WO2010105450A1 - 一种肌肽药物插层水滑石及其制备方法 - Google Patents

一种肌肽药物插层水滑石及其制备方法 Download PDF

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WO2010105450A1
WO2010105450A1 PCT/CN2009/071925 CN2009071925W WO2010105450A1 WO 2010105450 A1 WO2010105450 A1 WO 2010105450A1 CN 2009071925 W CN2009071925 W CN 2009071925W WO 2010105450 A1 WO2010105450 A1 WO 2010105450A1
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carnosine
nitrate
hydrotalcite
composite material
deionized water
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French (fr)
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卫敏
陈秋华
陆军
段雪
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Beijing University of Chemical Technology
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Beijing University of Chemical Technology
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/05—Dipeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/12—Ophthalmic agents for cataracts

Definitions

  • the invention belongs to the technical field of dipeptide drugs.
  • the present invention provides mesopeptide intercalated hydrotalcite and a process for its preparation. Since the microwave hydrothermal method is employed in the preparation process of the present invention, the crystallization time of the coprecipitation method and the reaction time of the ion exchange method are remarkably shortened. Background technique:
  • Carnosine is a natural water-soluble dipeptide substance present in the skeletal muscle of vertebrates. Its structural composition is ⁇ -alanine-L-histidine, and its molecular weight is 226.24. The physiological properties of carnosine, such as buffering, oxidation resistance, activity of neurotransmitters, and regulators of some enzymes, have been extensively studied. Carnosine is currently known to have a good application in the food additive and cosmetic industries.
  • dipeptides As a drug in clinical treatment is limited.
  • carnosine has made breakthroughs in the treatment of chronic diseases caused by low antioxidant function, such as cataracts and gastric ulcers. Harbin Medical University has reported that carnosine has a therapeutic effect on various types of cataracts (effectiveness of 80%).
  • routes of dipeptide administration such as oral, pulmonary inhalation, mucosal or subcutaneous administration, which typically require specific transport devices and/or penetration promotion and help dipeptide drugs from the point of release. Enter the body's circulatory system. The main goal of these improvements is not only to overcome the lack of bioavailability after oral administration, but also to avoid subcutaneous injections with poor patient compliance.
  • Bimetallic composite hydroxides also known as Layered Double Hydroxides (LDHs)
  • LDHs Layered Double Hydroxides
  • the ion species and ratio can be adjusted and changed within a certain range, and the interlayer anions are exchangeable.
  • hydrotalcite in this property can be carried with hydrophilic side groups
  • the dipeptide (such as coo_) is inserted into the layer of hydrotalcite by ion exchange to form a supramolecular structure system, which is effective for improving the stability of the dipeptide.
  • hydrotalcite as a "molecular container” will make it a novel carrier for the storage and release of dipeptide drugs, and at the same time contribute to the development of new and effective routes of administration for dipeptide drugs.
  • the object of the present invention is to provide a dipeptide drug intercalated hydrotalcite system and a preparation method thereof.
  • the present invention not only improves the stability of carnosine, but also applies hydrotalcite as a novel carrier to the storage and release of dipeptide drugs, and contributes to the development of a new and effective route of administration of dipeptide drugs.
  • the hydrotalcite acts as a drug carrier and controls the release of the drug, and therefore, the space confinement between the hydrotalcite layers can be maintained during storage to maintain the two inserted therein.
  • the structure of the peptide drug is stable, and the effect of sustained release of the drug is exerted by the interaction between the host and the guest of the hydrotalcite layered composite.
  • the dipeptide drug intercalated hydrotalcite according to the present invention is an anionic supramolecular layered material obtained by a coprecipitation method or an ion exchange method, and in the anionic supramolecular layered material, a dipeptide drug anion accounts for 20%-80% of the total number of moles of anions in the hydrotalcite layer.
  • the carnosine intercalated hydrotalcite of the present invention can be produced by a coprecipitation method or an ion exchange method.
  • the nitrate mixed solution prepared in the step A is slowly added dropwise to the mixed solution prepared in the step ⁇ under the condition of the protection, and stirred, and the pH range of the obtained solution is adjusted to 1-5 mol/L NaOH to 7-10, deionized with CO 2 removed after crystallization at 60 ° C - 70 ° C for 24 hours
  • the water was washed by centrifugation to neutrality, and dried at 70 ° C for 12-24 hours to obtain a carnosine intercalated hydrotalcite.
