WO2023178818A1 - 一种自发热微针载药贴片及其制备方法 - Google Patents

一种自发热微针载药贴片及其制备方法 Download PDF

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Publication number
WO2023178818A1
WO2023178818A1 PCT/CN2022/093517 CN2022093517W WO2023178818A1 WO 2023178818 A1 WO2023178818 A1 WO 2023178818A1 CN 2022093517 W CN2022093517 W CN 2022093517W WO 2023178818 A1 WO2023178818 A1 WO 2023178818A1
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Prior art keywords
self
microneedle
heating
drug
layer
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PCT/CN2022/093517
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English (en)
French (fr)
Inventor
黄鹏
李星星
邵俊东
林静
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深圳大学
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Publication of WO2023178818A1 publication Critical patent/WO2023178818A1/zh

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    • 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
    • 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
    • A61M2037/0007—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin having means for enhancing the permeation of substances through the epidermis, e.g. using suction or depression, electric or magnetic fields, sound waves or chemical 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
    • A61M2037/0023—Drug applicators using 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
    • A61M2037/0046—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
    • 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
    • A61M2205/00—General characteristics of the apparatus
    • A61M2205/36—General characteristics of the apparatus related to heating or cooling
    • A61M2205/364—General characteristics of the apparatus related to heating or cooling by chemical reaction
    • 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
    • Y02E—REDUCTION OF GREENHOUSE GAS [GHG] EMISSIONS, RELATED TO ENERGY GENERATION, TRANSMISSION OR DISTRIBUTION
    • Y02E60/00—Enabling technologies; Technologies with a potential or indirect contribution to GHG emissions mitigation
    • Y02E60/14—Thermal energy storage

Definitions

  • the invention relates to the technical field of biomedicine, and in particular to a self-heating microneedle drug-loaded patch and a preparation method thereof.
  • Transdermal drug delivery can allow drugs to enter the body circulation through the skin, release drugs at different rates, and even deliver drugs to local tissues of the skin to achieve targeted therapy, minimize adverse reactions, and improve patient compliance.
  • stratum corneum of human skin hinders the delivery of drugs, greatly reducing the delivery efficiency of the drugs, thereby affecting the efficacy of the drugs.
  • microneedle technology is easy and safe to apply and has the dual advantages of injection and transdermal drug delivery
  • microneedle technology is often used to achieve transdermal drug delivery.
  • the delivery efficiency is limited and cannot meet the percutaneous penetration amount to achieve the therapeutic effect within a certain period of time, thus affecting the efficiency of the drug.
  • the purpose of the present invention is to provide a self-heating microneedle drug-loaded patch and a preparation method thereof, aiming to solve the problem of the single function of the microneedle drug-loaded patch in the prior art and the problem of drug delivery. Low efficiency and poor percutaneous penetration.
  • a self-heating microneedle drug-loaded patch including:
  • At least one needle tip drug-loaded layer is distributed on one side of the microneedle backing layer;
  • Heat storage layer the side of the microneedle backing layer away from the needle tip drug-loaded layer is provided with a groove, and the self-heating material is filled in the groove to form the heat storage layer;
  • a sealing layer is provided covering the heat storage layer.
  • the self-heating microneedle drug-loaded patch wherein the needle tip size of the needle tip drug-loaded layer is 100-1000 ⁇ m; the needle tip base size of the needle tip drug-loaded layer is 5-20 mm, and the distance between the needle tip bases The spacing is 100-1000 ⁇ m.
  • the width of the groove is 5 ⁇ 20mm and the depth is 0.1 ⁇ 4mm.
  • the sealing layer is composed of non-woven fabric and adhesive tape.
  • the high molecular polymer is selected from one or more of hyaluronic acid and/or its derivatives, maltose, chitosan, and carboxymethyl cellulose.
  • the preparation method of the self-heating microneedle drug-loaded patch wherein the relative molecular weight of the hyaluronic acid is 1,000 to 10,000; the relative molecular weight of the dextran sodium hyaluronate is 10,000 to 100,000 .
  • the preparation method of the self-heating microneedle drug-loaded patch wherein the concentration of the hydrogel solution is 1 to 50% w/v.
  • the preparation method of the self-heating microneedle drug-loaded patch wherein when the high molecular polymer is hyaluronic acid, the molar ratio of hyaluronic acid to sodium hyaluronate in the hydrogel solution is 5:1 or 5:2.
  • the preparation method of the self-heating microneedle drug-loaded patch wherein the self-heating material is one or more of calcium oxide, iron powder, water, activated carbon, vermiculite, water-absorbent resin, and sodium oxide.
  • the preparation method of the self-heating microneedle drug-loaded patch wherein the conditions of the vacuum drying treatment are: drying at a pressure of -0.1Mpa for 2 to 10 minutes, repeated 1 to 10 times.
  • the invention provides a self-heating microneedle drug-loaded patch and a preparation method thereof.
  • the self-heating microneedle drug-loaded patch includes: a microneedle backing layer, at least one needle tip drug-loaded layer, a heat storage layer and a sealing layer.
  • the needle tip drug-loaded layer is distributed on one side of the microneedle backing layer; a groove is provided on the side of the microneedle backing layer away from the needle tip drug-loaded layer, and the self-heating material is filled in the groove.
  • the heat storage layer is formed; the sealing layer is covered above the heat storage layer.
  • the self-heating material filled in the groove structure can react with water and oxygen in the air to release heat during use, thereby promoting the penetration of the drug.
  • the sealing layer composed of waterproof and breathable non-woven fabric and tape isolates the self-heating material from the air, which facilitates long-term storage of the self-heating microneedle patch.
  • the tape When in use, the tape is peeled off to allow air to pass through the non-woven fabric. Comes into contact with and reacts with self-heating materials.
