WO2022152131A1 - 司美格鲁肽可溶性微针贴片及其制备方法 - Google Patents
司美格鲁肽可溶性微针贴片及其制备方法 Download PDFInfo
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- WO2022152131A1 WO2022152131A1 PCT/CN2022/071401 CN2022071401W WO2022152131A1 WO 2022152131 A1 WO2022152131 A1 WO 2022152131A1 CN 2022071401 W CN2022071401 W CN 2022071401W WO 2022152131 A1 WO2022152131 A1 WO 2022152131A1
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- WIPO (PCT)
- Prior art keywords
- semaglutide
- microneedle patch
- soluble microneedle
- solution
- needle body
- Prior art date
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Classifications
-
- 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
Definitions
- the invention relates to the field of medicine, in particular to a semaglutide soluble microneedle patch and a preparation method thereof.
- GLP-1RA Glucagon-like peptide 1 receptor agonists
- Semaglutide (formerly known as semaglutide) has 94% homology with natural GLP-1, its amino acid backbone is connected to fatty acid side chains, and its half-life is extended to 165h. It is administered by subcutaneous injection once a week. Compared with several other agonists, semaglutide has shown greater advantages in hypoglycemic, weight loss, cardiovascular system benefits and safety.
- the FDA approved once-daily oral semaglutide (Rybelsus), which uses 2-hydroxybenzamide as an absorption enhancer to improve bioavailability while eliminating injections inconvenience, pain and psychological distress.
- oral administration still has certain shortcomings. Its specific polypeptide structure is easily degraded by gastric acid after oral administration, and its stability is poor at room temperature.
- soluble microneedle technology can not only improve the infection and pain caused by injection, but also avoid the first-pass effect of the gastrointestinal tract and reduce the adverse reactions of the gastrointestinal tract. . It works by creating tiny holes in the sebum layer to increase the permeability of the drug, a method of administration that is somewhere between a transdermal patch and a subcutaneous injection.
- stratum corneum of the skin will hinder the transdermal absorption of the drug, even adding a penetrant cannot make the small molecule drug penetrate the skin to reach an effective drug concentration, especially for the semaglutide macromolecule drug, which is easier to intercept and retain It is difficult to enter the blood circulation in the epidermis of the skin. If the penetration causes slow absorption, it still cannot meet the corresponding therapeutic effect.
- the purpose of the present invention is to provide a soluble microneedle patch combining semaglutide with an amino acid penetration enhancer and a preparation method thereof, which significantly improves the intradermal release and penetration of semaglutide The speed significantly increases the concentration of semaglutide entering the blood circulation, and improves the bioavailability of polypeptide or protein drugs in vivo after administration by microneedle delivery.
- a first aspect of the present invention provides a semaglutide-soluble microneedle patch, comprising a base and a needle body on the base; the base is prepared from a material comprising a high molecular polymer backbone;
- the needle body is prepared from components including the following weight percentages:
- the penetration enhancer is at least one of amino acids.
- a second aspect of the present invention provides a method for preparing the above-mentioned soluble microneedle patch, comprising the following steps:
- the needle tip solution and the base solution are successively placed in a microneedle mold to prepare a soluble microneedle patch.
- the present invention has the following beneficial effects:
- the present invention provides for the first time a semaglutide and a suitable The soluble microneedle patch combined with amino acid-based penetration enhancer has good bioavailability.
- suitable amino acids are used as penetration enhancers for the first time, which are different from conventional enhancers to play a role in the superficial stratum corneum, but choose to play a role under the skin: the present invention
- the amino acid in the microneedle is combined with dosemaglutide, it can increase the biological penetration of semaglutide, thereby significantly improving the subcutaneous release and penetration rate of semaglutide, and increasing the concentration of the drug entering the blood circulation , which improved the bioavailability of semaglutide in vivo after administration by microneedle delivery.
- the semaglutide soluble microneedle patch of the present invention has a complete and good shape, the needle tip length is uniform, and the arrangement is regular.
- the mechanical strength is high, which meets the strength required for piercing the stratum corneum of human skin. And after contact with body fluids, the needle body can be quickly dissolved and separated from the base layer, which is convenient to use and has a short wearing time, and the patient has good compliance.
- Example 1 is a morphological diagram of the semaglutide-soluble microneedle patch in Example 1 under an electron microscope.
- FIG. 2 shows the results of in vivo pharmacokinetics of the penetration enhancer semaglutide soluble microneedle patch with different contents in Example 1; wherein, A represents the penetration enhancer histidine accounts for 40% of the semaglutide by mass ratio Gglutide-soluble microneedle patch; B represents semaglutide-soluble microneedle patch with penetration enhancer histidine accounting for 50% by mass; C represents penetration enhancer histidine accounting for 60% by mass Semaglutide soluble microneedle patch.
- Figure 3 is a graph showing the results of in vivo pharmacokinetics of the semaglutide soluble microneedle patch in Example 2; wherein, A represents the commercially available injection of semaglutide; B represents the semaglutide without penetration enhancer Glutide soluble microneedle patch; C represents semaglutide soluble microneedle patch containing arginine penetration enhancer; D represents semaglutide soluble microneedle patch containing glycine penetration enhancer; E represents Semaglutide soluble microneedle patch with lysine penetration enhancer.
- Figure 4 shows the results of the in vitro transdermal diffusion test of the semaglutide-soluble microneedle patch, where A represents the commercially available injection of semaglutide; B represents the semaglutide-soluble microneedle without penetration enhancer Patch; C represents semaglutide soluble microneedle patch containing arginine penetration enhancer; D represents semaglutide soluble microneedle patch containing glycine penetration enhancer; E represents lysine enhancer Penetrating semaglutide soluble microneedle patch.
- the "plurality” mentioned in the present invention means two or more.
- "And/or" which describes the association relationship of the associated objects means that there can be three kinds of relationships, for example, A and/or B, which can mean that A exists alone, A and B exist at the same time, and B exists alone.
- the character "/" generally indicates that the associated objects are an "or" relationship.
- the inventors of the present invention found in the long-term research on microneedle patch preparations that when the delivered drug is a polypeptide or protein macromolecule drug, the drug release effect of conventional soluble microneedle patches will be significantly worse, and The release rate could not be significantly improved after adding conventional penetration enhancers.