  • the temperature of the deionized water from which CO 2 is removed may be 40-80 ° C.
  • the temperature of the deionized water from which CO 2 is removed may be 60-70 ° C.
  • the amount of the nitrate mixed solution prepared in the step A used in the step C and the mixture prepared in the step B is such that the anion of the carnosine accounts for 20-80% of the total number of interlayer anions in the obtained anionic supramolecular layered material. .
  • the nitrate mixed solution prepared in step A is slowly added dropwise to the alkali solution prepared in step B under N 2 protection conditions, stirred, and the pH range of the obtained solution is obtained by using 1-5 mol/L NaOH. Adjusted to 8-10, crystallized at 60 ° C -100 ° C for 12-48 hours, then centrifuged with deionized water with CO 2 removed to neutrality to obtain a nitrate hydrotalcite precursor; wherein, the removal
  • the temperature of the deionized water of C0 2 may be 40-80 ° C.
  • the temperature of the deionized water from which C0 2 is removed is 60-70 ° C;
  • the carnosine is dissolved in deionized water, and the undried nitrate hydrotalcite precursor is obtained by adding step C, and ion exchange is carried out in a water bath at 60 ° C under N 2 protection for 12-24 hours, and C0 is removed. 2 , deionized water was centrifuged and washed to neutrality, and dried at 70 ° C for 12-24 hours to obtain intercalated hydrotalcite with interlayer material as carnosine. The amount of carnosine and nitrate hydrotalcite precursor was such that the anion produced was obtained. In the supramolecular layered material, the anion of carnosine accounts for 20-80% of the total number of moles of interlayer anions.
  • the amount of carnosine dissolved per 100 mL of deionized water is 0.05-4 g, preferably 1-2 g (0.0045-0.009 mol), and step C is added to obtain an undried nitrate hydrotalcite precursor.
  • the amount is 10-20 g, preferably 5-10 g.
  • the mass ratio of carnosine to nitrate hydrotalcite precursor is (0.5-1.5): 3.
  • the temperature of the deionized water from which C0 2 is removed may be 40-80 ° C, Preferably, the temperature of the deionized water from which CO 2 is removed is 60-70 ° C.
  • X-ray diffraction X-ray diffraction
  • IR infrared spectroscopy
  • NMR nuclear magnetic resonance
  • elemental analysis of the materials prepared above showed that the carnosine was successfully inserted into the hydrotalcite layer
  • in situ XRD In-situ XO
  • original The IR In-situ l
  • thermogravimetry-differential heat TG-DTA
  • thermogravimetry-mass analysis TG-MAS
  • the present invention preferably employs a microwave hydrothermal method in the preparation of the myopeptide intercalated hydrotalcite, so that the method according to the present invention can significantly shorten the crystallization time of the coprecipitation method and the reaction time for performing the ion exchange method;
  • the prepared dipeptide drug (gp, carnosine) intercalated hydrotalcite composite material has better thermal stability under normal conditions due to utilizing the spatial confinement effect of hydrotalcite and the interaction between host and guest. Certain sustained release properties facilitate the storage of dipeptide drugs and open up new routes of administration.
  • Figure 2 is a FT-IR spectrum obtained under the conditions of Specific Example 5 of the present invention; the abscissa is the wave number, the unit is cm; and the ordinate is the absorption intensity.
  • FT-IR spectra were obtained on VECTOR 22 (Brook, Germany), and samples were mixed with KBr After pressing, the film was scanned at room temperature under an air atmosphere.
  • the parameter indicators are: resolution of 4 cm - 1 and scanning range of 4000-400 cm.
  • Step A 3.846 g (0.015 mol) of solid Mg(N0 3 ) 2 *6H 2 0 and 2.8135 g (0.0075 mol) of solid ⁇ 1( ⁇ 0 3 ) 3 ⁇ 9 ⁇ 2 0 were dissolved in 50 mL to remove C0 2 Deionized water (solution I); another 4 g (about 0.018 mol) of carnosine and 2.5 g (0.0625 mol) of NaOH dissolved in 50 mL of deionized water removed in CO 2 (solution II
  • Step B The solution II was placed in a four-necked flask, and under the condition of N 2 gas protection, the solution I was slowly added dropwise to the solution II while vigorously stirring, and the solution was dropped in about 0.5 h. After the completion of the dropwise addition, the pH was adjusted to 7-10 with a 5 mol/L NaOH solution;
  • Step C The solution obtained in the step B is subjected to a crystallization reaction in a water bath at 60 ° C for 24 hours;
  • Step D centrifugation at 60 ° C with deionized water from which 0 2 is removed until the pH is about 7 and then at 70 ° C. After drying for 12-24 hours, a magnesium-aluminum myopeptide intercalated hydrotalcite composite material was obtained.
