WO2023040568A1 - 一种不可溶的透皮微针贴片及其制备方法和应用 - Google Patents

一种不可溶的透皮微针贴片及其制备方法和应用 Download PDF

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WO2023040568A1
WO2023040568A1 PCT/CN2022/113262 CN2022113262W WO2023040568A1 WO 2023040568 A1 WO2023040568 A1 WO 2023040568A1 CN 2022113262 W CN2022113262 W CN 2022113262W WO 2023040568 A1 WO2023040568 A1 WO 2023040568A1
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sodium alginate
cross
microneedles
transdermal
microneedle
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PCT/CN2022/113262
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English (en)
French (fr)
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高云华
周泽荃
张锁慧
杨国忠
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中国科学院理化技术研究所
中科微针（北京）科技有限公司
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Priority to JP2023537226A priority Critical patent/JP7529914B2/ja
Publication of WO2023040568A1 publication Critical patent/WO2023040568A1/zh
Priority to US18/329,399 priority patent/US11801373B1/en

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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
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • 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
    • 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
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • 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
    • A61M2037/0061—Methods for using 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 invention relates to the technical field of medicine. More specifically, it relates to an insoluble transdermal microneedle patch and its preparation method and application.
  • Transdermal drug delivery is a common delivery method that improves patient compliance while avoiding drug breakdown in the gastrointestinal tract, improving bioavailability, and eliminating the pain associated with subcutaneous injections.
  • the existence of the stratum corneum limits the scope of application of the drug from the molecular weight and water solubility of the drug. Only a few drugs can be administered transdermally, and the drug delivery efficiency is limited.
  • Microneedle array is a minimally invasive device that can pass through the stratum corneum of the skin painlessly, assisting drugs to cross the barrier in transdermal drug delivery routes and improving the bioavailability of drugs.
  • Microneedles have the advantages of mass production, low cost, many applicable drugs, and patients can administer their own medicines, etc., and have received extensive attention in recent years.
  • microneedles can be divided into dissolving microneedles and insoluble microneedles according to their dissolving properties. Before dissolving microneedles are applied clinically, it is necessary to study the metabolism and elimination pathways of the ingredients that can be dissolved in the skin to judge the biological safety of the materials, which will inevitably delay the commercialization process. Insoluble microneedles are mostly made of metal, single crystal silicon or polymer materials, and the microneedles can be completely removed after being applied to the skin, without material accumulation in the body and reducing the burden of material metabolism. Therefore, insoluble microneedles are still the main method in clinical application.
  • microneedles When the commonly used insoluble microneedles assist drug transdermal, it is necessary to smear or apply the drug after the microneedle is removed, so that the drug can pass through the skin channel formed by the microneedle.
  • the micropores on the skin begin to heal when the microneedles are removed, and the retention time of the microneedles is limited by the self-healing of the skin, making it difficult to further improve the overall efficiency of drug transdermal absorption.
  • the first object of the present invention is to provide an insoluble transdermal microneedle patch, which does not contain active substances, and after administration, after removing the transdermal microneedle patch , No need to smear or apply drugs to promote drug absorption to obtain good bioavailability.
  • the second object of the present invention is to provide a method for preparing an insoluble transdermal microneedle patch.
  • the third object of the present invention is to provide an application of an insoluble transdermal microneedle patch.
  • An insoluble transdermal microneedle patch comprising:
  • a microneedle the microneedle comprises a base and a needle tip located on the base, and the microneedle is mainly composed of cross-linked sodium alginate;
  • the backing is combined with the base, and the part of the backing corresponding to the needle point is a hollow part.
  • the base and the needle tip can be formed integrally or separately, which can be selected according to different processes.
  • the microneedle is mainly composed of cross-linked sodium alginate, so it can be understood that the main part of the microneedle is cross-linked sodium alginate.
  • the cross-linked sodium alginate is a structure formed by cross-linking sodium alginate and an in-situ cross-linking agent.
  • the cross-linked sodium alginate obtained by using this system as the microneedle body not only has high strength, but can be well applied to the skin; at the same time, it is non-irritating to the skin and is safe and harmless; in addition, the cross-linked alginate Sodium nitrate has a high degree of swelling, which can well deliver the active substance into the skin and has high bioavailability; finally, the microneedles are insoluble in water, and can be taken and stopped at any time during administration, which can be used very well. Control the dosage.
