Example 1A. The biological adhesive film had a substantially rectangular shape of 5 cm square in plan view, and had a transparent appearance. Further, the structure of the film for application to a living body according to Example 1A was analyzed by an X-ray diffraction method (XRD). As a result, it was confirmed that the bioadhesive membrane does not contain natural cellulose and is regenerated cellulose. The weight-average molecular weight of the regenerated cellulose of the bioadhesive membrane was determined by GPC measurement. The weight average molecular weight of regenerated cellulose was 224,000.

Here, the concentration of polyoxyethylene (4) (6) sorbitan monooleate contained in the biological adhesive film was determined by the method described below. Polyoxyethylene (4)(6) sorbitan monooleate was previously dissolved in water and multiple polyoxyethylene (4)(6) sorbitan having different polyoxyethylene (4)(6) sorbitan monooleate concentrations were prepared. An aqueous monooleate solution was prepared. Thereafter, the refractive index of each polyoxyethylene (4), (6) sorbitan monooleate aqueous solution was measured with a refractometer (manufactured by Atago, product name: RX-5000α-Plus). A calibration curve was prepared from the concentration and refractive index of the aqueous solutions of polyoxyethylene (4) and (6) sorbitan monooleate, and the slope a of the calibration curve was determined. The bioadhesive film according to Example 1A was immersed in water for 1 hour and subjected to ultrasonic treatment to extract polyoxyethylene (4) (6) sorbitan monooleate contained in the bioadhesive film. An extract of oxyethylene (4)(6) sorbitan monooleate was obtained. The refractive index n of this extract was measured with the above refractometer. Based on the refractive index n and the slope a of the calibration curve, the mass of polyoxyethylene (4)(6) sorbitan monooleate contained in the extract was determined. The mass of polyoxyethylene (4)(6) sorbitan monooleate contained in the extract was regarded as the mass of polyoxyethylene (4)(6) sorbitan monooleate contained in the bioadhesive membrane. The ratio of the mass of polyoxyethylene (4)(6) sorbitan monooleate contained in the bioadhesive film to the mass of the bioadhesive film was 20%.

(Example 1B)
A membrane to be applied to a living body according to Example 1B and a laminate according to Example 1B were produced in the same manner as in Example 1A except for the following points. A polyoxyethylene (4)(6) sorbitan monolaurate (HLB value: 13.3) aqueous solution was used instead of the polyoxyethylene (4)(6) sorbitan monooleate aqueous solution. The immersion conditions were adjusted so that the ratio of the mass of polyoxyethylene (4)(6) sorbitan monolaurate contained in the bioadhesive film to the mass of the bioadhesive film was 20%. The mass of polyoxyethylene (4)(6) sorbitan monolaurate contained in the biological adhesive film was determined according to the method described in Example 1A.

(Example 1C)
A membrane to be applied to a living body according to Example 1C and a laminate according to Example 1C were produced in the same manner as in Example 1A except for the following points. A polyoxyethylene (4) (20) sorbitan monolaurate (HLB value: 16.7) aqueous solution was used instead of the polyoxyethylene (4) (6) sorbitan monooleate aqueous solution. The immersion conditions were adjusted so that the ratio of the mass of polyoxyethylene (4)(20) sorbitan monolaurate contained in the bioadhesive membrane to the mass of the bioadhesive membrane was 20%. The mass of polyoxyethylene (4)(20) sorbitan monolaurate contained in the biological patch was determined according to the method described in Example 1A.

(Example 1D)
A membrane to be applied to a living body according to Example 1D and a laminate according to Example 1D were produced in the same manner as in Example 1A, except for the following points. A polyoxyethylene (4) (20) sorbitan monopalmitate (HLB value: 15.6) aqueous solution was used instead of the polyoxyethylene (4) (6) sorbitan monooleate aqueous solution. The immersion conditions were adjusted so that the ratio of the mass of polyoxyethylene (4)(20) sorbitan monopalmitate contained in the film for biological patch to the mass of the film for biological patch was 20%. The mass of polyoxyethylene (4)(20) sorbitan monopalmitate contained in the bioadhesive film was determined according to the method described in Example 1A.

(Example 1E)
A membrane for biological patch according to Example 1E and a laminate according to Example 1E were produced in the same manner as in Example 1A except for the following points. A polyoxyethylene (4) (20) sorbitan monostearate (HLB value: 14.9) aqueous solution was used instead of the polyoxyethylene (4) (6) sorbitan monooleate aqueous solution. The immersion conditions were adjusted so that the mass ratio of polyoxyethylene (4)(20) sorbitan monostearate contained in the bioadhesive film to the mass of the bioadhesive film was 20%. The mass of polyoxyethylene (4)(20) sorbitan monostearate contained in the biological patch was determined according to the method described in Example 1A.

