WO2024087985A1 - 一种用于预防或治疗皮肤感染的微针贴片及其制备方法 - Google Patents

一种用于预防或治疗皮肤感染的微针贴片及其制备方法 Download PDF

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WO2024087985A1
WO2024087985A1 PCT/CN2023/121299 CN2023121299W WO2024087985A1 WO 2024087985 A1 WO2024087985 A1 WO 2024087985A1 CN 2023121299 W CN2023121299 W CN 2023121299W WO 2024087985 A1 WO2024087985 A1 WO 2024087985A1
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parts
microneedle
microneedle patch
preventing
water
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PCT/CN2023/121299
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English (en)
French (fr)
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江林
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深圳青澜生物技术有限公司
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Publication of WO2024087985A1 publication Critical patent/WO2024087985A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/65—Tetracyclines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/29—Berberidaceae (Barberry family), e.g. barberry, cohosh or mayapple
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/71—Ranunculaceae (Buttercup family), e.g. larkspur, hepatica, hydrastis, columbine or goldenseal
    • A61K36/718—Coptis (goldthread)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/75—Rutaceae (Rue family)
    • A61K36/756—Phellodendron, e.g. corktree
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/906—Zingiberaceae (Ginger family)
    • A61K36/9062—Alpinia, e.g. red ginger or galangal
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/906—Zingiberaceae (Ginger family)
    • A61K36/9066—Curcuma, e.g. common turmeric, East Indian arrowroot or mango ginger
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/46—Ingredients of undetermined constitution or reaction products thereof, e.g. skin, bone, milk, cotton fibre, eggshell, oxgall or plant extracts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • 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
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/02—Local antiseptics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0046—Solid microneedles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0053—Methods for producing microneedles
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention belongs to the technical field of anti-infection drugs, and in particular relates to a microneedle patch for preventing or treating skin infection and a preparation method thereof.
  • Skin wounds are very common in daily life. After breaking through the effective protective barrier of the skin, various bacteria can easily come into direct contact with the wound and cause infection. The healing time of infected skin wounds is prolonged, and some may lead to chronic infection that prevents the skin from healing. In severe cases, it may lead to sepsis. In clinical practice, intravenous or oral antibacterial drugs are usually used to control infection, but systemic administration usually causes harm to the liver and kidneys of the human body, and in the end only a small number of drugs are effective in controlling wound infection, and the concentration of drugs acting on the wound is insufficient.
  • CN107405301A discloses a microneedle patch for delivering active ingredients to the skin, which includes a tip portion containing the therapeutic active ingredient and a fast-dissolving backing layer portion, which can continuously release the drug at the wound.
  • the drugs currently used in mainstream antibacterial microneedles are organic antibacterial agents, inorganic antibacterial agents, or composite antibacterial agents. These antibacterial agents are prone to drug resistance and have certain cytotoxicity, which makes the wound resistant to drug resistance and is not conducive to wound healing. Although some existing natural fungicides have low drug resistance and cytotoxicity, they are difficult to be actually applied to antibacterial microneedles. They have the following defects:
  • Natural fungicides generally have the problem of insufficient heat resistance. This problem is not obvious when preparing conventional liquid oral preparations, injection preparations or ointments. However, when preparing microneedle preparations, water-soluble polymers are required as skeleton materials, and water-soluble polymers are difficult to dissolve at room temperature. During the preparation process, a higher temperature is required to promote their dissolution and dispersion in water, which usually leads to partial failure of natural fungicides or reduction of volatile oil substances, thereby affecting their antibacterial effects.
  • Microneedles need to have a certain structural strength to pierce the epidermis to deliver drugs to the dermis, and natural fungicides are usually added in the form of essential oils, which will greatly affect the structural strength of the microneedles, resulting in low strength of the prepared microneedles, which are prone to premature breakage during the pressing process, thereby affecting the drug delivery effect.
  • the present invention provides a microneedle patch for preventing or treating skin infections and a preparation method thereof.
  • the present invention provides a microneedle patch for preventing or treating skin infection, comprising an outer layer of auxiliary materials and a plurality of microneedles disposed on a single side surface of the outer layer of auxiliary materials, wherein the microneedles comprise the following weight components:
  • modified natural fungicide 5-30 parts of modified natural fungicide, 2-7 parts of nano-tigecycline and 252-306 parts of the first water-soluble high molecular polymer;
  • the modified natural fungicide comprises the following components by weight:
  • the outer layer auxiliary materials include the following weight components:
  • the bagasse fiber has a diameter of 12 to 28 ⁇ m and a length of 0.42 to 3.77 mm.
  • the first water-soluble high molecular polymer is selected from one or more of polyvinyl alcohol, polyvinyl pyrrolidone, hyaluronic acid, collagen, silk fibroin, gelatin, hydroxypropyl methylcellulose, chondroitin sulfate, dextrin, carboxymethyl cellulose, carboxymethyl chitosan, dextran sulfate, glycogen, amylose, dextran, hydroxypropyl cellulose, glycoside, and chitosan.
  • the microneedle further comprises 48-52 parts of sugar and 12-18 parts of salt.
  • the sugar is selected from one or more of sucrose and trehalose, and the salt is selected from sodium chloride.
  • the antibacterial agent is selected from one or more of ethyl ⁇ -cyanoacrylate and silver-copper composite nanoparticles.
  • the hemostatic material is selected from nano silver-loaded zeolite.
  • the outer layer auxiliary material further includes 3 to 6 parts of analgesics, and the analgesics are selected from one or more of dezocine and ropivacaine.
  • the outer layer auxiliary material and the microneedles further include water, and the water content of the microneedles and the outer layer auxiliary material is 0.1% to 15% by mass.
  • the present invention provides a method for preparing the microneedle patch as described above, comprising the following steps: step:
  • the microneedle forming liquid is applied to the microneedle cavity of the microneedle forming mold, and the needle tip part of the microneedle is obtained by dehydration and shrinkage; the substrate forming liquid is continued to be applied to the microneedle forming mold, and dehydration is performed to obtain the needle body part connected to the needle tip part and the outer layer auxiliary material connected to the needle body part, and demolding is performed to obtain the microneedle patch.
  • microneedle patch in order to reduce the cytotoxicity of organic or inorganic fungicides, natural fungicides (cardamom, curcuma, coptis root, phellodendron, three needles) are used in combination with organic fungicide nano-tigecycline, which can maintain the inhibitory effect on bacterial growth under lower cytotoxicity.
