WO2010025630A1 - 一种胆酸钠包合脂溶性药物泼尼松插层水滑石及其制备方法 - Google Patents

一种胆酸钠包合脂溶性药物泼尼松插层水滑石及其制备方法 Download PDF

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WO2010025630A1
WO2010025630A1 PCT/CN2009/071955 CN2009071955W WO2010025630A1 WO 2010025630 A1 WO2010025630 A1 WO 2010025630A1 CN 2009071955 W CN2009071955 W CN 2009071955W WO 2010025630 A1 WO2010025630 A1 WO 2010025630A1
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prednisone
sodium cholate
solution
fat
hydrotalcite
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French (fr)
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卫敏
李复苏
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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents

Definitions

  • the invention belongs to the technical field of adrenocortical hormone drugs, in particular to a fat-soluble drug prednisone intercalated hydrotalcite and a preparation method thereof. More specifically, since prednisone is a fat-soluble drug that does not directly enter the hydrotalcite layer itself, the present invention relates to the use of a surfactant sodium cholate and ponisin to intercalate in a hydrotalcite layer. Between, the purpose of sustained release has been achieved. Background technique:
  • Prednisone is an adrenal corticosteroid (usually an acetate) that is a white or nearly white crystalline powder. Prednisone must be converted to prednisolone by reducing the 11-position keto group to the 11-hydroxyl group in the liver to show pharmacological activity. Prednisone has anti-inflammatory and anti-allergic effects, can inhibit the proliferation of connective tissue, reduce the permeability of capillary wall and cell membrane, reduce inflammatory exudation, and inhibit the formation and release of histamine and other toxic substances. However, long-term use of prednisone drugs can cause a variety of adverse reactions.
  • prednisone can increase the secretion of gastric juice and increase appetite, and can promote the decomposition of protein into sugar, reduce the utilization of glucose, and thus make blood sugar and liver glycogen Increased, leading to the appearance of diabetes, in addition to the adverse reactions common to mineralocorticoids and glucocorticoids, in the use of prednisone as an antiallergic drug, it is to the cardiovascular system, the central nervous system, endocrine, metabolism Have a great impact. Therefore, the new prednisone drug with sustained release ability has broad application prospects.
  • Sodinm Cholate has two hydrophilic and hydrophobic side chains, which can reduce the surface tension between the oil/water phases and is a strong emulsifier.
  • Sodium cholate can make hydrophobic lipids emulsified into fine micelles in water, which not only increases the contact area of fat with lipase in the small intestine, promotes the action of digestive enzymes, but also allows highly emulsified fat particles directly from the intestines. Mucosal absorption enhances the use of lipids.
  • Sodium cholate is used as a choleretic medicine to treat bile deficiency, intestinal fat indigestion, and long-term biliary fistula Drainage and chronic cholecystitis.
  • the main functions of sodium cholate include promoting the digestion and absorption of fat, promoting the absorption of fat-soluble drugs, activating pancreatic digestive enzymes, and promoting the dissolution of cholesterol in the gallbladder.
  • Bimetallic composite hydroxides also known as Layered Double Hydroxides (LDHs)
  • LDHs Layered Double Hydroxides
  • the micelles formed by prednisone, which is coated with the surfactant sodium cholate can be inserted into the hydrotalcite layer to form a supramolecular structure system, which can effectively improve the sustained release properties of prednisone. , reduce its toxicity.
  • hydrotalcite as a "molecular container” will make it a novel carrier for the storage and release of adrenocortical hormones, and at the same time contribute to the development of new and effective routes of administration for adrenocortical drugs.
  • the object of the present invention is to provide a fat-soluble drug prednisone intercalated hydrotalcite system and a preparation method thereof, and obtain a hydrotalcite corticosteroid drug with relatively stable drug efficacy during storage and administration, to solve At present, prednisone has a strong side effect during use.
  • the drug intercalated hydrotalcite adrenocortical hormone drug of the invention is chiral, and can maintain the stability of the drug during storage by the spatial confinement between the hydrotalcite layers to ensure the efficacy; and can pass the hydrotalcite layer
  • the interaction between the host and the guest of the composite material plays a role in the sustained release of the drug during the administration of the drug, wherein the main body functions as a controlled release agent.
  • the chemical formula of the product of the present invention is: ( ⁇ ⁇ ⁇ •m3 ⁇ 40, wherein X ranges from 0.25 to 0.33, and a ranges from 0.02 to 0.03.
  • the method comprises the steps of: forming a lipophilic drug, prednisone, by using a surfactant, sodium cholate, to form a micelle, and then synthesizing a hydrotalcite product co-intercalated with prednisone and sodium cholate by a coprecipitation method to form a fat-soluble drug.
