WO2012003640A1 - 生物纤维膜及其用途 - Google Patents

生物纤维膜及其用途 Download PDF

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Publication number
WO2012003640A1
WO2012003640A1 PCT/CN2010/075079 CN2010075079W WO2012003640A1 WO 2012003640 A1 WO2012003640 A1 WO 2012003640A1 CN 2010075079 W CN2010075079 W CN 2010075079W WO 2012003640 A1 WO2012003640 A1 WO 2012003640A1
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WIPO (PCT)
Prior art keywords
skin
membrane
biofiber
biofiber membrane
fiber
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PCT/CN2010/075079
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English (en)
French (fr)
Inventor
林宜全
魏育群
李美玲
Original Assignee
奈菲儿国际股份有限公司
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Application filed by 奈菲儿国际股份有限公司 filed Critical 奈菲儿国际股份有限公司
Priority to PCT/CN2010/075079 priority Critical patent/WO2012003640A1/zh
Priority to CN2010800017271A priority patent/CN102405293A/zh
Publication of WO2012003640A1 publication Critical patent/WO2012003640A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
    • A61L15/24—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/08—Antiseborrheics
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P19/00—Preparation of compounds containing saccharide radicals
    • C12P19/04—Polysaccharides, i.e. compounds containing more than five saccharide radicals attached to each other by glycosidic bonds

Definitions

  • the present invention relates to a biofiber membrane, particularly a biofiber membrane having a density gradient in the film thickness direction. Background technique
  • Microbial produced cellulose also known as Bacterial cellulose (BC) or biocellulose (Biocellulose) is a ⁇ -1,4 glucosidic bond, High purity, high water content, good ductility and good mechanical strength.
  • the strain producing microbial cellulose includes cetob ter xylinum.
  • the resulting cellulose is usually formed into a fibrous form, and a film of a reticular structure is formed on the surface of the medium in a nonwoven manner.
  • the diameter of biofibers is only 1/100 of that of plant fibers, about 2-100 nm, but the chemical structure is the same as that of plant fibers.
  • biofiber membranes Due to the unique physical properties of biofibers, it has a wide range of applications, including biomedical materials (EP1438975, EP0396344 and WO0161026), electronic materials (US2008220333), audio (EP0457474, US5274199 and JP6284495), special papers and cosmetics (JP10077302). , JP9183803 and FR2924342), etc.
  • bio-cellulose membrane As a medical material, bio-cellulose membrane is regarded as one of the best skin substitutes, which can reduce pain, absorb abscesses secreted by wounds, provide appropriate moisture for wounds, shorten healing time and improve healing effect, etc. Great biocompatibility and safety.
  • Johnson & Johnson Product Inc. NJ discloses a dressing for wounds and burns with biofiber membranes in US 4588400. Biofiber membranes can be added to pharmaceuticals.
  • WO86/02095 discloses Acetobacter xylinum To produce cellulose, using green tea (Tea Szwe ⁇ ) as a nitrogen source, glucose as a source of carbohydrates, and agitating at an effective temperature of about 28 ° C for 26 to 96 hours to obtain a bio-fiber membrane having a thickness of about 0.2 to 3 mm. It is cut, packaged, and used as artificial skin for the treatment of various skin injuries and sold under the BIOFILL® trademark.
  • Xylos Corporation also applies for a number of patent applications for biocellulose membranes, including US 2005/0019380 A1 for the treatment and healing of chronic wounds, WO2005018435 A2 and US 2007/0286884.
  • the biocellulose membrane is repaired or replaced as an implantable human soft and hard tissue, and EP1849463 uses a biocellulose membrane as a carrier for transdermal delivery of a drug.
  • L'oreal (L'oreal societie anonyne; FR) has applied for several patents related to biocellulose membranes in recent years, including FR2924340 for finger care and makeup, FR2924342 for skin and lip care and makeup, JP 2009051829
  • the biocellulose membrane contains a combination of powdered cosmetic ingredients
  • FR2916948 is a long-lasting fragrance design based on biocellulose membranes
  • FR2916971 is a biocellulose membrane-based patch for eye bags and weight loss.
  • the present invention provides a biofiber membrane comprising microbial fibers formed of microbial cellulose, characterized in that the arrangement of the microbial fibers has a density gradient in a film thickness direction of the biofiber membrane.
  • the invention further provides a use of a biofiber membrane comprising applying the biofiber membrane to a skin surface, the surface of the biofiber membrane contacting the skin being a lower density surface.
  • the present invention further provides a method for reducing oil on the surface of a skin comprising applying the above biofibrous membrane to a surface of the skin, wherein the surface of the biofiber membrane in contact with the skin is a surface having a lower density.
  • Fig. 1A shows an electron scanning micrograph of the surface of the biofiber membrane of Example 1.
  • Fig. 1B is a view showing an electron scanning micrograph of the biofiber membrane of Example 1 in the film thickness direction section.
  • Fig. 2 shows the manufacturing process of the biofiber membrane of Example 1.