  • cross-linked sodium alginate is formed by mixing an aqueous solution of sodium alginate and an aqueous solution of an in-situ cross-linking agent into a homogeneous aqueous solution, and then cross-linking.
  • the in-situ cross-linking agent is a mixture of calcium sodium edetate and gluconolactone; wherein, the molar ratio of calcium sodium edetate to gluconolactone is 1:0.8 ⁇ 1:1.2. Under this condition, the prepared microneedles have high strength and less skin irritation under the condition of ensuring high swelling degree.
  • the concentration of calcium sodium edetate is 0.3-1.0 mol/L.
  • volume ratio of the aqueous sodium alginate solution to the aqueous solution of the in-situ crosslinking agent is 20:1 ⁇ 4:1.
  • the solid content of the sodium alginate aqueous solution is 12-25%.
  • the molar ratio of gluconolactone to calcium sodium isosite is 0.8-1.2.
  • microneedle also contains a porogen.
  • the existence of the porogen helps the intradermal water molecules to enter into the matrix of the upper needle tip and regulate the release rate of the drug.
  • the added amount of the porogen accounts for 0.1-10wt% of the total weight of the microneedles.
  • the porogen is selected from sodium chloride, sodium carbonate, sodium bicarbonate, ammonium bicarbonate, polyvinylpyrrolidone, hyaluronic acid and its sodium salt, cellulose derivatives, trehalose, maltose, cyclodextrose One or more of the fine classes.
  • the backing is a backing film.
  • the choice of the backing film is based on the ability to combine well with the microneedle base.
  • a method for preparing an insoluble transdermal microneedle patch comprising the steps of:
  • the mixed solution is placed on the microneedle mold, vacuumized, so that the solution fills the pinholes of the mold while completing the crosslinking of sodium alginate and drying;
  • the dried microneedles are removed from the mold, and the base and backing are bonded.
  • drying is air drying, and the time is preferably 20-40min.
  • the vacuuming time is 15-30 minutes according to the different addition amount of cross-linking agent.
  • the active substance can be medicine, medicine cream, medicine gel and so on.
  • the medicine can be soluble medicine and insoluble medicine.
  • Insoluble drugs can be fat-soluble drugs such as tocopherol, antifungal/bacterial drugs, etc.; soluble drugs can be water-soluble acidic drugs such as L-ascorbic acid, water-soluble neutral drugs such as tranexamic acid, water-soluble bases such as matrine, Polypeptide drugs such as exenatide, polysaccharide drugs such as heparin, nucleic acid drugs such as ribavirin, etc.
  • the insoluble transdermal microneedle patch provided by the present invention can act on the skin for a long time.
  • the pores absorb into the body, thereby increasing the bioavailability of the drug when administered transdermally.
  • the microneedles can be completely removed without increasing the metabolic burden in the body, and avoiding the accumulation of soluble materials in the body, which has good biological safety.
  • FIG. 1 shows the fluorescence micrograph of microneedles swollen by sodium alginate in Example 1.
  • FIG. 2 shows the fluorescence micrograph of the microneedle swollen with sodium alginate in Example 1 after absorbing water.
  • Fig. 3 shows the transdermal penetration curves of sodium alginate swollen microneedles assisted in permeating L-ascorbic acid in Examples 4, 6, and 8.
  • Fig. 4 shows the transdermal penetration curves of sodium alginate swollen microneedles assisted in penetrating tranexamic acid in Examples 4, 6, and 8.
  • Fig. 5 shows the transdermal penetration curves of matrine assisted by sodium alginate swelling microneedles in Examples 4, 6, and 8.
  • the fluorescence microscope image of the obtained microneedle is shown in Figure 1, and the fluorescence microscope image of the obtained microneedle after absorbing water and swelling is shown in Figure 2. It can be seen that the shape can still be kept intact after absorbing water, and the volume becomes larger.
  • the formed cross-linked sodium alginate microneedles were taken out, and a backing film was pasted on the back of the microneedles.
