WO2016155082A1 - 一种溶胀型丝素蛋白微针给药系统及其制备方法 - Google Patents

一种溶胀型丝素蛋白微针给药系统及其制备方法 Download PDF

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WO2016155082A1
WO2016155082A1 PCT/CN2015/078338 CN2015078338W WO2016155082A1 WO 2016155082 A1 WO2016155082 A1 WO 2016155082A1 CN 2015078338 W CN2015078338 W CN 2015078338W WO 2016155082 A1 WO2016155082 A1 WO 2016155082A1
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silk fibroin
microneedle
swelling
drug delivery
drug
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PCT/CN2015/078338
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English (en)
French (fr)
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殷祝平
卢神州
夏婷婷
于盈盈
吴越
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苏州大学
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Priority to JP2017508733A priority Critical patent/JP2017514646A/ja
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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

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  • the invention relates to a medical microneedle drug delivery system, in particular to a microneedle drug delivery system made of silk fibroin as a substrate and a preparation method thereof.
  • micro-machining technology With the development of micro-machining technology, a micro-needle technology that can pierce the epidermis without damaging the dermis and nerves came out more than a decade ago, bringing new ideas for transdermal drug delivery.
  • the microneedle array of micron size penetrates the poorly permeable skin surface (stratum corneum) in a reversible and minimally invasive manner, causing mechanical passage through which biomacromolecules can pass without causing pain and skin trauma.
  • microneedle drug delivery technology still has many technical bottlenecks, including complex molding technology, high manufacturing cost, toxicity of microneedle material, poor biocompatibility, easy to break and residual in the skin, causing allergic reactions, and It is impossible to control the law of microneedle release more accurately.
  • the traditional metal, glass, and silicon microneedles have better penetration to change the skin permeability, the drug is generally applied to the surface of the microneedle, and the drug loading is small, which is difficult to achieve therapeutic effects.
  • the microneedle transdermal drug delivery system has attracted more and more attention in the field of transdermal absorption of hydrophilic small molecule drugs, polypeptides, protein drugs, and DNA.
  • the microneedle transdermal administration method avoids the problem that the conventional oral administration is low in the bioavailability of the drug due to the pH of the gastrointestinal tract, the digestive enzymes, and the effects of the liver, and avoids the acupuncture caused by the administration of the injection. Pain, skin damage and maintain a relatively stable blood concentration.
  • silk fibroin has been considered as a suitable biomedical material with good biocompatibility and biodegradability.
  • Silk fibroin has good biocompatibility and biology. Degradation performance, suitable for artificial skin, artificial cornea manufacturing. The hydrophilicity of silk fibroin imparts good affinity to water-soluble drugs, and facilitates the stable embedding of water-soluble drugs in silk fibroin.
  • a protein material which is excellent in mechanical properties in a dry state and rapidly swells in a wet state can be obtained. Therefore, silk fibroin is an ideal microneedle substrate.
  • the Chinese invention patent discloses a silk fibroin microneedle system and a method for preparing silk fibroin nanoparticles, which are coated with a soluble silk fibroin solidified material and coated with silk fibroin nanoparticles.
  • the microneedle penetrates into the skin, and the outer layer of the silk fibroin solidified material dissolves rapidly, releasing the drug-loaded nanoparticles to achieve the purpose of drug release.
  • this silk fibroin microneedle system uses soluble silk fibroin, and the outer silk fibroin will dissolve quickly in the body fluid, causing rapid release of the drug, which is not conducive to sustained release.
  • Chinese invention patent discloses another silk fibroin microneedle and its preparation method, which adopts steam annealing and exposure to methanol solution to post-process the drug-loaded and formed silk fibroin micro-needle to achieve control.
  • these insolubilization processes may result in a loss of activity of the drug.
  • the ⁇ -folded silk fibroin has a stable structure, is not prone to water swelling and swelling behavior, and the molecular gap is too small, so that the drug release is slow, the release rate is low, and it is difficult to achieve a therapeutic blood concentration.
  • the solution of the pre-crystal structure is formed by using super-vibration treatment of silk fibroin to form a gel-type microneedle.
  • the microneedle silk fibroin has a dense molecular structure and contains a large amount of Silkll type crystals, and has small water absorption and swelling property, which is unfavorable for rapid, long-lasting and stable release of the drug.
  • the object of the present invention is to provide a simple and feasible condition, mild conditions, high micro-needle release rate, high drug release rate and stable therapeutic dose.
  • the technical scheme adopted by the present invention is to provide a swelling type silk fibroin microneedle administration
  • the system is prepared by using natural silk fibroin as a raw material, wherein the microneedle administration system is composed of a silk fibroin swelling microneedle and a silk fibroin film, wherein the silk fibroin protein content is 75-97%. It also contains 1%-20% of small molecule swelling agent, and the rest is loaded drug.
  • the microneedle administration system is insoluble in water, has a swelling degree in deionized water of 100% to 1000%, a drug loading rate of 2% to 15%, and a drug release rate of >70%.
  • the above-mentioned swelling type silk fibroin microneedle drug delivery system is characterized in that the microneedle head piercing swelling portion and the microneedle tail silk fibroin film portion are combined to form a transdermal drug delivery system, and the system enables The linear release rate of insulin during transdermal delivery in 48h was over 80%.
  • the above-mentioned swelling type silk fibroin microneedle drug delivery system is characterized in that the small molecule swelling agent is ethylene glycol methyl ether, ethylene glycol ethyl ether, glucosamine hydrochloride, L-serine, biuret One of them.
  • the invention also provides a preparation method of a swelling type silk fibroin microneedle drug delivery system, which comprises the following steps:
  • step (3) pouring the mixed solution diluted in the step (2) onto the surface of the microporous PDMS mold, placing the cast microporous PDMS mold in a vacuum drying oven with a vacuum degree greater than 0.09 MPa for 20-30 min, removing the solution and The bubbles in the micropores of the mold allow the solution to fully enter the micropores of the mold. Finally, the defoamed PDMS system is placed in a constant temperature and humidity environment to be dry and balanced to a constant weight. After the mold release, a silk fibroin microneedle drug delivery system is obtained.