  • a supramolecular layered material that accounts for 4% of the total mass of the hydrotalcite product (ie, the intercalated hydrotalcite system).
  • the product of the present invention can make full use of the spatial confinement between the layers and the interaction between the host and the guest,
  • the fat-soluble drug can be continuously and effectively stored and sustained release.
  • the decomposition of the guest between the layers starts to occur at 340 ° or more, that is, the thermal stability is good.
  • the preparation steps of the fat-soluble drug prednisone intercalated hydrotalcite of the present invention are as follows:
  • nitrate mixed solution of soluble magnesium nitrate and soluble aluminum nitrate wherein the divalent metal magnesium has an ion concentration of 0.8-1.6 mol/L, and the magnesium and aluminum metal ion molar ratio ranges from 2-3, and further prepares 1-5 Mol/L NaOH alkaline solution;
  • nitrate mixed solution in d is added dropwise to the solution prepared in c at the same rate, and stirred under N 2 protection to adjust the pH to 7-9 at 70 ° C. After crystallization for 65-75 hours, it was centrifuged 3-4 times with water from which C0 2 was removed, and then dried in an oven at 60-70 ° C for 12-24 hours to obtain a sodium cholate-premixed prednisone intercalated hydrotalcite.
  • the two-drop co-precipitation method can synthesize the target product in one step, and the cumbersome steps of ion exchange are omitted, and the obtained composite material can fully utilize the space-limited interaction between the layers and the interaction between the host and the guest to make the fat-soluble drug. It can achieve continuous and effective storage and realize the function of sustained release drugs.
  • the materials prepared above were characterized by X-ray diffraction (XRD), infrared spectroscopy (IR), ultraviolet-visible spectroscopy (UV), fluorescence, thermogravimetry-differential heat (TG-DTA), and elemental analysis to characterize prednisone successfully. Intercalation between layers of hydrotalcite.
  • XRD X-ray diffraction
  • IR infrared spectroscopy
  • UV ultraviolet-visible spectroscopy
  • fluorescence fluorescence
  • thermogravimetry-differential heat (TG-DTA) thermogravimetry-differential heat
  • the invention has the advantages that: by utilizing the spatial confinement effect of the hydrotalcite layered material and the interaction between the host and the guest, the fat-soluble drug prednisone is intercalated into the hydrotalcite layer to realize the hydrotalcite-to-lipid The effective storage of the soluble drug; at the same time, the slow release effect of the hydrotalcite on the chiral drug can be realized, and the theoretical basis for applying the hydrotalcite to the new method of "storage-administration" of the drug is provided.
  • Figure 1 is an XRD spectrum obtained under the conditions of a specific embodiment of the present invention; the abscissa is 2 ⁇ , unit: degree; and the ordinate is intensity.
  • the FT-IR spectrum was obtained on VECTOR 22 (Brook, Germany), and the sample was mixed with KBr and compressed, and scanned at room temperature under an air atmosphere.
  • the parameter indicators are: resolution is 4 cm - 1 , scanning range is 4000-400 cm
  • Japan Shimadzu UV-2501PC UV-Vis spectrophotometer for quantitative and qualitative analysis of prednisone in the intercalated product (test range: 200 ⁇ 800 nm, maximum absorption wavelength is 244 nm).
  • Step A Weighing 1.72 g of cholic acid was dissolved in 150 ml of deionized water from which 0 2 was removed, and stirred well to obtain a solution I; 0.03 g of prednisone was weighed and dissolved in 20 mL of chloroform to obtain a solution II; The solution II is added to the solution I, and the chloroform is volatilized under the protection of N 2 for 4-5 hours. When the solution becomes transparent, it indicates that the chloroform is completely volatilized, and the desired sodium cholesteric micelle inclusion is obtained.
  • Step B Weigh 1.80 g of Mg(N0 3 ) 2 ⁇ 6H 2 0 and 1.32 g of A1(N0 3 ) 3 ⁇ 9H 2 0 dissolved in 25 mL of deionized water with CO 2 removed to prepare a nitrate mixture Solution, another 0.84 g of NaOH was dissolved in 25 mL of deionized water in which C0 2 was removed to obtain an alkali solution; the solution obtained in the step A was placed in a four-necked flask by double-drop coprecipitation: in a water bath at 70 ° C and Under the condition that N 2 is protected and vigorously stirred, the above nitrate mixed solution and the alkali solution are added dropwise to the solution obtained in the step A at the same rate, the pH is adjusted to 7-9, and then crystallized for 72 hours; the crystallization product is obtained. The mixture was washed to neutrality and dried at 70 ° C for about 12 hours to obtain a hydrotalcite layered composite material in
  • Step C In vitro release test, a certain amount of prednisone intercalated hydrotalcite product was placed in a 900 mL buffer solution with pH values of 7.6, 6.8, and 4.8, respectively, and the drug was administered under a 37 ° C water bath and stirring conditions. Release, remove 5 mL of solution at different time intervals, filter, and add 5 mL of buffer solution to the release solution, and obtain the in vitro release curve by UV detection.
  • hydrotalcite can be used as a carrier for sustained release materials.