  • Figure 3 is a graph showing the water dispersion loss of the skin surface of the Example 1 biofiber membrane and the commercially available biofiber membrane, wherein the column A indicates the skin surface to which no substance was used; and the column B indicates the saturation state of the biofiber membrane using the example 1. Upper surface; Column C indicates the lower surface in which the biofiber membrane of Example 1 was saturated; Column D indicates the upper surface in which the biofiber membrane of Example 1 was not saturated; and Column E indicates the use of a commercially available biofiber membrane. The ordinate is the loss rate of moisture on the surface of the skin compared to before use.
  • Fig. 4 is a graph showing the effect of the biofiber membrane of Example 1 and a commercially available biofiber membrane on the amount of oil on the surface of the skin which was not previously cleaned.
  • Fig. 5 is a graph showing the effect of the biofiber membrane of Example 1 and a commercially available biofiber membrane on the amount of oil on the skin surface which was previously cleaned.
  • Fig. 6 shows that after the biofiber membrane of the present invention is applied to the surface of the skin, the texture of the skin appears on the biofiber membrane, indicating good skin adhesion of the biofiber membrane.
  • Fig. 7 shows that after the biofiber membrane of the present invention is applied to the surface of the skin, the pore endothelial lipid of the skin is adsorbed on the biofiber membrane.
  • the bio-fiber membrane of the present invention is composed of Acetobacter xylinum (G/Mco « etobflcter) in a culture dish containing a glucose-containing liquid medium, which is monocultured and subjected to fermentation to produce cellulose.
  • the cellulose forms microbial fibers having a cross-sectional diameter of about 30 to 100 nm outside the cells.
  • a plurality of microbial fibers form a reticular structure on the surface of the medium in a nonwoven form to form a translucent biofiber membrane.
  • the formation of the biofiber membrane of the present invention is such that microorganisms are formed at the liquid level of the culture solution. Since the liquid level of the culture solution is in direct contact with the air, the dissolved oxygen amount is high, which can support the growth of microorganisms and the formation of biocellulose. When the microorganisms produce biocellulose, the previously produced biocellulose is liquid. Extend under the surface. Therefore, in the initial stage of cultivation, the number of microorganisms is small, so the network structure of microbial cellulose is loose and soft. Microbial proliferation is increased with time, and the microbial cellulose production is relatively increased after the relative increase in microbial concentration. At this time, the network structure formed by microbial cellulose is tight, and the density of microbial fibers is increased.
  • the side of each piece of bio-fiber membrane that is in contact with air (also referred to as the upper surface) is a later synthesized microbial cellulose.
  • the network structure formed by the microbial fibers on the upper surface is relatively tight, and the density of microbial fibers is relatively high. surface.
  • the other surface of the bio-fiber membrane is close to the bottom of the culture tray (also referred to as the lower surface), which is a portion deeper into the lower layer of the culture liquid.
  • the network structure is loose and soft, and the microbial fiber density is Lower surface.
  • the difference in the structure of the upper and lower sides of the biofiber membrane can be clearly observed under electron microscopy. From the cross-sectional view of the biofilm thickness direction of the biofiber membrane, it is clear that the microbial fiber density of the upper surface of the biofiber membrane of the present invention is high, and the microbial fiber density of the lower surface is low (e.g., Fig. 1B). This difference can also be detected by hand touch.
  • the biofiber membrane of the present invention has a density gradient in the film thickness direction which gradually decreases from the upper surface to the lower surface.
  • film thickness direction of the present invention is that the biofiber film accumulates to form a thickness at the time of formation.
  • the film thickness direction is perpendicular to the plane of the medium.
  • the so-called "density gradient" of the present invention means that in a biofiber membrane, the density of the composition from one surface to the other exhibits a gradual increase or decrease in density. For example, when the biofiber membrane is formed in the medium and the medium is not removed, the density of the microbial fibers gradually decreases from the upper surface of the biofiber membrane (away from the culture tray) to the lower surface (near the culture tray).
  • bio-cellulose membranes are mostly in China and Southeast Asian countries (such as Vietnam). It is a traditional culture method, which uses open cultured mixed culture to produce large-sized bio-cellulose pellets. Then cut through the slicer to form a flaky shape.
  • the cellulose film cut by the blocky biocellulose has a compact fiber composition on both surfaces and does not have the loose fiber structure of the present invention.
  • the aforementioned conventional cellulose film does not have a density gradient in the film thickness direction, and the slicer is thicker in thickness, and the formed cellulose film is relatively thick, and the film surface is liable to be formed by knife marks.
  • the cellulose film When it comes into contact with the skin of a human or animal, the cellulose film tends to fall off and does not completely adhere to the skin. Furthermore, since the biofiber can absorb 50-100 times or more of water, the thickness of the cellulose film is not only difficult to achieve a saturated or supersaturated water content, but also is not conducive to the active ingredient solution in the biocellulose film. Percutaneous absorption.
  • the novel biofiber membrane of the present invention has a density gradient in the film thickness direction, and the surface of the microfiber having a low density of microbial fibers is in contact with human skin, so that the biofiber membrane of the present invention is closely adhered to the skin and efficiently contained in the membrane.