  • the solution obtained in the step B in the first embodiment was transferred to a microwave rapid digestion tank (WX-4000 produced by Shanghai Shuguang Analytical Instruments Co., Ltd.), and the temperature was controlled by microwave heating at 80-100 ° C for 0.5 h.
  • the product was 70 ° C deionized water to remove the centrifuge 02 was washed to pH 7, dried at 70 ° C for 12-24h.
  • Step A Weigh 15.384 g of Mg(N0 3 ) 2 ⁇ 63 ⁇ 40 and 11.2539 g of A1(N0 3 ) 3 ⁇ 9H 2 0 dissolved in 100 mL of deionized water with 0 2 removed to prepare a mixture (salt solution i) Another 7.2 g of NaOH was dissolved in 100 mL of deionized water with CO 2 removed and placed in a 500 mL four-necked flask (alkaline solution ii);
  • Step B Slowly drip the salt solution i into the alkali solution ii in a 70 ° C water bath under N 2 protection and vigorous stirring, and adjust the pH to about 10.0 with 2 mol/L sodium hydroxide. Crystallization reaction for 40 h;
  • Step D 4 g (0.018 mol) of carnosine was dissolved in 200 mL of deionized water with CO 2 removed and placed in a 500 mL four-necked flask, and 12 g of the filter cake obtained in the step C was added thereto. The pH was adjusted to 7-9 with 2 mol/L sodium hydroxide;
  • Step E Ion exchange was carried out for 12-24 h under the protection and vigorous stirring and the temperature was controlled at 60 ° C.
  • the obtained product was washed with 60 ° C of deionized water with CO 2 removed and centrifuged. 3-6 times, the obtained precipitate was dried in a vacuum drying oven to obtain a layered composite material in which intermusing anion was interposed.
  • step D of Example 3 Transfer the mixed solution obtained in step D of Example 3 to a microwave rapid digestion tank (Shanghai In WX-4000 produced by Dawning Analytical Instruments Co., Ltd., the temperature was controlled by microwave heating at 80-100 °C for 0.5 h, and the obtained product was centrifuged to pH at 70 ° C with deionized water removed with CO 2 . It is about 7, dried at 70 ° C for 12-24 h.
  • a microwave rapid digestion tank Shanghai In WX-4000 produced by Dawning Analytical Instruments Co., Ltd.
  • Step A The mixed salt solution i in the step A of Example 3 was added all at once to the alkali solution ii under high-speed stirring, and after stirring for 20 minutes, the obtained product was washed with deionized water from which C0 2 was removed. And centrifuged 3-6 times;
  • Step B taking 12 g of the precipitate obtained in step A and 4 g of carnosine dissolved in deionized water with CO 2 removed, and adjusting the pH to 7-9 with 2 mol/L sodium hydroxide;
  • Step C The solution obtained in step B is transferred to an autoclave, and reacted at a constant temperature of 90 ° C for 16 h, and the pressure in the autoclave is 1-10 Mpa;
  • Step D The product was washed with deionized water from which CO 2 was removed and centrifuged for 3 to 6 times, and the precipitate was dried in a vacuum at room temperature to obtain a layered composite material having intermused anion peptide intercalated therebetween.