  • the preparation method of the above-mentioned swelling type silk fibroin microneedle administration system the small molecule swelling agent ethylene glycol methyl ether or ethylene glycol diethyl ether and silk fibroin is 1:100 by mass. Blending to 1:5; the small molecule swelling agent glucosamine hydrochloride and silk fibroin are blended by mass 1:10; the small molecule swelling agent L-serine and silk fibroin are 1:20 by mass Blending; the small molecule swelling agent biuret and silk fibroin are blended at a mass of 1:20.
  • the dry equilibrium time in the step (3) is at least 36 h.
  • the principle of the invention is that the silk fibroin solution modified by the swelling agent is injection molded, vacuum pumped, constant temperature and humidity drying, and the like, and several kinds of extremely weak dissolution behavior, excellent swelling property, penetration performance and the like are obtained.
  • the small molecule swelling agent is blended with the silk fibroin solution, and the small molecule compound is used to induce the crystallizing action, chemical cross-linking of the silk fibroin molecular chain, or self-polymerization in the silk fibroin solution to form an interpenetrating network structure, and the like. It has a small amount of solubility, excellent swelling performance, controllable swelling rate, and good biocompatibility.
  • the microneedle can biodegrade dry phase-changeable silk fibroin microneedle.
  • the microneedle In the dry state, the microneedle has sufficient strength to pierce the stratum corneum of the skin; in the case of cell interstitial, it can fully swell, resulting in a wet microgel release system that still has a strong and stable presence. Swelling forms a drug delivery channel that allows the drug to be released slowly.
  • a large amount of drug is stored in the silk fibroin film at the end of the microneedle, which can be continuously released through the microneedle after the release channel is formed.
  • the drug loading rate of the microneedle is high, and the silk fibroin storage sac is formed, which greatly increases the drug loading rate;
  • micro-needle release is stable and fast, and lasts for a long time. Since the swollen microneedle provides a drug release channel, the drug release rate is greatly improved; and the degree of swelling of the microneedle determines the size of the drug channel in the microneedle, making the drug undetermined; and at the same time, due to the presence of the silk fibroin reservoir The microneedle can be continuously released.
  • silk fibroin can stabilize the activity of the drug, and the microneedle array is formed by constant temperature, constant humidity and dry balance, the condition is mild, the stability of the embedded drug is good, and the biological activity is high.
  • Figure 1 is a graph showing the dissolution rate of a silk fibroin microneedle in which a small molecule swelling agent is ethylene glycol methyl ether.
  • FIG. 2 is a graph showing the swelling ratio of a silk fibroin microneedle in which a small molecule swelling agent is ethylene glycol methyl ether.
  • FIG. 3 is a photomicrograph of a silk fibroin microneedle array on the surface of a PDMS mold of one or more embodiments of the present invention.
  • FIG. 4 is a partial enlarged view of the silk fibroin microneedle array of FIG. 3.
  • Figure 5 is a representation of the silk fibroin microneedle in a dry state in accordance with one or more embodiments of the present invention. Micro photo.
  • Figure 6 is a photomicrograph of a silk fibroin microneedle after swelling in accordance with one or more embodiments of the present invention.
  • Figure 7 is a photomicrograph of a silk fibroin microneedle piercing hydrogel plane in accordance with one or more embodiments of the present invention.
  • Figure 8 is a photomicrograph of a silk fibroin microneedle inserted into a pig skin plane in accordance with one or more embodiments of the present invention.
  • Figure 9 is a photomicrograph of a silk fibroin microneedle inserted into a cut surface of a pig skin in accordance with one or more embodiments of the present invention.
  • Figure 10 is a photomicrograph of a silk fibroin microneedle inserted into a cut skin of a pig skin in accordance with one or more embodiments of the present invention.
  • Preparation of silk fibroin solution preparation of silk fibroin solution: take 80 g of silkworm raw silk into 4000ml of 0.06% sodium carbonate solution, boiled three times at 98 ⁇ 100 ° C, three times with deionized water, each treatment for 30min, remove the sericin in the raw silk, washed, loosened and placed at 60 ° C Drying in an oven gives a pure silk fibroin.
  • the dried silk fibroin fiber was dissolved in a 9.3 M lithium bromide solution at 60 ° C, the bath was 3:20, and the dissolution time was about 1 h. After it was cooled, it was taken out and placed in a dialysis bag and dialyzed in deionized water for 3 days.
  • the pure silk fibroin solution was filtered through a cotton wool, concentrated at room temperature, and placed in a refrigerator at 4 ° C for use.
  • Preparation of silk fibroin solution preparation of silk fibroin solution: take 80 g of silkworm raw silk into 4000ml of 0.06% sodium carbonate solution, boiled three times at 98 ⁇ 100 ° C, three times with deionized water, each treatment for 30min, remove the sericin in the raw silk, washed, loosened and placed at 60 ° C Drying in an oven gives a pure silk fibroin.
  • the dried silk fibroin fiber was dissolved in a 9.3 M lithium bromide solution at 60 ° C, the bath was 3:20, and the dissolution time was about 1 h. After it was cooled, it was taken out and placed in a dialysis bag and dialyzed in deionized water for 3 days.
  • the pure silk fibroin solution was filtered through a cotton wool, concentrated at room temperature, and placed in a refrigerator at 4 ° C for use.
  • Preparation of silk fibroin solution preparation of silk fibroin solution: take 80 g of silkworm raw silk into 4000ml of 0.06% sodium carbonate solution, boiled three times at 98 ⁇ 100 ° C, three times with deionized water, each treatment for 30min, remove the sericin in the raw silk, washed, loosened and placed at 60 ° C Drying in an oven gives a pure silk fibroin.
  • the dried silk fibroin fiber was dissolved in a 9.3 M lithium bromide solution at 60 ° C, the bath was 3:20, and the dissolution time was about 1 h. After it was cooled, it was taken out and placed in a dialysis bag and dialyzed in deionized water for 3 days.