  • the saturated or supersaturated moisture or active ingredient is effectively delivered to the human skin.
  • the invention further provides for the use of a biofibrous membrane comprising applying the biofibrous membrane to the surface of the skin of a human or animal body.
  • excellent skin adhesion and efficient transfer efficiency can be achieved.
  • Skin includes the epidermis of the human or animal body, the dermis, the subcutaneous tissue, the fingers, the hair, the glands of the skin, or the like.
  • the biofiber membrane of the present invention has a density gradient in the film thickness direction, the inventors have found that a surface having a low density is laid flat on the skin of a human or animal body to produce an excellent skin adhesion. This may be because the surface of the biofiber membrane with a lower density exposes more microbial nanofibers, and when it comes into contact with the skin, it can form a large contact area with the skin. In addition, by the large amount of hydroxyl groups (- ⁇ ) on the microbial fiber molecules, it is easy to generate hydrogen bonds with the skin of the human body or the animal body, and form a good adhesion effect with the skin.
  • the bio-fiber membrane of the present invention is applied to the surface of the skin of a human or animal body, and after about 15 to 30 minutes, the texture of the skin appears in the bio-fiber membrane (see Figure 6).
  • the biofiber membrane of the present invention is applied to the surface of the finger of a human or animal body.
  • the biofibrous membrane of the present invention is attached to the active joint of the arm, and the biofibrous membrane can be completely attached to the surface of the skin even if the arm is vigorously moved.
  • the biofiber membrane of the present invention when used as a mask, the user can freely move around, which can reduce the inconvenience of being unable to move freely when using a conventional mask.
  • the biofiber membrane of the present invention can adjust the weight (dry weight) of the biofiber membrane by controlling conditions such as the time of culture in the process, the concentration and volume of the culture solution.
  • the weight (dry weight) of the biofiber membrane of the present invention can be controlled at 5-20 g/m 2 , and the weight of the biofiber membrane of the present invention is reduced by 30 g/m 2 or more compared with the conventional method. At least 33.3%. Since the biofiber membrane of the present invention is relatively soft, the thickness of the compressed membrane can be adjusted to 0.1 mm to 0.5 mm, and the adhesion to the skin and the conformability can be improved.
  • the biofiber membrane of the present invention is light in weight (dry weight), and the microbial cellulose per membrane is small, and the water content is easily saturated or supersaturated. Improve the transdermal absorbability of the active ingredient in the biofiber membrane.
  • the “saturated state” in the present invention means that the water content of the biofiber membrane reaches a maximum at a normal temperature of one atmosphere.
  • the so-called “supersaturated state” means that the water content of the biofiber membrane exceeds the maximum amount of water that can be absorbed at atmospheric pressure at a normal temperature.
  • the water content of the biofiber membrane of the present invention may be from 90% to 99% by weight based on the total weight of the biofiber membrane (% by weight;
  • the biofiber membrane of the present invention may only contain water.
  • the biofiber membrane of the present invention may further comprise water or other active ingredient.
  • active ingredients are not particularly limited, and examples are antibiotics, antimicrobials, antivirals, hemostatics, anesthetics, inflammatory drugs, steroids, anti-tissue Amines, cell growth promoting agents, growth factors, proteins, nucleotides, enzymes, humectants, hyaluroic acid, ascorbic acid, kojic acid (kojic acid), arbutin, a similar compound, or a combination of these compounds.
  • Those skilled in the art can be appropriately added to the biofiber membrane according to market demand.
  • the biofiber membrane of the present invention when used for the skin with strong oil and fat, the nanofiber of the biofiber membrane can be in contact with the sebum in the pores of the skin due to the good adhesion and conformability of the biofiber membrane to the skin.
  • the moisture of the biofiber membrane is absorbed or volatilized by the skin, the sebum in the pores of the skin is adsorbed by the biofiber membrane by the siphon principle (see Figure 7). Therefore, the biofiber membrane of the present invention can remove excess sebum from the surface of the skin of the human or animal body, and can remove excess sebum in the pores of the skin.
  • the biofibrous of the present invention is used as compared to the amount of skin oil before use. The film can reduce the amount of oil on the skin surface by 50% to 100%.
  • the biofiber membrane of the present invention is not particularly limited in its use, and can be applied to the skin of any part of the human body or animal body.
  • the biofiber membrane is applied to the surface of a human or animal skin for about 15-60 minutes.
  • the biofiber membrane is applied to the surface of the human or animal skin until the biofiber membrane exhibits a thin, dry or transparent state. The biofiber membrane is then removed from the skin.
  • the biofiber membrane applied to the skin surface is moistened to facilitate removal from the skin surface.
  • the term "wet" as used herein includes water, an emulsion, or the like to moisturize, soften, and easily remove the biofiber membrane applied to the skin of a human or animal body.
  • the biofiber membrane was taken out, washed with 0.1% to 5% by weight of NaOH, sterilized, and then allowed to stand for one day. Then, it is washed 3 to 4 times with water, and then neutralized with citric acid (as shown in Fig. 2, S3) to obtain a microbial fiber membrane for subsequent use.
