CN101854954A - A methods for preparing the clathrate compound of steroid medicines utilizing hydrotalcite as carrier - Google Patents
A methods for preparing the clathrate compound of steroid medicines utilizing hydrotalcite as carrier Download PDFInfo
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- CN101854954A CN101854954A CN200980102989A CN200980102989A CN101854954A CN 101854954 A CN101854954 A CN 101854954A CN 200980102989 A CN200980102989 A CN 200980102989A CN 200980102989 A CN200980102989 A CN 200980102989A CN 101854954 A CN101854954 A CN 101854954A
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- 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
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
- A61P5/44—Glucocorticosteroids; Drugs increasing or potentiating the activity of glucocorticosteroids
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Abstract
The invention provides a method for entrapping steroid medicines by using hydrotalcite as a carrier, which belongs to the technical field of using an organic-inorganic composite material as a releaser. The steroid medicine undergoes the high polymer entrapping by utilizing the insertion-layer characteristics of the hydrotalcite, and is inserted into layers of the hydrotalcite, and the releasing conditions of the object product in phosphate and citric acid buffer solution with different pH values are observed. The method has the advantages that the layering nano carrier forming the hydrotalcite entraps the steroid medicine and performs the insertion-layer, the prepared product can be better released in the colon, and simultaneously the absorption of prednisone in gastric juices is overcome.
Description
It is a kind of using hydrotalcite as carrier to staying the method that body class medicine is included
Technical field：
The invention belongs to the technical field by the use of composite organic-inorganic material as dispensing device, a kind of method included using hydrotalcite as load body to body class medicine is in particular, provided.The present invention relates to construct a kind of intercalation configuration hydrotalcite composite material and study its behavior for body class medicine include release.Background technology：
With the development of life science, material science and nano science and correlation technique in recent years, biotech drug is continued to bring out with novel carriers material, particulate carrier is more varied with nanoparticulate carriers, the research and application of novel Drug Delivery Systems are further deeply and universal, and promoting the pharmacy of 21 century will deeply develop along cell, subcellsular level and molecular level.
LDHs are also known as hydrotalcite (Layered Double Hydroxides, it is abbreviated as LDHs) it is a kind of new multi-functional layered material, its chemical stability is good, with strong heat resistanceheat resistant performance, also it is widely used in terms of the sustained release of medicine, and LDHs laminates species of metal ion and ratio can modulation, interlayer anion has interchangeability.Block copolymer can will be used using such a performance（Such as isopropylacrylic acid methyl esters-ethyl acrylate-methacrylic acid copolymer）The micella of the metacortandracin formation of inclusion inserts hydrotalcite layers jointly, forms supramolecular structure system, this structural system can effectively improve the sustained release performance of metacortandracin, reduce its toxicity.Hydrotalcite will become the novel carriers of adrenal cortex hormones drug storage and release as the function of " cell reservoirs ", while helping to develop the new effective method of administration of adrenal cortex hormones drug
In now widely used drug molecule and pharmaceutical preparation, have targeting distribution seldom to diseased region in vivo.This makes the strong medicine of those pharmacological actions, easily occurs serious toxicity over the course for the treatment of.Therefore, designing can be with respect to Targeting distribution in the drug molecule or delivery system of diseased organ, tissue or cell（Drug delivery systems, DDS) be always medical scholar pursuit.
To intestines problem（Such as ulcerative colitis and colorectal cancer）Treatment, presently mainly using common oral tablet, suppository, enema etc..Because gastrointestinal tract environment factor is sufficiently complex, influenceed by these complex environment factors, by oral administration with after common oral preparation, general medicine has just been absorbed or degraded before colon and rectum is reached；Rectally（Including suppository or enema）In, such as enema is not only inconvenient for use but also medicine is big in the individual difference of colon, and skewness, medicine is only limited to, in rectum and sigmoid colon, not reach transverse colon and the colon ascendens；For suppository, treatment recial disease or whole body therapeutic are only used for, it is impossible to realize the purpose of colon administration.And after being administered with oral colon-target, medicine does not discharge in upper digestive tract, just start disintegration or corrosion in ileocecus and discharge, so that medicine plays locally or systemically therapeutic action in human body large intestine.Therefore, using chemistry or galenic pharmacy means, medicine is built into the oral colon specific targeting drug-delivery system of Colon-specific release（OCTDDS clinical meaning) is great.