  • the preparation process of the invention is simple, easy to operate, does not require complicated and expensive equipment, and is easy to realize industrial production.
  • Figure 1 is a schematic structural diagram of a self-heating microneedle drug-loaded patch of the present invention
  • Figure 2 is a picture under an optical microscope of the microneedle drug-loaded patch prepared in Example 1 of the present invention
  • Figure 3 is a picture under a scanning electron microscope of the microneedle drug-loaded patch prepared in Example 1 of the present invention
  • Figure 4 is a picture under an optical microscope of the microneedle drug-loaded patch prepared in Example 2 of the present invention.
  • Figure 5 is a picture under a scanning electron microscope of the microneedle drug-loaded patch prepared in Example 2 of the present invention.
  • Figure 6 is a graph showing the self-heating performance of the microneedle drug-loaded patch prepared in Example 2 of the present invention under different environmental humidity;
  • Figure 7 is a diagram showing the self-heating performance of the microneedle drug-loaded patch prepared in Example 2 of the present invention at different ambient temperatures.
  • the present invention provides a self-heating microneedle drug-loaded patch and a preparation method thereof.
  • the present invention is further described in detail below. It should be understood that the specific embodiments described here are only used to explain the present invention and are not intended to limit the present invention.
  • microneedle technology In order to achieve a therapeutic amount of percutaneous penetration of drugs within a certain period of time, in addition to traditional chemical penetration promotion methods, researchers have proposed many new physical penetration promotion methods, including microneedle technology, ultrasonic introduction technology, electroporation technology, ion Introduction technology, heating penetration promotion technology and electret technology, etc. Among them, microneedle technology is easy and safe to apply, has the dual advantages of injection and transdermal drug delivery, and has been widely studied.
  • Microneedles are patches composed of multiple tiny needle tips less than 1 mm in length connected to a base in an array.
  • the microneedle patch is attached to the skin to penetrate the stratum corneum on the skin surface.
  • a large number of tiny pores will be formed during the entire puncture process, allowing the drug to break through the skin delivery barrier and enter the human blood circulation to play a role, greatly enhancing the The absorption rate of drugs through the skin is suitable for the transdermal delivery of various drug molecules.
  • the microneedle only penetrates the papillary layer of the dermis, it will not cause damage to the dermal tissue, its nerve endings and capillaries, and can reduce pain.
  • the epidermis is at 24 ⁇ Regenerative repair within 48 hours will not promote bacteria to enter the body through micropores and cause infection, and can avoid potential risks of accidental injury.
  • microneedle technology with other penetration-promoting technologies to jointly promote the percutaneous penetration of drugs and improve drug delivery efficiency to a greater extent.
  • the present invention provides a self-heating microneedle drug-loaded patch, including:
  • Microneedle backing layer 10 at least one needle tip drug-loaded layer 20, heat storage layer 30 and sealing layer 40; the needle tip drug-loaded layer is distributed on one side of the microneedle backing layer; the microneedle backing layer A groove is formed on the side away from the drug-loaded layer of the needle tip, and the self-heating material is filled in the groove to form the heat storage layer; the sealing layer is covered above the heat storage layer.
  • the self-heating microneedle drug-loaded patch of the present invention has sufficient mechanical strength, can penetrate the stratum corneum of the skin, and can maintain the stability of the drug.
  • a groove is provided on the side of the microneedle backing layer away from the needle tip drug-loaded layer, and a self-heating material is filled in the groove, so that the self-heating material can interact with water (water molecules) in the air during use. Reacts with oxygen to release heat and improves drug penetration.
  • the present invention combines microneedle technology with heating penetration-promoting technology to jointly promote the transdermal penetration of drugs, improve drug delivery efficiency, and enable the transdermal penetration amount of drugs within a certain period of time to meet the therapeutic amount requirements.
  • the tip size of the needle tip drug-loaded layer is 100-1000 ⁇ m; the tip base size of the needle tip drug-loaded layer is 5-20 mm, and the distance between the needle tip bases is 100-1000 ⁇ m.
  • the needle tip drug-loaded layer matrix is arranged on one side of the microneedle backing layer.
  • the width of the groove is 5 ⁇ 20mm, and the depth is 0.1 ⁇ 4mm.
  • the groove is set to this size, which can effectively improve the drug delivery efficiency. If the groove size is too large, more self-heating material will be filled, and excessive heat will easily cause burns to the user's skin. If the groove size is too large, the user's skin will be scalded. Small, self-heating materials have poor heating effect and cannot improve drug delivery efficiency.
  • the sealing layer is composed of non-woven fabric and adhesive tape.
  • the non-woven fabric is a waterproof and breathable non-woven fabric. Except for passing through the non-woven fabric in the form of gas, liquid substances cannot pass through it.
  • a layer of non-woven fabric is arranged above the heat storage layer, and then a layer of tape is arranged above the non-woven fabric.
  • the tape When used, the tape is peeled off to expose the non-woven fabric, so that water vapor in the air and Oxygen can pass through the non-woven fabric and react with the self-heating material to produce an exothermic reaction, achieving the effect of heating the microneedle drug-loaded patch; and the sealing layer is composed of non-woven fabric and adhesive tape to facilitate self-heating Long-term storage of microneedle drug-loaded patches.
  • the shape of the needle body of the needle tip drug-loading layer is a cone, a triangular pyramid, a four-sided pyramid, a five-sided pyramid, a six-sided pyramid, a seven-sided pyramid, or an eight-sided pyramid.