  • the pure silk fibroin solution was filtered through a cotton wool, concentrated at room temperature, and placed in a refrigerator at 4 ° C for use.
  • Preparation of silk fibroin solution preparation of silk fibroin solution: take 80 g of silkworm raw silk into 4000ml of 0.06% sodium carbonate solution, boiled three times at 98 ⁇ 100 ° C, three times with deionized water, each treatment for 30min, remove the sericin in the raw silk, washed, loosened and placed at 60 ° C Drying in an oven gives a pure silk fibroin.
  • the dried silk fibroin fiber was dissolved in a 9.3 M lithium bromide solution at 60 ° C, the bath was 3:20, and the dissolution time was about 1 h. After it was cooled, it was taken out and placed in a dialysis bag and dialyzed in deionized water for 3 days.
  • the pure silk fibroin solution was filtered through a cotton wool, concentrated at room temperature, and placed in a refrigerator at 4 ° C for use.
  • Preparation of silk fibroin solution preparation of silk fibroin solution: take 80 g of silkworm raw silk into 4000ml of 0.06% sodium carbonate solution, boiled three times at 98 ⁇ 100 ° C, three times with deionized water, each treatment for 30min, remove the sericin in the raw silk, washed, loosened and placed at 60 ° C Drying in an oven gives a pure silk fibroin.
  • the dried silk fibroin fiber was dissolved in a 9.3 M lithium bromide solution at 60 ° C, the bath was 3:20, and the dissolution time was about 1 h. After it was cooled, it was taken out and placed in a dialysis bag and dialyzed in deionized water for 3 days.
  • the pure silk fibroin solution was filtered through a cotton wool, concentrated at room temperature, and placed in a refrigerator at 4 ° C for use.
  • Preparation of silk fibroin solution preparation of silk fibroin solution: take 80 g of silkworm raw silk into 4000ml of 0.06% sodium carbonate solution, boiled three times at 98 ⁇ 100 ° C, three times with deionized water, each treatment for 30min, remove the sericin in the raw silk, washed, loosened and placed at 60 ° C Drying in an oven gives a pure silk fibroin.
  • the dried silk fibroin fiber was dissolved in a 9.3 M lithium bromide solution at 60 ° C, the bath was 3:20, and the dissolution time was about 1 h. After it was cooled, it was taken out and placed in a dialysis bag and dialyzed in deionized water for 3 days.
  • the pure silk fibroin solution was filtered through a cotton wool, concentrated at room temperature, and placed in a refrigerator at 4 ° C for use.
  • a small molecule swelling agent was selected as the ethylene glycol methyl ether to prepare a series of micro-tests for the dissolution rate and swelling ratio.
  • the test results are shown in Figure 1 and Figure 2.
  • the test method for the dissolution rate is: weighing Silk fibroin microneedles 0.1g (m1) or so, each group of 5 parallel samples, according to the bath 1 / 100 10mL deionized water, in a 37 ° C water bath constant temperature oscillator for 24h, soaked after the sample After centrifugation for 10 min, the supernatant was taken at 278 nm to measure the UV absorbance and the silk fibroin concentration was calculated, and the silk fibroin dissolution rate (the amount of silk fibroin dissolved/the amount of silk fibroin in the microneedle) was calculated according to the formula (1).
  • the test method of swelling ratio is as follows: taking the above-mentioned silk fibroin microneedle after lyophilization, rinsing with deionized water, centrifuging three times, and removing the surface moisture by filter paper, weighing its wet weight m2, calculating according to formula (2) Needle swelling rate.
  • Ml in formula (2) mass of microneedle
  • m2 mass of microneedle after swelling
  • Microneedle solid content S: small molecule swelling agent and silk quality
  • the microneedle of the silk fibroin in the dry state and the microneedle microscopy after swelling were observed, as shown in Fig. 3, Fig. 2 and Fig. 5, respectively, and it can be seen that the swelling ratio of the microneedle is high.
  • the silk fibroin microneedle array prepared in one example was inserted into the hydrogel plane and the pig skin, and then immersed in formalin solution for 24 h, taken out and washed, and observed under the fluorescence stereo microscope; using Leica CM1950
  • the frozen microtome cut the pig skin into which the microneedles were cut into 15 ⁇ m thick sections, and observed under a fluorescence stereo microscope to photograph the microporous cut surface of the pig skin, as shown in Fig. 3-6. It can be seen from FIG.
  • Example 1 the silk fibroin microneedle puncture depth of Example 1 is between 200 and 250 ⁇ m, which proves that the silk fibroin microneedle under the scheme has a good ability to break through the stratum corneum of the skin, and the depth of the puncture is not Enter the subcutaneous layer, do not touch the pain nerve, no It will produce a tingling sensation and better achieve the effect of the microneedle.
  • the prepared silk fibroin micropuncture penetrated the pig skin of 400-500 ⁇ m thick, and applied the silk fibroin film to the pig skin of the same specification, covered in a 12 mL transdermal release tank, and padded with 1.5 cm thick foam and fixed with a clip. it is good.
  • Figure 13 and Figure 14 can get each gel microneedle
  • the transdermal delivery curve has a good linearity in the pre-stage, and the release rate and release rate per unit time are basically constant, and it is expected to achieve controlled release transdermal administration of large and small molecule drugs.
  • the microneedle prepared by the invention has high swelling ratio and small dissolution rate. After piercing into the skin, the microneedle swells to form a drug release channel, and the molecular gap is obviously increased, and the drug can be efficiently and stably released; At the same time, the microneedle is an insoluble silk fibroin microneedle, and the micropores pierced on the surface of the skin can be stably existed, maintaining the high efficiency and durability of the release rate during the whole release process, and the release rate is high, and it is expected to break through the microneedle.
  • the use of low drug loading and limited drug release is limited. Swelling microneedles do have a significant ability to promote drug release and are positively correlated with the swelling properties of hydrogel microneedles.