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Description

一种肌肽药物插层水滑石及其制备方法
技术领域：
本发明属于二肽类药物技术领域。 具体来说， 本发明提供了肌肽插层水 滑石及其制备方法。 由于本发明的制备过程中采用了微波水热的方法， 显著 缩短了共沉淀法的晶化时间和离子交换法的反应时间。 背景技术：
肌肽是存在于脊椎动物的骨骼肌肉中的一种天然的水溶性二肽物质， 其 结构组成是 β-丙氨酸 -L-组氨酸， 分子量为 226.24。 肌肽所具有的生理特性， 如缓冲性、 抗氧化性、 神经元传递基底物质的活性， 及作为一些酶的调节子 等作用已经得到十分广泛的研究。 目前所知肌肽在食品添加剂和化妆品行业 已经有较好的应用。
然而， 由于对化学物质和酶的敏感性， 二肽作为药物在临床治疗中的应 用很有限。近几年， 肌肽对治疗由于机体抗氧化功能低下所引起的慢性病有 了突破性进展， 如： 白内障、 胃溃疡等。 哈尔滨医科大学曾报道， 肌肽对多 种类型的白内障均有治疗作用 （有效率达 80%)。 已报道了几种可能的二肽 给药途径， 如口服、 肺吸入、 黏膜或皮下给药等途径， 这些给药途径通常需 要特定的转运装置和 /或渗透促进并帮助二肽药物从释放点进入体内的循环 系统。 这些改进的主要目标不仅仅是克服口服后生物利用率的不足， 而且还 可避免患者依从性较差的皮下注射。
双金属复合氢氧化物又称为水滑石 (Layered Double Hydroxides, 简写为 LDHs)是一种新型的多功能层状材料， 其化学稳定性良好， 具有强的抗热性 能， 且 LDHs的层板金属离子种类和比例可以在一定范围内进行调节改变， 层间阴离子具有可交换性。 利用水滑石的此种性能可以将带有亲水性侧基 (如 coo_) 的二肽通过离子交换的方法插入水滑石的层间， 形成超分子结 构体系， 这种结构体系可有效提高二肽的稳定性。 水滑石作为 "分子容器" 的功能， 将使其成为二肽药物贮存和释放的新型载体， 同时有助于开发二肽 药物新的有效的给药途径。 目前国内外尚无关于水滑石类层状材料与肌肽结 合的文献及专利报道。 发明内容：
本发明的目的在于提供一种二肽药物插层水滑石体系及其制备方法。本 发明不仅提高了肌肽的稳定性，而且将水滑石作为一种新型载体应用于二肽 药物的贮存和释放， 有助于开发二肽药物新的有效的给药途径。
本发明的二肽药物插层水滑石体系中， 水滑石起到了药物载体和控制药 物释放的作用， 因此， 可以在存贮过程中通过水滑石层间的空间限域作用来 保持插入其中的二肽药物的结构稳定， 并且通过水滑石层状复合材料的主客 体之间的相互作用来起到缓释药效的作用。 具体来说， 根据本发明的二肽药 物插层水滑石为通过共沉淀法或离子交换法得到的阴离子型超分子层状材 料， 所述阴离子型超分子层状材料中， 二肽药物阴离子占水滑石层间阴离子 摩尔数总数的 20%-80%。
本发明的肌肽插层水滑石可以采用共沉淀法或离子交换法制备。
共沉淀法的制备步骤如下：
A. 配制可溶性硝酸镁和可溶性硝酸铝的硝酸盐混合溶液， 其中二价金 属镁的离子浓度为 0.8-1.6 M, 镁、 铝金属离子摩尔比范围为 2-3;
B. 配制层间客体 （L-肌肽） 与 NaOH的混合溶液；
C. 将步骤 A配制的硝酸盐混合溶液在 护的条件下缓慢滴加到步骤 Β配制的混合溶液中， 搅拌， 利用 l-5 mol/L的 NaOH将所得到的溶液的 pH 值范围调节至 7-10，在 60°C-70°C下晶化 24小时后采用除去了 C02的去离子 水离心洗涤至中性，在 70°C下干燥 12-24小时，得到肌肽插层水滑石。其中， 所述除去了 C02的去离子水的温度可以为 40-80°C，优选地，所述除去了 C02 的去离子水的温度可以为 60-70°C。
步骤 C中使用的步骤 A配制的硝酸盐混合溶液和步骤 B中配制的混合 物的用量使制得的阴离子型超分子层状材料中，肌肽的阴离子占层间阴离子 摩尔数总数的 20-80%。
离子交换法的制备步骤如下：