(Example 1F)
A membrane to be attached to a living body according to Example 1F and a laminate according to Example 1F were produced in the same manner as in Example 1A, except for the following points. An aqueous solution of bisPEG-18 methyl ether dimethylsilane (HLB value: 17.8) was used instead of the aqueous solution of polyoxyethylene (4) (6) sorbitan monooleate. The immersion conditions were adjusted so that the ratio of the mass of the bisPEG-18 methyl ether dimethylsilane contained in the bioadhesive membrane to the mass of the bioadhesive membrane was 20%. The mass of bisPEG-18 methyl ether dimethylsilane contained in the biological patch was determined according to the method described in Example 1A.

(Example 1G)
A membrane to be applied to a living body according to Example 1G and a laminate according to Example 1G were produced in the same manner as in Example 1A, except for the following points. A PEG-11 methyl ether dimethicone (HLB value: 14.5) aqueous solution was used instead of the polyoxyethylene (4) (6) sorbitan monooleate aqueous solution. The immersion conditions were adjusted so that the ratio of the mass of PEG-11 methyl ether dimethicone contained in the bioadhesive membrane to the mass of the bioadhesive membrane was 20%. The mass of PEG-11 methyl ether dimethicone contained in the biological patch was determined according to the method described in Example 1A.

(Example 1H)
A membrane to be applied to a living body according to Example 1H and a laminate according to Example 1H were produced in the same manner as in Example 1A except for the following points. A PEG-9 dimethicone (HLB value: 10.0) aqueous solution was used instead of the polyoxyethylene (4) (6) sorbitan monooleate aqueous solution. The immersion conditions were adjusted so that the ratio of the mass of PEG-9 dimethicone contained in the bioadhesive membrane to the mass of the bioadhesive membrane was 20%. The mass of PEG-9 dimethicone contained in the bioadhesive membrane was determined according to the method described in Example 1A.

(Example 1I)
A membrane to be applied to a living body according to Example 1I and a laminate according to Example 1I were produced in the same manner as in Example 1A, except for the following points. A PEG/PPG-20/22 butyl ether dimethicone (HLB value: 7.0) aqueous solution was used instead of the polyoxyethylene (4) (6) sorbitan monooleate aqueous solution. The immersion conditions were adjusted so that the ratio of the mass of PEG/PPG-20/22 butyl ether dimethicone contained in the bioadhesive membrane to the mass of the bioadhesive membrane was 20%. The mass of PEG/PPG-20/22 butyl ether dimethicone contained in the biological patch was determined according to the method described in Example 1A.

(Example 1J)
A membrane to be applied to a living body according to Example 1J and a laminate according to Example 1J were produced in the same manner as in Example 1A except for the following points. A PEG-9 methyl ether dimethicone (HLB value: 4.5) aqueous solution was used instead of the polyoxyethylene (4) (6) sorbitan monooleate aqueous solution. The immersion conditions were adjusted so that the ratio of the mass of PEG-9 methyl ether dimethicone contained in the bioadhesive membrane to the mass of the bioadhesive membrane was 20%. The mass of PEG-9 methyl ether dimethicone contained in the biological patch was determined according to the method described in Example 1A.

(Comparative Example 1A)
In the same manner as in Example 1A, except that the washed polymer gel sheet was dried as it was without being immersed in the polyoxyethylene (4) (6) sorbitan monooleate aqueous solution, the bioadhesive membrane according to Comparative Example 1A and the A laminate according to Comparative Example 1A was produced.

(Comparative Example 2A)
A film to be applied to a living body according to Comparative Example 2A and a laminate according to Comparative Example 2A were produced in the same manner as in Example 1A, except for the following points. A sorbitan tristearate (HLB value: 2.1) aqueous solution was used instead of the polyoxyethylene (4)(6) sorbitan monooleate aqueous solution. The immersion conditions were adjusted so that the ratio of the mass of the sorbitan tristearate contained in the biological patch to the mass of the biological patch was 20%. The mass of sorbitan tristearate contained in the biological patch was determined according to the method described in Example 1A.