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Abstract

一种溶胀型丝素蛋白微针给药系统及其制备方法，所述微针给药系统包含丝素蛋白和小分子溶胀剂，在去离子水中的溶胀度为200％-1000％。该微针给药系统的载药率为2％-15％，释药率＞70％，其制备方法为：将丝素蛋白溶液与小分子溶胀剂复合后与模型药物共混，浇筑于PDMS模具，经真空干燥、恒温恒湿干燥平衡，即得。

Description

一种溶胀型丝素蛋白微针给药系统及其制备方法
本申请要求了申请日为2015年04月03日，申请号为201510155449.X，发明名称为“一种溶胀型丝素蛋白微针给药系统及其制备方法”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明涉及一种医疗用微针给药系统，具体涉及一种以丝素蛋白为基材制成的微针给药系统及其制备方法。
背景技术
随着微加工技术的发展，一种可刺透表皮但不伤及真皮和神经的微针技术早在十几年前问世，为透皮给药带来了新的思路。尺寸在微米级的微针点阵以可逆微创的方式刺穿渗透性极差的皮肤表层(角质层)，造成生物大分子得以通过的机械通道，却不产生痛感和皮肤创伤。然而目前的微针给药技术仍然存在诸多技术上的瓶颈，主要包括成型技术复杂、制造成本过高，微针材质的毒性、生物相容性差、易断裂并残留于皮肤内造成过敏反应，以及无法较为精确的控制微针释药规律等。传统金属、玻璃、硅质微针虽具备较好的刺入以改变皮肤通透性能力，但是一般将药物涂抹于微针表面，载药量小，难以达到治疗效果。
目前微针透皮给药系统在亲水性小分子药物、多肽以及蛋白质药物、DNA等的透皮吸收领域越来越引起人们的关注。微针透皮给药方式避免了传统口服给药受肠胃道pH、消化酶以及肝脏的受过效应等带来的药物生物活性利用度低的问题，避免了注射给药给患者带来的针刺痛苦、皮肤损害并能维持相对稳定的血药浓度。
近年来，丝素蛋白已被认为是合适的生物医学材料，具有良好的生物相容性、生物降解性能，丝素蛋白具有良好的生物相容性和生物 降解性能，适用于人工皮肤、人工眼角膜的制造等。丝素蛋白的亲水性之赋予了其与水溶性药物亲和性良好，利于水溶性药物稳定包埋于丝素蛋白内部。通过改性处理，可得到干态下力学性能优异，湿态下迅速吸水溶胀的蛋白材料。所以，丝素蛋白是一种理想的微针基材。
在本专利申请前，中国发明专利(CN10258032A)公开了一种丝素蛋白微针系统及丝素纳米颗粒的制备方法，采用可溶的丝素蛋白固化物包裹载药丝素纳米颗粒，然后制成微针，此微针刺入皮肤后，外层的丝素蛋白固化物迅速溶解，释放出载药的纳米颗粒，达到药物释放的目的。但是这种丝素微针系统采用可溶性丝素蛋白，外层丝素蛋白遇到体液会很快溶解，造成药物的快速释放，不利于缓释。溶液可能受到压力挤出，对于药物的缓释也不利。微针溶解后，表皮微孔消失，不利于药物的持久、稳定性释放。中国发明专利(CN103260693A)公开了另一种基于丝素蛋白微针及其制备方法，采用水蒸气退火、暴露于甲醇溶液中等方法对载药并成形后的丝素微针进行后处理，达到控制丝素蛋白β折叠结构的含量，从而使微针不溶于水，进一步控制药物释放的速率。但是这些不溶化处理过程可能会使药物的活性有所损失。β折叠的丝素蛋白结构稳定，不易发生吸水溶胀行为，分子间隙过小，从而药物释放缓慢，释药率低，难以达到具治疗效果的血药浓度。中国发明专利(201410061578.8)公开的丝素蛋白微针及其制备中，采用超生震荡处理丝素蛋白形成具预结晶结构的溶液，形成凝胶型微针。该微针丝素分子结构致密，含大量的Silkll型结晶，吸水性、溶胀性小，不利于药物的快速、持久、稳定性释放。
发明内容
针对现有技术在微针不溶化处理方式、微针溶胀释药行为方面的不足，本发明的目的在于提供一种简便可行，条件温和，微针释药率、释药速率高且具有稳定治疗剂量血药浓度的微针系统及其制备方法。
本发明所采用的技术方案是：提供一种溶胀型丝素蛋白微针给药 系统，以天然家蚕丝素蛋白为原料制成，其特征在于，该微针给药系统由丝素蛋白溶胀微针与丝素蛋白膜构成，其中包含丝素蛋白质量分数为75-97％，还包含有小分子溶胀剂1％-20％，其余为装载的药物。该微针给药系统不溶于水，在去离子水中的溶胀度为100％-1000％，载药率为2％-15％，释药率＞70％。
上述的一种溶胀型丝素蛋白微针给药系统，其特征在于，所述微针头部刺入溶胀部分与微针尾部丝素膜部分复合后形成一种透皮释药系统，该系统使胰岛素在48h内透皮释药过程线性释药率超过80％。
上述的一种溶胀型丝素蛋白微针给药系统，其特征在于，所述小分子溶胀剂为乙二醇甲醚、乙二醇乙醚、氨基葡萄糖盐酸盐、L-丝氨酸、缩二脲中的一种。
本发明还提供一种溶胀型丝素蛋白微针给药系统的制备方法，其特征在于，包括如下步骤：
(1)将丝素溶液与小分子溶胀剂进行共混；
(2)将步骤(1)中的共混溶液与药物均匀混合后，加入纯水稀释；
(3)将步骤(2)中稀释后的混合溶液浇注于微孔PDMS模具表面，将浇注好的微孔PDMS模具置于真空度大于0.09MPa的真空干燥箱中20-30min，脱去溶液以及模具微孔中的气泡并使溶液充分进入模具微孔，最后将脱泡后的PDMS系统置于恒温恒湿环境中干燥平衡至恒重，脱模后即得到丝素微针给药系统。
作为该技术方案的优选，上述的一种溶胀型丝素蛋白微针给药系统的制备方法，所述小分子溶胀剂乙二醇甲醚或乙二醇乙醚与丝素按质量此1∶100至1∶5进行共混；所述小分子溶胀剂氨基葡萄糖盐酸盐与丝素按质量此1∶10进行共混；所述小分子溶胀剂L-丝氨酸与丝素按质量此1∶20进行共混；所述小分子溶胀剂缩二脲与丝素按质量此1∶20进行共混。
作为该技术方案的优选，所述步骤(3)中的干燥平衡时间至少为36h。