  • bagasse fiber is used to modify the natural fungicide. The modification method is to add bagasse fiber to one or more materials in the above-mentioned natural fungicides for blending. Bagasse fiber has good liquid absorption and is compatible with natural fungicides.
  • the capacity is good, and the heat resistance of the modified natural fungicide has been greatly improved, which can reach a heat resistance of nearly 150 degrees Celsius, meeting the preparation temperature requirement of the microneedle forming liquid.
  • the natural fungicide is adsorbed on the sugarcane bagasse fiber, and has a certain sustained-release effect, which can prolong the antibacterial effect of the microneedle patch.
  • the inventor unexpectedly discovered that the added sugarcane bagasse fiber can form a three-dimensional interwoven mesh support structure in the molded microneedle, and the strength of the microneedle is not only not deteriorated due to the addition of the natural fungicide, but is improved, thereby achieving a better epidermal puncture effect, which is beneficial to improving the stability of the dosage.
  • the microneedle By adding an antibacterial agent to the outer layer of auxiliary materials, the microneedle can effectively prevent subsequent infection while delivering the modified natural bactericide and nano-tigecycline, and achieve long-term antibacterial effect.
  • the hemostatic material contained in the outer layer of auxiliary materials can accelerate wound scab formation, accelerate hemostasis, and help prevent bacterial invasion.
  • the embodiment of the present invention provides a microneedle patch for preventing or treating skin infection, comprising an outer layer auxiliary material and a plurality of microneedles arranged on a single side surface of the outer layer auxiliary material, wherein the microneedles include the following weight components:
  • modified natural fungicide 5-30 parts of modified natural fungicide, 2-7 parts of nano-tigecycline and 252-306 parts of the first water-soluble high molecular polymer;
  • the modified natural fungicide comprises the following components by weight:
  • the outer layer auxiliary materials include the following weight components:
  • Microneedles are used as drug delivery carriers. Acupuncture itself will mobilize the body's stress response ability, contact excitement and muscle tension. The analgesic effect of acupuncture can increase the endorphins in the body. This polypeptide substance can produce a certain anesthetic effect.
  • natural fungicides cardamom, zedoary, coptis root, phellodendron, trifoliate needles
  • organic fungicide nano-tigecycline which can maintain the inhibitory effect on bacterial growth under lower cytotoxicity.
  • bagasse fiber is used to modify the natural fungicide. The modification method is to add bagasse fiber to one or more materials in the above-mentioned natural fungicides for blending. Bagasse fiber has good liquid absorption and good compatibility with natural fungicides.
  • the heat resistance of the natural fungicide has been greatly improved, and can reach a heat resistance of nearly 150 degrees Celsius, which meets the preparation temperature requirement of the microneedle forming liquid.
  • the natural fungicide is adsorbed on the sugarcane bagasse fiber, and has a certain sustained-release effect, which can prolong the antibacterial effect of the microneedle patch.
  • the inventors unexpectedly discovered that the added sugarcane bagasse fiber can form a three-dimensional interwoven mesh support structure in the molded microneedles.
  • the strength of the microneedles not only did not deteriorate due to the addition of natural fungicides, but was improved, thereby achieving a better epidermal puncture effect, which is beneficial to improving the stability of the dosage.
  • the microneedle By adding an antibacterial agent to the outer layer of auxiliary materials, the microneedle can effectively prevent subsequent infection while delivering the modified natural bactericide and nano-tigecycline, and achieve long-term antibacterial effect.
  • the hemostatic material contained in the outer layer of auxiliary materials can accelerate wound scab formation, accelerate hemostasis, and help prevent bacterial invasion.
  • the amount of bagasse fiber added is related to the heat resistance of the modified natural fungicide. And it is related to the strength of the microneedle.
  • the added amount of the bagasse fiber is too little, the natural fungicide cannot be fully adsorbed, the heat resistance of the modified natural fungicide is low, and it is not conducive to the improvement of the microneedle strength; when the added amount of the bagasse fiber is too much, it will lead to a decrease in the content of other components, such as natural fungicide, nano-tigecycline and the first water-soluble high molecular polymer, and the bagasse fiber cannot be completely infiltrated, thereby affecting its inhibitory effect on bacterial growth, and it is also not conducive to the improvement of the microneedle strength.
  • sugarcane bagasse fiber in the present microneedle cannot be replaced by water-soluble fiber or other fiber without adsorption capacity.
  • cardamom mainly contains volatile oils such as eucalyptol, humulene, trans-musk oil alcohol, camphor; flavonoids such as gingerol, pyrocatechol, cardamom; also contains alder ketone, saponins, etc. It has anti-ulcer, anti-pathogenic microorganism, sepsis improvement, anti-oxidation and anti-inflammatory effects.
  • Curcuma Contains volatile oil components. Among them, Curcuma wenjin contains a-pinene, ⁇ -pinene, camphor, 1,8-cineole, borneol, curcumol, isocurcumenol, etc. Curcuma guangxiensis contains a-pinene, ⁇ -pinene, limonene, borneol, camphor, eugenol, gingerene, curcumol, curcumone, zingerone, turmeric, dehydrated curcumone, etc. It has antibacterial, anti-inflammatory, white blood cell enhancement and analgesic effects.
  • Coptis chinensis contains isoquinoline alkaloids such as berberine, coptisine, jatrorrhizine, palmatine, palmitoyl alkaloids, tertralidine, berberine, and epiberberine. It also contains phellodendron, phellodendron lactone, ferulic acid, chlorogenic acid, and other ingredients, which have the pathological effects of clearing away heat and dampness, purging fire and detoxifying, and resisting pathogenic microorganisms.
  • Phellodendron It mainly contains berberine, berberine, phellodendronine, jatrorrhizine, palmitoyl tetrandrine and other alkaloids. In addition, it also contains bitter substances such as phellodendron lactone, phellodendronone, phellodendron acid and steroidal components such as 7-dehydrostigmasterol, ⁇ -sitosterol and campesterol. It has the effects of clearing away heat and dampness, detoxifying and curing sores. Specifically, it has antibacterial effects on hemolytic streptococci, Staphylococcus aureus, gonococci, and Shigella dysenteriae, and enhances the phagocytosis of leukocytes.
  • San Ke Zhen The main ingredients are berberine, jatrorrhizine and palmatine. Berberine, also known as berberine, is relatively abundant in San Ke Zhen. Therefore, San Ke Zhen also has similar effects as Coptis chinensis in clearing heat and dampness, purging fire and detoxifying, and resisting pathogenic microorganisms.