A. 配制可溶性硝酸镁和可溶性硝酸铝的硝酸盐混合溶液， 其中二价金 属镁的离子浓度为 0.8-1.6 M, 镁、 铝金属离子摩尔比范围为 2-3 ;
B. 配制 NaOH碱溶液；
C. 将步骤 A配制的硝酸盐混合溶液在 N2保护的条件下缓慢滴加到步骤 B配制的碱溶液中，搅拌，利用 1-5 mol/L的 NaOH将所得到的溶液的 pH值 范围调节至 8-10，在 60°C-100°C下晶化 12-48小时后采用除去了 C02的去离 子水离心洗涤至中性， 得到硝酸根水滑石前体； 其中， 所述除去了 C02的去 离子水的温度可以为 40-80°C， 优选地， 所述除去了 C02的去离子水的温度 为 60-70 °C ;
D. 取肌肽溶于去离子水中， 加入步骤 C得到未干燥的硝酸根水滑石前 体， 在 60 °C水浴中和在 N2保护的条件下进行离子交换 12-24小时， 采用除 去了 C02的去离子水离心洗涤至中性后在 70°C干燥 12-24小时，得到层间物 质为肌肽的插层水滑石，所述肌肽和硝酸根水滑石前体的量使制得的阴离子 型超分子层状材料中， 肌肽的阴离子占层间阴离子摩尔数总数的 20-80%。 具体来说， 在每 100 mL的去离子水中溶解的肌肽的量 0.05-4 g， 优选为 1-2 g (0.0045-0.009 mol)， 同时加入的步骤 C得到未干燥的硝酸根水滑石前体 的量为 10-20 g， 优选为 5-10 g。优选地， 肌肽与硝酸根水滑石前体的质量比 为 （0.5-1.5 ): 3。 其中， 所述除去了 C02的去离子水的温度可以为 40-80°C， 优选地， 所述除去了 C02的去离子水的温度为 60-70°C。
将上述所制备的材料进行 X射线衍射 （XRD)、 红外光谱 （IR)、 核磁 共振（NMR)、 元素分析表征显示肌肽成功插入水滑石层间； 进行原位 XRD (In-situ X O ) , 原位 IR (In-situ l ) , 热重 -差热 （TG-DTA)、 热重-质量分 析 （TG-MAS ) 表征显示该复合材料的热稳定性有了显著提高； 进行体外模 拟释放实验表明该复合材料体系能够达到一定的缓释性能。
此外， 本发明优选在制备肌肽插层水滑石的过程中采用了微波水热的方 法， 因此根据本发明的方法能显著缩短了共沉淀法的晶化时间和进行离子交 换法的反应时间； 并且所制得的二肽药物 （gp， 肌肽）插层水滑石复合材料 由于利用了水滑石的空间限域作用和主客体之间的相互作用， 因而在通常情 况下具有较好的热稳定性和一定的缓释性能， 有利于二肽药物的存贮和开拓 新的给药途径。 附图说明：
图 1为本发明具体实施例 5条件下得到的 XRD谱图； 横坐标为 2Θ， 单 位： 度； 纵坐标为强度；
图 2为本发明具体实施例 5条件下得到的 FT-IR谱图； 横坐标为波数， 单位： cm ; 纵坐标为吸收强度。 具体实施方式：
通过下面实施例对本发明予以具体说明。
在以下实施例中， 使用如下方法测定各实施例中制得的产品：
以日本岛津 XRD-6000型 X射线衍射仪进行结构分析， Cu Ka光源（λ = 0.154 nm)， 电压 40 Kv， 电流 30 mA， 连续扫描， 扫描速度 5 min。
FT-IR光谱在 VECTOR 22 (德国布鲁克公司） 上获得， 样品与 KBr混 合后压片， 室温、 空气气氛下扫描。 参数指标为： 分辨率为 4 cm—1 , 扫描范 围 4000-400cm 。 实施例 1
步骤 A: 将 3.846 g (0.015mol)的固体 Mg(N03)2*6H20 和 2.8135 g (0.0075mol)的固体 Α1(Ν03)3·9Η20溶于 50 mL的除去了 C02的去离子水中 (；溶 液 I ); 另将 4 g (约 0.018mol)的肌肽和 2.5g (0.0625mol)的 NaOH溶于 50 mL 除去了 C02的去离子水中 (溶液 II