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Description

一种胆酸钠包合脂溶性药物泼尼松插层水滑石及其制备方法 技术领域：
本发明属于肾上腺皮质激素类药物技术领域，特别是提供了一种脂溶性 药物泼尼松插层水滑石及其制备方法。 更具体来说， 由于泼尼松为一种脂溶 性药物， 本身不能直接进入水滑石层间， 因此， 本发明涉及使用一种表面活 性剂胆酸钠与波尼松共插层于水滑石层间， 达到了缓释的目的。 背景技术：
泼尼松 （Prednisone) 是肾上腺皮质激素类药 （常用其醋酸酯）， 为白色 或接近白色的结晶性粉末。 泼尼松必须通过在肝内将 11-位酮基还原为 11-羟 基从而转化为泼尼松龙后， 才能显示出药理活性。 泼尼松具有抗炎及抗过敏 作用， 能抑制结缔组织的增生， 降低毛细血管壁和细胞膜的通透性， 减少炎 症性渗出， 并能抑制组胺及其它毒性物质的形成与释放。 然而长期服用泼尼 松类药物会引起多种不良反应， 例如， 泼尼松在增加胃液分泌、 增进食欲的 同时能促进蛋白质分解转变为糖， 降低葡萄糖的利用， 因而使血糖及肝糖原 都增加， 导致出现糖尿， 此外， 除具有盐皮质激素和糖皮质激素所共有的不 良反应外，在将泼尼松用做抗过敏药物时，它对心血管系统、中枢神经系统、 内分泌、 代谢都有很大的影响。 因此具有缓释能力的新型泼尼松药物具有广 阔的应用前景。
胆酸钠 （Sodinm Cholate) 具有亲水和疏水两个侧链， 能降低油 /水两相 之间的表面张力， 是较强的乳化剂。 胆酸钠能使疏水的脂类在水中乳化成细 小的微团， 从而既增加了脂肪在小肠中与脂肪酶的接触面积， 促进消化酶的 作用， 又可使高度乳化的脂肪微粒直接由肠黏膜吸收， 提高了脂类的利用。 胆酸钠做为利胆药， 可以治疗胆汁缺乏、 肠道脂肪消化不良、 胆道痿管长期 引流和慢性胆囊炎等。 胆酸钠的主要功效包括促进脂肪的消化和吸收， 促进 脂溶性药物的吸收， 激活胰消化酶， 促进胆囊中胆固醇的溶解。
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， 在药物的缓释方面也有广泛的应用， 且 LDHs层板金属离子种类和比例 可调变， 层间阴离子具有可交换性。 利用此种性能可以将用表面活性剂胆酸 钠包合的泼尼松形成的胶束共同插入水滑石层间， 形成超分子结构体系， 这 种结构体系可有效提高泼尼松的缓释性能， 降低其毒性。 水滑石作为 "分子 容器" 的功能， 将使其成为肾上腺皮质激素类药物贮存和释放的新型载体， 同时有助于开发肾上腺皮质激素类药物新的有效的给药途径。 发明内容：
本发明的目的在于提供一种脂溶性药物泼尼松插层水滑石体系及其制 备方法，得到一种在存贮和服用过程中药效相对比较稳定的水滑石肾上腺皮 质激素类药物， 以解决目前泼尼松在使用过程中有很强副作用的问题。
本发明的药物插层水滑石肾上腺皮质激素类药物为手性的， 可通过水滑 石层间的空间限域作用保持药物在存贮过程中的稳定性而确保药效； 并且可 以通过水滑石层状复合材料的主客体之间的相互作用， 使得在药物被服用的 过程中起到缓释药效的作用， 其中的主体起到控释剂的作用。
本发明的产品的化学式为： （Μ^ΚΜ^^ΟΗΜί^Η^ΟΑ^ΜΗ θ χ •m¾0， 其中， X的取值范围为 0.25-0.33， a的取值范围为 0.02-0.03。 本发 明的方法包括， 将脂溶性药物泼尼松利用表面活性剂胆酸钠包合形成胶束， 然后用共沉淀法一步合成泼尼松与胆酸钠共插层的水滑石产物， 构成脂溶性 药物占水滑石产物（即， 插层水滑石体系）总质量的 4%的超分子层状材料。 本发明的产品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， 使脂溶性药物能得到持续有效的存贮和缓释功能。并且，在层间的客体在 340 °〇以上才开始发生分解， 即热稳定性良好。
本发明的脂溶性药物泼尼松插层水滑石制备步骤如下：
a. 将胆酸钠溶于水中，得到胆酸钠胶束溶液， 其中胆酸钠浓度应比临界 胶束浓度值高 10-20%;