  • the blended solution of the sodium alginate solution and the cross-linking solution cannot maintain a stable and uniform viscosity in the process of making the microneedle, resulting in inaccurate solution volume of the microneedle unit.
  • Experimental animal New Zealand white rabbit, weighing 2.5kg.
  • Test samples 4 samples of the patch of each embodiment were selected in parallel, and each sample was cut into a disc with a diameter of 2 cm.
  • Example 1 159.80 0.25 (non-irritating)
  • Example 2 137.57 0.25 (non-irritating)
  • Example 3 146.49 0.25 (non-irritating)
  • Example 4 111.04 0.25 (non-irritating)
  • Example 5 117.32 0.25 (non-irritating)
  • Example 6 109.19 0.5 (mild irritation)
  • Example 7 114.16 0.25 (non-irritating)
  • Example 8 105.68 0.25 (non-irritating) Comparative example 1 0 (dissolved) 0.25 (non-irritating) Comparative example 2 0 (dissolved) 0.25 (non-irritating) Comparative example 3 0 (disintegrated) 0.25 (non-irritating) Comparative example 4 135.29 (disintegration) 1.5 (mild irritation)
  • dissolution means that the microneedles form a uniform phase with water
  • disintegration means that the microneedles are dispersed into several parts in water and do not form a uniform phase with water.
  • the device used is the SYSTEM 912-24 automatic transdermal diffusion sampling system from Lugen Company of the United States, and the effective permeation area of the transdermal cup used is 0.625 cm 2 .
  • the skin used was fresh 800 ⁇ m thick pig ear skin.
  • the cross-linked sodium alginate microneedles of each embodiment are applied to the horny layer side of the skin, and the dermis faces the receiving pool.
  • the volume of the receiving pool was 2.7 mL, and the microneedle patches obtained in each embodiment were subjected to in vitro percutaneous permeability tests. Among them, Examples 4, 6, and 8 were tested for in vitro percutaneous permeability, and the control groups were skin punctured with monocrystalline silicon and skin without treatment.