Colon is a significant points of drug absorption.Although the surface area of colon is less than small intestine, the absorption rate of medicine is relatively small, due to medicine in colon residence time length and the uptake of medicine can be made to obtain part compensation.In addition, colon has more selection absorbability than small intestine, hydrophobic drug may pass through mucosa cells and be absorbed, thus preferable in colonic absorption.Human gastrointestinal tract pH is gradually incremented by from low to high, and wherein colon pH is of a relatively high, and this is the physiological foundation of colon targeting drug administration pH dependent form medicine-releasing systems.At present, the pH dependent forms medicine-releasing system main method being coated by using pH sensitive materials is realized.As preferable segmented intestine targeted coating material, it must possess two conditions：One is to be resistant to acidic gastric juice and be not dissolved；Two be to be dissolved under the conditions of the neutrality or weak base of terminal ileum or erosion solution.
The segmented intestine targeted performance of pH dependent form medicine-releasing systems is influenceed by material solubility, clothing film thickness and preparation in each section of residence time of stomach and intestine.Dissolution characteristics of the coating material in different pH solution, have large effect to the targeting of preparation.Acrylate copolymer Eudragit S part carboxymethyl group can obtain the polymer dissolved in higher pH solution by Guo Shengrong etc., and in vivo studies demonstrates the validity segmented intestine targeted Eudragit S that methylates.Guo Shengrong etc. has synthesized Eudragit S100（PMMA-co-MAA), the naproxen coating micro-pill for employing PMMA-co-MAA is studied, it was confirmed that being coated by PMMA-co-MAA can be drug delivery to colon drug delivery, and the relation of copolymer pH sensitiveness and acid number is studied.
The content of the invention：
It is an object of the invention to provide a kind of method included using hydrotalcite as load body to body class medicine, this method inserts hydrotalcite layers after being included using stratified material hydrotalcite as load body to body class medicine, solves the problem in large intestine Targeting delivery such as body class medicine Bo Nisong.
The present invention is using the intercalation of hydrotalcite by body class medicine（Such as Bo Nisong）Pass through high polymer (isopropylacrylic acid methyl esters-ethyl acrylate-methacrylic acid copolymer）After inclusion, the medicine of inclusion is inserted into by hydrotalcite layers using coprecipitation, release conditions of the target product in the phosphate and citric acid solution of different pH value are then investigated.
Coprecipitation：
A. the high polymer for weighing 0.15-0.60 g amounts is dissolved in 300ml deionized waters, and the concentration for obtaining solution is 0.5-2.0 g/1;
B. the Bo Nisong for weighing 0.01-0.05g is dissolved in 20ml acetone, is then transferred to 1 ml/s-3 ml/s in step A；
C. the nitrate mixed solution of soluble magnesium nitrate and soluble aluminum nitrate is prepared, the wherein ion concentration of divalent metal magnesium is 0.02-0.05 mol/l.
D. NaOH solution is prepared；
E. the NaOH solution prepared the step C nitrate mixed solutions prepared and step D is in N2It is added drop-wise under conditions of protection with 1 ml/s-3 ml/s in step A（That is, the solution of the step A after addition B）, the pH value range of obtained solution adjusted to 10-11, used at 40 °C -60 °C after lower crystallization 12-48 hour and eliminate C0 by stirring using 1-5 mol/L NaOH2Deionization hot water centrifuge washing to neutrality, under 70 °C -100 °C dry 12-24 hours, obtain body class compound intercalated houghite.
The release of target product
A. take 0.05-0.10g body class medicament intercalated houghites product to add in cushioning liquid, be slowly stirred；
B. 2 ml solution was extracted every 0.5-4 hours, in ultraviolet-visible light after filtering（UV-vis the Bo Nisong of solution absorption intensity is detected under).The method of the filtering can be filtered including the use of 0.45 μ η ι filter membranes.
The release solution of obtained intercalated houghite and product is subjected to X-ray diffraction（XRD), Fourier transform infrared spectroscopy（FT-IR the sign) and after UV-vis shows that ripple Buddhist nun's loose micelle after inclusion is successfully entered interlayer.The UV-vis detections data discharged through different pH buffer can be seen that, under sour environment, ripple Buddhist nun's pine oil puts relatively slow, and pH is near neutral, ripple Buddhist nun's pine oil is put than very fast, it is achieved thereby that function of the hydrotalcite as nano-carrier Targeting delivery.