(Comparative Example 2B)
A film to be applied to a living body according to Comparative Example 2B and a laminate according to Comparative Example 2B were produced in the same manner as in Example 1A, except for the following points. An aqueous solution of polyethylene glycol distearate (140 E.O.) (HLB value: 18.9) was used instead of the aqueous solution of polyoxyethylene (4) (6) sorbitan monooleate. The immersion conditions were adjusted so that the mass ratio of polyethylene glycol distearate (140 E.O.) contained in the bioadhesive film to the mass of the bioadhesive film was 20%. The mass of polyethylene glycol distearate (140 E.O.) contained in the biological patch was determined according to the method described in Example 1A.

(Comparative Example 3A)
Polylactic acid having a weight average molecular weight of 250,000 was dissolved in chloroform to prepare a chloroform solution of polylactic acid (concentration of polylactic acid: 2.4% by mass). A chloroform solution of polylactic acid was applied by spin coating onto a substrate having a surface formed of polyvinyl alcohol having a weight average molecular weight of about 500 to form a coating film. Chloroform was volatilized from this coating film to form a polylactic acid sheet. Thereafter, the polylactic acid sheet was immersed in water to dissolve the polyvinyl alcohol, and the water adhering to the polylactic acid sheet was dried to form a polylactic acid film. A polylactic acid film was immersed in an aqueous solution of polyoxyethylene (4)(6) sorbitan monolaurate and then dried to obtain a biological adhesive film according to Comparative Example 3A. The immersion conditions were adjusted so that the ratio of the mass of polyoxyethylene (4)(6) sorbitan monolaurate contained in the bioadhesive film to the mass of the bioadhesive film was 20%. A laminate according to Comparative Example 3A was obtained by laminating the membrane for bioadhesive application according to Comparative Example 3A on a nonwoven fabric. The mass of polyoxyethylene (4)(6) sorbitan monolaurate contained in the biological adhesive film was determined according to the method described in Example 1A.

(Comparative Example 3B)
A film to be applied to a living body according to Comparative Example 3B and a laminate according to Comparative Example 3B were produced in the same manner as in Comparative Example 3A, except for the following points. A polyoxyethylene (4) (20) sorbitan monolaurate aqueous solution was used instead of the polyoxyethylene (4) (6) sorbitan monolaurate aqueous solution. The immersion conditions were adjusted so that the ratio of the mass of polyoxyethylene (4)(20) sorbitan monolaurate contained in the bioadhesive membrane to the mass of the bioadhesive membrane was 20%. The mass of polyoxyethylene (4)(20) sorbitan monolaurate contained in the biological patch was determined according to the method described in Example 1A.

(Comparative Example 3C)
A film to be applied to a living body according to Comparative Example 3C and a laminate according to Comparative Example 3C were produced in the same manner as in Comparative Example 3A, except for the following points. A polyoxyethylene (4) (20) sorbitan monopalmitate aqueous solution was used instead of the polyoxyethylene (4) (6) sorbitan monolaurate aqueous solution. The immersion conditions were adjusted so that the ratio of the mass of polyoxyethylene (4)(20) sorbitan monopalmitate contained in the film for biological patch to the mass of the film for biological patch was 20%. The mass of polyoxyethylene (4)(20) sorbitan monopalmitate contained in the bioadhesive film was determined according to the method described in Example 1A.

(Comparative Example 3D)
A film to be applied to a living body according to Comparative Example 3D and a laminate according to Comparative Example 3D were produced in the same manner as in Comparative Example 3A, except for the following points. A polyoxyethylene (4) (20) sorbitan monostearate aqueous solution was used instead of the polyoxyethylene (4) (6) sorbitan monolaurate aqueous solution. The immersion conditions were adjusted so that the mass ratio of polyoxyethylene (4)(20) sorbitan monostearate contained in the bioadhesive film to the mass of the bioadhesive film was 20%. The mass of polyoxyethylene (4)(20) sorbitan monostearate contained in the biological patch was determined according to the method described in Example 1A.

(Comparative Example 3E)
A film to be applied to a living body according to Comparative Example 3E and a laminate according to Comparative Example 3E were produced in the same manner as in Comparative Example 3A, except for the following points. A bisPEG-18 methyl ether dimethylsilane aqueous solution was used in place of the polyoxyethylene (4)(6) sorbitan monolaurate aqueous solution. The immersion conditions were adjusted so that the ratio of the mass of the bisPEG-18 methyl ether dimethylsilane contained in the bioadhesive membrane to the mass of the bioadhesive membrane was 20%. The mass of bisPEG-18 methyl ether dimethylsilane contained in the biological patch was determined according to the method described in Example 1A.