- the inventors of the present invention have conducted long-term research and finally found that the main reason for the unsatisfactory subcutaneous release of polypeptide or protein drugs (such as semaglutide) microneedle patches is the poor subcutaneous release effect. : (1) Polypeptide or protein drugs usually have a certain charge and are easy to combine with the epidermis or subcutaneous tissue.
- the present invention provides for the first time a semaglutide soluble microneedle patch, which uses amino acids as penetration enhancers.
- the charge of the osmotic agent and the polypeptide or protein drug can be effectively combined to form a neutral charge complex, and effectively relieve the interception effect of the epidermis or subcutaneous tissue on the polypeptide or protein drug.
- the present invention is the first time by selecting at least one amino acid As the penetration enhancer of the semaglutide drug microneedle patch, the rapid release of the semaglutide drug microneedle patch is realized.
- a semaglutide-soluble microneedle patch which includes a base and needles on the base; the base is a polymer backbone material;
- the material for preparing the needle body can be prepared from the following components by weight:
- the penetration enhancer is at least one of amino acids.
- the total ratio of the above four components is 100%, which is the core material for preparing the needle body.
- the core material is added to the solvent, and other auxiliary materials can also be added according to needs.
- the preparation method of the semaglutide soluble microneedle patch comprises the following steps:
- the needle tip solution and the base solution are then placed in a microneedle mold successively, and a soluble microneedle patch is prepared according to the prior art mastered by those skilled in the art.
- the needle body of the semaglutide microneedle patch is prepared from the following components by weight:
- the amino acid is glutamic acid, glycine, lysine, histidine, aspartic acid, arginine, alanine, valine, leucine, isoleucine , methionine, proline, tryptophan, serine, tyrosine, cysteine, phenylalanine, asparagine, glutamine, threonine, selenocysteine, and pyrrolysine at least one of the amino acids.
- the amino acid is at least one of lysine, glycine, arginine, and histidine. More preferably, the amino acid is glycylic acid.
- the semaglutide in the microneedle patch is present in the microneedles in a solid state.
- Biomacromolecular drugs are stored in solid form, which effectively protects the activity of the drug, and does not require the harsh cold chain storage and transportation of injections.
- the high molecular polymer backbone material in the needle body or the base is independently selected from polyvinyl alcohol, dextran, hyaluronic acid, mannitol, chitosan, gelatin, silk fibroin, carboxylate At least one of methyl cellulose, polyvinyl pyrrolidone, and vinyl propionate copolymer.
- the stabilizer is at least one of trehalose, sucrose, glucose, decanoyl sucrose, and mannitol.
- each composition is further optimized for appropriate amino acids, so as to improve the intradermal release and penetration speed of semaglutide, so that the effect is better.
- the dissolvable microneedle patch is prepared from the following components by weight:
- the needle body is prepared from components including the following weight percentages:
- Semaglutide 7-15%, polymer backbone material: 35-40%, arginine: 35-40%, mannitol: 5-10%;
- semaglutide 10-15%
- polymer backbone material 35-40%
- arginine 35-40%
- mannitol 5-8%.
- the needle body is prepared from the following components by weight: semaglutide: 10-12%, polymer backbone material: 40-45%, lysine: 40- 45%, sucrose: 5-10%; more preferably: semaglutide: 10-12%, polymer backbone material: 42-45%, lysine: 40-43%, sucrose: 5-8% .
- the needle body is prepared from the following components by weight: semaglutide: 15-18.6%, polymer backbone material: 30-40%, glycine: 45-50% , Trehalose: 3-7%.
- the needle body is prepared from the following components by weight: semaglutide: 16.5-17.5%, polymer backbone material: 33-37.5%, glycine: 45- 48%, Trehalose: 3-5%.
- the polymer backbone material in the needle body is vinyl propionate copolymer.
- the polymer backbone material in the needle body is dextran, preferably the molecular weight of the dextran is (30-60) kDa, further (30-50) kDa, further (40 ⁇ 5) kDa.
- the high molecular polymer backbone material in the substrate is polyvinylpyrrolidone, preferably polyvinylpyrrolidone-K90.
- the solvent for preparing the needle tip solution is at least one of deionized water, acetic acid solution, and phosphoric acid solution.
- the concentration of the high molecular polymer backbone material in the needle tip solution is 0.07-0.50 g/mL, further 0.07-0.2 g/mL, and more preferably 0.07-0.15 g/mL.
- the solvent for preparing the base solution is absolute ethanol.
- the concentration of the high molecular polymer framework material in the base solution is 0.2-0.4 g/mL.
- the purity of semaglutide is >98%, which is a commercially available product, purchased from Zhejiang Pai Pei Biotechnology Co., Ltd.;
- PVP/VA vinyl propionate copolymer
- Histidine purchased from Merck Chemical Technology (Shanghai) Co., Ltd.;
- Glycine purchased from Xi'an Tianzheng Pharmaceutical Excipients Co., Ltd.;
- Lysine purchased from Shaanxi Sunray Pharmaceutical Technology Co., Ltd.;
- L-Arginine purchased from Pfanstiehl, Inc.;
- Trehalose purchased from Luofu Pharmaceutical Technology Co., Ltd.;
- Dextran molecular weight 40kDa, purchased from Shanghai Aladdin Biochemical Technology Co., Ltd.;
- Sucrose purchased from Guangxi Tiantianle Pharmaceutical Co., Ltd.
- the macromolecular polymer skeleton material is selected from dextran
- the penetration enhancer is histidine
- the stabilizer is selected from mannitol.
- the high molecular polymer framework material in the base is selected from PVP K90, and the concentration in the base solution is 0.3 g/mL.
- the mass ratios of the semaglutide, dextran, histidine, and mannitol are shown in the following groups (1) to (3).
- the penetration enhancer histidine accounts for 40% by mass, and the mass ratio of semaglutide (5%), dextran (50%), histidine (40%), and mannitol (5%) is 0.5 :5:4:0.5.
- the penetration enhancer histidine accounts for 50% by mass, and the mass ratio of semaglutide, dextran, histidine and mannitol is 0.5:4:5:0.5.