  • the biofiber membrane of Example 1 and a commercially available biofilm membrane cut by a microtome were each cut into a 5 cm diameter round moon, soaked in a 10% aqueous glycerin solution (glycerol). It is a commonly used moisturizer). Then, the upper surface (B) and the lower surface (C) of the first embodiment of the biofiber membrane in the saturated state, the upper surface (D) of the unsaturated state of the biofiber membrane of Example 1, and the commercially available biofiber membrane (E) were applied. 30 minutes in human skin.
  • the biofiber membrane was removed, and after 15 minutes, the skin surface loss was measured with a CK Electronic Multi-Function Skin Tester, MPA Model 580 (Cutometer). The above procedure was carried out in the same place as the skin without any substance, as a control group (A;).
  • Example 1 biofiber membrane saturation The lower surface treated skin also has a negative water dispersion loss rate.
  • glycerin can be transported to the skin, so that the water dispersion of the skin is not reduced.
  • the water dispersion loss was 14.9% and 9.4%, respectively. This result shows that the unsaturated and commercially available biofiber membranes are inefficient in introducing glycerin into the skin and are not effective in reducing water loss on the surface of the skin.
  • the saturated state of the bio-fiber membrane of Example 1 and the commercially available biofibrous membrane (ChiaMeei Food Industrial Corp., Taichung, Taiwan) were applied to a 5 cm-diameter circular body surface, and applied to the forehead skin of the human face which was previously cleaned and unwashed. After about 15 to 40 minutes, the biofiber membrane of Example 1 was completely dried and rendered transparent. Commercially available biofiber membranes are still wet. After a little wet water, remove the bio-fiber membrane, and after 5 minutes, use CK Electronic Multi-Function Skin Tester MPA 580
  • the film was applied to the skin which had not been cleaned beforehand, and the biofiber membrane of Example 1 reduced the amount of oil on the surface of the skin by about 92%, and the commercially available biofiber membrane reduced the amount of oil by only about 30%.
  • the film was applied to the previously cleaned skin, and the biofiber membrane of Example 1 was able to reduce the amount of oil on the skin surface by almost 100%, but the commercially available biofiber membrane only reduced the amount of oil by about 62%. .