本发明的原理是将经溶胀剂改性后的丝素溶液注模、真空抽气、恒温恒湿干燥等程序，制得若干种具备极弱溶失行为，极优溶胀性能、刺入性能以及药物控释性能，可生物降解的溶胀型干凝胶丝素微针释药体系。小分子溶胀剂与丝素蛋白溶液共混，利用小分子化合物对丝素蛋白分子链的诱导致晶作用、化学交联作用，或者于丝素溶液中自身聚合形成互穿网络结构等机理，制备出若干溶失性小，溶胀性能优，溶胀速率可控，且生物相容性好，可生物降解干态可相变丝素凝胶微针。干态时，微针具备足够的强力刺破皮肤角质层；遇细胞间质可充分溶胀，产生仍然具备一定强力而稳定存在的湿态水凝胶微针释药体系，该系统中由于微针溶胀形成释药通道，可以使药物缓慢释放。另外，微针尾部的丝素膜内储存了大量的药物，可以在释药通道形成后，源源不断的通过微针释放出来。
与现有技术相此，本发明的优势在于：
1、微针载药率高，形成丝素膜储药囊，大大提高载药率；
2、微针释药稳定快速，持续时间长。由于溶胀的微针提供了释药通道，大大提高了药物释放速率；而微针的溶胀程度则决定了微针中药物通道的大小，使释药未定；同时由于丝素膜储药囊的存在，可以使微针持续释药。
3、丝素蛋白可以稳定药物的活性，恒温恒湿干燥平衡方式成型微针阵列，条件温和，包埋药物稳定性好，生物活性高。
附图说明
图1为小分子溶胀剂为乙二醇甲醚的丝素蛋白微针的溶失率曲线。
图2为小分子溶胀剂为乙二醇甲醚的丝素蛋白微针的溶胀率曲线。
图3为本发明的一个或多个实施例的PDMS模具表面的丝素蛋白微针阵列的显微照片。
图4为图3的丝素蛋白微针阵列的局部放大图。
图5为本发明的一个或多个实施例的的丝素蛋白微针干态下的显 微照片。
图6为本发明的一个或多个实施例的的丝素蛋白微针溶胀后的显微照片。
图7为本发明的一个或多个实施例的的丝素蛋白微针刺入水凝胶平面的显微照片。
图8为本发明的一个或多个实施例的的丝素蛋白微针刺入猪皮平面的显微照片。
图9为本发明的一个或多个实施例的的丝素蛋白微针刺入猪皮切面一的显微照片。
图10为本发明的一个或多个实施例的的丝素蛋白微针刺入猪皮切面二的显微照片。
图11为药物为辣椒素(M药物/M丝素＝1/50)制备的一个实施例的的丝素蛋白微针中药物累积释放曲线图。
图12为药物为胰岛素(M药物/M丝素＝1/20)制备的一个实施例的的丝素蛋白微针中药物累积释放曲线图。
图13为药物为辣椒素(M药物/M丝素＝1/50)制备的一个实施例的的丝素蛋白微针中辣椒素累积释放的线性拟合图。
图14为药物为胰岛素(M药物/M丝素＝1/20)制备的一个实施例的的丝素蛋白微针中胰岛素累积释放的线性拟合图。
具体实施方式
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。此外应理解，在阅读了本发明表述的内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。
实施例1
(1)丝素溶液的制备：丝素溶液的制备：取80g家蚕生丝放入 4000ml浓度为0.06％的碳酸钠溶液中，于98～100℃下煮三次，三次均用去离子水，每次处理30min，脱去生丝中的丝胶，洗净，拉松后放于60℃的烘箱中烘干，即得纯丝素纤维。将烘干所得的丝素纤维在60℃下溶解于9.3M的溴化锂溶液中，浴此为3∶20，溶解时间约1h，待其冷却后取出装入透析袋置于去离子水中透析3d，用脱脂棉过滤得到纯丝素溶液，室温下将其浓缩，放于4℃冰箱备用。
(2)丝素溶液的制备与改性：将小分子溶胀剂乙二醇甲醚以纯水稀释至0.2g/mL，与(1)中纯丝素溶液按质量此(M溶胀剂/M丝素)＝1/10共混。
(3)模型药物的包埋：将模型药物辣椒素与(2)中的共混溶液按质量此(M药物/M丝素＝1/50)均匀混合，并进一步加入纯水稀释至丝素浓度为0.09g/mL，备用。
(4)丝素微针的浇注与成型：将(3)中的混合溶液浇注于15*15微孔阵列的PDMS模具表面，160μL每单位阵列。将浇注好的PDMS模具至于真空度为0.09MPa以上的真空干燥箱20-30min，脱出溶液以及模具微孔中的气泡并使溶液充分进入模具微孔。最后将脱泡后的PDMS系统至于恒温恒湿环境(
Figure PCTCN2015078338-appb-000001
T＝278K)中干燥平衡36h以上，即得到微针及其底座一体化的高溶胀、不溶失、高载药率丝素微针给药系统，脱模后即可使用。
实施例2
(1)丝素溶液的制备：丝素溶液的制备：取80g家蚕生丝放入 4000ml浓度为0.06％的碳酸钠溶液中，于98～100℃下煮三次，三次均用去离子水，每次处理30min，脱去生丝中的丝胶，洗净，拉松后放于60℃的烘箱中烘干，即得纯丝素纤维。将烘干所得的丝素纤维在60℃下溶解于9.3M的溴化锂溶液中，浴此为3∶20，溶解时间约1h，待其冷却后取出装入透析袋置于去离子水中透析3d，用脱脂棉过滤得到纯丝素溶液，室温下将其浓缩，放于4℃冰箱备用。
(2)丝素溶液的制备与改性：将小分子溶胀剂乙二醇甲醚以纯水稀释至0.2g/mL，与(1)中纯丝素溶液按质量此(M溶胀剂/M丝素)＝1/20共混。
(3)模型药物的包埋：将模型药物辣椒素与(2)中的共混溶液按质量此(M药物/M丝素＝1/50)均匀混合，并进一步加入纯水稀释至丝素浓度为0.09g/mL，备用。
(4)丝素微针的浇注与成型：将(3)中的混合溶液浇注于15*15微孔阵列的PDMS模具表面，160μL每单位阵列。将浇注好的PDMS模具至于真空度为0.09MPa以上的真空干燥箱20-30min，脱出溶液以及模具微孔中的气泡并使溶液充分进入模具微孔。最后将脱泡后的PDMS系统至于恒温恒湿环境(
Figure PCTCN2015078338-appb-000002