  • L-ascorbic acid, tranexamic acid and matrine were selected as permeable drugs respectively.
  • Skin treated with monocrystalline silicon puncture and untreated skin were used as control groups.
  • the curve drawing results are shown in Fig. 3, Fig. 4, and Fig. 5.
  • cross-linked sodium alginate microneedles were used as auxiliary permeation of ascorbic acid, the cumulative permeation amount was 2.74 to 2.08 times that of the single crystal silicon microneedle control group. through.
  • cross-linked sodium alginate microneedles were used as assisted permeation tranexamic acid, the cumulative permeation amount was 2.35-1.75 times that of the single crystal silicon microneedle control group, and there was no permeation on untreated skin.
  • the cumulative permeation amount was 1.83-1.5 times that of the single crystal silicon microneedle control group, and 3.16-2.68 times higher than that of the no-treatment control group.
  • Example 1 23.1 43.5 50.3
  • Example 2 26.6 47.8 55.5
  • Example 3 30.8 49.3 65.3
  • Example 4 37.6 55.1 68.1
  • Example 5 43.4 55.3 65.6
  • Example 6 46.1 59.2 61.7
  • Example 7 55.4 65.2 73.5
  • Example 8 51.5 71.6 74.7 Monocrystalline silicon 17.6 32.1 40.6 directly through 1.3 0 13.2

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Abstract

一种不可溶的透皮微针贴片，包括：微针，该微针包含基底以及位于基底上的针尖，且所述微针主要由交联的海藻酸钠构成；背衬，与所述基底相结合，且所述背衬中与针尖相对应的部分为镂空部。该微针贴片的制备方法和应用。该微针贴片可长时间作用于皮肤，且其用于透皮给药时，药物可通过作用于皮肤上的溶胀的微针吸水后的孔道，进入皮肤微孔吸收至体内，由此增加药物在透皮给药时的生物利用度。在给药结束后，微针可被完整地取出，不会增加体内的代谢负担。

Description

一种不可溶的透皮微针贴片及其制备方法和应用 技术领域
本发明涉及医药技术领域。更具体地，涉及一种不可溶的透皮微针贴片及其制备方法和应用。
背景技术