  • the addition of natural fungicides is mainly in the form of essential oils, for example, the essential oils corresponding to cardamom, zedoary zedoary, coptis root, phellodendron and trifoliate needles are used as the Natural fungicide, the essential oil can be obtained by distillation, solvent extraction, pressing, supercritical extraction and the like, preferably by supercritical extraction.
  • the microneedles on the microneedle patch are conical structures, such as round-pointed cones, elliptical-pointed cones, regular polygonal-pointed cones, irregular polygonal-pointed cones, etc.
  • the height of the microneedles is 0.001 ⁇ m-1000 ⁇ m, and the maximum diameter is 0.005-3000 ⁇ m.
  • the distance between the microneedles is 4 ⁇ m-1000 ⁇ m.
  • the microneedles on the microneedle patch are formed by providing a plurality of microneedle cavities on a microneedle forming mold, and filling the microneedle forming liquid in the microneedle cavities and drying and curing the liquid to obtain the microneedles.
  • the bagasse fibers have a diameter of 12 to 28 ⁇ m and a length of 0.42 to 3.77 mm.
  • the bagasse fibers In order to ensure that the bagasse fibers can be fully dispersed in the microneedle forming liquid and can smoothly enter the microneedle cavity of the microneedle forming mold, the bagasse fibers need to have a smaller diameter and length. In some cases, the bagasse fibers can be refined by ball milling and hydrolysis.
  • the first water-soluble high molecular polymer is selected from one or more of polyvinyl alcohol, polyvinyl pyrrolidone, hyaluronic acid, collagen, silk fibroin, gelatin, hydroxypropyl methylcellulose, chondroitin sulfate, dextrin, carboxymethyl cellulose, carboxymethyl chitosan, dextran sulfate, glycogen, amylose, dextran, hydroxypropyl cellulose, glycoside, and chitosan.
  • the microneedle further comprises 48-52 parts of saccharide and 12-18 parts of salt.
  • sugars are mainly used as stabilizers. They are carbohydrates with good biocompatibility, high stability, low cost and good safety.
  • the prepared microneedles have good mechanical strength and can quickly release active ingredients in the skin when administered. When the skin absorbs sugars, they are biodegradable in the body and are gradually cleared by the kidneys.
  • the salts serve to balance the osmotic pressure.
  • the sugar is selected from one or more of sucrose and trehalose, and the salt is selected from sodium chloride.
  • the first water-soluble high molecular polymer is selected from one or more of polyvinyl alcohol, polyvinyl pyrrolidone, hyaluronic acid, collagen, silk fibroin, gelatin, hydroxypropyl methylcellulose, chondroitin sulfate, dextrin, carboxymethyl cellulose, carboxymethyl chitosan, dextran sulfate, glycogen, amylose, dextran, hydroxypropyl cellulose, glycoside, and chitosan.
  • the antibacterial agent is selected from one or more of ethyl ⁇ -cyanoacrylate and silver-copper composite nanoparticles.
  • the hemostatic material is selected from nano silver-loaded zeolite.
  • the outer layer excipients further include 3 to 6 parts of analgesics, and the analgesics are selected from one or more of dezocine and ropivacaine.
  • the analgesic is used to reduce wound pain.
  • the microneedles and the outer layer of auxiliary materials also include water.
  • the water contained in the microneedles and the outer layer of auxiliary materials comes from the water added during the preparation process, and is used to disperse the components to obtain a liquid molding liquid. During the drying and curing process, it is usually impossible to completely remove it. Therefore, a certain amount of water will remain in the microneedles and the outer layer of auxiliary materials. The amount of residual water varies depending on the drying method. In some embodiments, the water content of the microneedles and the outer layer of auxiliary materials is 0.1% to 15% by mass.
  • Another embodiment of the present invention provides a method for preparing the microneedle patch as described above, comprising the following steps:
  • the microneedle forming liquid is applied to the microneedle cavity of the microneedle forming mold, and the needle tip part of the microneedle is obtained by dehydration and shrinkage; the substrate forming liquid is continued to be applied to the microneedle forming mold, and dehydration is performed to obtain the needle body part connected to the needle tip part and the outer layer auxiliary material connected to the needle body part, and demolding is performed to obtain the microneedle patch.
  • 48-52 parts of sugars and 12-18 parts of salts are further added to the microneedle forming solution.
  • 3 to 6 parts of analgesic are also added to the substrate forming liquid.
  • the microneedle molding mold includes a support plate and multiple microneedle molding areas, the shape of the microneedle molding areas is consistent with the shape of the outer layer auxiliary material of the microneedle patch to be prepared, and the multiple microneedle molding areas are embedded in the support plate at intervals, and the support plate is a rigid material, and the microneedle molding areas are flexible and breathable material.
  • the rigid material is selected from single crystal silicon, stainless steel, aluminum plate, titanium plate, silicate glass, quartz glass, ceramic, polytetrafluoroethylene, polyetheretherketone (PEEK), propane sulfonate pyridinium salt, etc.
  • the flexible material is selected from siloxane.
  • the present embodiment adopts a combination of flexible materials and rigid materials to prepare a microneedle molding mold.
  • the microneedle molding area of the flexible material is fixed on a support plate of the rigid material, so that the support plate has a supporting and fixing effect on the microneedle molding area, which is used to maintain the stability of the shape of the microneedle molding area; the microneedle cavity provided on the microneedle molding area is used for the curing and molding of the microneedles.
  • the use of flexible materials is conducive to reducing the stress on the microneedles during the demolding process and improving the integrity of the microneedles after demolding.
  • the shape of the microneedle molding area is fixed by the support plate of the rigid material, which can avoid the deformation of the microneedle molding area during the curing and shrinkage of the molding liquid, thereby effectively improving the molding effect and demolding integrity of the microneedles.
  • the microneedle forming mold when the microneedle forming liquid and the substrate forming liquid are applied to the microneedle forming mold, the microneedle forming mold is vacuumed to promote filling and the filling rate of the microneedle forming mold while avoiding residual bubbles in the formed microneedles.
  • the microneedle forming liquid and the substrate forming liquid can be introduced into the microneedle forming mold by pressurized spraying, atomized spraying, roller coating, brush coating, injection, screen printing, or scraping.
  • the microneedle forming liquid and the substrate forming liquid are applied to the microneedle forming mold by blade coating.
  • the dehydration operation is cold air dehydration, specifically, air drying at a temperature of -40-35°C for 3-4 hours.
  • the wind speed is controlled within the range of 0.5-5m/s, so that the molding liquid will not be blown out of the microneedle molding mold, and the curing rate will not be reduced due to too low wind speed, affecting the production efficiency.