  • Moisture content (W1 - W2) ⁇ W2,
  • the fiber area per unit area (W3) W2 ⁇ 25 cm 2 ;
  • Unit fiber moisture content (W 1 -W2) ⁇ W3
  • Example 1 there was a significant difference in the amount of fiber per unit surface between Example 1 and the commercially available biofiber membrane.
  • the commercially available biofiber membrane unit surface fiber amount is more than 2 times that of the Example 1 biofiber membrane, and this difference is also shown in the unit fiber and the water content per unit area. This result shows that the biofiber membrane of Example 1 can be saturated only by requiring a small amount of water, and is also one of the reasons why the biofilm of the present invention is lighter and more compliant than the commercially available biofiber membrane.

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Abstract

一种生物纤维膜，包括由微生物纤维素所形成的微生物纤维，其特征在于，该微生物纤维的排列在该生物纤维膜的膜厚方向具有密度梯度。

Description

生物纤维膜及其用途 技术领域
本发明关于一种生物纤维膜， 特别是在膜厚方向具有密度梯度的生物纤 维膜。 背景技术
微生物产出之纤维素 (cellulose), 又称为微生物纤维素 (Bacterial cellulose, BC)或是生物纤维素 (Biocellulose) , 为 β-1 ,4糖苷键 (β-1 ,4 glucosidic bonds) , 具有高纯度、 高含水力、 延展性佳及良好的机械强度等特性。 生产微生物纤 维素的菌种包括木醋杆菌 cetob ter xylinum). 生成的纤维素通常形成纤维 状， 以非织造 (nonwoven)的方式， 在培养基的表面形成网状结构 (reticular structure)的膜。 生物纤维的直径只有植物纤维的 1/100 , 约 2-100 nm左右， 但化学结构上与植物纤维相同。 由于生物纤维具有的独特物理性质， 故其应 用范围非常广泛， 包含生医材料 (EP1438975、 EP0396344及 WO0161026)、 电子材料 (US2008220333)、 音响 (EP0457474、 US5274199及 JP6284495)、 特 殊用纸及化妆品 (JP10077302、 JP9183803及 FR2924342)等。 作为医材上， 生 物纤维素膜被视为最佳的皮肤替代物之一， 可以减少疼痛、 吸收伤口所分泌 的脓疮、 提供伤口适当水份， 缩短愈合时间与改善愈合效果等， 并拥有绝佳 的生物兼容性与安全性。 娇生公司（Johnson & Johnson Product Inc. NJ)在 US 4588400 中揭露以生物纤维膜用于伤口及烧烫伤的敷料， 生物纤维膜可添加 药剂使用。
WO86/02095揭露以木醋杆菌
Figure imgf000002_0001
)生产纤维素， 使用绿 茶 (Tea Szwe^^)作为氮源， 葡萄糖为碳水化合物的来源， 在有效温度约 28 °C 下搅动培养 26~96小时， 获得厚度约 0.2~3mm的生物纤维膜。 经过切割、 包 装， 作为人造皮肤， 用于治疗各种皮肤损伤， 并以 BIOFILL®商标销售。
Xylos公司（Xylos Corporation)也申请多件生物纤维素膜的专利应用， 包 括 US 2005/0019380 A1将生物纤维素膜用于慢性伤口（chronic wound)的治疗 与愈合， WO2005018435 A2及 US 2007/0286884以生物纤维素膜作为可植入 式的人体软硬组织的修复或取代， 及 EP1849463以生物纤维素膜作为药物经 皮传输的载体。 L'oreal(L'oreal societie anonyne; FR)近年申请数个生物纤维素膜相关的 专利， 包括 FR2924340为应用于手指的保养与化妆、 FR2924342为应用于皮 肤及嘴唇的照护与化妆、 JP 2009051829为生物纤维素膜含有粉末状化妆成份 的组合设计、 FR2916948 为以生物纤维素膜为主架构的长效型香水设计及 FR2916971为以生物纤维素膜为主的贴布用于消除眼袋及减肥用。
对于微生物纤维所具有的独特物理性质， 尚可有多种的应用及开发。
发明内容