经皮给药是一种常见的给药方式，可改善患者依从性，同时避免胃肠道药物分解，提高生物利用度，并消除皮下注射带来的疼痛。角质层的存在从药物分子量和药物水溶性限制其适用范围，仅少数药物可以通过透皮方式进行给药，且给药效率有限。近年来随着微纳加工技术的发展，微针给药的研究进程被快速推进。微针阵列是一种微创设备，可以无痛地穿过皮肤角质层，辅助药物在经皮给药途径中穿过屏障，提高药物的生物利用度。微针具有可批量生产，成本低廉，适用药物众多，患者可自主给药等优点，近年来受到了广泛的关注。
微针的研究众多，以微针的溶解性能可分为溶解微针和不可溶解微针。溶解微针在应用于临床前，需要对可溶解于皮内的成分进行代谢和消除途径的研究，判断材料的生物安全性，由此会不可避免地延迟商业化进程。不可溶解微针多由金属，单晶硅或高分子为材料组成，微针在应用于皮肤后可被完整地移除，在体内不产生材料蓄积并减轻材料代谢负担。由此，目前在临床应用中仍以不可溶解微针为主。常用的不可溶微针在辅助药物透皮时，需要在微针移除后涂抹或敷贴药物，使药物通过微针形成的皮肤孔道。皮肤上的微孔道在移除微针时开始愈合，微针孔道的存留时间受皮肤自修复的限制，使药物透皮吸收的整体效率难以得到进一步提升。
发明内容
本发明的第一个目的在于提供一种不可溶的透皮微针贴片，该透皮微针贴片中不含活性物质，且施药后，在移除该透皮微针贴片后，无需再涂抹或敷贴药物促进药物的吸收即可获得好的生物利用度。
本发明的第二个目的在于提供一种不可溶的透皮微针贴片的制备方法。
本发明的第三个目的在于提供一种不可溶的透皮微针贴片的应用。
为达到上述第一个目的，本发明采用下述技术方案：
一种不可溶的透皮微针贴片，包括：
微针，该微针包含基底以及位于基底上的针尖，且所述微针主要由交联的海藻酸钠构成；
背衬，与所述基底相结合，且所述背衬中与针尖相对应的部分为镂空部。
该透皮微针贴片中，基底和针尖可一体成型，也可分别成型，具体可根据不同的工艺进行选择。此外，该微针主要由交联的海藻酸钠构成，可以理解成该微针的主体部分为交 联的海藻酸钠。
进一步地，所述交联的海藻酸钠为由海藻酸钠与原位交联剂交联而成的结构。采用该体系得到的交联的海藻酸钠作为微针主体不仅具有较高的强度，能很好的施加于皮肤内；同时，其对皮肤无刺激，安全无害；此外，该交联的海藻酸钠具有较高的溶胀度，能很好的将活性物质给入皮下，具有高的生物利用度；最后，该微针不溶于水，给药时，可随取随停，能很好的控制给药量。
进一步地，所述交联的海藻酸钠由海藻酸钠水溶液与原位交联剂的水溶液混合成均匀的水溶液后，交联而成。
进一步地，所述原位交联剂为依地酸钙钠和葡萄糖酸内酯的混合；其中，所述依地酸钙钠与葡萄糖酸内酯的摩尔比为1:0.8～1:1.2。在此条件下，制备得到的微针在保证具有高溶胀度的条件下，微针具有高的强度且皮肤刺激性更小。
进一步地，所述原位交联剂的水溶液中，依地酸钙钠的浓度为0.3-1.0mol/L。
进一步地，所述海藻酸钠水溶液与原位交联剂的水溶液的体积比为20:1～4:1。
进一步地，所述海藻酸钠水溶液的固含量为12-25％。
进一步地，所述原位交联剂中，葡萄糖酸内酯与异地酸钙钠摩尔比为0.8～1.2。
进一步地，所述微针中还包含致孔剂。致孔剂的存在有助于皮内水分子进入上段针尖基质内部，调控药物释放速率。
进一步地，所述致孔剂的添加量占微针总重量的0.1～10wt％。
进一步地，所述致孔剂选自氯化钠、碳酸钠、碳酸氢钠、碳酸氢铵、聚乙烯吡咯烷酮、透明质酸及其钠盐、纤维素类衍生物、海藻糖、麦芽糖、环糊精类中的一种或几种。
进一步地，背衬为背衬膜。背衬膜的选择以能够很好的与微针基底结合为准。
为达到上述第二个目的，本发明采用下述技术方案：
一种不可溶的透皮微针贴片的制备方法，包括如下步骤：
将海藻酸钠水溶液与原位交联剂的水溶液混合，形成均匀的混合液；
将该混合液置于微针模具上，抽真空，使溶液填充模具针孔的同时完成海藻酸钠交联，干燥；
将干燥后得到的微针从模具上取下，并将基底与背衬结合。
进一步地，所述干燥为吹风干燥，时间优选为20-40min。
进一步地，在注液成型时，根据交联剂的不同添加量，抽真空时间为15-30min。
为达到上述第三个目的，本发明采用下述技术方案：
一种不可溶的透皮微针贴片在透皮给药中的应用。
进一步地，该应用包括如下步骤：
将该透皮微针贴片的微针施加于人体皮肤内；
通过背衬的镂空部，向微针上施加活性物质；
待给药完毕，取出该透皮微针贴片，即可。