  • This example is used to illustrate the microneedle patch and its preparation method disclosed in the present invention, including the following operations:
  • Example 1 cardamom, curcuma, coptis root, phellodendron, three needles and bagasse fiber are weighed for blending and modification, and then nano-tigecycline as shown in Table 1 Example 1 is added, and then mixed with polyvinyl alcohol, polyvinyl pyrrolidone, sucrose, sodium chloride and water, and heated at 85°C to 95°C and ultrasonically dispersed to obtain a microneedle forming liquid;
  • Dezocine or ropivacaine, ethyl ⁇ -cyanoacrylate, silver-copper composite nanoparticles, nano silver-loaded zeolite, polyvinyl alcohol, polyvinyl pyrrolidone and water were weighed according to the weight parts shown in Example 1 in Table 1, and heated at 85° C. to 95° C. and ultrasonically dispersed to obtain a substrate forming liquid;
  • the microneedle forming liquid is applied to the microneedle cavity of the microneedle forming mold, vacuum suction is performed, and dehydration and shrinkage are performed to obtain the needle tip part of the microneedle; the substrate forming liquid is continuously applied to the microneedle forming mold, vacuum suction is performed, and dehydration is performed to obtain the needle body part connected to the needle tip part and the outer layer auxiliary material connected to the needle body part, and demolding is performed to obtain the microneedle patch.
  • Examples 2 to 7 are used to illustrate the microneedle patch and the preparation method thereof disclosed in the present invention, and include most of the operation steps in Example 1, and the difference is that:
  • Comparative Examples 1 to 4 are used to compare and illustrate the microneedle patch and the preparation method thereof disclosed in the present invention, including the following steps: Most of the steps in Example 1 are different in that:
  • Universal material testing machine direct pressure to test needle strength: Place the microneedle patches prepared in Examples 1 to 7 and Comparative Examples 1 to 4 on the universal material test plate, start the instrument, and move the pressure sensor downward. When the pressure sensor detects that the microneedle is broken, record the breaking point pressure.
  • the pressure sensor has an upper pressure head diameter of 8 mm, and presses about 194 needles in total. The following experimental results are obtained:
  • the bacterial solution (Staphylococcus aureus, 10 5 CFU/mL or Escherichia coli, 10 8 CFU/mL) treated with the microneedle forming solution prepared in Examples 1 to 7 and Comparative Examples 1 to 4 was co-cultured in a 37° C. incubator for 4 h. Take 10 ⁇ L of bacterial solution and add it to the LB solid medium to coat the plate, with 3 parallel samples in each group. After the plate is inverted and placed in a 37°C incubator for 12 hours, take out the plate, take pictures and record the number of bacterial colonies.