T＝278K)中干燥平衡36h以上，即得到微针及其底座一体化的高溶胀、不溶失、高载药率丝素微针给药系统，脱模后即可使用。
实施例3
(1)丝素溶液的制备：丝素溶液的制备：取80g家蚕生丝放入 4000ml浓度为0.06％的碳酸钠溶液中，于98～100℃下煮三次，三次均用去离子水，每次处理30min，脱去生丝中的丝胶，洗净，拉松后放于60℃的烘箱中烘干，即得纯丝素纤维。将烘干所得的丝素纤维在60℃下溶解于9.3M的溴化锂溶液中，浴此为3∶20，溶解时间约1h，待其冷却后取出装入透析袋置于去离子水中透析3d，用脱脂棉过滤得到纯丝素溶液，室温下将其浓缩，放于4℃冰箱备用。
(2)丝素溶液的制备与改性：将小分子溶胀剂乙二醇乙醚以纯水稀释至0.2g/mL，与(1)中纯丝素溶液按质量此(M溶胀剂/M丝素)＝1/10共混。
(3)模型药物的包埋：将模型药物胰岛素与(2)中的共混溶液按质量比(M药物/M丝素＝1/20)均匀混合，并进一步加入纯水至0.09g/mL丝素浓度，备用。
(4)丝素微针的浇注与成型：将(3)中的混合溶液浇注于15*15微孔阵列的PDMS模具表面，160μL每单位阵列。将浇注好的PDMS模具至于真空度为0.09MPa以上的真空干燥箱20-30min，脱出溶液以及模具微孔中的气泡并使溶液充分进入模具微孔。最后将脱泡后的PDMS系统至于恒温恒湿环境(
Figure PCTCN2015078338-appb-000003
T＝278K)中干燥平衡36h以上，即得到微针及其底座一体化的高溶胀、不溶失、高载药率丝素微针给药系统，脱模后即可使用。
实施例4
(1)丝素溶液的制备：丝素溶液的制备：取80g家蚕生丝放入 4000ml浓度为0.06％的碳酸钠溶液中，于98～100℃下煮三次，三次均用去离子水，每次处理30min，脱去生丝中的丝胶，洗净，拉松后放于60℃的烘箱中烘干，即得纯丝素纤维。将烘干所得的丝素纤维在60℃下溶解于9.3M的溴化锂溶液中，浴此为3∶20，溶解时间约1h，待其冷却后取出装入透析袋置于去离子水中透析3d，用脱脂棉过滤得到纯丝素溶液，室温下将其浓缩，放于4℃冰箱备用。
(2)丝素溶液的制备与改性：将小分子溶胀剂L-丝氨酸以纯水稀释至0.2g/mL，与(1)中纯丝素溶液按质量此(M溶胀剂/M丝素)＝1/20共混。
(3)模型药物的包埋：将模型药物胰岛素与(2)中的共混溶液按质量此(M药物/M丝素＝1/10)均匀混合，并进一步加入纯水至丝素浓度为0.09g/mL，备用。
(4)丝素微针的浇注与成型：将(3)中的混合溶液浇注于15*15微孔阵列的PDMS模具表面，160μL每单位阵列。将浇注好的PDMS模具至于真空度为0.09MPa以上的真空干燥箱20-30min，脱出溶液以及模具微孔中的气泡并使溶液充分进入模具微孔。最后将脱泡后的PDMS系统至于恒温恒湿环境(
Figure PCTCN2015078338-appb-000004
T＝278K)中干燥平衡36h以上，即得到微针及其底座一体化的高溶胀、不溶失、高载药率丝素微针给药系统，脱模后即可使用。
实施例5
(1)丝素溶液的制备：丝素溶液的制备：取80g家蚕生丝放入 4000ml浓度为0.06％的碳酸钠溶液中，于98～100℃下煮三次，三次均用去离子水，每次处理30min，脱去生丝中的丝胶，洗净，拉松后放于60℃的烘箱中烘干，即得纯丝素纤维。将烘干所得的丝素纤维在60℃下溶解于9.3M的溴化锂溶液中，浴此为3∶20，溶解时间约1h，待其冷却后取出装入透析袋置于去离子水中透析3d，用脱脂棉过滤得到纯丝素溶液，室温下将其浓缩，放于4℃冰箱备用。
(2)丝素溶液的制备与改性：将小分子溶胀剂氨基葡萄糖盐酸盐以纯水稀释至0.2g/mL，与(1)中纯丝素溶液按质量此(M溶胀剂/M丝素)＝1/10共混。
(3)模型药物的包埋：将模型药物胰岛素与(2)中的共混溶液按质量此(M药物/M丝素＝1/20)均匀混合，并进一步加入纯水至丝素浓度为0.09g/mL，备用。
(4)丝素微针的浇注与成型：将(3)中的混合溶液浇注于15*15微孔阵列的PDMS模具表面，160μL每单位阵列。将浇注好的PDMS模具至于真空度为0.09MPa以上的真空干燥箱20-30min，脱出溶液以及模具微孔中的气泡并使溶液充分进入模具微孔。最后将脱泡后的PDMS系统至于恒温恒湿环境(
Figure PCTCN2015078338-appb-000005
T＝278K)中干燥平衡36h以上，即得到微针及其底座一体化的高溶胀、不溶失、高载药率丝素微针给药系统，脱模后即可使用。
实施例6
(1)丝素溶液的制备：丝素溶液的制备：取80g家蚕生丝放入 4000ml浓度为0.06％的碳酸钠溶液中，于98～100℃下煮三次，三次均用去离子水，每次处理30min，脱去生丝中的丝胶，洗净，拉松后放于60℃的烘箱中烘干，即得纯丝素纤维。将烘干所得的丝素纤维在60℃下溶解于9.3M的溴化锂溶液中，浴此为3∶20，溶解时间约1h，待其冷却后取出装入透析袋置于去离子水中透析3d，用脱脂棉过滤得到纯丝素溶液，室温下将其浓缩，放于4℃冰箱备用。
(2)丝素溶液的制备与改性：将小分子溶胀剂缩二脲以纯水稀释至0.2g/mL，与(1)中纯丝素溶液按质量此(M溶胀剂/M丝素)＝1/20共混。
(3)模型药物的包埋：将模型药物胰岛素与(2)中的共混溶液按质量此(M药物/M丝素＝1/20)均匀混合，并进一步加入纯水至丝素浓度为0.09g/mL，备用。
(4)丝素微针的浇注与成型：将(3)中的混合溶液浇注于15*15微孔阵列的PDMS模具表面，160μL每单位阵列。将浇注好的PDMS模具至于真空度为0.09MPa以上的真空干燥箱20-30min，脱出溶液以及模具微孔中的气泡并使溶液充分进入模具微孔。最后将脱泡后的PDMS系统至于恒温恒湿环境(