b. 将脂溶性药物泼尼松加入氯仿（氯仿用量为能使加入的泼尼松量溶解 为宜） 中， 使其溶解， 从而得到泼尼松的氯仿溶液；
c 将 b中得到溶液加入到 a中溶液中， 在N2保护并进行机械搅拌下， 使氯仿挥发， 得到胆酸钠胶束包合泼尼松的水溶液；
d. 制备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 mol/L, 镁、 铝金属离子摩尔比范围为 2-3， 另外 配制 1-5 mol/L的 NaOH碱溶液；
e. 将 d中的硝酸盐混合溶液与碱溶液以相同速度滴加到 c中所制得的 溶液中， 在 N2保护下进行搅拌， 将 pH值调节为 7-9， 在 70°C下晶化 65-75 小时， 用除去了 C02的水离心 3-4次后置于 60-70°C烘箱干燥 12-24小时， 得到胆酸钠包合泼尼松插层水滑石。
双滴共沉淀法一步即可合成目标产物， 而省去了离子交换的繁琐步骤， 得到的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， 使脂溶性药物能得到持续有效的存贮并实现缓释药物的功能。
将上述所制备的材料进行 X射线衍射 （XRD)、 红外光谱 （IR)、 紫外- 可见光谱 （UV)、 荧光、 热重 -差热 （TG-DTA)、 元素分析来表征泼尼松成 功地在水滑石层间插层。通过在体外进行模拟释放实验表明本发明的复合材 料体系能够达到一定的缓释性能。
本发明的优点在于： 利用水滑石层状材料的空间限域作用以及主客体之 间的相互作用， 将脂溶性药物泼尼松插层进入水滑石层间， 实现水滑石对脂 溶性药物的有效存贮； 同时还能实现水滑石对该手性药物的缓释作用， 为将 水滑石应用于该药物的"存贮一给药"新途径提供理论基础。
附图说明：
图 1为本发明具体实施方式条件下得到的 XRD谱图； 横坐标为 2Θ， 单 位： 度； 纵坐标为强度。
图 2为本发明具体实施方式条件下得到的插层产物的体外释放的曲线； 横坐标为时间， 单位： 分钟； 纵坐标为释放率。
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根据本发明的产 ρ 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
日本岛津 UV-2501PC型紫外可见分光光度计，对插层产物中泼尼松进行 定量和定性分析 （测试范围： 200 ~800 nm， 最大吸收波长为 244 nm)。
实施例 1：
步骤 A: 称取胆酸 1.72 g溶解于 150 ml的除去了 02的去离子水中， 充分搅拌， 得到溶液 I； 称取 0.03 g的泼尼松溶解于 20 mL的氯仿中， 得到 溶液 II；将溶液 II加入溶液 I中，在 N2保护下搅拌使氯仿进行 4-5小时挥发， 待观察到溶液变为透明时表示氯仿挥发完全，得到所需要的胆酸钠胶束包合 步骤 B: 称取 1.80 g的 Mg(N03)2 · 6H20和 1.32 g的 A1(N03)3 · 9H20 溶于 25 mL的除去了 C02的去离子水中配制成硝酸盐混合溶液， 另取 0.84 g 的 NaOH溶于 25 mL的除去了 C02的去离子水中得到碱溶液； 将步骤 A所 得溶液置于四口烧瓶中， 采用双滴共沉淀法： 在 70°C水浴和 N2保护并进行 强烈搅拌的条件下，将上述硝酸盐混合溶液和碱溶液以相同速度滴加到步骤 A所得溶液中， 调节 pH值到 7-9， 然后晶化 72小时； 将晶化产物洗涤至中 性， 在 70°C下干燥约 12小时， 即得胆酸钠包合泼尼松插层的水滑石层状复 合材料。
步骤 C: 体外释放测试， 将一定量的泼尼松插层的水滑石产物置于 pH 值分别为 7.6、 6.8、 4.8的 900 mL的缓冲溶液中， 在 37°C水浴和搅拌条件下 进行药物释放， 隔不同时间段取出 5 mL溶液， 过滤， 同时向释放溶液中添 加 5 mL的缓冲溶液， 通过紫外检测得到体外释放曲线。
通过 XRD、 UV、 IR谱图可知泼尼松分子成功的进入了水滑石层间， 从缓释曲线可以看出， 水滑石可以做为一种药物缓释材料的载体。