(Example 2A)
A membrane to be applied to a living body according to Example 2A and a laminate according to Example 2A were produced in the same manner as in Example 1A, except for the following points. A polyoxyethylene (4)(20) sorbitan monostearate aqueous solution was used instead of the polyoxyethylene (4)(6) sorbitan monooleate aqueous solution. The immersion conditions were adjusted so that the mass ratio of polyoxyethylene (4)(20) sorbitan monostearate contained in the bioadhesive film to the mass of the bioadhesive film was 15%. The mass of polyoxyethylene (4)(20) sorbitan monostearate contained in the biological patch was determined according to the method described in Example 1A.

(Example 2B)
A membrane to be applied to a living body according to Example 2B and a laminate according to Example 2B were produced in the same manner as in Example 1A, except for the following points. A polyoxyethylene (4)(20) sorbitan monostearate aqueous solution was used instead of the polyoxyethylene (4)(6) sorbitan monooleate aqueous solution. The immersion conditions were adjusted so that the mass ratio of polyoxyethylene (4)(20) sorbitan monostearate contained in the bioadhesive film to the mass of the bioadhesive film was 10%. The mass of polyoxyethylene (4)(20) sorbitan monostearate contained in the biological patch was determined according to the method described in Example 1A.

(Example 3A)
A membrane to be applied to a living body according to Example 3A and a laminate according to Example 3A were produced in the same manner as in Example 1A, except for the following points. A bisPEG-18 methyl ether dimethylsilane aqueous solution was used instead of the polyoxyethylene (4)(6) sorbitan monooleate aqueous solution. The immersion conditions were adjusted so that the ratio of the mass of the bisPEG-18 methyl ether dimethylsilane contained in the bioadhesive membrane to the mass of the bioadhesive membrane was 15%. The mass of bisPEG-18 methyl ether dimethylsilane contained in the biological patch was determined according to the method described in Example 1A.

(Example 3B)
A membrane to be applied to a living body according to Example 3A and a laminate according to Example 3A were produced in the same manner as in Example 1A, except for the following points. A bisPEG-18 methyl ether dimethylsilane aqueous solution was used instead of the polyoxyethylene (4)(6) sorbitan monooleate aqueous solution. The immersion conditions were adjusted so that the ratio of the mass of the bisPEG-18 methyl ether dimethylsilane contained in the bioadhesive membrane to the mass of the bioadhesive membrane was 10%. The mass of bisPEG-18 methyl ether dimethylsilane contained in the biological patch was determined according to the method described in Example 1A.

(Example 4A)
A membrane to be applied to a living body according to Example 4A and a laminate according to Example 4A were produced in the same manner as in Example 1A, except for the following points. A PEG-9 dimethicone aqueous solution was used in place of the polyoxyethylene (4)(6) sorbitan monooleate aqueous solution. The immersion conditions were adjusted so that the ratio of the mass of PEG-9 dimethicone contained in the bioadhesive membrane to the mass of the bioadhesive membrane was 15%. The mass of PEG-9 dimethicone contained in the bioadhesive membrane was determined according to the method described in Example 1A.

(Example 4B)
A membrane to be applied to a living body according to Example 4B and a laminate according to Example 4B were produced in the same manner as in Example 1A, except for the following points. A PEG-9 dimethicone aqueous solution was used in place of the polyoxyethylene (4)(6) sorbitan monooleate aqueous solution. The immersion conditions were adjusted so that the ratio of the mass of PEG-9 dimethicone contained in the bioadhesive membrane to the mass of the bioadhesive membrane was 10%. The mass of PEG-9 dimethicone contained in the bioadhesive membrane was determined according to the method described in Example 1A.

