CN101366948A - Sodium cholate coated liposoluble medicament metacortandracin intercalation hydrotalcite and preparation method thereof - Google Patents

Sodium cholate coated liposoluble medicament metacortandracin intercalation hydrotalcite and preparation method thereof Download PDF

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Publication number
CN101366948A
CN101366948A CNA2008101196818A CN200810119681A CN101366948A CN 101366948 A CN101366948 A CN 101366948A CN A2008101196818 A CNA2008101196818 A CN A2008101196818A CN 200810119681 A CN200810119681 A CN 200810119681A CN 101366948 A CN101366948 A CN 101366948A
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prednisone
sodium cholate
hydrotalcite
soluble medicine
fat
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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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Priority to PCT/CN2009/071955 priority patent/WO2010025630A1/en
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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

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Abstract

The invention provides a sodium cholate entrapped fat soluble medicine prednisone insertion-layer hydrotalcite and a method for preparing the same, which belongs to the technical field of the adrenalocortical hormone medicine. The chemical formula of the sodium cholate entrapped fat soluble medicine prednisone insertion-layer hydrotalcite is as follows: (M<2+>)1-x(M<3+>)x(OH<->)2(C21H26O5)a(C24H39O5<->)x.mH2O; the fat soluble medicine prednisone is entrapped to form micelle by utilizing a surface active agent of sodium cholate, and one-step synthesized into the hydrotalcite product with the mutual insertion-layer of the prednisone and the sodium cholate by the coprecipitation method so as to form the supermolecule layering material in which the weight of the fat soluble medicine molecules is 4 percent of the total weight of the hydrotalcite. The preparation method comprises the following steps: firstly, aqueous solution with the sodium cholate micelle entrapped the prednisone is prepared, and the hydrotalcite layering material with the sodium cholate micelle entrapped the prednisone is synthesized by the double-drip coprecipitation method. The hydrotalcite and the method for preparing the same have the advantages that by utilizing the restricted space action and the interaction between the main body and the object, the fat soluble medicine prednisone is inserted in layers of the hydrotalcite by the insertion-layer, thereby realizing the effective storage of the fat soluble medicine in the hydrotalcite and simultaneously achieving the slow-release performance of the chiral medicines in the hydrotalcite.