  • the bacteria co-cultured with Zr-Fc MOF are the test group, and the bacteria not co-cultured with Zr-Fc MOF are the negative control group.
  • Nnegative is the number of bacterial colonies in the negative group
  • Nsample is the number of bacterial colonies in the test group.
  • mice Use streptozotocin to induce diabetic Balb/c mice. There are 13 groups, each with ten mice. A strip-shaped wound was cut into the epidermis of the mouse. The depth of the wound was based on penetrating the epidermis and dermis and exposing the subcutaneous tissue. The length of the incision was 20 mm. A cotton swab was dipped in a mixed bacterial solution of 1 ⁇ 10 8 CFU/mL of Staphylococcus aureus and Escherichia coli and lightly applied to the wound surface for bacterial inoculation to establish a bacterial infection wound model.
  • microneedle patches prepared in Examples 1 to 7 and Comparative Examples 1 to 4 were attached to the wounds of one group of mice, respectively, and continuous pressing was performed for 1 minute. At the same time, a blank microneedle patch was set as a control group, and the microneedle patch was replaced once a day. The wound healing of each group of mice was recorded every day, with scab formation and no obvious inflammation as the healing standard, and the test results were filled in Table 4.

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Abstract

为克服现有天然杀菌剂微针存在耐热性不足和结构强度不足的问题，提供了一种用于预防或治疗皮肤感染的微针贴片，其特征在于，包括外层辅料以及设置于所述外层辅料单侧表面的多个微针，所述微针包括以下重量组分：改性天然杀菌剂5～30份、纳米替加环素2～7份和第一水溶性高分子聚合物252～306份；所述改性天然杀菌剂包括以下重量组分：草豆蔻3～7份、莪术1～2份、黄连1～3份、黄柏2～4份、三颗针1～4份和甘蔗渣纤维4～10份。同时，还公开了上述微针贴片的制备方法。提供的微针贴片具有较好的微针结构强度和优异的创口防感染效果。

Description

一种用于预防或治疗皮肤感染的微针贴片及其制备方法 技术领域
本发明属于抗感染药物技术领域，具体涉及一种用于预防或治疗皮肤感染的微针贴片及其制备方法。
背景技术
皮肤伤口在日常生活中很容易发生，在突破了皮肤这层有效的保护屏障后，各类细菌容易直接接触伤口后造成感染，受感染的皮肤伤口愈合时间延长，部分会导致慢性感染使皮肤无法愈合，严重时导致败血症的发生。在临床上，通常使用静脉注射或口服抗菌药物来控制感染，但系统性给药通常会对人体的肝脏和肾脏产生危害，而且最后仅有少部分药物对控制伤口感染起作用，作用于伤口部分的药物浓度不足。
采用微针给药的方式来治疗伤口感染具有很大的前景，其能直接作用于伤口处进行持续的细菌消杀。例如CN107405301A公开了一种用于向皮肤递送活性成分的微针贴片，该微针贴片包括含有治疗活性成分的尖端部分和快速溶解性背衬层部分，可以使药物在伤口处持续释放。
然而目前主流抗菌微针采用的药物都是有机抗菌剂或无机抗菌剂或是复合抗菌剂，这些抗菌剂都容易产生耐药性并具有一定的细胞毒性，使得伤口产生抗药性，不利于伤口的愈合。而现有的一些天然杀菌剂虽然耐药性和细胞毒性较低，却难以实际应用至抗菌微针中，其存在的缺陷为：
1、天然杀菌剂普遍存在耐热性不足的问题，在制备常规液体口服制剂、注射制剂或药膏时，该问题不明显，而在制备微针制剂时，由于需要采用水溶性高分子聚合物作为骨架材料，而水溶性高分子聚合物难以在常温下溶解，在制备过程中需要较高的温度以促进其在水中的溶解和分散，这通常会导致天然杀菌剂的部分失效或是挥发油类物质的减少，进而影响其抗菌效果；
2、微针需要具备一定的结构强度以刺穿表皮层以将药物递送至真皮层，而天然杀菌剂通常以精油的形式添加，会极大影响微针的结构强度，进而使得制备得到微针强度偏低，容易在按压过程中提前断裂，进而影响药物递送效果。
发明内容
针对现有天然杀菌剂微针存在耐热性不足和结构强度不足的问题，本发明提供了一种用于预防或治疗皮肤感染的微针贴片及其制备方法。
本发明解决上述技术问题所采用的技术方案如下：
一方面，本发明提供了一种用于预防或治疗皮肤感染的微针贴片，包括外层辅料以及设置于所述外层辅料单侧表面的多个微针，所述微针包括以下重量组分：
改性天然杀菌剂5～30份、纳米替加环素2～7份和第一水溶性高分子聚合物252～306份；
所述改性天然杀菌剂包括以下重量组分：
草豆蔻3～7份、莪术1～2份、黄连1～3份、黄柏2～4份、三颗针1～4份和甘蔗渣纤维4～10份；
所述外层辅料包括以下重量组分：
抑菌剂3～8份、止血材料13～18份和第二水溶性高分子聚合物252～306份。