本发明中，活性物质可为药物、药物乳膏、药物凝胶等。其中、所述药物可为可溶性药物和不可溶性药物。不可溶性药物可为脂溶性药物如生育酚、抗真菌/细菌药物等；可溶性药物可为水溶酸性药物如L-抗坏血酸、水溶性中性药物如氨甲环酸、水溶性碱如苦参碱、 多肽类药物如艾塞那肽、多糖类药物如肝素、核酸类药物如三氮唑核苷等。
本发明的有益效果如下：
本发明提供的不可溶的透皮微针贴片可长时间作用于皮肤，且其用于透皮给药时，药物可通过作用于皮肤上的溶胀的微针吸水后的孔道，进入皮肤微孔吸收至体内，由此增加药物在透皮给药时的生物利用度。在给药结束后，微针可被完整地取出，不会增加体内的代谢负担，并且避免了可溶材料在体内蓄积，具有良好生物安全性。
附图说明
下面结合附图对本发明的具体实施方式作进一步详细的说明。
图1示出实施例1中海藻酸钠溶胀微针的荧光显微镜图。
图2示出实施例1中海藻酸钠溶胀微针吸水后的荧光显微镜图。
图3示出实施例4、6、8中海藻酸钠溶胀微针辅助透过L-抗坏血酸的经皮渗透曲线。
图4示出实施例4、6、8中海藻酸钠溶胀微针辅助透过氨甲环酸的经皮渗透曲线。
图5示出实施例4、6、8中海藻酸钠溶胀微针辅助透过苦参碱的经皮渗透曲线。
具体实施方式
为了更清楚地说明本发明，下面结合优选实施例和附图对本发明做进一步的说明。附图中相似的部件以相同的附图标记进行表示。本领域技术人员应当理解，下面所具体描述的内容是说明性的而非限制性的，不应以此限制本发明的保护范围。
实施例1
按照表1数据，称取1g海藻酸钠粉末，溶于9mL超纯水中，为海藻酸钠溶液。称取0.112g依地酸钙钠，0.0534g葡萄糖酸内酯，溶于1mL超纯水中，为交联液。将海藻酸钠溶液与交联液共混，将共混后的溶液平铺于微针模具上，每个微针单元加入溶液体积为40μL。模具抽真空20min，吹风干燥30min后，将成型的交联海藻酸钠微针取出，在微针背部贴背衬膜。所得微针的荧光显微镜图如图1所示，所得微针吸水溶胀后的荧光显微镜图如图2所示，可知，其在吸水后仍能保持形状完整，且体积变大。
实施例2
按照表1数据，称取1g海藻酸钠粉末，溶于9mL超纯水中，为海藻酸钠溶液。称取0.224g依地酸钙钠，0.125g葡萄糖酸内酯，溶于1mL超纯水中，为交联液。将海藻酸钠溶液与交联液共混，将共混后的溶液平铺于微针模具上，每个微针单元加入溶液体积为40μL。模具抽真空20min，吹风干燥30min后，将成型的交联海藻酸钠微针取出，在微针背部贴背衬膜。
实施例3
按照表1数据，称取1.5g海藻酸钠粉末，溶于8.5mL超纯水中，为海藻酸钠溶液。称取0.281g依地酸钙钠，0.133g葡萄糖酸内酯，溶于1.5mL超纯水中，为交联液。将海藻酸钠溶液与交联液共混，将共混后的溶液平铺于微针模具上，每个微针单元加入溶液体 积为40μL。模具抽真空20min，吹风干燥30min后，将成型的交联海藻酸钠微针取出，在微针背部贴背衬膜。
实施例4
按照表1数据，称取1.5g海藻酸钠粉末，溶于8.5mL超纯水中，为海藻酸钠溶液。称取0.393g依地酸钙钠，0.214g葡萄糖酸内酯，溶于1.5mL超纯水中，为交联液。将海藻酸钠溶液与交联液共混，将共混后的溶液平铺于微针模具上，每个微针单元加入溶液体积为40μL。模具抽真空20min，吹风干燥30min后，将成型的交联海藻酸钠微针取出，在微针背部贴背衬膜。
实施例5
按照表1数据，称取2g海藻酸钠粉末，溶于8mL超纯水中，为海藻酸钠溶液。称取0.449g依地酸钙钠，0.214g葡萄糖酸内酯，溶于2mL超纯水中，为交联液。将海藻酸钠溶液与交联液共混，将共混后的溶液平铺于微针模具上，每个微针单元加入溶液体积为40μL。模具抽真空20min，吹风干燥30min后，将成型的交联海藻酸钠微针取出，在微针背部贴背衬膜。
实施例6
按照表1数据，称取2g海藻酸钠粉末，溶于8mL超纯水中，为海藻酸钠溶液。称取0.598g依地酸钙钠，0.285g葡萄糖酸内酯，溶于2mL超纯水中，为交联液。将海藻酸钠溶液与交联液共混，将共混后的溶液平铺于微针模具上，每个微针单元加入溶液体积为40μL。模具抽真空20min，吹风干燥30min后，将成型的交联海藻酸钠微针取出，在微针背部贴背衬膜。
实施例7
按照表1数据，称取1g海藻酸钠粉末，溶于9mL超纯水中，为海藻酸钠溶液。称取0.561g依地酸钙钠，0.267g葡萄糖酸内酯，溶于2.5mL超纯水中，为交联液。将海藻酸钠溶液与交联液共混，将共混后的溶液平铺于微针模具上，每个微针单元加入溶液体积为40μL。模具抽真空20min，吹风干燥30min后，将成型的交联海藻酸钠微针取出，在微针背部贴背衬膜。