- the concentration of the high molecular polymer backbone material (dextran) in the needle tip solution is 0.075-0.1 g/mL.
- the solvent for preparing the base solution is absolute ethanol, and the solvent for preparing the needle tip solution is deionized water.
- Dissolve the corresponding penetration enhancer in the solvent (ionized water)
- the material in the needle tip is selected from vinyl propionate copolymer, and the penetration enhancer is arginine, glycine or lysine
- the penetration enhancer is arginine, glycine or lysine
- One of the stabilizers is selected from mannitol, or sucrose or trehalose.
- the macromolecular polymer skeleton material in the substrate is selected from PVP K90, the concentration in the substrate solution is 0.3 g/mL, the solvent for preparing the substrate solution is absolute ethanol, and the solvent for preparing the needle tip solution is deionized water.
- the mass ratios of semaglutide, vinyl propionate copolymer, penetration enhancer, and mannitol are shown in the following groups (1) to (3).
- the mass ratio is:
- Semaglutide (15%): polymer backbone material (40%): arginine (40%): mannitol (5%) in a ratio of 1.5:4:4:0.5.
- the high molecular polymer backbone material is PVP/VA (vinyl propionate copolymer), and the concentration in the needle tip solution is 0.1-0.15 g/mL.
- the semaglutide soluble microneedles with lysine as penetration enhancer were obtained.
- the semaglutide soluble microneedles with glycine as penetration enhancer were obtained.
- Test Example 1 Scanning electron microscope experiment of semaglutide soluble microneedle patch
- Example 2 Taking the drug-loaded soluble microneedle patch with glycine as the penetration enhancer in Example 2 as an example, the experimental results are shown in the scanning electron microscope image in Figure 1. The results show that the semaglutide soluble microneedle patch is compatible with the design of the main mold. Consistently, during the preparation process, the polymer solution has good fluidity and can be fully filled in the micropores of the negative mold, and maintains the array shape of the microneedles during the drying process. Regular shape.
- the area under the curve of the microneedle administration is 1.94 times that when the dosage of histidine is 50%, and when the dosage of histidine is 50%
- the area under the curve of microneedle administration is 3.78 times that of histidine when the dosage is 40%
- amino acids can combine with semaglutide to form a neutral charge complex, which promotes semaglutide
- the greater the amount of amino acid used the greater the transdermal penetration of semaglutide.
- the amount of amino acid will also affect the mechanical strength of the microneedles, so the preferred amount of histidine in the present invention is 60%.
- mice weighing 200-250 g were randomly divided into 5 groups, with 3 rats in each group.
- Use a pet-specific razor to remove the long hairs on the back skin, and then use a depilatory cream to completely cover the back area for 5 minutes, scrape the fluff on the skin surface, and clean the remaining hair removal cream, and use qualitative filter paper to wipe the skin surface.
- the initial body weight of the rats was recorded for use.
- the results show that the soluble microneedle patch without penetration enhancer group has lower blood drug concentration after administration.
- the molecular weight of the peptide is relatively large, about 4113.58.
- After percutaneous administration of microneedles it is easy to be trapped in the epidermis or difficult to diffuse into the plasma in the subcutaneous tissue, resulting in a low blood concentration and a relative bioavailability of about 14.48%.
- After adding glycine, lysine or arginine the blood concentration and relative bioavailability of the drug in vivo were improved.
- the relative bioavailability of the microneedle group added with lysine was 24.80%; the relative bioavailability of the microneedle group added with arginine was 36.90%; the microneedle group added with glycine was administered
- the relative bioavailability of the latter is the highest, which is 53.54%; for the combination of semaglutide microneedle patch and glycine, the optimal relative bioavailability can be achieved, which promotes the penetration of the drug into the blood.
- glycine group D
- group D adding glycine
- group D has the best effect on promoting the penetration of semaglutide, and the cumulative penetration rate is about 50%.
- glycine has a small molecular weight, simple structure, and is an amphoteric amino acid, which is easier to combine with semaglutide to form a neutral charge complex, which promotes the percutaneous penetration of semaglutide.
- arginine and lysine the cumulative penetration rates of semaglutide after adding arginine and lysine were about 36% and 28%, respectively, which were relatively close.
- Both arginine (group C) and lysine (group E) are basic amino acids, and the effect of promoting permeability is similar.
- the addition of glycine to the prescription can better promote the penetration of semaglutide.