Description

A kind of sodium cholate coated liposoluble medicament metacortandracin intercalation hydrotalcite and preparation method thereof
Technical field
The invention belongs to the adrenal cortex hormones drug technical field, a kind of fat-soluble medicine prednisone intercalated houghite and preparation method thereof particularly is provided.Because prednisone is a kind of fat-soluble medicine, itself can not directly enter hydrotalcite layers, so make its common intercalation in hydrotalcite layers with a kind of surfactant sodium cholate, has reached the purpose of slow release.
Technical background
Prednisone (Prednisone) is an Aeroseb-Dex, and its acetate commonly used is white or white crystalline powder almost.Prednisone must be reduced to the 11-hydroxyl with 11-position ketone group in liver, be converted into prednisolone side and show pharmacologically active.It has antiinflammatory and anti-allergic effects, can suppress the hypertrophy of connective tissue, reduces the permeability of capillary wall and cell membrane, reduces inflammatory exudation, and can suppress the formation and the release of histamine and other toxicant.Can also promote protein to decompose and change sugar into, reduce the utilization of glucose.Thereby blood glucose and hepatic glycogen are all increased, and glycosuria can appear, increase gastric secretion, appetite stimulator simultaneously.Yet take prednisone class medicine for a long time and can cause multiple untoward reaction, except that having the common untoward reaction of mineralocorticoid and glucocorticoid, in being used as Claritin, cardiovascular system, central nervous system, endocrine, metabolism are all had very big influence, and the newtype drug that therefore has slow-release capability has broad application prospects.
Sodium cholate (Sodinm Cholate) has hydrophilic and hydrophobic two sides, can reduce the surface tension of oil/water between biphase, is stronger emulsifying agent.Make hydrophobic lipid in water, be emulsified into tiny micelle, both increased fat in small intestinal with the contact area of lipase, help the effect of digestive enzyme, highly emulsive lipomicron is directly absorbed by intestinal mucosa, promote the utilization of lipid.Be choleretic, treatment acholia, intestinal fat indigestion, the long-term drain of biliary tract fistula and chronic cholecystitis etc.Main effect has digestion and the absorption that promotes fat, promotes the absorption of fat-soluble medicine, activates the pancreas digestive enzyme, promotes the dissolving of cholesterol in the gallbladder.
The bimetallic complex hydroxide is called brucite (Layered Double Hydroxides again, be abbreviated as LDHs) be a kind of novel multifunctional stratified material, its chemical stability is good, has strong heat resistanceheat resistant performance, also be widely used aspect the slow release of medicine, and LDHs laminate species of metal ion and adjustable ratio become, and interlayer anion has interchangeability.The micelle that utilizes this kind performance the prednisone with surfactant sodium cholate enclose can be formed inserts hydrotalcite layers jointly, forms the supramolecular structure system, and this structural system can effectively improve the sustained release performance of prednisone, reduces its toxicity.Brucite with making it become the novel carriers that adrenal cortex hormones drug is stored and discharged, helps to develop the new effective route of administration of adrenal cortex hormones drug as the function of " molecule container " simultaneously.
Summary of the invention
The object of the present invention is to provide a kind of fat-soluble medicine prednisone intercalated houghite system and preparation method thereof, obtain a kind of drug effect storing and taking brucite adrenal cortex hormones drug relatively stable in the process, the problem of very strong side effect is in use arranged to solve present prednisone.
Chiral drug intercalation hydrotalcite adrenal cortex hormones drug of the present invention can keep stability of drug to guarantee drug effect in its storage process by the space confinement effect of hydrotalcite layers; Take the effect that can play the drug effect slow release in the process by the host-guest interaction of brucite laminar composite at it, main body wherein also can play the effect of controlled release agent simultaneously.
Chemical formula of the present invention is: (M 2+) 1-x(M 3+) x(OH -) 2(C 21H 26O 5) a(C 24H 39O 5 -) xMH 2O, the span of x is 0.25-0.33, a span is 0.02-0.03; Utilize surfactant sodium cholate enclose to form micelle the fat-soluble medicine prednisone, use coprecipitation one-step synthesis prednisone and the sodium cholate hydrotalcite product of intercalation altogether, constitute the supermolecule stratified material that the fat-soluble medicine molecule accounts for the sum 4% of brucite quality.This material can make full use of the space confinement effect of its interlayer and the interaction between the Subjective and Objective, fat-soluble medicine is played the storage and the slow-release function of continuous and effective.The interlayer object decomposes just beginning more than 340 ℃, i.e. good thermal stability.
Fat-soluble medicine prednisone intercalated houghite preparation process of the present invention is as follows:
A. sodium cholate is soluble in water, sodium cholate concentration should be higher than critical micelle concentration value 10-20%, obtains sodium cholate micellar solution;
B. the fat-soluble medicine prednisone is added in the chloroform (the chloroform consumption is to make the prednisone amount of adding be dissolved as suitable), make its dissolving, thereby obtain the chloroformic solution of prednisone;
C. join among a N with obtaining solution among the b 2Protection, under the mechanical agitation, the volatilization chloroform obtains the aqueous solution of sodium cholate micelle enclose prednisone;
D. make the mixing salt solution of solubility bivalence magnesium nitrate and solubility trivalent aluminum nitrate, wherein bivalent metal ion concentration is 0.8-1.6mol/l, and magnesium, aluminum metal ion molar ratio range are 2-3, are saline solution, prepare the NaOH solution of 1-5mol/L in addition, be aqueous slkali;
E. saline solution and aqueous slkali are added drop-wise in the c solution that has made N with identical speed 2Protection is stirred, and pH value is adjusted to 7-9,70 ℃ crystallization 65-75 hour, spend CO 2Centrifugal 3-4 time of water placed 60-70 ℃ of oven drying 12-24 hour, obtained sodium cholate enclose prednisone intercalated houghite.
Two coprecipitation one-step synthesis target product, and saved the loaded down with trivial details step of ion exchange, this composite can make full use of the space confinement effect of its interlayer and the interaction between the Subjective and Objective, fat-soluble medicine is played the storage and the slow-release function of continuous and effective.
Above-mentioned prepared material is carried out XRD, IR, UV, fluorescence, TG-DTA, elemental analysis prednisone in the success of hydrotalcite layers intercalation.Carry out in-vitro simulated release experiment and show that this composite system can reach certain sustained release performance.
The invention has the advantages that: utilize the space confinement effect of brucite stratified material and the interaction between the Subjective and Objective, fat-soluble medicine prednisone intercalation is entered hydrotalcite layers, realize the effective storage of brucite fat-soluble medicine; Reach the sustained release performance of brucite simultaneously, for " storage-administration " new way that brucite is applied to this medicine is provided fundamental basis to this chiral drug.
Description of drawings
The XRD spectra of Fig. 1 for obtaining under the specific embodiment of the invention condition; Abscissa is 2 θ, unit: degree; Vertical coordinate is an intensity.
Fig. 2 is the curve of the intercalation product release in vitro that obtains under the specific embodiment of the invention condition; Abscissa is the time, unit: minute; Vertical coordinate is a release rate.
The specific embodiment
Steps A: take by weighing cholic acid 1.72g and be dissolved in 150ml and remove CO 2Deionized water in, fully stir, solution I; Take by weighing the 0.03g prednisone and be dissolved in the 20ml chloroform, get solution II; Solution II is added in the solution I N 2Protection, volatilization chloroform 4-5 hour, solution to be seen become when transparent be the chloroform volatilization fully, obtain the aqueous solution of needed sodium cholate micelle enclose prednisone.
Step B: take by weighing 1.80g Mg (NO 3) 26H 2O and 1.32g Al (NO 3) 39H 2O is dissolved in 25ml and removes CO 2, deionized water preparation mixing salt solution, other gets 0.84g NaOH and is dissolved in 25ml and removes CO 2, deionized water gets aqueous slkali; Steps A gained solution is placed four-hole boiling flask, adopt two coprecipitations of dripping, at 70 ℃ of water-baths, N 2Under protection, the strong agitation condition saline solution is added drop-wise in the steps A gained solution with identical speed with aqueous slkali, regulates pH value to 7-9, crystallization 72 hours; Product washing is to neutral, 70 ℃ dry about 12 hours down, promptly get the laminar composite of sodium cholate enclose prednisone intercalation.
Step C: externally be released into test, place pH value to be respectively 37 ℃ of water-baths of 900ml buffer solution of 7.6,6.8,4.8 a certain amount of prednisone intercalation product, under stirring condition, carry out drug release, pipette 5ml solution every different time sections, filter, in being released into solution, add the buffer solution of same volume simultaneously,, obtain the release in vitro curve by ultraviolet detection.
By XRD, UV, IR spectrogram as can be known the success of prednisone molecule entered hydrotalcite layers, by elution profiles as can be seen, brucite can be as a kind of carrier of medicament slow release material.