  • the present invention provides a method for preparing a self-heating microneedle drug-loaded patch as described above, which includes the steps:
  • Step S10 Dissolve the high molecular polymer and dextran sodium hyaluronate in water and stir evenly to obtain a hydrogel solution;
  • Step S20 Pour the hydrogel solution into a microneedle mold, and perform vacuum drying on the microneedle mold;
  • Step S30 After vacuum drying, dry and solidify to obtain a microneedle patch with the groove structure;
  • Step S40 Add self-heating material into the groove, and perform packaging processing to prepare the self-heating microneedle patch;
  • the high molecular polymer is selected from hyaluronic acid (hyaluronic acid) acid, HA) and/or its derivatives, maltose, chitosan, carboxymethylcellulose (Carboxymethyl Cellulose) one or more.
  • the invention provides a method for preparing a self-heating microneedle drug-loaded patch, using a hydrogel solution as a base material, and preparing a self-heating microneedle patch with a multi-layer structure through a vacuum drying method.
  • the hydrogel of the invention The base material has good biocompatibility, biodegradability, viscoelasticity and hydrophilicity; the microneedles prepared using this hydrogel solution have sufficient mechanical strength to pierce the stratum corneum of the skin and can maintain the stability of the drug. .
  • the drying method dries the hydrogel solution so that it can completely fill the microneedle mold and avoid the appearance of bubble holes. Combined with the drying and solidification treatment, the preparation process of the present invention is simple, easy to operate, does not require complicated and expensive equipment, and is easy to implement. Industrial production.
  • the microneedle mold is made according to the shape of the self-heating microneedle patch and is a needle-shaped container with multiple microneedle drug-loaded layers, and a filler is provided at the solution inlet. , so that the produced product has a groove structure.
  • the relative molecular weight of the hyaluronic acid is 1,000 to 10,000; the relative molecular weight of the dextran sodium hyaluronate is 10,000 to 100,000.
  • the concentration of the hydrogel solution is 1 ⁇ 50% w/v; preferably, the concentration of the hydrogel solution is 10 ⁇ 20% w/v.
  • the molar ratio of high molecular polymer to sodium hyaluronate in the hydrogel solution is 5: (1-2).
  • the molar ratio of hyaluronic acid to sodium hyaluronate in the hydrogel solution is 5:1 or 5:2.
  • the self-heating material is one or more of calcium oxide, iron powder, water, activated carbon, vermiculite, water-absorbent resin, and sodium oxide.
  • the self-heating material is one or more of calcium oxide, iron powder, water, activated carbon, vermiculite, water-absorbent resin, and sodium oxide.
  • the conditions for the vacuum drying process are: drying for 2 to 10 minutes at a pressure of -0.1Mpa, repeated 1 to 10 times; as a preferred embodiment, the conditions for the vacuum drying process are: at a pressure of -0.1Mpa -0.1Mpa, dry for 3 to 5 minutes, and repeat 3 to 5 times. Under this condition, the hydrogel solution has a better effect of filling the microneedle grinding tool, and structural defects caused by bubbles are less likely to occur.
  • ultrapure water, purified water or deionized water is used as the water used to dissolve the high molecular polymer and dextran sodium hyaluronate in step S10.
  • the conditions for the drying and curing treatment in step S30 are: drying and curing for 4 to 12 hours at a temperature of 20 to 40°C; as a preferred embodiment, the conditions for the drying and curing treatment are: at a temperature of Dry and solidify at 30 ⁇ 37°C for 8 ⁇ 10 hours.
  • the non-woven fabric is selected from one of medical SMS, SMMS, and SSMMS.
  • the preparation method of the self-heating microneedle drug-loaded patch includes the steps :
  • Step S1 Dissolve hyaluronic acid and dextran sodium hyaluronate in water, stir evenly to obtain a HA hydrogel solution;
  • Step S20 pour the HA hydrogel solution into a microneedle mold, and vacuum dry the microneedle mold so that the HA hydrogel solution completely fills the microneedle mold;
  • Step S30 After vacuum drying, dry and solidify to obtain a microneedle patch with the groove structure;
  • Step S40 Add self-heating material calcium oxide into the groove, and perform encapsulation processing to prepare the self-heating microneedle patch.
  • HA is used as the base material and a self-heating microneedle patch with a multi-layer structure is prepared through a vacuum drying method.
  • the HA base material of the present invention has good biocompatibility, biodegradability, viscoelasticity and hydrophilicity.
  • the prepared microneedles have sufficient mechanical strength to pierce the stratum corneum of the skin and can maintain the stability of the drug.
  • the calcium oxide filled in the grooves can provide a heat source for the self-heating microneedle patch during use, thereby improving the percutaneous penetration of the drug.
  • Step 1 Dissolve 1.8 g of hyaluronic acid in 12 mL of ultrapure water at room temperature and stir for 30 minutes to form a hyaluronic acid solution with a concentration of 15% (w/v).
  • Step 2 Dissolve 0.36 g sodium hyaluronate in the hyaluronic acid solution obtained in step 1 at room temperature and stir for 30 minutes to prepare a hyaluronic acid hydrogel (HA) with a concentration of 18% (w/v). Hydrogels).
  • HA hyaluronic acid hydrogel
  • Step 3 Take 0.4 mL of hyaluronic acid hydrogel with a concentration of 18% (w/v) and fill it into the entire space of the PDMS mold. Use an air pump to perform negative pressure vacuum treatment on the microneedle mold to ensure that the solution completely enters the pinholes. Vacuum to -0.1 Mpa, vacuum dry for 3 to 5 minutes each time, repeat 3 to 5 times.
  • Step 4 Put the sample prepared in Step 3 into a 37°C oven and dry it for 8 to 10 hours. After the microneedles are solidified, carefully demould to obtain a microneedle patch with a groove structure.