本发明提供一种生物纤维膜， 包括由微生物纤维素所形成的微生物纤 维， 其特征在于， 该微生物纤维的排列在该生物纤维膜的膜厚方向具有密度 梯度。
本发明更提供一种生物纤维膜的用途， 包括将上述生物纤维膜施于皮肤 表面， 该生物纤维膜与皮肤接触的表面为密度较低的表面。
本发明更提供一种用于减少皮肤表面油脂的方法， 包括将上述生物纤维 膜施于皮肤表面， 其中该生物纤维膜与皮肤接触的表面为密度较低的表面。 附图说明
第 1A图显示实施例 1之生物纤维膜表面的电子扫描显微照片。
第 1B图显示实施例 1之生物纤维膜在膜厚方向切面的电子扫描显微照 片。
第 2图显示实施例 1之生物纤维膜的制造流程。
第 3图显示实施例 1生物纤维膜与市售生物纤维膜对皮肤表面的水分散 失率， 其中柱 A表示未使用任何物质的皮肤表面； 柱 B表示使用实施例 1之 生物纤维膜饱和状态的上表面； 柱 C表示使用实施例 1之生物纤维膜饱和状 态的下表面； 柱 D表示使用实施例 1之生物纤维膜未饱和状态的上表面； 及 柱 E表示使用市售生物纤维膜。 纵坐标为， 与使用前相比， 皮肤表面水份的 散失率。
第 4图显示实施例 1之生物纤维膜与市售生物纤维膜对未事先清洗的皮 肤表面之油脂量的影响。
第 5图显示实施例 1之生物纤维膜与市售生物纤维膜对事先清洗过的皮 肤表面之油脂量的影响。 图 6显示以本发明之生物纤维膜敷于皮肤表面后， 该处的皮肤紋理出现 于该生物纤维膜上， 显示该生物纤维膜的良好皮肤密合性。
图 7显示以本发明之生物纤维膜敷于皮肤表面后， 该处皮肤的毛孔内皮 脂吸附于该生物纤维膜上。
主要组件符号说明
S1,S2, S3〜生物纤维膜的制造流程
具体实施方式
本发明之生物纤维膜， 由木醋杆菌 (G/Mco« etobflcter )在含有葡 萄糖的液体培养基的培养盘中， 进行单片培养， 经过发酵程序 (fermentation) 产生的纤维素所构成。 该纤维素在菌体外形成横断面直径为约 30~100nm的 微生物纤维。 复数个微生物纤维以非织造 (nonwoven)的形态在培养基的表面 形成网状结构 (reticular structure), 形成半透明的生物纤维膜。
本发明之生物纤维膜的形成是微生物在培养液的液面处生成。 由于培养 液的液面处是培养液与空气直接接触， 溶氧量较高， 可支持微生物的生长及 生物纤维素的生成.当微生物生产生物纤维素时，先前产生的生物纤维素被往 液面下延伸。 所以在培养初期， 微生物的数量较少， 故微生物纤维素的网状 结构较松散柔软。 随时间增加微生物增生， 微生物浓度相对增加后， 微生物 纤维素的产量也相对增加。 此时微生物纤维素所形成的网状结构较紧密， 微 生物纤维密度增高。所以每一片的生物纤维膜与空气接触的一面（亦称为上表 面）， 为较晚合成的微生物纤维素， 上表面的微生物纤维所形成的网状结构较 紧密， 为微生物纤维密度较高的表面。 生物纤维膜的另一表面， 接近培养盘 的底部（亦称为下表面）， 为较深入培养液下层的部分， 为培养初期生成的纤 维素， 其网状结构较松散柔软， 为微生物纤维密度较低的表面。
生物纤维膜上下两面结构的差异性， 可在电子显微下明显观察到。 由生 物纤维膜的电子显微镜膜厚方向的切面图， 可清楚看到本发明之生物纤维膜 的上表面的微生物纤维密度较高， 下表面的微生物纤维密度较低 （如第 1B 图）。 此差异亦可经由手触摸而察觉。 换句话说， 本发明之生物纤维膜在膜厚 方向上具有密度梯度 (density gradient) , 该密度梯度由上表面向下表面的方向 渐减。
本发明所谓的 "膜厚方向"为生物纤维膜在生成时累积形成一个厚度的 方向， 该膜厚方向与培养基的平面形成垂直。
本发明所谓的 "密度梯度"是指， 在一个生物纤维膜中， 从一表面至另 一表面的组成密度呈现逐渐增加或减少的密度变化。 例如当生物纤维膜在培 养基中形成、 未移出培养基时， 从生物纤维膜的上表面 (远离培养盘)向下表 面 (靠近培养盘)移动的方向， 微生物纤维的密度逐渐减少。
目前具规模的生物纤维素膜量产多在中国与东南亚国家 (如越南）， 为传 统的培养方式， 其系以开放式人工培养混合菌株 (mixed culture) , 生成大块状 的生物纤维素块， 再经由切片机切出薄片状。 然而， 由块状的生物纤维素所 切割的纤维素膜， 两表面皆呈现紧密的纤维组成， 不具有本发明之疏松的纤 维结构。 换句话说， 前述传统的纤维素膜在膜厚方向不具有密度梯度， 而且 以切片机切片的厚度较厚， 形成的纤维素膜比较厚重， 且膜表面容易有刀痕 产生。 在与人体或动物的皮肤接触时， 前述纤维素膜容易有脱落、 无法完全 与皮肤密合的问题。 再者， 由于生物纤维可吸收 50-100倍以上的水分， 以前 述纤维素膜的厚度， 不但难以达到含水量呈饱和或过饱和的状态， 也不利于 生物纤维素膜中的活性成份溶液的经皮吸收。
而本发明之新颖生物纤维膜， 在膜厚方向具有密度梯度， 利用微生物纤 维密度低的表面与人体皮肤接触， 使本发明之生物纤维膜与皮肤紧密贴合及 有效率地将膜中所含的饱和或过饱和的水分或活性成分有效地传输至人体皮 肤。 本发明更提供一种生物纤维膜的用途， 包括将该生物纤维膜敷于人体或 动物体的皮肤表面。 特别是， 将本发明之微生物纤维密度较低的表面与人体 或动物体的皮肤接触， 可达到优良的皮肤密合度及有效率的传输功效。 此述
"皮肤" 包括人体或动物体之表皮、 真皮、 皮下组织、 指曱、 毛发、 皮肤的 腺体、 或类似之组织。
