WO2010025630A1

WO2010025630A1 - Sodium cholate-included prednisone intercalated layered double hydroxides and preparation method thereof

Info

Publication number: WO2010025630A1
Application number: PCT/CN2009/071955
Authority: WO
Inventors: 卫敏; 李复苏; 陆军; 段雪
Original assignee: 北京化工大学
Priority date: 2008-09-05
Filing date: 2009-05-25
Publication date: 2010-03-11
Also published as: CN101366948A

Abstract

The formula of the sodium cholate-included prednisone intercalated layered double hydroxides is provided, (M²⁺)_1-x(M³⁺)_x(OH^-)₂(C₂₁H₂₆O₅)_a(C₂₄H₃₉O₅ ^-)_x·mH₂O, wherein x is 0.25-0.33 and a is 0.02-0.03. The preparation method for the sodium cholate-included prednisone intercalated layered double hydroxides comprises preparing sodium cholate micelle water solution, adding prednisone/chloroform solution in nitrogen ambient, stirring to volatilize chloroform to obtain sodium cholate-included prednisone solution, preparing mixed solution of magnesium nitrate and aluminum nitrate with Mg/Al molar ratio 2-3, dropping into the sodium cholate-included prednisone solution in nitrogen ambient, stirring, adjusting pH to 7-9, crystallizing at 70 centigrade degree for 65-75 hours, centrifugating with CO2-removing water 3-4 times, and drying at 60-70 centigrade degree for 12-24 hours. The drug delivery system of the sodium cholate-included prednisone intercalated layered double hydroxides has advantages of good thermal stability and sustained release effect.

Description

Sodium cholate inclusion fat-soluble drug prednisone intercalated hydrotalcite and preparation method thereof

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. For example, 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), are a new type of multifunctional layered material with good chemical stability and strong heat resistance, in terms of sustained release of drugs. There are also a wide range of applications, and the type and proportion of metal ions in the LDHs laminate can be changed, and the interlayer anions are exchangeable. Using this property, 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. The function of 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. Summary of the invention:

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: (Μ^ΚΜ^^ΟΗΜί^Η^ΟΑ^ΜΗ θ χ •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. Moreover, 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:

a. Dissolving sodium cholate in water to obtain a sodium bicarbonate micelle solution, wherein the concentration of sodium cholate should be 10-20% higher than the critical micelle concentration;

b. adding the fat-soluble drug prednisone to chloroform (the amount of chloroform is such that the amount of prednisone added is dissolved), and dissolving it to obtain a prednisone chloroform solution;

c adding the solution obtained in b to the solution in a, volatilizing the chloroform under N ₂ protection and mechanical stirring to obtain an aqueous solution of sodium cholate micelles containing prednisone;

d. preparing a 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;

e. The 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. The simulated release test in vitro showed that the composite material system of the present invention can achieve a certain sustained release property.

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.

BRIEF DESCRIPTION OF THE DRAWINGS:

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is an XRD spectrum obtained under the conditions of a specific embodiment of the present invention; the abscissa is 2 Θ, unit: degree; and the ordinate is intensity.

2 is a graph showing the in vitro release of the intercalated product obtained under the conditions of the specific embodiment of the present invention; the abscissa is time, the unit is: minute; and the ordinate is the release rate.

detailed description:

The invention is specifically illustrated by the following examples.

In the following examples, the production according to the present invention prepared in each of the examples was measured by the following method. Structural analysis by a Japanese Shimadzu XRD-6000 X-ray diffractometer, Cu Ka light source (λ = 0.154 nm), voltage 40 Kv, current 30 mA, continuous scan, scan speed 5 min.

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).

Example 1:

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 which sodium cholate was coated with prednisone.

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.

XRD, UV and IR spectra show that prednisone molecules have successfully entered the hydrotalcite layer. It can be seen from the sustained release curve that hydrotalcite can be used as a carrier for sustained release materials.

Claims

Claim

A fat-soluble drug prednisone intercalated hydrotalcite characterized in that: the chemical formula of the fat-soluble drug prednisone intercalated hydrotalcite is: (M ²⁺ ) _1-x (M ³⁺ ) _x (OH — ) ₂ (C ₂₁ H ₂₆ 0 ₅ ) _a (C ₂₄ H ₃₉ 0 ₅ — ) _χ · m3⁄40, wherein x ranges from 0.25 to 0.33, and a ranges from 0.02 to 0.03; The drug prednisone intercalated hydrotalcite is a hydrotalcite co-intercalated with prednisone and sodium cholate by coprecipitation method after the fat-soluble drug prednisone is coated with a surfactant sodium cholate. a product, and a supramolecular layered material formed, wherein the fat-soluble drug prednisone accounts for 4% of the total mass of the hydrotalcite product; the supramolecular layered material can make full use of the The spatial confinement between the layers and the interaction between the host and the object provide a continuous and effective storage and sustained release function for the fat-soluble drug.

The fat-soluble drug prednisone intercalated hydrotalcite according to claim 1, wherein the inter-layer guest starts to decompose at 340 ° C or higher, and the thermal stability is good.

A method of preparing a fat-soluble drug intercalated hydrotalcite according to claim 1, characterized in that the method comprises the following preparation steps:

a. Dissolving sodium cholate in water to obtain a sodium bicarbonate micelle solution, wherein the concentration of sodium cholate is 10-20% higher than the critical micelle concentration;

b. adding the fat-soluble drug prednisone to the chloroform in an amount sufficient to dissolve the added prednisone, so that the prednisone is dissolved, thereby obtaining a prednisone chloroform solution;

c adding the solution obtained in b to the solution in a, volatilizing the chloroform under the condition of mechanical stirring, to obtain an aqueous solution of sodium cholate micelles containing prednisone;

d. preparing a nitrate mixed solution of soluble magnesium nitrate and soluble aluminum nitrate, wherein the ion concentration of the divalent metal magnesium is 0.8-1.6 mol/L, the molar ratio of magnesium and aluminum metal ions is 2-3, and further preparing l-5 mol /L NaOH alkaline solution;

e. The nitrate mixed solution described in d is added dropwise to the solution prepared in the step c at the same rate, and stirred under N ₂ protection to adjust the pH to 7-9, 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 hydrotalcite in which sodium cholate was coated with prednisone.