可选的，所述甘蔗渣纤维的直径为12～28μm，长度为0.42～3.77mm。
可选的，所述第一水溶性高分子聚合物选自聚乙烯醇、聚乙烯吡咯烷酮、透明质酸、胶原蛋白、丝素蛋白、明胶、羟丙基甲基纤维素、硫酸软骨素、糊精、羧甲基纤维素、羧甲基壳聚糖、硫酸葡聚糖、糖原、直链淀粉、葡聚糖、羟丙基纤维素、糖苷、壳聚糖中的一种或多种。
可选的，所述微针还包括糖类48-52份和盐12-18份。
可选的，所述糖类选自蔗糖、海藻糖中的一种或多种，所述盐选自氯化钠。
可选的，所述抑菌剂选自α-氰基丙烯酸乙酯和银-铜复合纳米粒子中的一种或多种。
可选的，所述止血材料选自纳米载银沸石。
可选的，所述外层辅料还包括止痛剂3～6份，所述止痛剂选自地佐辛和罗哌卡因中的一种或多种。
可选的，所述外层辅料和所述微针还包括水，以质量计，所述微针和所述外层辅料的含水量为0.1％～15％。
另一方面，本发明提供了如上所述的微针贴片的制备方法，包括以下操作 步骤：
按重量份称取草豆蔻3～7份、莪术1～2份、黄连1～3份、黄柏2～4份、三颗针1～4份和甘蔗渣纤维4～10份进行混合，得到改性天然杀菌剂；
按重量份称取改性天然杀菌剂5～30份、纳米替加环素2～7份、第一水溶性高分子聚合物252～306份和水517～620份，在85℃～95℃条件下加热并超声分散得到微针成型液；
按重量份称取抑菌剂3～8份、止血材料13～18份、第二水溶性高分子聚合物252～306份和水517～620份，在85℃～95℃条件下加热并超声分散得到衬底成型液；
将微针成型液施加于微针成型模具的微针腔中，脱水收缩得到微针的针尖部分；继续施加衬底成型液于微针成型模具上，脱水得到连接所述针尖部分的针体部分以及连接所述针体部分的外层辅料，脱模得到微针贴片。
根据本发明提供的微针贴片，为了降低有机或无机杀菌剂的细胞毒性，采用天然杀菌剂(草豆蔻、莪术、黄连、黄柏、三颗针)与有机杀菌剂纳米替加环素配合，能够在较低的细胞毒性下保持对于细菌生长的抑制效果，同时，为了避免天然杀菌剂的加入对于耐热性和微针强度的影响，采用了甘蔗渣纤维对天然杀菌剂进行改性，该改性方法为在上述天然杀菌剂中的一种或多种物料中加入甘蔗渣纤维进行共混，甘蔗渣纤维具有良好的吸液性，与天然杀菌剂相容性较好，改性后天然杀菌剂的耐热性得到了较大的提升，能够达到接近150摄氏度的耐热效果，满足微针成型液的制备温度需求，且天然杀菌剂吸附于甘蔗渣纤维上，具有一定的缓释效果，能够延长该微针贴片的抗菌效果；同时，发明人意外发现，加入的甘蔗渣纤维能够在成型的微针中形成三维交织的网状支撑结构，微针的强度不仅没有因为天然杀菌剂的加入劣化，反而有所提升，进而达到了较好的表皮穿刺的效果，有利于提升给药剂量的稳定性。
通过在所述外层辅料中加入抑菌剂，在微针递送改性天然杀菌剂和纳米替加环素的同时还能有效避免后续性感染，长效抑菌。同时，所述外层辅料中含有的止血材料能够加速创口结痂，加速止血，有利于避免细菌侵入。
具体实施方式
为了使本发明所解决的技术问题、技术方案及有益效果更加清楚明白，以下结合实施例，对本发明进行进一步详细说明。应当理解，此处所描述的具体 实施例仅仅用以解释本发明，并不用于限定本发明。
本发明实施例提供了一种用于预防或治疗皮肤感染的微针贴片，包括外层辅料以及设置于所述外层辅料单侧表面的多个微针，所述微针包括以下重量组分：
改性天然杀菌剂5～30份、纳米替加环素2～7份和第一水溶性高分子聚合物252～306份；
所述改性天然杀菌剂包括以下重量组分：
草豆蔻3～7份、莪术1～2份、黄连1～3份、黄柏2～4份、三颗针1～4份和甘蔗渣纤维4～10份；
所述外层辅料包括以下重量组分：
抑菌剂3～8份、止血材料13～18份和第二水溶性高分子聚合物252～306份。
采用微针作为药物递送载体，针刺本身会调动机体应激能力，接触兴奋和肌肉紧张，针刺镇痛作用能使体内的内啡肽升高，这种多肽类物质可产生一定麻醉作用。
为了降低有机或无机杀菌剂的细胞毒性，采用天然杀菌剂(草豆蔻、莪术、黄连、黄柏、三颗针)与有机杀菌剂纳米替加环素配合，能够在较低的细胞毒性下保持对于细菌生长的抑制效果，同时，为了避免天然杀菌剂的加入对于耐热性和微针强度的影响，采用了甘蔗渣纤维对天然杀菌剂进行改性，该改性方法为在上述天然杀菌剂中的一种或多种物料中加入甘蔗渣纤维进行共混，甘蔗渣纤维具有良好的吸液性，与天然杀菌剂相容性较好，改性后天然杀菌剂的耐热性得到了较大的提升，能够达到接近150摄氏度的耐热效果，满足微针成型液的制备温度需求，且天然杀菌剂吸附于甘蔗渣纤维上，具有一定的缓释效果，能够延长该微针贴片的抗菌效果；同时，发明人意外发现，加入的甘蔗渣纤维能够在成型的微针中形成三维交织的网状支撑结构，微针的强度不仅没有因为天然杀菌剂的加入劣化，反而有所提升，进而达到了较好的表皮穿刺的效果，有利于提升给药剂量的稳定性。
通过在所述外层辅料中加入抑菌剂，在微针递送改性天然杀菌剂和纳米替加环素的同时还能有效避免后续性感染，长效抑菌。同时，所述外层辅料中含有的止血材料能够加速创口结痂，加速止血，有利于避免细菌侵入。
所述微针中，所述甘蔗渣纤维的添加量与所述改性天然杀菌剂的耐热性以 及所述微针的强度具有关联性，当所述甘蔗渣纤维的添加量过少时，无法充分吸附天然杀菌剂，对于所述改性天然杀菌剂的耐热性提升较低，同时也不利于微针强度的提升；当所述甘蔗渣纤维的添加量过多时，会导致其他组分，如天然杀菌剂、纳米替加环素和第一水溶性高分子聚合物的含量的下降，且甘蔗渣纤维无法完全浸润，进而影响其对细菌生长的抑制效果，同时也不利于微针强度的提升。
需要说明的是，为保证甘蔗渣纤维对于天然杀菌剂的吸附改性，本微针中的甘蔗渣纤维不能替换为水溶性纤维或其他不具有吸附能力的纤维。
采用草豆蔻、莪术、黄连、黄柏和三颗针作为组合的天然杀菌剂，通过多种天然杀菌剂和纳米替加环素的配伍使用，能够极大地避免病原体产生耐药性的情况。
其中，草豆蔻：主要含有桉油精、蛇麻烯、反麝子油醇、樟脑等挥发油；姜素、乔松素、小豆蔻明等黄酮类成分；还含有桤木酮、皂苛类等。具有抗溃疡、抗病原微生物、改善脓毒血症、抗氧化和抗炎等作用。
莪术：含挥发油类成分。其中温郁金含有a-蒎烯、β-蒎烯、樟脑、1,8-桉叶醇、龙脑、莪术醇、异莪术烯醇等。广西莪术含有a-蒎烯、β-蒎烯、柠檬烯、龙脑、樟脑、丁香酚、姜烯、莪术醇、莪术酮、芳姜酮、姜黄酮、去水莪术酮等。具有抗菌、抗炎、提高白细胞作用、止痛的功效。
黄连：含有小檗碱、黄连碱、药根碱、巴马汀(掌叶防己碱)、棕榈碱、非洲防己碱、栏碱、表小檗碱等异喹啉类生物碱。还含有黄柏酮、黄柏内酯、阿魏酸、绿原酸等成分，具有清热燥湿、泻火解毒和抗病原微生物的病理作用。
黄柏：主要含小檗碱、栏花碱、黄柏碱、药根碱、掌叶防己碱等多种生物碱。此外，还含有黄柏内酯、黄柏酮、黄柏酮酸等苦味质成分及7-脱氢豆甾醇、β-谷甾醇、菜油甾醇等甾体成分。具有清热燥湿、解毒疗疮的功效，具体的，对溶血性链球菌，金黄色葡萄球菌，淋球菌和弗氏、志贺氏痢疾杆菌等均有抗菌作用，并有增强白血球吞噬作用。