由于本发明之生物纤维膜在膜厚方向具有密度梯度的特性， 本发明人发 现以密度较低的表面平铺于人体或动物体的皮肤上，产生优异的皮肤密合度。 这可能是因为密度较低的生物纤维膜表面， 曝露出较多的微生物纳米纤维， 当其与皮肤接触时， 可与皮肤形成较大的接触面积。 此外， 藉由微生物纤维 分子上大量的羟基 (-ΟΗ),容易与人体或动物体皮肤产生氢键， 而与皮肤形成 良好的密合效果。 一实施例中， 将本发明之生物纤维膜敷于人体或动物体皮 肤表面， 经过约 15~30分钟的时间， 该生物纤维膜出现该处皮肤的紋理 (请见 图 6)。在一实施例中，将本发明的生物纤维膜敷于人体或动物体的指曱表面。 在另一实施例中， 将本发明之生物纤维膜贴附于手臂活动关节处， 即使手臂 激烈活动， 该生物纤维膜仍可完整贴附在该处皮肤表面。 在另一实施例中， 使用本发明的生物纤维膜作为面膜时， 使用者可以自由走动， 可降低使用传 统敷面膜时无法自由活动的不方便性。
本发明之生物纤维膜可经由控制制程中培养的时间、 培养液浓度与体积 等条件， 来调整生物纤维膜的重量 (干重)。 本发明之生物纤维膜的重量 (干重) 可控制在 5-20g/m2, 相较于传统方式生产的生物纤维膜重量为 30 g/m2以上， 本发明之生物纤维膜的重量减轻至少 33.3%。 由于本发明之生物纤维膜较为 柔软， 可经由加工压缩膜厚度至 0.1mm~0.5mm, 可提高对皮肤的密合度及服 贴性。 在后续添加水或其它含有活性成份的溶液时， 本发明之生物纤维膜因 为重量 (干重)轻、 每片膜的微生物纤维素较少， 容易达到含水量为饱和或过 饱和的状态， 可提高生物纤维膜中活性成份的经皮吸收性。
本发明中所谓的 "饱和状态"是指， 在常温一大气压下生物纤维膜的含 水量达到最大值。 所谓的 "过饱和状态"是指， 在常温一大气压下生物纤维 膜的含水量超过其可吸收的水量的最大值。 本发明之生物纤维膜的含水量， 可为该生物纤维膜总重的 90%~99% (；重量百分比；)。
一实施例中， 本发明之生物纤维膜可仅还含有水。 另一实施例中， 本发 明之生物纤维膜可还含有水或其它活性成份。前述的活性成分没有特别限制 , 例^口为抗生素 (antibiotics)、 抗菌剂 (antimicrobials)、 抗病毒药物 (antivirals)、 止 血剂（hemostatics), 麻醉剂（anesthetics), 减緩发炎药物、 类固醇、 抗组织胺、 促进细胞生长药剂、 生长激素（growth factors) , 蛋白质（proteins)、 核苷酸 (nucleotides)、 酶 (enzymes)、 保湿剂、 透明质酸 (hyaluroic acid)、 抗坏血酸 (ascorbic acid)、 曲酸 (kojic acid)、 熊果苷 (arbutin)、 类似的化合物、 或这些化 合物的组合。 熟知该技术领域之人士可根据市场需求， 适量添加于生物纤维 膜中。
再一实施例中， 使用本发明之生物纤维膜于油脂旺盛的皮肤时， 由于生 物纤维膜与皮肤的良好密合度及服贴性， 生物纤维膜的纳米纤维可与皮肤毛 孔内的皮脂接触。 当该生物纤维膜的水分被皮肤吸收或挥发至干后， 皮肤毛 孔内的皮脂会因虹吸原理被生物纤维膜吸附 (请见图 7)。 因此， 本发明之生物 纤维膜可移除人体或动物体皮肤表面的多余皮脂， 更可移除皮肤毛孔中多余 的皮脂。 在一实施例中， 相较于使用前的皮肤油脂量， 使用本发明之生物纤 维膜可减少 50%~100%的皮肤表面油脂量。
本发明之生物纤维膜在使用上没有特别限定， 可敷于人体或动物体任何 部位的皮肤。 在一实施例中， 将生物纤维膜敷于人体或动物皮肤表面， 约 15-60分钟。 另一实施例中， 将生物纤维膜敷于人体或动物皮肤表面， 直到 该生物纤维膜呈现变薄、 变干或变透明的状态。 之后将生物纤维膜自皮肤上 移除。 本发明之一实施例中， 使敷于皮肤表面的生物纤维膜湿润， 以利于自 皮肤表面移除。 此述的 "湿润" 包含用水、 乳液、 或类似的溶液使敷于人体 或动物体皮肤上的生物纤维膜潮湿、 软化， 容易取下。
本发明之具体实施详细说明如下， 然而以下的实施例仅用于进一步揭露 本发明之技术内容， 不应藉以限制本案的发明范畴。
[实施例 1]生物纤维膜的制造
取葡萄糖 10-30 g/L、 酵母萃取粉 5-10g/L添加至液态培养基， 经灭菌后， 接入醋杆菌 (G yco cetobi7cter x_y/ m«), 于 30°C、 150 rpm下振荡培养， 培养 2-5天（如第 2图所示之 Sl)。 之后以 1-10重量％比例加入 10-30 g/L葡萄糖、 5-10g/L酵母萃取粉， 2-10 g/L 的 Na2HP04、 1-5 g/L 的柠檬酸水溶液 (121 °C 灭菌 30分钟)中，于 A4大小的培养盆中进行 25-32°C静置培养 (如第 2图所示 之 S2)。 5-10天后取出生物纤维膜， 以 0.1%-5重量％的 NaOH清洗、 除菌， 然后静置一天。 再以清水清洗 3~4次， 再以柠檬酸中和后 (如第 2 图所示之 S3), 取得微生物纤维膜， 以供后续使用。
[实施例 2]皮肤表面水份散失试验
取实施例 1 的生物纤维膜及市售以切片机切割的生物纤维膜 (ChiaMeei Food Industrial Corp., Taichung, Taiwan), 各切割为 5cm直径圓形月莫， 浸泡在 10%甘油水溶液中 (甘油为常用之保湿剂）。然后将实施例 1生物纤维膜饱和状 态的上表面 (B)及下表面 (C)、 实施例 1生物纤维膜未饱和状态的上表面 (D)、 及市售生物纤维膜 (E), 敷在人体皮肤 30分钟。 取下生物纤维膜， 再经过 15 分钟后， 以 CK Electronic多功能皮肤检测仪， MPA 580 型 (Cutometer)检测皮 肤表面水 失。 以未敷有任何物质的同处皮肤同样进行上述步骤， 作为对 照组 (A；)。