  • Step 5 Fill the grooves of the microneedle patch obtained in step 4 with self-heating material, and encapsulate the microneedles with non-woven fabric in the glove box to obtain a self-heating microneedle carrier with self-heating function.
  • Medicinal patch
  • the morphology and structure of the self-heating microneedle patches prepared in the examples were analyzed by optical microscopy and scanning electron microscopy (scanning Electron microscope, SEM) was observed, and the results are shown in Figure 2 (Photograph under the optical microscope) and Figure 3 (Photograph under the Scanning Electron Microscope, the scale bar from left to right is 500 ⁇ m, 200 ⁇ m, 100 ⁇ m), indicating that the prepared
  • the self-heating microneedle patch has a multi-layer structure, in which the length of the tip layer of the microneedle is 600 um, the length of the backing layer is 2 mm, and the groove depth of the heat storage layer is 1.8 mm.
  • the self-heating microneedle patch prepared in Example 1 was applied to mouse skin.
  • the results showed that the self-heating microneedle patch had good mechanical properties and could penetrate the stratum corneum of the skin to release drugs.
  • the patch is removed from the skin, and the mouse skin regenerates and repairs within 6 hours. This will not cause bacteria to enter the body through the micropores and cause infection, and can avoid potential risks of accidental injury.
  • Step 1 Dissolve 1.8 g of hyaluronic acid in 14 mL of ultrapure water at room temperature and stir for 30 minutes to form a hyaluronic acid solution with a concentration of 15% (w/v).
  • Step 2 Dissolve 0.72 g of sodium hyaluronate in the hyaluronic acid solution obtained in step 1 at room temperature and stir for 30 minutes to prepare a hyaluronic acid hydrogel with a concentration of 18% (w/v).
  • Step 3 Take 0.5 mL of hyaluronic acid hydrogel with a concentration of 18% (w/v) and fill it into the entire space of the PDMS mold. Use an air pump to perform negative pressure vacuum treatment on the microneedle mold to ensure that the solution completely enters the pinholes. Vacuum to -0.1 Mpa, vacuum dry for 3 to 5 minutes each time, repeat 3 to 5 times.
  • Step 4 Put the sample prepared in Step 3 into an oven at 37°C and dry for 8 to 10 hours. After the microneedles are solidified, carefully demould to obtain a microneedle patch with a groove structure.
  • Step 5 Fill the groove structure of the microneedle patch obtained in step 4 with self-heating material, and encapsulate the microneedles with non-woven fabric in the glove box to obtain self-heating microneedles with self-heating function Medicinal patches.
  • the morphology and structure of the self-heating microneedle patch prepared in Example 2 were observed through an optical microscope and a scanning electron microscope. The results are shown in Figure 4 (photograph under an optical microscope, scale bar is 500 ⁇ m) and Figure 5 (scanning electron microscope). The photos under the microscope (the scale from left to right are 500 ⁇ m and 200 ⁇ m) show that the self-heating microneedle patch has a multi-layer structure, in which the length of the tip layer of the microneedle is 800 um, the backing layer length is 4 mm, and the groove depth in the heat storage layer is 3.8 mm.
  • the sealing tape of the self-heating microneedle drug-loaded patch prepared in Example 2 was peeled off, and when the ambient temperature was 26°C and the ambient humidity was 60%, 70% and 80%, use infrared thermal imaging to The instrument detects the self-heating performance and heat conduction ability of the self-heating microneedle patch from bottom to top.
  • the sealing tape of the self-heating microneedle patch prepared in Example 2 was peeled off, and when the ambient humidity was 50%, the ambient temperature was 20°C, 26°C and 30°C, and an infrared thermal imaging camera was used to automatically Detect the self-heating performance and heat conduction ability of the self-heating microneedle patch from bottom to top.
  • the infrared thermal image transmitted from the heat storage layer to the needle tip layer; c is the infrared thermal image transmitted from the heat storage layer to the needle tip layer in the self-heating microneedle patch when the ambient temperature is 30°C; d is the needle tip at different ambient temperatures.
  • the self-heating microneedle patch has good self-heating performance under different humidity and environmental temperature conditions, and the needle tip layer can be heated to 40 degrees.
  • the present invention provides a self-heating microneedle drug-loaded patch and a preparation method thereof.
  • the self-heating microneedle drug-loaded patch includes: a microneedle backing layer, at least one needle tip drug-loaded layer, a heat storage layer and sealing layer, the needle tip drug-loaded layer is distributed on one side of the microneedle backing layer; the microneedle backing layer has a groove on the side away from the needle tip drug-loaded layer, and the groove is
  • the heat storage layer is formed by filling the self-heating material inside; the sealing layer is covered above the heat storage layer.
  • the self-heating material filled in the groove structure can react with water and oxygen in the air to release heat during use, thereby promoting the penetration of the drug.
  • the sealing layer composed of waterproof and breathable non-woven fabric and tape isolates the self-heating material from the air, which facilitates long-term storage of the self-heating microneedle patch.
  • the tape When in use, the tape is peeled off to allow air to pass through the non-woven fabric. Comes into contact with and reacts with self-heating materials.
  • the preparation process of the invention is simple, easy to operate, does not require complicated and expensive equipment, and is easy to realize industrial production.