Claims (3)

1. fat-soluble medicine prednisone intercalated houghite, it is characterized in that: its chemical formula is: (M 2+) 1-x(M 3+) x(OH -) 2(C 21H 26O 5) a(C 24H 39O 5 -) xMH 2O, the span of x is 0.25-0.33, a span is 0.02-0.03; Utilize surfactant sodium cholate enclose to form micelle the fat-soluble medicine prednisone, use coprecipitation one-step synthesis prednisone and the sodium cholate hydrotalcite product of intercalation altogether, constitute the supermolecule stratified material that the fat-soluble medicine molecule accounts for the sum 4% of brucite quality; This material can make full use of the space confinement effect of its interlayer and the interaction between the Subjective and Objective, fat-soluble medicine is played the storage and the slow-release function of continuous and effective.
2. according to right 1 described fat-soluble medicine prednisone intercalated houghite, it is characterized in that: the interlayer object is just beginning to decompose good thermal stability more than 340 ℃.
3. a method for preparing right 1 described fat-soluble medicine intercalated houghite is characterized in that, preparation process is:
A. sodium cholate is soluble in water, sodium cholate concentration should be higher than critical micelle concentration value 10-20%, obtains sodium cholate micellar solution;
B. the fat-soluble medicine prednisone is added in the chloroform, make its dissolving, obtain the chloroformic solution of prednisone from face;
C. join among a N with obtaining solution among the b 2Protection, machinery stirs and stops, and the volatilization chloroform obtains the aqueous solution of sodium cholate micelle enclose prednisone;
D. make the mixing salt solution of solubility bivalence magnesium nitrate and solubility trivalent aluminum nitrate, wherein bivalent metal ion concentration is 0.8-1.6mol/l, and magnesium, aluminum metal ion molar ratio range are 2-3, are saline solution, prepare the NaOH solution of 1-5mol/L in addition, be aqueous slkali;
E. saline solution and aqueous slkali are added drop-wise in the solution that the c step made with identical speed, the N2 protection is stirred; pH value is adjusted to 7-9,70 ℃ crystallization 65-75 hour, spend centrifugal 3-4 time of CO2 water; placed 60-70 ℃ of oven drying 12-24 hour, and obtained sodium cholate enclose prednisone intercalated houghite.
CNA2008101196818A 2008-09-05 2008-09-05 Sodium cholate coated liposoluble medicament metacortandracin intercalation hydrotalcite and preparation method thereof Pending CN101366948A (en)

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CNA2008101196818A CN101366948A (en) 2008-09-05 2008-09-05 Sodium cholate coated liposoluble medicament metacortandracin intercalation hydrotalcite and preparation method thereof
PCT/CN2009/071955 WO2010025630A1 (en) 2008-09-05 2009-05-25 Sodium cholate-included prednisone intercalated layered double hydroxides and preparation method thereof

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010025630A1 (en) * 2008-09-05 2010-03-11 北京化工大学 Sodium cholate-included prednisone intercalated layered double hydroxides and preparation method thereof

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CN1272002C (en) * 2004-01-07 2006-08-30 北京化工大学 Supermolecular intercalation-structure slow-release captopril and its preparing method
CN100368300C (en) * 2005-10-08 2008-02-13 北京化工大学 Surfactant intercalated magnetic hydrotalcite material and its prepn
CN101366948A (en) * 2008-09-05 2009-02-18 北京化工大学 Sodium cholate coated liposoluble medicament metacortandracin intercalation hydrotalcite and preparation method thereof

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010025630A1 (en) * 2008-09-05 2010-03-11 北京化工大学 Sodium cholate-included prednisone intercalated layered double hydroxides and preparation method thereof

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Application publication date: 20090218