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Abstract
一种司美格鲁肽可溶性微针贴片及其制备方法。可溶性微针贴片包括基底和基底上的针体；针体包括以下组分：高分子聚合物骨架材料、司美格鲁肽、促渗剂；基底包括高分子聚合物骨架材料；促渗剂为氨基酸中的至少一种。微针贴片用于司美格鲁肽经皮给药，明显改善了司美格鲁肽在皮内的释放和渗透速度，显著增加了药物进入血液循环的浓度，提高了司美格鲁肽经微针递送给药后在体内的生物利用度。
Description
本发明涉及医药领域，特别是涉及一种司美格鲁肽可溶性微针贴片及其制备方法。
据国际糖尿病联盟2019年发布的数据显示，全球约有4.63亿成年人患有糖尿病，预计2045年这一数字将增至7亿。2019年，我国糖尿病患者约有1.16亿，且呈逐年增加的趋势，预计2030年将达到1.43亿。我国已成为世界上糖尿病患者最多的国家，其中约95％为2型糖尿患者。长期有效控制血糖对于预防和减少糖尿病并发症有重大意义。胰高血糖素样肽1受体激动剂(Glucagon-like peptide 1 receptor agonists，GLP-1RA)可以激动GLP-1受体，刺激胰岛素分泌和抑制胰高血糖素释放。
司美格鲁肽(原名索马鲁肽)与天然GLP-1有94％同源性，其氨基酸骨架连接脂肪酸侧链，延长半衰期达到165h，每周1次经皮下注射给药。相对于其他几种激动剂，司美格鲁肽在降糖、减重、心血管系统获益以及安全性等方面表现出更大的优势。2019年9月20日，FDA批准每日1次的口服型司美格鲁肽(Rybelsus)上市，该制剂采用2-羟基本甲酰胺基作为促吸收剂，提高了生物利用度，同时摆脱注射带来的不便、疼痛和心理折磨。但是口服给药仍存在一定的缺点，其特定的多肽结构口服后会易被胃酸降解，在常温环境下稳定性差，因此口服片剂的生物利用度较低，其所需给药剂量远高于皮下注射剂，口服给药后易出现胃肠道的不良反应，症状包括恶心、呕吐、腹泻、腹痛及便秘等；且片剂每日需口服一次，患者容易漏服，导致疗效不稳定。
可溶性微针技术作为一种新型经皮给药的传递技术，既能改善注射给药而引起的感染和痛苦，同时又能避免胃肠道的首过效应，也可以减少胃肠道的不良反应。其工作原理是通过在皮脂层产生微小孔洞来提升药物的渗透性，此方法是一种介于透皮贴剂以及皮下注射剂之间的给药方式。但是由于皮肤的角质 层会阻碍药物的透皮吸收，即使是加入渗透剂也不能使得小分子药物穿透皮肤达到有效的药物浓度，尤其是对于司美格鲁肽大分子药物更加容易截留、滞留在皮肤表皮层中而难以进入血液循环。如果渗透造成吸收速度缓慢，仍然不能够满足相应的治疗效果。
发明内容
基于此，本发明的目的是提供一种司美格鲁肽与氨基酸类促渗剂结合的可溶性微针贴片及其制备方法，其明显改善了司美格鲁肽在皮内的释放和渗透速度，显著增加了司美格鲁肽进入血液循环的浓度，提高了多肽或蛋白质类药物经微针递送给药后在体内的生物利用度。
本发明的第一个方面，提供了一种司美格鲁肽可溶性微针贴片，包括基底和基底上的针体；所述基底由包括高分子聚合物骨架材料制备而成；
所述针体由包括以下重量百分比的组分制备而成：
所述促渗剂为氨基酸中的至少一种。
本发明的第二个方面，是提供一种上述的可溶性微针贴片的制备方法，包括以下步骤：
将所述促渗剂溶于溶剂中，加入所述高分子骨架材料后进行溶解，调节pH至7.0～9.0，加入所述司美格鲁肽搅拌，混合均匀后得到针尖溶液；
再将所述高分子聚合物骨架材料溶于溶剂中，得到基底溶液；
将所述针尖溶液和基底溶液先后置于微针模具中，制备可溶性微针贴片。
与现有技术相比，本发明具有以下有益效果：
为了解决司美格鲁肽经微针给药后在皮下与皮下组织结合力强，从而阻碍药物进入血液循环、生物利用度低的技术问题，本发明首次提供一种司美格鲁肽与合适氨基酸类的促渗剂结合的可溶性微针贴片，其具有很好的生物利用度。
在本发明的司美格鲁肽可溶性微针贴片中，首次采用合适的氨基酸类作为促渗剂，其不同于常规促进剂在表层角质层发挥作用，而是选择在皮下发挥作用：本发明微针中的氨基酸与多司美格鲁肽结合后，可以增加司美格鲁肽的生物透皮，从而显著提高司美格鲁肽在皮下的释放和渗透速度，增加药物进入血液循环的浓度，提高了司美格鲁肽经微针递送给药后在体内的生物利用度。
本发明的司美格鲁肽可溶性微针贴片形态完整良好，针尖长度统一，排列规整。机械强度较高，满足刺穿人体皮肤角质层所需要的强度。并且在接触体液后，针体可以迅速溶解与基底层分离，使用方便且佩戴时间短，患者的顺应性良好。
图1为实施例1中司美格鲁肽可溶性微针贴片在电镜下的形态图。
图2实施例1中含量不同的促渗剂司美格鲁肽可溶性微针贴片的体内药物代谢动力学结果图；其中，A代表促渗剂组氨酸占质量比为40％的司美格鲁肽可溶性微针贴剂；B代表促渗剂组氨酸占质量比为50％的司美格鲁肽可溶性微针贴剂；C代表促渗剂组氨酸占质量比为60％的司美格鲁肽可溶性微针贴剂。
图3为实施例2中司美格鲁肽可溶性微针贴片的体内药物代谢动力学结果图；其中，A代表司美格鲁肽市售注射剂；B代表不含促渗剂的司美格鲁肽可溶性微针贴剂；C代表含有精氨酸促渗剂的司美格鲁肽可溶性微针贴剂；D代表含有甘氨酸促渗剂的司美格鲁肽可溶性微针贴剂；E代表含有赖氨酸促渗剂的司美格鲁肽可溶性微针贴剂。
图4为司美格鲁肽可溶性微针贴片的体外透皮扩散试验结果，其中，A代表司美格鲁肽市售注射剂；B代表不含促渗剂的司美格鲁肽可溶性微针贴剂；C代表含有精氨酸促渗剂的司美格鲁肽可溶性微针贴剂；D代表含有甘氨酸促渗剂的司美格鲁肽可溶性微针贴剂；E代表含有赖氨酸促渗剂的司美格鲁肽可溶性微针贴剂。