步骤 B: 将溶液 II置于四口瓶中， 在N2气保护的条件下， 一边剧烈搅 拌，一边将溶液 I缓慢滴加入溶液 II，约 0.5 h滴完。滴加完成后，用 5 mol/L 的 NaOH溶液将其 pH值调节至 7-10;
步骤 C: 将步骤 B得到的溶液在 60 °C的水浴中进行晶化反应 24h; 步骤 D: 用 60°C的除去了 02的去离子水离心洗涤至 pH约为 7后在 70°C下干燥 12-24h， 得到镁铝型肌肽插层水滑石复合材料。
由 XRD谱图、 FT-IR谱图、 NMR和元素分析可知， 得到的水滑石层间 阴离子为肌肽阴离子。 实施例 2
按照与实施例 1相同的方式进行， 不同的是：
将实施例 1 中的步骤 B得到的溶液转移到微波快速消解罐 （上海屹光 分析仪器公司生产的 WX-4000) 中， 在 80-100°C下通过微波加热进行控温 0.5 h后将得到的产物用 70°C的除去了 02的去离子水离心洗涤至 pH约为 7， 在 70 °C下干燥 12-24h。
由 XRD谱图、 FT-IR谱图、 NMR和元素分析可知， 得到的水滑石层间 阴离子为肌肽阴离子。 实施例 3
步骤 A:称取 15.384 g的 Mg(N03)2 ^6¾0和 11.2539 g的 A1(N03)3 <9H20 溶于 100 mL的除去了 02的去离子水中配制混合 （盐溶液 i)， 另取 7.2 g 的 NaOH溶于 100 mL的除去了 C02的去离子水并置于 500 mL的四口烧瓶 中 （碱溶液 ii) ;
步骤 B: 在 70°C水浴中和在 N2保护以及强烈搅拌条件下将盐溶液 i缓 慢滴加到碱溶液 ii中， 用 2 mol/L的氢氧化钠将 pH值调节到 10.0左右后进 行晶化反应 40 h;
步骤 C: 将步骤 B得到的产物用 40 的除去了 C02的去离子水洗涤过 滤至 pH<8.0; 保留大量新鲜滤饼以备离子交换用， 仅取出少量样品在 70°C 下干燥 18 h 后用 XRD 进行表征， 证实得到了 N03-Mg2Al-LDHs， 其中 Mg2+/Al3+=2;
步骤 D: 取 4 g ( 0.018mol)的肌肽溶于 200 mL的除去了 C02的去离子 水并置于 500 mL的四口烧瓶中， 再取 12 g的步骤 C得到的滤饼加入其中， 用 2 mol/L的氢氧化钠将 pH调节为 7-9 ;
步骤 E: 在 护下和在强烈搅拌并将温度控制在 60 °C的条件下进行 离子交换 12-24 h， 将得到的产物用 60°C的除去了 C02的去离子水洗涤并离 心分离 3-6次， 将得到的沉淀在真空干燥箱中干燥， 即可得到层间插有肌肽 阴离子的层状复合材料。
由 XRD谱图、 FT-IR谱图、 NMR和元素分析可知， 得到的水滑石层间 阴离子为肌肽阴离子。 实施例 4
按照实施例 3的方法进行， 不同的是：
将实施例 3中的步骤 D得到的混合溶液转移到微波快速消解罐 （上海 屹光分析仪器公司生产的 WX-4000) 中， 在 80- 100 °C下通过微波加热进行 控温 0.5h后将得到的产物用 70°C的除去了 C02的去离子水离心洗涤至 pH 约为 7， 在 70°C下干燥 12-24h。
由 XRD谱图、 FT-IR谱图、 NMR和元素分析可知， 得到的水滑石层间 阴离子为肌肽阴离子。 实施例 5
步骤 A:将实施例 3的步骤 A中的混合盐溶液 i在高速搅拌的条件下一 次性全部加入碱溶液 ii中， 搅拌 20分钟后， 将得到的产物用除去了 C02的 去离子水洗涤并离心分离 3-6次；
步骤 B: 取 12 g的步骤 A得到的沉淀和 4 g肌肽溶于除去了 C02的去 离子水中， 用 2mol/L的氢氧化钠将 pH调节为 7-9;
步骤 C: 将步骤 B得到的溶液转移到高压釜中， 在 90 °C的恒温下反应 16 h， 釜内压力为 1-10 Mpa;
步骤 D: 将产物用除去了 C02的去离子水洗涤并离心分离 3-6次，将沉 淀在真空中进行室温干燥， 即可得到层间插有肌肽阴离子的层状复合材料。
由 XRD谱图、 FT-IR谱图、 NMR和元素分析可知， 得到的水滑石层间 阴离子为肌肽阴离子。

Claims

权利要求书