Figure PCTCN2015078338-appb-000006
T＝278K)中干燥平衡36h以上，即得到微针及其底座一体化的高溶胀、不溶失、高载药率丝素微针给药系统，脱模后即可使用。
选取小分子溶胀剂为乙二醇甲醚制备一系列的微针对其进行溶失率和溶胀率的测试，测试结果见图1和图2所示，其中溶失率的测试方法为：称取丝素蛋白微针0.1g(m1)左右，每组5个平行样，按浴此1/100加入10mL去离子水，于37℃水浴恒温振荡器中24h，浸泡后样 品离心10min，取上清液于278nm测定紫外吸光度并计算丝素蛋白浓度，按照公式(1)计算丝素蛋白溶失率(溶出的丝素蛋白质量/微针中丝素蛋白质量)。
Figure PCTCN2015078338-appb-000007
公式(1)中的C1：丝素蛋白浓度，m1：微针质量，
Figure PCTCN2015078338-appb-000008
微针含固率，S：小分子溶胀剂与丝素质量此
溶胀率的测试方法为：取上述溶离心后下层丝素微针，去离子水冲洗、离心三3次，并以滤纸吸去表面水分，称量其湿重m2，按照公式(2)计算微针溶胀率。
Figure PCTCN2015078338-appb-000009
公式(2)中的ml：微针质量，m2：溶胀后微针质量，
Figure PCTCN2015078338-appb-000010
微针含固率，S：小分子溶胀剂与丝素质量此
在电子显微镜下观察干态下的丝素蛋白微针和溶胀后的微针显微照片，分别见图3、图2、图5、，可以看出该微针的溶胀率较高。
选取一个实施例中制备的丝素蛋白微针阵列刺入水凝胶平面和猪皮，然后浸泡于福尔马林溶液24h固定，取出洗净，荧光立体显微镜下观察刺入面；采用Leica CM1950冷冻切片机对微针刺入的猪皮切成15μm厚的切片，于荧光立体显微镜下观察，拍摄猪皮上刺入的微孔切面图，如图3-6所示。由图3-6可见，实施例1的丝素微针刺破深度在200～250μm之间，证明了该方案下的丝素微针具备良好突破皮肤角质层的能力，并且刺破的深度没有进入皮下层，不会碰到痛觉神经，不 会产生刺痛感，较好的实现了微针的效果。
分别选取药物为辣椒素(M药物/M丝素＝1/50)制备的一个实施例制备的丝素微针和药物为胰岛素(M药物/M丝素＝1/20)制备的一个实施例制备的丝素微针刺入400～500μm厚的猪皮，并将丝素膜贴敷于相同规格的猪皮，包覆于12mL透皮释放池，并垫上1.5cm厚的泡沫后以夹子固定好。从取样口加入12mL(V)PBS缓冲液以及转子，致于TT-6/TT-8透皮释放仪恒温释放，水浴温度32℃，转子转速500r/min。分别于1、2、3、4、6、8、16、24、28、32h取样1mL(Vi)，采用FM4P-TCSPC荧光光谱仪，于激发波长：280nm、检测波长：290～550nm、狭缝宽度：2nm条件下检测，记录316nm波长处的衍射强度，计算释药池药物浓度Ci并描绘微针累积释药率随时间变化曲线，分别得到图11(药物为辣椒素)和图12(药物为胰岛素)的曲线图。由此可见该方法值得的微针释药率高，释药速率快，有利于药物的透皮吸收。
对图11和图12中得到的各点进行拟合，以得出本发明的丝素蛋白微针的透皮释药过程线性规律，拟合图如图13和图14所示，图13中，拟合得到的线性方程为：y＝4.46943+6.79271x，因此线性阶段释药率为y＝4.46943+6.79271*6＝45.23％，单位时间释药率为：6.79271％，所以LJS/SF＝1/50时，45％左右的药物可于6h内以6.79271％/h的速率稳定释放；图14中，拟合得到的线性方程为：y＝0.39037+1.84749x，可得稳定释药阶段的释药率为：y＝0.39037+1.84749*44＝81.68％，单位时间释药率为：1.84749％，即INS/SF＝1/20时，该微针中80％以上INS可于44h内以1.84749％的速率稳定释放。图13和图14可得各凝胶微针 透皮释药曲线前阶段都具备良好的线性规律，释药速率及单位时间释放率基本恒定，有望实现大、小分子药物的控释性透皮给药。
以上数据说明通过控制微针载药量或者提高微针使用数量，可以实现为患者提供恒定治疗剂量的血药浓度，彻底避免了传统注射给药因血药浓度过高带来的冲击性，控释性好。
综上所述，通过本发明制得的微针溶胀率高、溶失率小，在刺入皮肤后，微针溶胀，形成释药通道，分子间隙明显增大，药物得以高效、稳定释放；与此同时，该微针属不溶性丝素微针，皮肤表面刺出的微孔可稳定存在，保持整个释放过程中的释药速率的高效性与持久性，释药率高，有望突破微针载药量低，释药量少的使用局限。溶胀型微针的确具备显著的促进释药能力，且与水凝胶微针溶胀性能正相关。
以上所述仅是本发明的优选实施方式，并不用于限制本发明，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明技术原理的前提下，还可以做出若干改进和变型，这些改进和变型也应视为本发明的保护范围。

Claims (9)

  1. 一种溶胀型丝素蛋白微针给药系统，以天然家蚕丝素蛋白为原料制成，其特征在于，该微针给药系统由丝素蛋白溶胀微针与丝素蛋白膜构成，其中包含丝素蛋白质量分数为75-97％，还包含有小分子溶胀剂1％-20％，其余为装载的药物。该微针给药系统不溶于水，在去离子水中的溶胀度为100％-1000％，载药率为2％-15％，释药率＞70％。
  2. 根据权利要求1所述的一种溶胀型丝素蛋白徼针给药系统，其特征在于，所述微针头部刺入溶胀部分与微针尾部丝素膜部分复合后形成一种透皮释药系统，该系统使胰岛素在48h内透皮释药过程线性释药率超过80％。