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Abstract

一种自发热微针载药贴片及其制备方法，所述自发热微针载药贴片包括：微针背衬层、至少一个针尖载药层、储热层和密封层，针尖载药层分布于微针背衬层的其中一面；微针背衬层远离针尖载药层的一面开设有凹槽，在凹槽内填充自发热材料形成储热层；密封层盖设于储热层上方。在凹槽结构中填充的自发热材料可以在使用时与空气中的水和氧气反应放热，促进药物的渗透。而由防水透气无纺布和胶布组成的密封层则将自发热材料与空气隔绝开，便于自发热微针贴片的长期储存，而在使用时，揭开胶布使得空气可以透过无纺布与自发热材料接触并发生反应。所述贴片制备工艺简单、操作方便，不需要复杂昂贵的设备，易于实现工业化生产。

Description

一种自发热微针载药贴片及其制备方法 技术领域
本发明涉及生物医药技术领域，尤其涉及一种自发热微针载药贴片及其制备方法。
 背景技术
近年来，经皮给药越来越受到人们的关注。经皮给药的方式可以使药物透过皮肤进入体内循环，以不同的速度释放药物，甚至可以将药物递送到皮肤局部组织以实现靶向治疗，最大限度地减少不良反应，提高患者的依从性。然而，人体皮肤的角质层阻碍了药物的传递，大大降低了药物的传递效率，进而影响药物的药效。
由于微针技术应用简便安全，具有注射给药和透皮给药的双重优点，因此，目前常采用微针技术实现经皮给药。但是，单一的微针技术在给皮肤递送药物时，递送效率有限，不能够满足在一定时间内的经皮渗透量达到治疗量的效果，进而影响药物的效率。
因此，现有技术还有待于改进和发展。
 技术问题
鉴于上述现有技术的不足，本发明的目的在于提供一种自发热微针载药贴片及其制备方法，旨在解决现有技术中的微针载药贴片功能较为单一，药物的递送效率较低，经皮渗透效果较差的问题。
 技术解决方案
本发明的技术方案如下：
一种自发热微针载药贴片，包括：
微针背衬层；
至少一个针尖载药层，所述针尖载药层分布于所述微针背衬层的其中一面；
储热层，所述微针背衬层远离所述针尖载药层的一面开设有凹槽，在所述凹槽内填充自发热材料，形成所述储热层；
密封层，所述密封层盖设于所述储热层上方。
所述的自发热微针载药贴片，其中，所述针尖载药层的针尖尺寸为100-1000μm；所述针尖载药层的针尖底座尺寸为5-20mm，且所述针尖底座之间的间距为100-1000μm。
所述的自发热微针载药贴片，其中，所述凹槽的宽度为5~20mm，深度为0.1~4mm。
所述的自发热微针载药贴片，其中，所述密封层由无纺布和胶布组成。
一种如上所述的自发热微针载药贴片的制备方法，包括步骤：
将高分子聚合物和葡聚糖醛酸透明质酸钠溶于水中，搅拌均匀后得到水凝胶溶液；
将所述水凝胶溶液倒入微针模具中，对所述微针模具进行真空干燥处理；
真空干燥处理后进行干燥固化，得到具有所述凹槽结构的微针贴片；
向所述凹槽中加入自发热材料，并进行封装处理，制得所述自发热微针贴片；
其中，所述高分子聚合物选自透明质酸和/或其衍生物、麦芽糖、壳聚糖、羧甲基纤维素中的一种或多种。
所述的自发热微针载药贴片的制备方法，其中，所述透明质酸的相对分子量为1000至10000；所述葡聚糖醛酸透明质酸钠的相对分子量为1万至10万。
所述的自发热微针载药贴片的制备方法，其中，所述水凝胶溶液的浓度为1~50%w/v。
所述的自发热微针载药贴片的制备方法，其中，当所述高分子聚合物为透明质酸时，所述水凝胶溶液中的透明质酸与透明质酸钠的摩尔比为5:1或5:2。
所述的自发热微针载药贴片的制备方法，其中，所述自发热材料为氧化钙、铁粉、水、活性炭、蛭石、吸水性树脂、氧化钠中的一种或多种。
所述的自发热微针载药贴片的制备方法，其中，所述真空干燥处理的条件为：在压强-0.1Mpa下，干燥2~10min，重复1~10次。
 有益效果
本发明提供一种自发热微针载药贴片及其制备方法，所述自发热微针载药贴片包括：微针背衬层、至少一个针尖载药层、储热层和密封层，所述针尖载药层分布于所述微针背衬层的其中一面；所述微针背衬层远离所述针尖载药层的一面开设有凹槽，在所述凹槽内填充自发热材料形成所述储热层；所述密封层盖设于所述储热层上方。在所述凹槽结构中填充的自发热材料可以在使用时与空气中的水和氧气发生反应放热，促进药物的渗透。而由防水透气无纺布和胶布组成的密封层则将自发热材料与空气隔绝开，便于自发热微针贴片的长期储存，而在使用时，揭开胶布使得空气可以透过无纺布与自发热材料接触并发生反应。本发明的制备工艺简单、操作方便，不需要复杂昂贵的设备，易于实现工业化生产。
 附图说明
图1为本发明一种自发热微针载药贴片的结构示意图；
图2为本发明实施例1制得的微针载药贴片在光学显微镜下的图片；
图3为本发明实施例1制得的微针载药贴片在扫描电子显微镜下的图片；
图4为本发明实施例2制得的微针载药贴片在光学显微镜下的图片；
图5为本发明实施例2制得的微针载药贴片在扫描电子显微镜下的图片；
图6为本发明实施例2制得的微针载药贴片在不同环境湿度下的自发热表现图；
图7为本发明实施例2制得的微针载药贴片在不同环境温度下的自发热表现图。
 本发明的最佳实施方式