Tables 1 and 2 show the results (wearing time) of the wearing test for the membranes to be applied to a living body according to each example and each comparative example. In addition, in all the examples, it was confirmed that the device could be worn continuously for at least 30 minutes after being worn. Comparing Examples 1A-1J with Comparative Example 1A, polyoxyethylene (4)(6) sorbitan monooleate, polyoxyethylene (4)(6) sorbitan monolaurate, polyoxyethylene (4)(20) ) sorbitan monolaurate, polyoxyethylene (4)(20) sorbitan monopalmitate, polyoxyethylene (4)(20) sorbitan monostearate, bisPEG-18 methyl ether dimethylsilane, PEG-11 methyl ether dimethicone, The inclusion of PEG-9 dimethicone, PEG/PPG-20/22 butyl ether dimethicone, or PEG-9 methyl ether dimethicone was shown to dramatically reduce the application time of the biopatch. From the results of Comparative Example 2A, it was not possible to shorten the wearing time of the bioadhesive membrane even when sorbitan tristearate with an HLB value of 2.1 was contained. From the results of Comparative Example 2B, even if polyethylene glycol distearate (140 E.O.) with an HLB value of 18.9 was contained, the wearing time of the bioadhesive membrane could not be shortened. According to Comparative Examples 3A to 3E, even if a polylactic acid film containing a component having an HLB value of 13.3, 14.9, 15.6, 16.7, or 17.8 was used, the bioadhesive film could not be produced. Installation time could not be shortened. From the above, it was shown that the bioadhesive film containing regenerated cellulose and an additive having an HLB value of 4 to 18 can be applied to the skin in a short period of time.

According to Table 2, when the bioadhesive membrane contains 10% by mass or more of polyoxyethylene (4)(20) sorbitan monostearate, it is shown that the attachment time of the bioadhesive membrane can be dramatically shortened. . In addition, it was shown that when the bioadhesive membrane contains 10% by mass or more of bisPEG-18 methyl ether dimethylsilane, the wearing time of the bioadhesive membrane can be dramatically shortened. Furthermore, it was shown that when the biological adhesive membrane contains 10% by mass or more of PEG-9 dimethicone, the wearing time of the biological adhesive membrane can be dramatically shortened. From the above, it was shown that when the concentration of the additive having an HLB value of 4 to 18 in the biological patch film is 10% by mass or more, the biological patch film can be attached to the skin in a short time.

REFERENCE SIGNS LIST 10 film for attachment to a living body 11 first main surface 12 second main surface 21 first protective layer 22 second protective layer 50a, 50b laminate

Claims (10)

Containing regenerated cellulose and an accelerator that promotes attachment of the regenerated cellulose to living tissue,
is self-supporting with a thickness of 20 to 5000 nm,
the accelerator has an HLB value of 4 to 18;
A film to be attached to a living body. The biological patch according to claim 1, wherein the regenerated cellulose has a weight average molecular weight of 30,000 or more. 3. The biological adhesive film according to claim 1, which has a thickness of 20 to 1300 nm. The biological patch according to any one of claims 1 to 3, wherein the regenerated cellulose has a weight average molecular weight of 150,000 or more. The biological patch according to any one of claims 1 to 4, wherein the accelerator is a compound having an ethylene glycol chain or a polyethylene glycol chain. The accelerator is at least one selected from the group consisting of a compound represented by the following formula (A), a compound represented by the following (B), and a compound represented by the following (C). 6. The bioadhesive film according to any one of 1 to 5.

In formulas (A), (B), and (C), each of a, b, c, d, and e is an integer of 0 or more, at least one of a and b is an integer of 1 or more, and c , d, and at least one of e is an integer of 1 or more, f is an integer of 1 or more, and R ₁ and R ₂ are each independently an alkyl group, an alkoxy group, a (poly)ethylene glycol (alkyl ether) group or (poly)propylene glycol group. The biological adhesive membrane according to any one of claims 1 to 6, wherein the content of the accelerator in the biological adhesive membrane is 10 to 90% by weight. Said accelerators are bisPEG-18 methyl ether dimethylsilane, polyoxyethylene (4)(6) sorbitan monooleate, polyoxyethylene (4)(6) sorbitan monolaurate, polyoxyethylene (4)(20) ) sorbitan monolaurate, polyoxyethylene (4) (20) sorbitan monopalmitate, polyoxyethylene (4) (20) sorbitan monostearate, PEG-11 methyl ether dimethicone, PEG-9 dimethicone, PEG-9 methyl The biological patch according to any one of claims 1 to 7, which is at least one selected from the group consisting of ether dimethicone and PEG/PPG-20/22 butyl ether dimethicone. A cosmetic method for attaching a film to be attached to a living body, comprising:
The bioadhesive membrane contains regenerated cellulose and an accelerator having an HLB value of 4 to 18 that promotes attachment of the regenerated cellulose to a living tissue, and is a self-supporting type having a thickness of 20 to 5000 nm. and
attaching an adhesive containing an oily component to a biological tissue and the biological adhesive film, and attaching the biological adhesive film to the biological tissue;
beauty method. The cosmetic method according to claim 9, wherein the oily component is at least one selected from the group consisting of fatty acids, paraffins, naphthenes, cycloparaffins, and silicone oils.

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