Claims

权利要求书
1. 一种脂溶性药物泼尼松插层水滑石，其特征在于：该脂溶性药物泼尼 松插层水滑石的化学式为： （M2+)1-x(M3+)x(OH— )2(C21H2605)a(C24H3905— )χ· m¾0， 其中， x的取值范围为 0.25-0.33， a取值范围为 0.02-0.03; 所述脂溶 性药物泼尼松插层水滑石是通过将脂溶性药物泼尼松利用表面活性剂胆酸 钠包合形成胶束后，用共沉淀法一步合成泼尼松与胆酸钠共插层的水滑石产 物， 而形成的超分子层状材料， 所述超分子层状材料中所述脂溶性药物泼尼 松占所述水滑石产物总质量的 4% ; 所述超分子层状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，对脂溶性药物起到持续有效的存 贮和缓释功能。
2. 根据权利要求 1所述的脂溶性药物泼尼松插层水滑石， 其特征在于： 层间客体在 340 °C以上才开始发生分解， 热稳定性良好。
3. 一种制备权利要求 1所述的脂溶性药物插层水滑石的方法， 其特征在 于， 该方法包括以下制备步骤：
a. 将胆酸钠溶于水中， 得到胆酸钠胶束溶液， 其中， 胆酸钠浓度比临界 胶束浓度值高 10-20%;
b. 将脂溶性药物泼尼松加入用量足以使加入的泼尼松溶解的氯仿中， 使 泼尼松溶解， 从而得到泼尼松的氯仿溶液；
c 将 b中得到溶液加入到 a中的溶液中， 在 护并进行机械搅拌的 条件下， 使氯仿挥发， 得到胆酸钠胶束包合泼尼松的水溶液；
d.制备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 mol/L, 镁、 铝金属离子摩尔比范围为 2-3， 另外配 制 l-5mol/L的 NaOH的碱溶液；
e.将 d中所述硝酸盐混合溶液与碱溶液以相同速度滴加到步骤 c中所制 得的溶液中， 在 N2保护下进行搅拌， 将 pH值调节为 7-9， 70°C晶化 65-75 小时， 用除去了 C02的水离心 3-4次后置于 60-70°C烘箱内干燥 12-24小时， 得到胆酸钠包合泼尼松插层的水滑石。
PCT/CN2009/071955 2008-09-05 2009-05-25 一种胆酸钠包合脂溶性药物泼尼松插层水滑石及其制备方法 Ceased WO2010025630A1 (zh)

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