本发明提供一种自发热微针载药贴片及其制备方法，为使本发明的目的、技术方案及效果更加清楚、明确，以下对本发明进一步详细说明。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。
 本发明的实施方式
为了使药物在一定时间内的经皮渗透量达到治疗量，除传统的化学促透方法外，研究人员提出许多新型物理促透方法，包括微针技术、超声导入技术、电致孔技术、离子导入技术、加热促渗技术和驻极体技术等。其中，微针技术应用简便安全，具有注射给药和透皮给药的双重优点，得到人们的广泛研究。
微针是多个长度小于1 mm的细小针尖以阵列方式连接在基座上组成的贴片。将微针贴片贴在皮肤上以穿透皮肤表面的角质层，整个穿刺的过程中会形成大量微小的孔道，从而使药物能突破皮肤给药屏障，进入人体血液循环发挥作用，大大增强了皮肤对药物的吸收率，适合各种药物分子的经皮给药。同时，由于微针只刺穿真皮乳头层，不会对真皮组织及其神经末梢和毛细血管造成损伤，可以降低疼痛。而且，表皮在 24 ~ 48 小时内的再生修复，不会促使细菌通过微孔进入体内而引起感染，可以避免潜在的意外伤害风险。
然而，目前使用微针贴片经皮给药的效果较为单一，不能够使药物在一定时间内的经皮渗透量达到治疗量的要求。因此，急需将微针技术与其它促渗技术相结合，共同促进药物的经皮渗透，能更大程度的提高药物的递送效率。
基于此，如图1所示，本发明提供一种自发热微针载药贴片，包括：
微针背衬层10、至少一个针尖载药层20、储热层30和密封层40；所述针尖载药层分布于所述微针背衬层的其中一面；所述微针背衬层远离所述针尖载药层的一面开设有凹槽，在所述凹槽内填充自发热材料，形成所述储热层；所述密封层盖设于所述储热层上方。
本发明的自发热微针载药贴片具有足够的机械强度，可以刺穿皮肤角质层，并且能够保持药物的稳定性。在所述微针背衬层远离所述针尖载药层的一面开设凹槽，并在凹槽内填充自发热材料，可以在使用时使得所述自发热材料与空气中的水（水分子）和氧气反应放热，提高药物的渗透效果。本发明通过将微针技术结合加热促渗技术，共同促进药物的经皮渗透，提高药物的递送效率，使药物在一定时间内的经皮渗透量达到治疗量的要求。
在一些实施方式中，所述针尖载药层的针尖尺寸为100-1000μm；所述针尖载药层的针尖底座尺寸为5-20mm，且所述针尖底座之间的间距为100-1000μm。所述针尖载药层矩阵排列在所述微针背衬层的一面。
在一些实施方式中，所述凹槽的宽度为5~20mm，深度为0.1~4mm。所述凹槽设定为该尺寸，可以有效提高药物的递送效率，凹槽尺寸过大，填充的自发热材料就越多，发热过多，容易导致烫伤使用者的皮肤；凹槽的尺寸过小，自发热材料的发热效果差，起不到提高药物递送效率的效果。
在一些实施方式中，所述密封层由无纺布和胶布组成。所述无纺布为防水透气的无纺布，除了以气体形式透过无纺布，液态物质无法透过。本发明在所述储热层的上方设一层无纺布，然后在无纺布的上方设置一层胶布，当使用时，将胶布揭开，露出无纺布，使得空气中的水蒸气和氧气可以透过无纺布，并与所述自发热材料接触发生放热反应，达到为微针载药贴片加热的效果；并且，利用无纺布和胶布组成所述密封层，便于自发热微针载药贴片的长期存放。
在一些实施方式中，所述针尖载药层的针体形状为圆锥、三棱锥、四棱锥、五棱锥、六棱锥、七棱锥或八棱锥。
除此之外，本发明提供一种如上所述的自发热微针载药贴片的制备方法，包括步骤：
步骤S10：将高分子聚合物和葡聚糖醛酸透明质酸钠溶于水中，搅拌均匀后得到水凝胶溶液；
步骤S20：将所述水凝胶溶液倒入微针模具中，对所述微针模具进行真空干燥处理；
步骤S30：真空干燥处理后进行干燥固化，得到具有所述凹槽结构的微针贴片；
步骤S40：向所述凹槽中加入自发热材料，并进行封装处理，制得所述自发热微针贴片；
其中，所述高分子聚合物选自透明质酸（hyaluronic acid，HA）和/或其衍生物、麦芽糖（maltose）、壳聚糖（chitosan）、羧甲基纤维素（Carboxymethyl Cellulose）中的一种或多种。
本发明提供的一种自发热微针载药贴片的制备方法，以水凝胶溶液为基底材料，通过真空干燥法制备具有多层结构的自发热微针贴片，本发明的水凝胶基底材料具有好的生物相容性、生物可降解性、粘弹性和亲水性；利用该水凝胶溶液制备的微针具有足够的机械强度刺穿皮肤角质层，并且能够保持药物的稳定性。在凹槽中加入自发热材料，并使用无纺布和胶布组成密封层进行封装处理，可以将自发热材料与空气隔绝开，便于自发热微针载药贴片的长期储存；而是要真空干燥法对水凝胶溶液进行干燥，可以使其完全填充微针模具，避免气泡孔出现，再结合干燥固化处理，使得本发明的制备工艺简单，操作方便，不需要复杂昂贵的设备，易于实现工业化生产。
需要说明的是，所述微针模具是根据所述自发热微针贴片的形状制作，为一个具有多个微针载药层的针体形状的容器，且其溶液入口处设有一填充物，使得制得的产品具有凹槽结构。
在一些实施方式中，所述透明质酸的相对分子量为1000至10000；所述葡聚糖醛酸透明质酸钠的相对分子量为1万至10万。
在一些实施方式中，所述水凝胶溶液的浓度为1~50%w/v；优选地，所述水凝胶溶液的浓度为10~20%w/v。