本发明下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。实施例中所用到的各种常用化学试剂，均为市售产品。
除非另有定义，本发明所使用的所有的技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。本发明的说明书中所使用的术语只是为了描述具体的实施例的目的，不用于限制本发明。
本发明的术语“包括”和“具有”以及它们任何变形，意图在于覆盖不排他的包含。例如包含了一系列步骤的过程、方法、装置、产品或设备没有限定于已列出的步骤或模块，而是可选地还包括没有列出的步骤，或可选地还包括对于这些过程、方法、产品或设备固有的其它步骤。
在本发明中提及的“多个”是指两个或两个以上。“和/或”，描述关联对象的关联关系，表示可以存在三种关系，例如，A和/或B，可以表示：单独存在A，同时存在A和B，单独存在B这三种情况。字符“/”一般表示前后关联对象是一种“或”的关系。
本发明的发明人在长期对微针贴片制剂的研究过程中发现，当所递送的药物为多肽或蛋白质类大分子药物时，常规的可溶性微针贴片的药物释放效果会明显变差，并且添加常规的促渗剂后都不能明显提高其释放速度。为了解决这一难题，本发明的发明人进行了长期的研究，最终发现导致多肽或蛋白质类药物(例如司美格鲁肽)微针贴片皮下释药不理想的主要原因在于皮下释放效果差：(1)多肽或蛋白质类药物通常带有一定的电荷，易于与表皮或皮下组织结合，微针给药后容易截留在表皮部位或者皮下组织中难以扩散进入血液，导致血药浓度低；(2)多肽或蛋白质类药物分子结构大，并且具有两亲性，容易在皮下脂溶性环境中聚集吸附。在此基础上，本发明首次提供了一种司美格鲁肽可溶性微针贴片，其选用氨基酸作为促渗剂，在不改变载药量和微针机械强度的前提下，氨基酸类的促渗剂与多肽或蛋白质类药物的电荷可以有效结合形成中性电荷复合物，并有效解除表皮或皮下组织对多肽或蛋白质类药物的截留作用，最终，本发明首次通过选用氨基酸中的至少一种作为司美格鲁肽药物微针 贴片的促渗剂，实现了司美格鲁肽药物微针贴片的快速释药。
本发明的一些实施例中，涉及司美格鲁肽可溶性微针贴片，其包括基底和基底上的针体；所述基底为高分子聚合物骨架材料；
制备针体的材料除溶剂之外，可由包括以下重量百分比的组分制备而成：
所述促渗剂为氨基酸中的至少一种。
上述四种组分的比例在一些实施例中，总和为100％，其是制备针体的核心材料，在制备时，核心材料加入溶剂中，也可以适应性地根据需要加入其他辅助材料。
所述司美格鲁肽可溶性微针贴片的制备方法，包括以下步骤：
将所述促渗剂溶于溶剂中，加入所述高分子骨架材料后进行溶解，调节pH至7.0～9.0，加入所述司美格鲁肽搅拌，混合均匀后得到针尖溶液；
将所述高分子聚合物骨架材料溶于溶剂中，得到基底溶液；
再将所述针尖溶液和基底溶液先后置于微针模具中，根据本领域技术人员所掌握的已有技术，制备可溶性微针贴片。
在其中一些实施例中，所述司美格鲁肽微针贴片的针体由包括以下重量百分比的组分制备而成：
在其中一些实施例中，所述氨基酸为谷氨酸、甘氨酸、赖氨酸、组氨酸、天冬氨酸、精氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、甲硫氨酸、脯氨酸、色氨酸、丝氨酸、酪氨酸、半胱氨酸、苯丙氨酸、天冬酰胺、谷氨酰胺、苏氨酸、硒半胱氨酸和吡咯赖氨酸中的至少一种。
在其中一些实施例中，所述氨基酸为赖氨酸、甘基酸、精氨酸、组氨酸中的至少一种。更优选为，所述氨基酸为甘基酸。
在其中一些实施例中，所述微针贴片中的所述司美格鲁肽以固态形式存在于微针中。生物大分子药物以固态形式存储，有效的保护了药物的活性，同时也不需要注射液苛刻的冷链储存运输。
在其中一些实施例中，所述针体或基底中的高分子聚合物骨架材料分别独立地选自聚乙烯醇、右旋糖酐、透明质酸、甘露醇、壳聚糖、明胶、丝素蛋白、羧甲基纤维素、聚乙烯吡咯烷酮、丙酸乙烯酯共聚物中的至少一种。
在其中一些实施例中，所述稳定剂为海藻糖、蔗糖、葡萄糖、癸酰基蔗糖和甘露醇中的至少一种。
在其中一些优选的实施例中，进一步针对合适的氨基酸，对各组成做进一步的优化，以改善司美格鲁肽在皮内的释放和渗透速度，使效果更优。
在其中一些实施例中，所述可溶性微针贴片由以下重量百分比的组分制备而成：
在其中一些实施例中，所述针体由包括以下重量百分比的组分制备而成：
司美格鲁肽：7-15％,高分子骨架材料：35-40％，精氨酸：35-40％，甘露醇：5-10％；
更进一步优选为：司美格鲁肽：10-15％，高分子骨架材料：35-40％,精氨酸：35-40％，甘露醇：5-8％。
在其中一些实施例中，所述针体由包括以下重量百分比的组分制备而成：司美格鲁肽：10-12％,高分子骨架材料：40-45％，赖氨酸：40-45％,蔗糖：5-10％；更优选为：司美格鲁肽：10-12％,高分子骨架材料：42-45％,赖氨酸：40-43％,蔗 糖：5-8％。
在其中一些实施例中，所述针体由包括以下重量百分比的组分制备而成：司美格鲁肽：15-18.6％，高分子骨架材料：30-40％,甘氨酸：45-50％,海藻糖：3-7％。
在其中一些优选的实施例中，所述针体由包括以下重量百分比的组分制备而成：司美格鲁肽：16.5-17.5％,高分子骨架材料：33-37.5％,甘氨酸：45-48％,海藻糖：3-5％。
在上述的所述司美格鲁肽微针贴片中，一些实施例中，针体中的所述高分子聚合物骨架材料为丙酸乙烯酯共聚物。