实施例8
按照表1数据，称取1g海藻酸钠粉末，溶于9mL超纯水中，为海藻酸钠溶液。称取0.748g依地酸钙钠，0.356g葡萄糖酸内酯，溶于2.5mL超纯水中，为交联液。将海藻酸钠溶液与交联液共混，将共混后的溶液平铺于微针模具上，每个微针单元加入溶液体积为40μL。模具抽真空20min，吹风干燥30min后，将成型的交联海藻酸钠微针取出，在微针背部贴背衬膜。
表格1实施例1-8物质组成
Figure PCTCN2022113262-appb-000001
对比例1
称取1g海藻酸钠粉末，溶于9mL超纯水中，为海藻酸钠溶液。称取0.561g依地酸钙钠，溶于2.5mL超纯水中，为无葡萄酸内酯的交联液。将海藻酸钠溶液与交联液共混，将共混后的溶液平铺于微针模具上，每个微针单元加入溶液体积为40μL。模具抽真空20min，吹风干燥30min后，将成型的交联海藻酸钠微针取出，在微针背部贴背衬膜。
对比例2
称取1g海藻酸钠粉末，溶于9mL超纯水中，为海藻酸钠溶液。称取0.438g乙二胺四乙酸，0.267g葡萄糖酸内酯，溶于2.5mL超纯水中，为交联液。将海藻酸钠溶液与交联液共混，将共混后的溶液平铺于微针模具上，每个微针单元加入溶液体积为40μL。模具抽真空20min，吹风干燥30min后，将成型的交联海藻酸钠微针取出，在微针背部贴背衬膜。
对比例3
称取1g海藻酸钠粉末，溶于9mL超纯水中，为海藻酸钠溶液。称取0.112g依地酸钙钠，0.0267g葡萄糖酸内酯，溶于1mL超纯水中，为交联液。此时交联液中依地酸钙钠与葡萄糖酸内酯的摩尔比为1:0.5。将海藻酸钠溶液与交联液共混，将共混后的溶液平铺于微针模具上，每个微针单元加入溶液体积为40μL。模具抽真空20min，吹风干燥30min后，将成型的交联海藻酸钠微针取出，在微针背部贴背衬膜。
对比例4
称取1g海藻酸钠粉末，溶于9mL超纯水中，为海藻酸钠溶液。称取0.561g依地酸钙钠，0.401g葡萄糖酸内酯，溶于2.5mL超纯水中，为交联液。此时交联液中依地酸钙钠与葡萄糖酸内酯的摩尔比为1:1.5。将海藻酸钠溶液与交联液共混，将共混后的溶液平铺于微针模具上，每个微针单元加入溶液体积为40μL。模具抽真空20min，吹风干燥30min后，将成型的交联海藻酸钠微针取出，在微针背部贴背衬膜。该海藻酸钠溶液与交联液的共混溶液在制作微针过程中无法保持稳定均一的黏度，导致微针单元的溶液体积不准确。制作出的微针中有肉眼可见的未溶解的依地酸钙钠与葡萄糖酸内酯颗粒。
溶胀度测试
将实施例1-8的溶胀微针干燥至恒重，测定其质量为m1，浸泡在纯水中在37℃恒温箱中浸泡至质量恒定，取出，将表面水分擦净后称重，质量记为m2，按下式计算水凝胶溶胀率：
SR＝(m2-m1)/m1×100
皮肤刺激性试验
实验动物：新西兰白兔，体重2.5kg。
试验样本：每个实施例的贴剂平行选取4个样本，每个样本裁剪成直径为2cm的圆片。
试样方法：采用国家食品药品监督管理局颁发的《化学药物刺激性、过敏性和溶血性研究技术指导原则》中的有关规定和内容。将贴片贴于白兔背部单侧，7日后揭下，按照评分标准：(1)0-0.49为无刺激性；(2)0.5-2.99为轻度刺激性；(3)3.0-5.99为中度刺激性；(4)6.0-8.00为强刺激性。将所得的分数取平均值后评价贴片对皮肤的刺激性，其结果列于表2。
表格2实施例1-8测试结果
  溶胀度(％) 皮肤刺激性
实施例1 159.80 0.25(无刺激性)
实施例2 137.57 0.25(无刺激性)
实施例3 146.49 0.25(无刺激性)
实施例4 111.04 0.25(无刺激性)
实施例5 117.32 0.25(无刺激性)
实施例6 109.19 0.5(轻刺激性)
实施例7 114.16 0.25(无刺激性)
实施例8 105.68 0.25(无刺激性)
对比例1 0(溶解) 0.25(无刺激性)
对比例2 0(溶解) 0.25(无刺激性)
对比例3 0(崩解) 0.25(无刺激性)
对比例4 135.29(崩解) 1.5(轻度刺激)
其中：溶解指微针与水形成均匀相；崩解指微针在水中分散成若干个部分，与水不形成均匀相。
药物经皮渗透性试验