结果如第 3图所示， 以实施例 1生物纤维膜饱和状态的上表面敷于皮肤 后， 该处皮肤的水份散失速率减少 36.1%。 以实施例 1生物纤维膜饱和状态 的下表面处理的皮肤， 也具有负值的水分散失率。 换句话说， 以本发明之生 物纤维膜在饱和状态下， 不论上下表面， 可将甘油传输到皮肤， 使得皮肤的 水分散失降低。 对于以未饱和的实施例 1生物纤维及市售的生物纤维膜处理 的皮肤， 水分散失率分别为 14.9%及 9.4%。 此结果显示未饱和及市售的生物 纤维膜将甘油导入皮肤的效率较差， 无法有效的降低皮肤表面的水分散失。
[实施例 3] 皮肤油脂吸附试验
取 5cm直径圓形的实施例 1生物纤维膜加水后的饱和状态及市售生物纤 维膜 (ChiaMeei Food Industrial Corp., Taichung, Taiwan), 敷在事先清洗及未清 洗的人体脸部额头皮肤。 经过约 15~40分钟后， 实施例 1的生物纤维膜完全 干掉， 呈现透明。 市售生物纤维膜仍呈现潮湿状。 经少许清水拍湿后， 取下 生物纤维膜，再经 5分钟后，以 CK Electronic多功能皮肤检测仪 MPA 580 型
(Cutometer)检测该处的皮肤的油脂。
如第 4图所示， 将膜敷在事先未经过清洗的皮肤上， 实施例 1生物纤维 膜可减少约 92%的皮肤表面油脂量， 市售生物纤维膜则仅减少约 30%的油脂 量。 如第 5图所示， 将膜敷在事先清洗过的皮肤上， 实施例 1之生物纤维膜 可减少几乎 100%的皮肤表面油脂量， 但市售生物纤维膜仅减少约 62%的油 脂量。
[实施例 4] 含水量及干重试验
取 5cm直径圓形的实施例 1生物纤维膜加水后的饱和状态及市售生物纤 维膜 ((ChiaMeei Food Industrial Corp., Taichung, Taiwan))秤重 (Wl)后， 于 50°C 烘箱中烘干后秤重 (W2), 计算含水率、 单位面积含水量、 单位面积纤维量及 单位纤维含水量。 结果数据如下表 1。
[表 1 ] 生物纤维膜的含水量及干重
Figure imgf000009_0001
含水率 =(W1 -W2)÷W2 ,
单位面积含水量 = [ ( W 1 -W2)÷W2 ] ÷25 cm
单位面积纤维量（W3 )=W2÷25 cm2；
单位纤维含水量 =(W 1 -W2)÷W3
如上表 1所示， 实施例 1与市售生物纤维膜的在单位面纤维量上， 有明 显的差异。 市售生物纤维膜单位面纤维量约为实施例 1生物纤维膜的 2倍以 上， 此一差异也显示在单位纤维及单位面积的含水量上。 此结果显示， 实施 例 1之生物纤维膜仅需较少量的水即可达到饱和状态， 也是形成本发明之生 物纤维膜较市售生物纤维膜为轻薄、 服贴之原因之一。
虽然本发明已以较佳实施例揭露如上， 然其并非用以限定本发明， 任何 熟悉此项技艺者，在不脱离本发明之精神和范围内， 当可做些许更动与润饰， 因此本发明之保护范围当视后附之申请专利范围所界定者为准。

Claims

权利要求书
1.一种生物纤维膜， 包括由微生物纤维素所形成的微生物纤维， 其特征 在于， 该微生物纤维的排列在该生物纤维膜的膜厚方向具有密度梯度。
2.根据权利要求 1所述之生物纤维膜， 其系由醋杆菌 (G yco« etobi7cter) 经适当发酵过程所形成。
3.根据权利要求 1所述之生物纤维膜， 该生物纤维膜的干重为 5-20g/m2。
4.根据权利要求 1-3中任一项所述之生物纤维膜， 其还包括水。
5.根据权利要求 4所述之生物纤维膜， 其还包括活性成分， 该活性成分 包括化妆品原料、保湿剂、美白成份、抗皱成份、去角质成份、生长因子 (growth factors)、 酶 (enzymes)或它们的组合。
6.根据权利要求 4所述之生物纤维膜， 其还包括活性成分， 该活性成分 包括药物、抗生素 (antibiotics)、抗菌剂 (antimicrobials)、抗病毒药物 (antivirals)、 减緩发炎药剂、 止血剂（hemostatics),麻醉剂（anesthetics), 促进伤口愈合药剂 或它们的组合。
7.根据权利要求 4所述之生物纤维膜， 其中， 含水量为该生物纤维膜总 重的 90重量％~99重量％。
8.根据权利要求 4 所述之生物纤维膜， 其中， 该生物纤维膜的厚度为 0.1mm~0.5 mm。
9.一种生物纤维膜的用途， 包括将权利要求 1-8 中任一项所述之生物纤 维膜施于皮肤表面， 其中， 该生物纤维膜与该皮肤接触的表面为密度较低的 表面。
10.根据权利要求 9所述之用途， 其中， 该皮肤包括表皮、 真皮、 皮下组 织、 指曱、 毛发或皮肤的腺体。
11.一种用于减少皮肤表面油脂的方法， 包括将权利要求 1-8中任一项所 述之生物纤维膜施于皮肤表面， 其中， 该生物纤维膜与皮肤接触的表面为密 度较低的表面。
12.根据权利要求 10所述之方法， 其中， 使用后的该皮肤表面油脂量， 相较 于使用前的皮肤表面油脂量， 减少 50~100%。
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WO2017113262A1 (zh) * 2015-12-31 2017-07-06 奈菲儿生医股份有限公司 抗氧化生物纤维素及其制造方法

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