在其中一些实施例中，针体中的高分子聚合物骨架材料为右旋糖酐，优选所述右旋糖酐的分子量为(30～60)kDa，进一步为(30～50)kDa，进一步为(40±5)kDa。
在其中一些实施例中，基底中的所述高分子聚合物骨架材料为聚乙烯吡咯烷酮，优选为聚乙烯吡咯烷酮-K90。
在其中一些实施例中，制备针尖溶液的溶剂为去离子水、醋酸溶液、磷酸溶液中的至少一种。
在其中一些实施例中，所述高分子聚合物骨架材料在针尖溶液中的浓度为0.07～0.50g/mL，进一步为0.07～0.2g/mL更优选为0.07～0.15g/mL。
在其中一些实施例中，制备基底溶液的溶剂为无水乙醇。
在其中一些实施例中，所述高分子聚合物骨架材料在基底溶液中的浓度为0.2～0.4g/mL。
本发明实施例所用部分原料如下：
司美格鲁肽的纯度>98％，为市售产品，购自浙江湃肽生物科技有限公司；
PVP/VA(丙酸乙烯酯共聚物)：购自上海巴斯夫科技有限公司；
组氨酸：购自默克化工技术(上海)有限公司；
甘氨酸：购自西安天正药用辅料有限公司；
赖氨酸：购自陕西圣瑞医药科技有限公司；
L-精氨酸：购自Pfanstiehl,Inc.；
海藻糖：购自罗辅医药科技有限公司；
右旋糖酐：分子量40kDa，购自上海阿拉丁生化科技股份有限公司；
甘露醇：购自深圳市优普惠药品股份有限公司；
蔗糖：购自广西天天乐药业股份有限公司。
以下结合具体实施例对本发明作进一步详细的说明。
实施例1
本实施所述的司美格鲁肽可溶性微针贴片的药物，针尖中材料中：高分子聚合物骨架材料选自右旋糖酐，促渗剂为组氨酸，稳定剂选自甘露醇。基底中的高分子聚合物骨架材料选自PVP K90，在所述基底溶液中的浓度为0.3g/mL。所述司美格鲁肽、右旋糖酐、组氨酸、甘露醇的质量比如以下(1)～(3)组所示。
(1)促渗剂组氨酸占质量比40％，司美格鲁肽(5％)、右旋糖酐(50％)、组氨酸(40％)、甘露醇(5％)的质量比为0.5：5：4：0.5。
(2)促渗剂组氨酸占质量比50％，司美格鲁肽、右旋糖酐、组氨酸、甘露醇的质量比为0.5：4：5：0.5。
(3)促渗剂组氨酸占质量比60％，司美格鲁肽、右旋糖酐、组氨酸、甘露醇的质量比为0.5：3：6：0.5。
其中，高分子聚合物骨架材料(右旋糖酐)在针尖溶液中的浓度为0.075-0.1g/mL。
所述制备基底溶液的溶剂为无水乙醇，制备针尖溶液的溶剂为去离子水。
将相应促渗剂溶于溶剂(离子水)中，加入高分子骨架材料后进行溶解，调节pH至7.0～9.0，加入司美格鲁肽搅拌，混合均匀后得到针尖溶液多。使用移液枪将制备得到的药物溶液滴加至聚二甲基硅氧烷模具中，并铺满于模具的孔洞上方；将模具放入离心机吊篮的正中央，设置离心机的参数为0-10℃，转速为4000rpm离心10min，调转转杯180度后，继续在相同的参数条件下离心10min，使针尖溶液充分填满于阴模的微小空洞里；随后，刮去并回收上层残留 的多余溶液；取基底的高分子骨架材料溶于无水乙醇中(PVP K90，浓度为0.30g/mL)加至阴模中，同样的离心参数条件下，离心3min；离心后，放置在干燥器中室温干燥36h，用镊子将微针贴片轻轻脱模取出即制备得到可溶性微针。
实施例2
本实施所述的司美格鲁肽可溶性微针贴片的药物，针尖中材料：高分子聚合物骨架材料选自丙酸乙烯酯共聚物，促渗剂为精氨酸、甘氨酸或赖氨酸中的一种，稳定剂选自甘露醇，或蔗糖或海藻糖。基底中的高分子聚合物骨架材料选自PVP K90，在所述基底溶液中的浓度为0.3g/mL，所述制备基底溶液的溶剂为无水乙醇，制备针尖溶液的溶剂为去离子水。
司美格鲁肽、丙酸乙烯酯共聚物、促渗剂、甘露醇的质量比如以下(1)～(3)组所示。
(1)促渗剂为精氨酸时，质量比为：
司美格鲁肽(15％)：高分子骨架材料(40％)：精氨酸(40％)：甘露醇(5％)为1.5：4：4：0.5。
(2)促渗剂为赖氨酸时，质量比为：
司美格鲁肽(10％)：高分子骨架材料(45％)：赖氨酸(40％)：蔗糖(5％)为1：4.5：4：0.5。
(3)促渗剂为甘氨酸时，质量比为：
司美格鲁肽(17％)：高分子骨架材料(35％)：甘氨酸(45％)：海藻糖(3％)为1.7：3.5：4.5：0.3。
其中，高分子聚合物骨架材料为PVP/VA(丙酸乙烯酯共聚物)在针尖溶液中的浓度为0.1-0.15g/mL。
本实施例所述司美格鲁肽可溶性微针贴片的制备方法如下：
一、促渗剂为精氨酸的司美格鲁肽可溶性微针的制备方法，包括下列步骤：
(1)针尖溶液的配制：
精密称取120mg精氨酸、120mg PVP/VA和15mg甘露醇于5mL离心管中，加入1mL的超纯水，搅拌溶解，得到辅料溶液。在辅料溶液中逐滴加入一定量的0.25mol/L NaOH溶液，调节pH到7.0左右。精密称取45mg司美格鲁肽加到调节pH的辅料溶液中，搅拌溶解，得到含精氨酸的针尖溶液。
(2)基底溶液的配制：
称取10g的PVP K90加入到50mL离心管中，加入30mL无水乙醇，搅拌溶胀过夜，得到基底溶液。
(3)可溶性微针的制备：
吸取上述针尖溶液200μL到微针阴模中，在0～10℃以4000rpm转速离心10min；离心结束后将模具翻转180°，继续在0～10℃以4000rpm转速离心10min。取出模具，刮去上层残余的针尖溶液，回收利用；加入一定量上述基底溶液到已填充针孔的阴模中，在0～10℃以4000rpm转速离心5min；置干燥器中干燥36h，小心剥离模具。得到以精氨酸为促渗剂的司美格鲁肽可溶性微针。
二、促渗剂为赖氨酸的司美格鲁肽可溶性微针的制备方法，包括下列步骤：
(1)针尖溶液的配制：