三颗针：主要成分为小檗碱、药根碱和掌叶防己碱等，其中小檗碱又称为黄连素，在三颗针中含量比较丰富，因此，三颗针也与黄连具有类似的清热燥湿、泻火解毒和抗病原微生物的功效。
需要说明的是，在本发明的描述中，天然杀菌剂的添加主要通过精油的形式添加，例如采用草豆蔻、莪术、黄连、黄柏和三颗针所对应的精油作为所述 天然杀菌剂，所述精油可通过蒸馏、溶剂萃取、压榨、超临界萃取等方式获取，优选采用超临界萃取的方式进行精油的获取。
在一些实施例中，所述微针贴片上微针为锥形结构，如圆尖锥、椭圆形尖锥、规则多边形尖锥、不规则多边形尖锥等。所述微针的高度为0.001μm-1000μm，最大直径为0.005-3000μm。同时，为了保证微针阵列具有一定密度，所述微针之间的距离为4μm-1000μm。
所述微针贴片上的微针成型方式为：在微针成型模具上设置多个微针腔，通过在微针腔中填充微针成型液并干燥固化得到微针。
在一些实施例中，所述甘蔗渣纤维的直径为12～28μm，长度为0.42～3.77mm。
为保证所述甘蔗渣纤维能够充分分散于微针成型液中，同时能够顺利进入到微针成型模具的微针腔中，所述甘蔗渣纤维需具有较小的直径和长度，在一些情况下，可通过球磨和水解等方式使甘蔗渣纤维细化。
在一些实施例中，所述第一水溶性高分子聚合物选自聚乙烯醇、聚乙烯吡咯烷酮、透明质酸、胶原蛋白、丝素蛋白、明胶、羟丙基甲基纤维素、硫酸软骨素、糊精、羧甲基纤维素、羧甲基壳聚糖、硫酸葡聚糖、糖原、直链淀粉、葡聚糖、羟丙基纤维素、糖苷、壳聚糖中的一种或多种。
在一些实施例中，所述微针还包括糖类48-52份和盐12-18份。
在微针贴剂中，糖类主要用作稳定剂。是一种生物相容性佳、稳定性高、成本低、安全性好的碳水化合物。制备的微针机械强度佳，给药时能在皮肤中快速释放有效成分，当皮肤吸收糖类时，其在体内可生物降解的，肾脏会逐渐将其清除。
所述盐用于平衡渗透压。
在一些实施例中，所述糖类选自蔗糖、海藻糖中的一种或多种，所述盐选自氯化钠。
在一些实施例中，所述第一水溶性高分子聚合物选自聚乙烯醇、聚乙烯吡咯烷酮、透明质酸、胶原蛋白、丝素蛋白、明胶、羟丙基甲基纤维素、硫酸软骨素、糊精、羧甲基纤维素、羧甲基壳聚糖、硫酸葡聚糖、糖原、直链淀粉、葡聚糖、羟丙基纤维素、糖苷、壳聚糖中的一种或多种。
在一些实施例中，所述抑菌剂选自α-氰基丙烯酸乙酯和银-铜复合纳米粒子中的一种或多种。
在一些实施例中，所述止血材料选自纳米载银沸石。
在一些实施例中，所述外层辅料还包括止痛剂3～6份，所述止痛剂选自地佐辛和罗哌卡因中的一种或多种。
所述止痛剂用于减少创口疼痛。
在一些实施例中，所述微针和所述外层辅料还包括水，所述微针和所述外层辅料中含有的水来源于制备过程中加入的水，用于分散各组分以得到液态的成型液，在干燥固化的过程中，通常无法完全去除，因此，会在所述微针和所述外层辅料残留一定的水，残留的水量通过干燥方式的不同具有不同的量，在一些实施例中，以质量计，所述微针和所述外层辅料的含水量为0.1％～15％。
本发明的另一实施例提供了如上所述的微针贴片的制备方法，包括以下操作步骤：
按重量份称取草豆蔻3～7份、莪术1～2份、黄连1～3份、黄柏2～4份、三颗针1～4份和甘蔗渣纤维4～10份进行混合，得到改性天然杀菌剂；
按重量份称取改性天然杀菌剂5～30份、纳米替加环素2～7份、第一水溶性高分子聚合物252～306份和水517～620份，在85℃～95℃条件下加热并超声分散得到微针成型液；
按重量份称取抑菌剂3～8份、止血材料13～18份、第二水溶性高分子聚合物252～306份和水517～620份，在85℃～95℃条件下加热并超声分散得到衬底成型液；
将微针成型液施加于微针成型模具的微针腔中，脱水收缩得到微针的针尖部分；继续施加衬底成型液于微针成型模具上，脱水得到连接所述针尖部分的针体部分以及连接所述针体部分的外层辅料，脱模得到微针贴片。
在一些实施例中，所述微针成型液中还加入有糖类48-52份和盐12-18份。
在一些实施例中，所述衬底成型液中还加入有止痛剂3～6份。
在一些实施例中，所述微针成型模具包括支撑板和多个微针成型区，所述微针成型区的形状与所需制备的微针贴片的外层辅料形状一致，多个所述微针成型区间隔嵌入于所述支撑板上，且所述支撑板为刚性材料，所述微针成型区为柔性透气材料。
在一些实施例中，所述刚性材料选自单晶硅、不锈钢、铝板、钛板、硅酸盐玻璃、石英玻璃、陶瓷、聚四氟乙烯、聚醚醚酮(PEEK)、丙烷磺酸吡啶嗡盐等，所述柔性材料选自硅氧烷。
本实施例采用柔性材料和刚性材料结合制备微针成型模具，通过将柔性材料的微针成型区固定于刚性材料的支撑板上，使得所述支撑板对于所述微针成型区具有支撑和固定作用，用于保持所述微针成型区形态的稳定性；所述微针成型区上设置的微针腔用于微针的固化成型，采用柔性材料有利于减小微针脱模过程中所受应力的作用，提高微针脱模后的完整性，同时，通过刚性材料的支撑板对微针成型区进行形态固定，可避免所述微针成型区在成型液固化收缩的过程中发生形变，进而有效改善微针的成型效果和脱模完整性。
在一些实施例中，将微针成型液和衬底成型液施加于微针成型模具时，对所述微针成型模具进行抽真空处理，以促进填充也对于微针成型模具的填充速率，同时避免在成型的微针中残留气泡。
在不同实施例中，施加成型液时，可采用加压喷射、雾化喷射、辊涂、刷涂、注射、丝网印刷、刮涂的方式将微针成型液和衬底成型液导入到所述微针成型模具中。
在优选的实施例中，采用刮涂的方式在所述微针成型模具中施加微针成型液和衬底成型液。
在一些实施例中，所述脱水操作为冷风脱水，具体的，在-40-35℃的温度下风干3-4h。同时，将风速控制在范围风速为0.5-5m/s内，这样既不会将成型液吹出微针成型模具，也不会因风速太低导致固化速率降低，影响生产效率。
以下通过实施例对本发明进行进一步的说明。
表1

实施例1
本实施例用于说明本发明公开的微针贴片及其制备方法，包括以下操作：
按表1实施例1所示重量份称取草豆蔻、莪术、黄连、黄柏、三颗针与甘蔗渣纤维进行共混改性，再加入如表1实施例1所示的纳米替加环素，再与聚乙烯醇、聚乙烯吡咯烷酮、蔗糖、氯化钠和水共混，在85℃～95℃条件下加热并超声分散得到微针成型液；
按表1实施例1所示重量份称取地佐辛或罗哌卡因、α-氰基丙烯酸乙酯、银-铜复合纳米粒子、纳米载银沸石、聚乙烯醇、聚乙烯吡咯烷酮和水，在85℃～95℃条件下加热并超声分散得到衬底成型液；
将微针成型液施加于微针成型模具的微针腔中，真空抽吸，脱水收缩得到微针的针尖部分；继续施加衬底成型液于微针成型模具上，真空抽吸，脱水得到连接所述针尖部分的针体部分以及连接所述针体部分的外层辅料，脱模得到微针贴片。
实施例2～7