1. 一种肌肽插层水滑石复合材料， 其特征在于： 该肌肽插层水滑石复合 材料为通过共沉淀法或通过离子交换法制得的阴离子型超分子层状材料， 该 阴离子型超分子层状材料中， 肌肽的阴离子占层间阴离子摩尔数总数的
20-80%； 该复合材料能充分利用其层间的空间限域作用和主客体之间的相 互作用， 在通常情况下具有较好的热稳定性和一定的缓释性能。
2. 按照权利要求 1所述的复合材料， 其特征在于， 所述共沉淀法包括： a. 配制可溶性硝酸镁和可溶性硝酸铝的硝酸盐混合溶液， 其中二价金属 镁的离子浓度为 0.8-1.6 M, 镁、 铝金属离子摩尔比范围为 2-3;
b. 配制层间客体 L-肌肽与 NaOH的混合溶液；
c 将步骤 a配制得到的硝酸盐混合溶液在N2保护的条件下缓慢滴加到步 骤 b配制的混合溶液中， 搅拌， 利用 1-5 mol/L的 NaOH将所得到的溶液的 pH值范围调节至 7-10， 在 60°C-70°C下晶化 24小时后采用除去了 C02的去 离子水离心洗涤至中性， 在 70°C下干燥 12-24小时， 得到肌肽插层水滑石。
3. 按照权利要求 2所述的复合材料， 其特征在于， 在所述共沉淀法中的 步骤 c的晶化过程中， 使用微波水热的方法。
4. 按照权利要求 1所述的复合材料，其特征在于，所述离子交换法包括: a. 配制可溶性硝酸镁和可溶性硝酸铝的硝酸盐混合溶液， 其中二价金属 镁的离子浓度为 0.8-1.6 M, 镁、 铝金属离子摩尔比范围为 2-3;
b. 配制 NaOH碱溶液；
c 将步骤 a配制的硝酸盐混合溶液在 护的条件下缓慢滴加到步骤 b 配制的碱溶液中， 搅拌， 利用 1-5 mol/L的 NaOH将所得到的溶液的 pH值 范围调节至 8-10，在 60°C-100°C下晶化 12-48小时后用除去了 C02的去离子 水离心洗涤至中性， 得到硝酸根水滑石前体；
d. 取肌肽溶于水中， 加入步骤 c中得到的未干燥的硝酸根水滑石前体， 所述肌肽和硝酸根水滑石前体的量使制得的阴离子型超分子层状材料中，肌 肽的阴离子占层间阴离子摩尔数总数的 20-80% ,在 60°C水浴和在N2保护的 条件下进行离子交换 12-24小时后采用除去了 C02的去离子水离心洗涤至中 性， 在 70°C下干燥 12-24小时， 得到层间物质为肌肽的插层水滑石。
5. 按照权利要求 4所述的复合材料， 其特征在于， 在所述离子交换法中 的步骤 d的离子交换过程中， 使用微波水热的方法。
6. 按照权利要求 4或 5所述的复合材料， 其特征在于， 在所述离子交换 法的步骤 d的离子交换过程中， 压力为 l-10 Mpa。
7.一种制备权利要求 1所述的二肽药物插层水滑石的方法，其特征在于， 该方法包括：
步骤 a: 配制可溶性硝酸镁和可溶性硝酸铝的混合盐溶液， 其中二价金属 镁的离子浓度为 0.8-1.6 M, 镁、 铝金属离子摩尔比范围为 2-3， 配制 NaOH 碱溶液， 将混合盐溶液在高速搅拌的条件下快速加入碱溶液中， 搅拌 20分 钟后， 得到的产物用除去了 C02的去离子水洗涤并离心分离 3-6次；
步骤 b: 取适量的由步骤 a得到的沉淀和适量的肌肽溶于除去了 02的 去离子水中， 将 pH调节为 7-9， 所述沉淀和肌肽的量使制得的阴离子型超 分子层状材料中， 肌肽的阴离子占层间阴离子摩尔数总数的 20-80% ;
步骤 c: 将步骤 b得到的溶液转移到高压釜中， 在 90°C下恒温反应 16 h; 步骤 d:将产物用除去了 C02的去离子水洗涤离心分离 3-6次，将沉淀在 真空中进行室温干燥， 即可得到层间插有肌肽阴离子的层状复合材料。
8. 根据权利要求 7所述的二肽药物插层水滑石的方法， 其中， 所述步骤 b中用 1-5 mol/L的氢氧化钠将 pH调节为 7-9。
9. 根据权利要求 7或 8所述的二肽药物插层水滑石的方法， 其中， 所述 步骤 c中高压釜内的压力为 1-10 Mpa。
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