精密称取120mg赖氨酸、135mg PVP/VA和15mg蔗糖于5mL离心管中，加入1mL的超纯水，搅拌溶解，得到辅料溶液。在辅料溶液中逐滴加入一定量的0.25mol/L NaOH溶液，调节pH到7.0左右。精密称取30mg司美格鲁肽加到调节pH的辅料溶液中，搅拌溶解，得到含赖氨酸的针尖溶液。
(2)基底溶液的配制：同上。
(3)可溶性微针的制备：同上。
得到以赖氨酸为促渗剂的司美格鲁肽可溶性微针。
三、促渗剂为甘氨酸的司美格鲁肽可溶性微针的制备方法，包括下列步骤：
(1)针尖溶液的配制：
精密称取135mg甘氨酸、105mg PVP/VA和9mg海藻糖于5mL离心管中，加入1mL的超纯水，搅拌溶解，得到辅料溶液。在辅料溶液中逐滴加入一定量的0.25mol/L NaOH溶液，调节pH到7.0左右。精密称取51mg司美格鲁肽加到调节pH的辅料溶液中，搅拌溶解，得到含甘氨酸的针尖溶液。
(2)基底溶液的配制：同上。
(3)可溶性微针的制备：同上。
得到以甘氨酸为促渗剂的司美格鲁肽可溶性微针。
试验例1 司美格鲁肽可溶性微针贴片扫描电镜实验
实验方法：取制备得到的载有司美格鲁肽的可溶性微针用导电胶布固定于V字型铜片上，通过喷金后，使用电子扫描显微镜(Scanning Electron Microscope，SEM)设置工作电压为15kV，观察微针贴片的形态，并采集图像。
以实施例2中的促渗剂为甘氨酸的载药可溶性微针贴片为例，实验结果如图1所示扫描电镜图，结果表明司美格鲁肽可溶性微针贴片与主模具设计相一致，在制备过程中聚合物溶液有良好的流动性可以充分填充在阴模微孔内，并在干燥的过程中保持微针的阵列形状，由四棱柱与四棱锥的组合，长度统一，外观形态规整。
试验例2 实施例1所述的司美格鲁肽微针贴片体内药物代谢动力学实验
实施例1所述的司美格鲁肽微针贴片实验方法：将9只200～250g的SD大鼠随机分为3组，每组3只。给药前禁食12h，使用脱毛膏去除大鼠颈背部区域多余的毛，并将皮肤表面的水分擦拭干净。将实施例1制备干燥后的3种微针(n＝3)垂直按压在大鼠颈背部3min，使用医用胶带将其固定在皮肤上，并记录给药时间。分别在给药后定时从大鼠的眼眶后静脉处取血约0.5mL。置于离心管中，将各个组别的血样于低温离心机在4℃，rpm下离心min，收集上 清血样，并检测上清中的各药物含量，计算药物浓度，绘制药物的代谢动力学曲线。
本试验例中加入不同比例的组氨酸后，药动学实验结果见图2。结果表明，随着组氨酸在处方中的比例增加，司美格鲁肽从皮肤渗透进入血液循环的量就越多，组氨酸的促渗作用就越好。其中当组氨酸的用量占比为60％时，微针给药的药时曲线下面积是组氨酸的用量占比为50％时的1.94倍，而当组氨酸的用量占比为60％时，微针给药的药时曲线下面积是组氨酸的用量占比为40％时的3.78倍；氨基酸可与司美格鲁肽结合形成中性电荷复合物，促进司美格鲁肽的经皮渗透，氨基酸的用量越大，司美格鲁肽的经皮渗透量越多。但是氨基酸的用量也会对微针的机械强度有影响，所以本发明优选的组氨酸用量占比为60％。
试验例3 实施例2所述司美格鲁肽微针贴片体内药物代谢动力学实验
实验方法：将200～250g的SD大鼠随机分为5组，每组3只。用宠物专用剃毛刀将背部皮肤上较长的毛发剔除干净，再采用脱毛膏完全覆盖背部区域5min后，刮取皮肤表面的绒毛，并清洗干净残存的脱毛膏，使用定性滤纸擦拭干净皮表带水分后放置10min后记录大鼠的初始体重待用。使用双面胶和医用胶布将微针贴片固定在拉力计的探头处，将老鼠的背部皮肤区域固定在接收板上，设置拉力计的参数为100N、速度为60mm/min进行给药5min，后用医用胶布固定住，微针保持2h后除去。
并在给药后的15min、30min、1h、2h、4h、8h、12h、24h、48h、72h眼眶采血0.5mL，置于内壁涂有肝素钠的离心管中。在5000rpm下离心10min，收集上清血样，并检测上清中的各药物含量，计算药物浓度，绘制药物的代谢动力学曲线。
表3.1 司美格鲁肽可溶性微针贴片的体内药物代谢检测结果
参见表3.1和图3，结果表明不含有促渗剂组的可溶性微针贴片在给药后的血药浓度较低虽然可溶性微针贴片打破了皮肤角质层的屏障，但是司美格鲁肽的分子量较大，约为4113.58，微针经皮给药后容易截留在表皮部位或在皮下组织中难以扩散进入血浆，导致血药浓度较低，相对生物利用度约为14.48％。加入甘氨酸、赖氨酸或者精氨酸后均提高了药物在体内的血药浓度和相对生物利用度。其中，加入赖氨酸的微针组给药后的相对生物利用度为24.80％；加入精氨酸的微针组给药后的相对生物利用度为36.90％；加入甘氨酸的微针组给药后的相对生物利用度最高，为53.54％；针对司美格鲁肽微针贴片与甘氨酸结合后可以达到最优的相对生物利用度，促进药物渗透入血。
试验例4 司美格鲁肽溶性微针贴片体外透皮给药实验
透皮扩散实验的实验方法：大鼠麻醉后用宠物专用剃毛刀剃去背部长毛，再用脱毛膏除去剩余短毛，并洗干净残存的脱毛膏，处死。剪取背部皮肤，小心刮去皮下的脂肪，用生理盐水清洗浸泡，-20℃保存。临用时用生理盐水浸泡解冻，剪成小块，滤纸完全吸干水分。使用双面胶和医用胶布将微针贴片固定在拉力计的探头处，设置拉力计的参数为100N、速度为60mm/min作用于鼠皮上5min，然后固定在Franz扩散池上。其中供给池用封口膜密封，接收池加入超纯水作为接收液。Franz扩散池保持37℃，100rpm在透皮扩散仪上进行实验，特定时间(0.5、1、2、4、8、12、24h)取出0.5mL接收液，同时补上等量新鲜的接收液。高效液相色谱测各时间点接收液中的药量，计算释放百分率，以时间为横坐标，释放百分率为纵坐标制作透皮释放曲线。