在一些实施方式中，所述水凝胶溶液中的高分子聚合物与透明质酸钠的摩尔比为5:（1-2）。
在一些实施方式中，当所述高分子聚合物为透明质酸时，所述水凝胶溶液中的透明质酸与透明质酸钠的摩尔比为5:1或5:2。
在一些实施方式中，所述自发热材料为氧化钙、铁粉、水、活性炭、蛭石、吸水性树脂、氧化钠中的一种或多种。当氧化钙、铁粉、水、活性炭、蛭石、吸水性树脂、氧化钠中的一种或多种与氧气和水蒸气接触时，会发生放热反应，从而达到为所述自发热微针贴片提供热源，进而提高药物的经皮渗透效果。
在一些实施方式中，所述真空干燥处理的条件为：在压强-0.1Mpa下，干燥2~10min，重复1~10次；作为优选的实施方式，所述真空干燥处理的条件为：在压强-0.1Mpa下，干燥3~5min，重复3~5次，在该条件下，所述水凝胶溶液填充所述微针磨具的效果更好，不易出现气泡导致的结构缺陷。
在一些实施方式中，所述步骤S10用于溶解高分子聚合物和葡聚糖醛酸透明质酸钠的水使用超纯水、纯净水或去离子水。
在一些实施方式中，所述步骤S30中的干燥固化处理的条件为：在温度为20~40℃下，干燥固化4~12小时；作为优选地实施方式，干燥固化处理的条件为：在温度为30~37℃下，干燥固化8~10小时。
在一些实施方式中，所述无纺布选自医用SMS、SMMS、SSMMS中的一种。
为了更好地解释本发明，本实施方式中，以所述高分子聚合物为透明质酸，自发热材料为氧化钙为例，所述自发热微针载药贴片的制备方法，包括步骤：
步骤S1：将透明质酸和葡聚糖醛酸透明质酸钠溶于水中，搅拌均匀后得到HA水凝胶溶液；
步骤S20：将所述HA水凝胶溶液倒入微针模具中，对所述微针模具进行真空干燥处理，使所述HA水凝胶溶液完全填充微针模具；
步骤S30：真空干燥处理后进行干燥固化，得到具有所述凹槽结构的微针贴片；
步骤S40：向所述凹槽中加入自发热材料氧化钙，并进行封装处理，制得所述自发热微针贴片。
本实施方式以HA为基底材料,通过真空干燥法制备具有多层结构的自发热微针贴片。本发明的HA基底材料具有好的生物相容性、生物可降解性、粘弹性和亲水性。所制备的微针具有足够的机械强度刺穿皮肤角质层，并且能够保持药物的稳定性。并且，利用填充在凹槽内的氧化钙，可以在使用时为自发热微针贴片提供热源，进而提高药物经皮渗透的效果。
下面进一步举例实施例以详细说明本发明。同样应理解，以下实施例只用于对本发明进行进一步说明，不能理解为对本发明保护范围的限制，本领域的技术人员根据本发明的上述内容作出的一些非本质的改进和调整均属于本发明的保护范围。
实施例1
步骤1：室温下，将1.8 g透明质酸溶解在 12 mL超纯水中并搅拌30 min形成浓度为15% (w/v) 的透明质酸溶液。
步骤2：室温下，将0.36 g透明质酸钠溶解在步骤1中所得到的透明质酸溶液并搅拌30 min，制备得到浓度为18% (w/v) 的透明质酸水凝胶（HA水凝胶）。
步骤3：取0.4 mL，浓度为18% (w/v)的透明质酸水凝胶，填充至PDMS模具的整个空间。通过气泵对微针模具进行负压抽真空处理，保证溶液完全进入针孔中。抽真空至-0.1 Mpa，每次真空干燥3～5 min，重复3～5次。
步骤4：将步骤3所制备的样品放入37℃烘箱，干燥8～10 h，待微针固化后，小心脱模，得到一个具有凹槽结构的微针贴片。
步骤5：在步骤4所得到的微针贴片的凹槽中填充自发热材料，并在手套箱中，用无纺布将微针进行封装，即得到具有自发热功能的自发热微针载药贴片。
对实施例制得的自发热微针贴片的形貌和结构通过光学显微镜和扫描电子显微镜（scanning electron microscope, SEM）进行了观察，结果如图2（光学显微镜下的照片）和图3（扫描电子显微镜下的照片，自左向右标尺为500μm、200μm、100μm）所示，表明所制得的自发热微针贴片具有多层结构，其中微针的针尖层长度为600 um，背衬层长度为2 mm，储热层的凹槽深度为1.8 mm。
将实施例1制得的自发热微针贴片应用于用于小鼠皮肤，结果表示，自发热微针贴片具有良好的力学性能，可以穿透皮肤的角质层释放药物。并且在将微针按压小鼠皮肤2 min 后，从皮肤上去除贴片，小鼠皮肤在6 h内再生修复，不会促使细菌通过微孔进入体内而引起感染，可以避免潜在的意外伤害风险。
实施例2
步骤1：室温下，将1.8 g 透明质酸溶解在 14 mL 超纯水中并搅拌 30 min形成浓度为15% (w/v) 的透明质酸溶液。
步骤2：室温下，将0.72 g透明质酸钠溶解在步骤1中所得到的透明质酸溶液并搅拌30 min，制备得到浓度为18% (w/v) 的透明质酸水凝胶。
步骤3：取0.5 mL，浓度为18% (w/v)的透明质酸水凝胶，填充至PDMS模具的整个空间。通过气泵对微针模具进行负压抽真空处理，保证溶液完全进入针孔中。抽真空至-0.1 Mpa，每次真空干燥3～5 min，重复3～5次。
步骤4：将步骤3所制备的样品放入37 ℃烘箱，干燥8～10 h，待微针固化后，小心脱模，得到一个具有凹槽结构的微针贴片。
步骤5：在步骤4所得到的微针贴片的凹槽结构中填充自发热材料，并在手套箱中，用无纺布将微针进行封装，即得到具有自发热功能的自发热微针载药贴片。