所用装置为美国禄根公司的SYSTEM 912-24全自动透皮扩散取样系统，所用的透皮杯的有效透过面积为0.625cm 2。所使用的皮肤为新鲜的800μm厚猪耳皮肤。将各实施例的交联海藻酸钠微针应用于皮肤的角质层一侧，真皮层朝向接收池。接收池体积为2.7mL，分别对各实施例所得微针贴片进行体外经皮透过性试验。其中，实施例4、6、8做体外经皮透过性试验，对照组为单晶硅穿刺处理的皮肤和无处理皮肤。分别选用L-抗坏血酸，氨甲环酸和苦参碱作为透过药物。使用单晶硅穿刺处理过的皮肤和无处理皮肤作为对照组。曲线绘制结果如图3、图4、图5，在使用交联海藻酸钠微针作辅助透过抗坏血酸时，累计 透过量为单晶硅微针对照组的2.74～2.08倍，无处理皮肤无透过。在使用交联海藻酸钠微针作辅助透过氨甲环酸时，累计透过量为单晶硅微针对照组的2.35～1.75倍，无处理皮肤无透过。在使用交联海藻酸钠微针作辅助透过苦参碱时，累计透过量为单晶硅微针对照组的1.83～1.5倍，与无处理对照组对比提升了3.16～2.68倍。
实施例1～8的24小时累积经皮渗透率如表3所示：
表格3实施例1～8的24小时累积经皮渗透率
  L-抗坏血酸(％) 氨甲环酸(％) 苦参碱(％)
实施例1 23.1 43.5 50.3
实施例2 26.6 47.8 55.5
实施例3 30.8 49.3 65.3
实施例4 37.6 55.1 68.1
实施例5 43.4 55.3 65.6
实施例6 46.1 59.2 61.7
实施例7 55.4 65.2 73.5
实施例8 51.5 71.6 74.7
单晶硅 17.6 32.1 40.6
直接透过 1.3 0 13.2
显然，本发明的上述实施例仅仅是为清楚地说明本发明所作的举例，而并非是对本发明的实施方式的限定，对于所属领域的普通技术人员来说，在上述说明的基础上还可以做出其它不同形式的变化或变动，这里无法对所有的实施方式予以穷举，凡是属于本发明的技术方案所引伸出的显而易见的变化或变动仍处于本发明的保护范围之列。

Claims (10)

  1. 一种不可溶的透皮微针贴片，其特征在于，包括：
    微针，该微针包含基底以及位于基底上的针尖，且所述微针主要由交联的海藻酸钠构成；
    背衬，与所述基底相结合，且所述背衬中与针尖相对应的部分为镂空部。
  2. 根据权利要求1所述的透皮微针贴片，其特征在于，所述交联的海藻酸钠为由海藻酸钠与原位交联剂交联而成的结构。
  3. 根据权利要求2所述的透皮微针贴片，其特征在于，所述交联的海藻酸钠由海藻酸钠水溶液与原位交联剂的水溶液混合成均匀的水溶液后，交联而成。
  4. 根据权利要求3所述的透皮微针贴片，其特征在于，所述原位交联剂为依地酸钙钠和葡萄糖酸内酯的混合；其中，所述依地酸钙钠与葡萄糖酸内酯的摩尔比为1:0.8～1:1.2；
    优选地，所述原位交联剂的水溶液中，依地酸钙钠的浓度为0.3-1.0mol/L。
  5. 根据权利要求3所述的透皮微针贴片，其特征在于，所述海藻酸钠水溶液与原位交联剂的水溶液的体积比为20:1～4:1。
  6. 根据权利要求3所述的透皮微针贴片，其特征在于，所述海藻酸钠水溶液的固含量为12-25％。
  7. 根据权利要求1所述的透皮微针贴片，其特征在于，所述微针中还包含致孔剂；
    优选地，所述致孔剂的添加量占微针总重量的0.1～10wt％；
    优选地，所述致孔剂选自氯化钠、碳酸钠、碳酸氢钠、碳酸氢铵、聚乙烯吡咯烷酮、透明质酸及其钠盐、纤维素类衍生物、海藻糖、麦芽糖、环糊精类中的一种或几种。
  8. 如权利要求1-7任一项所述的透皮微针贴片的制备方法，其特征在于，包括如下步骤：
    将海藻酸钠水溶液与原位交联剂的水溶液混合，形成均匀的混合液；
    将该混合液置于微针模具上，抽真空，使溶液填充模具针孔的同时完成海藻酸钠交联，干燥；
    将干燥后得到的微针从模具上取下，并将基底与背衬结合。
  9. 如权利要求1-7任一项所述的透皮微针贴片在透皮给药中的应用。
  10. 根据权利要求9所述的应用，其特征在于，包括如下步骤：
    将该透皮微针贴片的微针施加于人体皮肤内；
    通过背衬的镂空部，向微针上施加活性物质；
    待给药完毕，取出该透皮微针贴片，即可。
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