表4.1 司美格鲁肽可溶性微针贴片的体外透皮释放检测结果
参见表4.1和图4，结果表明处方中加入促渗剂不同程度地改善了司美格鲁肽在皮内的释放和渗透速度，显著增加了药物进入血液循环的浓度。其中原研注射剂组由于药物几乎不存在透皮的过程，在给药后8h注射到皮下的药物基本完全透过皮肤，累积渗透率达95％以上。而不含促渗剂的微针(B组)它的经皮释放速率和释放量都是各组中最低，24h的累积渗透率仅有12％左右。原因可能是司美格鲁肽的分子量较大，在皮肤中的滞留性较强。加入促渗剂后，累积渗透率显著增加。其中加入甘氨酸(D组)对司美格鲁肽的促渗作用最好，累积渗透率达50％左右。原因可能是甘氨酸分子量小，结构简单，且为两性氨基酸，更容易与司美格鲁肽结合形成中性电荷复合物，促进了司美格鲁肽的经皮渗透。其次是精氨酸和赖氨酸，加入精氨酸和赖氨酸后司美格鲁肽的累积渗透率分别约为36％和28％，两者比较接近。精氨酸(C组)和赖氨酸(E组)均为碱性氨基酸，促渗的作用相似。综上所述，在处方中加入甘氨酸更能促进司美格鲁肽的渗透。
以上实验说明本发明的所述司美格鲁肽可溶性微针贴片改善了司美格鲁肽在皮内的释放和渗透速度，显著增加了药物进入血液循环的浓度。
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。
Claims (17)
- 一种司美格鲁肽可溶性微针贴片，包括基底和基底上的针体，其特征在于，所述基底由包括高分子聚合物骨架材料制备而成；所述针体由包括以下重量百分比的组分制备而成：
所述促渗剂为氨基酸中的至少一种。 - 根据权利要求1所述的司美格鲁肽可溶性微针贴片，其特征在于，所述针体由包括以下重量百分比的组分制备而成：
- 根据权利要求1或2所述的司美格鲁肽可溶性微针贴片，其特征在于，所述氨基酸为谷氨酸、甘氨酸、赖氨酸、组氨酸、天冬氨酸、精氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、甲硫氨酸、脯氨酸、色氨酸、丝氨酸、酪氨酸、半胱氨酸、苯丙氨酸、天冬酰胺、谷氨酰胺、苏氨酸、硒半胱氨酸和吡咯赖氨酸中的至少一种。
- 根据权利要求3所述的司美格鲁肽可溶性微针贴片，其特征在于，所述氨基酸为赖氨酸、甘基酸、精氨酸、组氨酸中的至少一种。
- 根据权利要求1所述的司美格鲁肽可溶性微针贴片，其特征在于，所述针体或基底中的高分子聚合物骨架材料分别独立地选自聚乙烯醇、右旋糖酐、透明质酸、甘露醇、壳聚糖、明胶、丝素蛋白、羧甲基纤维素、聚乙烯吡咯烷酮、丙酸乙烯酯共聚物中的至少一种。
- 根据权利要求5所述的司美格鲁肽可溶性微针贴片，其特征在于，针体中的所述高分子聚合物骨架材料为丙酸乙烯酯共聚物；和/或基底中的所述高分子聚合物骨架材料为聚乙烯吡咯烷酮，优选为聚乙烯吡咯烷酮-K30或聚乙烯吡咯烷 酮-K90。
- 根据权利要求5所述的司美格鲁肽可溶性微针贴片，其特征在于，所述针体中的高分子聚合物骨架材料为右旋糖酐，优选所述右旋糖酐的分子量为30～60kDa，进一步为30～50kDa，优选为40±5kDa。
- 根据权利要求1所述的司美格鲁肽可溶性微针贴片，其特征在于，所述稳定剂为海藻糖、蔗糖、葡萄糖、癸酰基蔗糖和甘露醇中的至少一种。
- 根据权利要求1所述的司美格鲁肽可溶性微针贴片，其特征在于，所述针体由包括以下重量百分比的组分制备而成：
- 根据权利要求1所述的司美格鲁肽可溶性微针贴片，其特征在于，所述针体由包括以下重量百分比的组分制备而成：司美格鲁肽：7-15％高分子骨架材料：35-40％精氨酸：35-40％甘露醇：5-10％。
- 根据权利要求1所述的司美格鲁肽可溶性微针贴片，其特征在于，所述针体由包括以下重量百分比的组分制备而成：司美格鲁肽：10-12％高分子骨架材料：40-45％赖氨酸：40-45％蔗糖：5-10％。
- 根据权利要求1所述的司美格鲁肽可溶性微针贴片，其特征在于，所述针体由包括以下重量百分比的组分制备而成：司美格鲁肽：15-18.6％高分子骨架材料：30-40％甘氨酸：45-50％海藻糖：3-7％。
- 一种权利要求1-12任一项所述的司美格鲁肽可溶性微针贴片的制备方法，其特征在于，包括以下步骤：将所述促渗剂溶于溶剂中，加入所述高分子骨架材料后进行溶解，调节pH至7.0～9.0，加入司美格鲁肽搅拌，混合均匀后得到针尖溶液；将所述高分子聚合物骨架材料溶于溶剂中，得到基底溶液；将所述针尖溶液和所述基底溶液先后置于微针模具中，制备可溶性微针贴片。
- 根据权利要求13所述的制备方法，其特征在于，制备针尖溶液的溶剂为去离子水、醋酸溶液、磷酸溶液的至少一种。
- 根据权利要求13所述的制备方法，其特征在于，制备基底溶液的溶剂为无水乙醇。
- 根据权利要求13所述的制备方法，其特征在于，所述高分子聚合物骨架材料在针尖溶液中的浓度为0.07～0.50g/mL，优选为0.07～0.20g/mL。
- 根据权利要求13所述的制备方法，其特征在于，所述高分子聚合物骨架材料在所述基底溶液中的浓度为0.2～0.4g/mL。
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| CN114306917A (zh) | 2022-04-12 |
| CN114272511A (zh) | 2022-04-05 |
| CN114272511B (zh) | 2023-08-01 |
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