对实施例2制得的自发热微针贴片的形貌和结构通过光学显微镜和扫描电子显微镜进行了观察，结果如图4（光学显微镜下的照片，标尺为500μm）和图5（扫描电子显微镜下的照片，自左向右标尺为500μm、200μm）所示，表明所制得的自发热微针贴片具有多层结构，其中微针的针尖层长度为800 um，背衬层长度为4 mm，储热层中的凹槽深度为3.8 mm。
实施例3
检测实施例2中制备的自发热微针贴片的自发热表现，具体步骤如下：
将实施例2所制备的自发热微针载药贴片的密封胶布揭开，在环境温度为26 ℃时，分别在环境湿度为60%、70%和80%的条件下，用红外热像仪自下而上检测自发热微针贴片的自发热表现和热传导能力。
将实施例2所制备的自发热微针贴片的密封胶布揭开，在环境湿度为50%时，分别在环境温度为20 ℃、26 ℃和30 ℃的条件下，用红外热像仪自下而上检测自发热微针贴片的自发热表现和热传导能力。
结果如图6（其中a为自发热微针贴片中由储热层传至针尖层的红外热像图；b为对应的在不同环境湿度下针尖层的升温曲线）、图7（其中a为在环境温度为20℃ 时，自发热微针贴片中由储热层传至针尖层的红外热像图；b为在环境温度为26℃ 时，自发热微针贴片中由储热层传至针尖层的红外热像图；c为在环境温度为30℃ 时，自发热微针贴片中由储热层传至针尖层的红外热像图；d为在不同环境温度下针尖层的升温曲线）所示，自发热微针贴片在不同湿度、不同环境温度条件下，均具有良好的自发热表现，针尖层均可以升温至40度。
 工业实用性
综上所述，本发明提供一种自发热微针载药贴片及其制备方法，所述自发热微针载药贴片包括：微针背衬层、至少一个针尖载药层、储热层和密封层，所述针尖载药层分布于所述微针背衬层的其中一面；所述微针背衬层远离所述针尖载药层的一面开设有凹槽，在所述凹槽内填充自发热材料形成所述储热层；所述密封层盖设于所述储热层上方。在所述凹槽结构中填充的自发热材料可以在使用时与空气中的水和氧气反应放热，促进药物的渗透。而由防水透气无纺布和胶布组成的密封层则将自发热材料与空气隔绝开，便于自发热微针贴片的长期储存，而在使用时，揭开胶布使得空气可以透过无纺布与自发热材料接触并发生反应。本发明的制备工艺简单、操作方便，不需要复杂昂贵的设备，易于实现工业化生产。
应当理解的是，本发明的应用不限于上述的举例，对本领域普通技术人员来说，可以根据上述说明加以改进或变换，所有这些改进和变换都应属于本发明所附权利要求的保护范围。

Claims (10)

  1. 一种自发热微针载药贴片，其特征在于，包括：
    微针背衬层；
    至少一个针尖载药层，所述针尖载药层分布于所述微针背衬层的其中一面；
    储热层，所述微针背衬层远离所述针尖载药层的一面开设有凹槽，在所述凹槽内填充自发热材料，形成所述储热层；
    密封层，所述密封层盖设于所述储热层上方。
  2. 根据权利要求1所述的自发热微针载药贴片，其特征在于，所述针尖载药层的针尖尺寸为100-1000μm；所述针尖载药层的针尖底座尺寸为5-20mm，且所述针尖底座之间的间距为100-1000μm。
  3. 根据权利要求1所述的自发热微针载药贴片，其特征在于，所述凹槽的宽度为5~20mm，深度为0.1~4mm。
  4. 根据权利要求1所述的自发热微针载药贴片，其特征在于，所述密封层由无纺布和胶布组成。
  5. 一种如权利要求1-4任一所述的自发热微针载药贴片的制备方法，其特征在于，包括步骤：
    将高分子聚合物和葡聚糖醛酸透明质酸钠溶于水中，搅拌均匀后得到水凝胶溶液；
    将所述水凝胶溶液倒入微针模具中，对所述微针模具进行真空干燥处理；
    真空干燥处理后进行干燥固化，得到具有所述凹槽结构的微针贴片；
    向所述凹槽中加入自发热材料，并进行封装处理，制得所述自发热微针贴片；
    其中，所述高分子聚合物选自透明质酸和/或其衍生物、麦芽糖、壳聚糖、羧甲基纤维素中的一种或多种。
  6. 根据权利要求5所述的自发热微针载药贴片的制备方法，其特征在于，所述透明质酸的相对分子量为1000至10000；所述葡聚糖醛酸透明质酸钠的相对分子量为1万至10万。
  7. 根据权利要求5所述的自发热微针载药贴片的制备方法，其特征在于，所述水凝胶溶液的浓度为1~50%w/v。
  8. 根据权利要求5所述的自发热微针载药贴片的制备方法，其特征在于，当所述高分子聚合物为透明质酸时，所述水凝胶溶液中的透明质酸与透明质酸钠的摩尔比为5:1或5:2。
  9. 根据权利要求5所述的自发热微针载药贴片的制备方法，其特征在于，所述自发热材料为氧化钙、铁粉、水、活性炭、蛭石、吸水性树脂、氧化钠中的一种或多种。
  10. 根据权利要求5所述的自发热微针载药贴片的制备方法，其特征在于，所述真空干燥处理的条件为：在压强-0.1Mpa下，干燥2~10min，重复1~10次。
PCT/CN2022/093517 2022-03-23 2022-05-18 一种自发热微针载药贴片及其制备方法 WO2023178818A1 (zh)

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