  3. 根据权利要求1所述的一种溶胀型丝素蛋白微针给药系统，其特征在于，所述小分子溶胀剂为乙二醇甲醚、乙二醇乙醚、氨基葡萄糖盐酸盐、L-丝氨酸、缩二脲中的一种。
  4. 一种溶胀型丝素蛋白微针给药系统的制备方法，其特征在于，包括如下步骤：
    (1)将丝素溶液与小分子溶胀剂进行共混；
    (2)将步骤(1)中的共混溶液与药物均匀混合后，加入纯水稀释；
    (3)将步骤(2)中稀释后的混合溶液浇注于微孔PDMS模具表面，将浇注好的徼孔PDMS模具置于真空度大于0.09MPa的真空干燥箱中20-30min，脱去溶液以及模具微孔中的气泡并使溶液充分进入模具微孔，最后将脱泡后的PDMS系统置于恒温恒湿环境中干燥平衡至恒重，脱模后即得到丝素微针给药系统。
  5. 根据权利要求4所述的一种溶胀型丝素蛋白微针给药系统的制备方法，其特征在于，所述小分子溶胀剂乙二醇甲醚或乙二醇乙醚与丝素按质量比为1∶100至1∶5进行共混。
  6. 根据权利要求4所述的一种溶胀型丝素蛋白微针给药系统的制备方法，其特征在于，所述小分子溶胀剂氨基葡萄糖盐酸盐与丝素按质量比1∶10进行共混。
  7. 根据权利要求4所述的一种溶胀型丝素蛋白微针给药系统的制备方法，其特征在于，所述小分子溶胀剂L-丝氨酸与丝素按质量比1∶20进行共混。
  8. 根据权利要求4所述的一种溶胀型丝素蛋白微针给药系统的制备方法，其特征在于，所述小分子溶胀剂缩二脲与丝素按质量比1∶20进行共混。
  9. 根据权利要求4所述的一种溶胀型丝素蛋白微针给药系统的制备方法，其特征在于，所述步骤(3)中的干燥平衡时间至少为36h。
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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109420250A (zh) * 2018-02-11 2019-03-05 西南民族大学 一种新型微针及其制备方法
WO2019195350A1 (en) * 2018-04-03 2019-10-10 Vaxess Technologies, Inc. Microneedle comprising silk fibroin applied to a dissolvable base
CN112370654A (zh) * 2020-11-17 2021-02-19 南京工业大学 一种基于激光雕刻技术的微针贴片制作方法
CN113679657A (zh) * 2021-07-30 2021-11-23 苏州大学 用于治疗失眠的丝素蛋白微针透皮贴片及其制备方法
WO2022042799A1 (de) * 2020-08-28 2022-03-03 Lts Lohmann Therapie-Systeme Ag Mucosa-perforierung
CN114834066A (zh) * 2022-04-25 2022-08-02 武汉纺织大学 复合多层微针的制备方法
CN116509768A (zh) * 2023-04-24 2023-08-01 广东瀚润生物科技有限公司 基于纯天然中草药、蚕丝提取的抗氧化抗皱效果的纳米微针化妆品及其制备工艺

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101530402A (zh) * 2009-04-23 2009-09-16 苏州大学 丝素蛋白复层膜及其制备方法
CN103260693A (zh) * 2010-10-19 2013-08-21 塔夫茨大学信托人 基于丝素蛋白的微针及其制造方法

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2739876A1 (en) * 2008-10-07 2010-04-15 Tuo Jin Phase-transition polymeric microneedles
CN102580232B (zh) * 2012-02-23 2013-12-18 游学秋 一种丝素微针系统和丝素纳米颗粒及其制备方法
CN103800998B (zh) * 2014-02-24 2016-03-30 苏州大学 一种丝素蛋白凝胶微针系统及其制备方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101530402A (zh) * 2009-04-23 2009-09-16 苏州大学 丝素蛋白复层膜及其制备方法
CN103260693A (zh) * 2010-10-19 2013-08-21 塔夫茨大学信托人 基于丝素蛋白的微针及其制造方法

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WO2019195350A1 (en) * 2018-04-03 2019-10-10 Vaxess Technologies, Inc. Microneedle comprising silk fibroin applied to a dissolvable base
WO2022042799A1 (de) * 2020-08-28 2022-03-03 Lts Lohmann Therapie-Systeme Ag Mucosa-perforierung
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CN114834066A (zh) * 2022-04-25 2022-08-02 武汉纺织大学 复合多层微针的制备方法
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