实施例2～7用于说明本发明公开的微针贴片及其制备方法，包括实施例1中的大部分操作步骤，其不同之处在于：。
采用表1中实施例2～7所示的物质组分和添加量。
对比例1～4
对比例1～4用于对比说明本发明公开的微针贴片及其制备方法，包括实施 例1中的大部分操作步骤，其不同之处在于：。
采用表1中对比例1～4所示的物质组分和添加量。
性能测试
1、万能材料试验机直压以测试针强度：将上述实施例1～7和对比例1～4制备得到的微针贴片置于万能材料实验压盘上，启动仪器，压力传感器向下位移，当压力传感器检测到微针断裂时记录断裂点压力。压力传感器上压头直径8mm，约共压到194根针，得到如下实验结果：
表2
由表2的测试结果可以看出，通过在微针成型液中加入甘蔗渣纤维，能够有效提高微针的结构强度，而不添加甘蔗渣纤维的对比例1中，可以看出微针强度具有明显的劣化，推测是由于草豆蔻、莪术、黄连、黄柏、三颗针等精油的加入导致微针强度的下降，而加入过量甘蔗渣纤维的对比例2中，微针强度同样不足，说明过量甘蔗渣纤维同样不利于微针强度的提高。
2、经实施例1～7和对比例1～4制得的微针成型液处理后的菌液(金黄色葡萄球菌，105CFU/mL或大肠杆菌，108CFU/mL)在37℃培养箱中共培养4h， 取10μL菌液滴加到LB固体培养基上涂板，每组3个平行样。平板倒置放到37℃培养箱中12h后，取出平板拍照并记录细菌菌落数，与Zr-Fc MOF共培养的细菌为试验组，未与Zr-Fc MOF共培养的细菌为阴性对照组，通过试验组和对照组的菌落数计算抗菌率(Ra)，计算公式如下：
Ra＝(1-Nsample/Nnegative)×100％
Nnegative为阴性组的细菌菌落数，Nsample为试验组的细菌菌落数。
表3
由实施例1～7和对比例3、4的测试结果可以看出，草豆蔻、莪术、黄连、黄柏、三颗针等天然杀菌剂与有机杀菌剂纳米替加环素在抑制细菌生长方面具有较好的协同作用，能够更加有效地杀灭细菌。从实施例1～7和对比例1的测试结果可以看出，对比例1中即使同时添加了天然杀菌剂与有机杀菌剂，但其对于细菌生长的抑制作用仍劣于实施例1～7，推测是由于对比例1中没有加入甘蔗渣纤维，从而天然杀菌剂的耐热性不足，在混合的加热过程中出现部分挥发或活性成分的失效，同时加热过程对于纳米替加环素的活性也存在影响，进而导致了其细菌抑制效果的下降。
3、使用链脲佐菌素诱导Balb/c小鼠成为糖尿病小鼠，将Balb/c小鼠随机分 为13组，每组数量为十只。对小鼠的表皮层切割条形的创口，创口深度以深入表皮层和真皮层并露出皮下组织为准，切口长度为20mm，将1×108CFU/mL的金黄色葡萄球菌与大肠杆菌混合菌液棉签蘸取轻涂在伤口表面，以进行细菌接种，建立细菌感染创面模型。分别将实施例1～7和对比例1～4制得的微针贴片贴附于其中一组小鼠的创口上，并进行1min的持续按压，同时设置空白的微针贴片作为对照组，微针贴片每日更换一次。每天对各组小鼠伤口愈合情况进行记录，以创口结痂且无明显炎症作为愈合标准，测试结果填入表4。
表4
由表4的测试结果可知，采用本发明提供的微针贴片能够有效抑制小鼠创口上细菌的生长，从而起到较好的促进创口愈合的作用，同时，从对比例2的测试结果可以看出，其小鼠愈合比例甚至低于其他对比例，结合表2数据，说明加入有过量的甘蔗渣纤维会导致微针强度的下降，进而在进行微针贴片的给药时，微针出现折断问题，进而使得给药剂量过小而影响给药效果。
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明 的保护范围之内。

Claims (10)

  1. 一种用于预防或治疗皮肤感染的微针贴片，其特征在于，包括外层辅料以及设置于所述外层辅料单侧表面的多个微针，所述微针包括以下重量组分：
    改性天然杀菌剂5～30份、纳米替加环素2～7份和第一水溶性高分子聚合物252～306份；
    所述改性天然杀菌剂包括以下重量组分：
    草豆蔻3～7份、莪术1～2份、黄连1～3份、黄柏2～4份、三颗针1～4份和甘蔗渣纤维4～10份；
    所述外层辅料包括以下重量组分：
    抑菌剂3～8份、止血材料13～18份和第二水溶性高分子聚合物252～306份。
  2. 根据权利要求1所述的用于预防或治疗皮肤感染的微针贴片，其特征在于，所述甘蔗渣纤维的直径为12～28μm，长度为0.42～3.77mm。
  3. 根据权利要求1所述的用于预防或治疗皮肤感染的微针贴片，其特征在于，所述第一水溶性高分子聚合物选自聚乙烯醇、聚乙烯吡咯烷酮、透明质酸、胶原蛋白、丝素蛋白、明胶、羟丙基甲基纤维素、硫酸软骨素、糊精、羧甲基纤维素、羧甲基壳聚糖、硫酸葡聚糖、糖原、直链淀粉、葡聚糖、羟丙基纤维素、糖苷、壳聚糖中的一种或多种。
  4. 根据权利要求1所述的用于预防或治疗皮肤感染的微针贴片，其特征在于，所述微针还包括糖类48-52份和盐12-18份。
  5. 根据权利要求4所述的用于预防或治疗皮肤感染的微针贴片，其特征在于，所述糖类选自蔗糖、海藻糖中的一种或多种，所述盐选自氯化钠。
  6. 根据权利要求1所述的用于预防或治疗皮肤感染的微针贴片，其特征在于，所述抑菌剂选自α-氰基丙烯酸乙酯和银-铜复合纳米粒子中的一种或多种。
  7. 根据权利要求1所述的用于预防或治疗皮肤感染的微针贴片，其特征在 于，所述止血材料选自纳米载银沸石。
  8. 根据权利要求1所述的用于预防或治疗皮肤感染的微针贴片，其特征在于，所述外层辅料还包括止痛剂3～6份，所述止痛剂选自地佐辛和罗哌卡因中的一种或多种。
  9. 根据权利要求1所述的用于预防或治疗皮肤感染的微针贴片，其特征在于，所述外层辅料和所述微针还包括水，以质量计，所述微针和所述外层辅料的含水量为0.1％～15％。
  10. 如权利要求1～9任意一项所述的微针贴片的制备方法，其特征在于，包括以下操作步骤：
    按重量份称取草豆蔻3～7份、莪术1～2份、黄连1～3份、黄柏2～4份、三颗针1～4份和甘蔗渣纤维4～10份进行混合，得到改性天然杀菌剂；
    按重量份称取改性天然杀菌剂5～30份、纳米替加环素2～7份、第一水溶性高分子聚合物252～306份和水517～620份，在85℃～95℃条件下加热并超声分散得到微针成型液；
    按重量份称取抑菌剂3～8份、止血材料13～18份、第二水溶性高分子聚合物252～306份和水517～620份，在85℃～95℃条件下加热并超声分散得到衬底成型液；
    将微针成型液施加于微针成型模具的微针腔中，脱水收缩得到微针的针尖部分；继续施加衬底成型液于微针成型模具上，脱水得到连接所述针尖部分的针体部分以及连接所述针体部分的外层辅料，脱模得到微针贴片。
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