The advantage of the invention is that：The laminar nano for constructing hydrotalcite carries intercalation after body to body class medicine is included, and the product of preparation can preferably be discharged in colon, be absorbed while avoiding Bo Nisong in gastric juice.
Brief description of the drawings-Fig. 1 is obtained XRD spectra under the conditions of the specific embodiment of the invention；Abscissa is 2 Θ, unit：Degree；Ordinate is intensity.
Fig. 2 is the curve of the release in vitro of intercalation product obtained under the conditions of the specific embodiment of the invention；Abscissa is time, unit：Hour；Ordinate is release percentage.
Embodiment：
The present invention is illustrated by example below.
In the examples below, make to determine obtained product in each embodiment with the following method：
Structural analysis, Cu Κ α light sources are carried out with Japanese Shimadzu XRD-6000 types X-ray diffractometer（The nm of λ=0.154), the Kv of voltage 40, the mA of electric current 30, continuous scanning, the min of sweep speed 5.
FT-IR spectrum are in (the German Brooker companies of VECTOR 22）Scanned under upper acquisition, tabletting after sample is mixed with KBr, room temperature, air atmosphere.Parameter index is：Resolution ratio be 4 cm-1, scanning range 4000-400cm.
The ultraviolet visible spectrophotometers of Shimadzu UV-2501PC are used for intercalation product medium wave Buddhist nun's pinidine
Amount and intermolecular force analyze (test scope:200 ~ 800nm, a length of 240nm of maximum absorption wave).Embodiment 1
Step A. weighs a certain amount of high polymer and is dissolved in 300 ml deionized water, obtain the concentration of solution for 3 X 10-4 M。
The Bo Nisong that step B. weighs 0.05 g is dissolved in 20 ml acetone, is then slowly transferred in the solution that step A is obtained, and is stirred 20 hours at 40 °C.
Step C. is by 1.5414 g (0.006mol) solid Mg (N03)2*6H20 and 1.1306 g (the 0.003mol) (Ν 0 of solid Α 13)3·9Η20 be dissolved in 50 mL eliminate C02Deionized water in (；Solution 1);It is another to eliminate C0 by what 0.7202 g (0.018mol) NaOH was dissolved in 50 mL2Deionized water in (；Solution 2) prepare NaOH solution.
Step D. is in N2Under conditions of gas shielded, solution 2 and solution 1 are respectively placed in there-necked flask in two constant pressure funnels, while being stirred vigorously, while during the solution that step A is obtained is slowly added dropwise（After adding B）, drip off within about 1 hour.
Step E. is adjusted the pH value range of the obtained solution of step D to 10-11 using 1-5 mol/L NaOH, using eliminating C0 after 40 °C of lower crystallization 48 hours2Deionization hot water centrifuge washing to neutrality, 70 °C of -100 °C of dryings 12 hours obtain intercalated houghite product.
From XRD, FT-IR spectrogram, UV-vis, hydrotalcite layers are inserted into after high polymer inclusion Bo Nisong.
The product as made from above-mentioned steps is weighed 0.5 g and is dissolved in 200 ml pH respectively by step F. is
In 4.8 and 7.2 phosphate and the cushioning liquid of citric acid, it is slowly stirred under 37 °C, 2 ml above-mentioned solution was extracted every 30 minutes, the absorption intensity for detecting its Bo Nisong after membrane filtration under UV-vis is filtered with 0.45 μ η ι.
From UV-vis, over time, Bo Nisong burst size increase, its intensity also can accordingly strengthen.
Claims (2)
- ClaimsIt is 1st, a kind of to be used as the method for carrying intercalation after body to body class medicine is included using hydrotalcite, it is characterised in that：After this method is included body class medicine by high polymer using the intercalation of hydrotalcite, medicine after inclusion is inserted into by hydrotalcite layers using coprecipitation, release conditions of the target product in different pH value phosphate and citric acid solution are then investigated；The body class medicine is Bo Nisong, and the high polymer is isopropylacrylic acid methyl esters-ethyl acrylate-methacrylic acid copolymer.2nd, in accordance with the method for claim 1, it is characterised in that：The described method for including body class medicine by high polymer includes：A, body class medicament intercalated houghite is prepared using coprecipitation：(a) high polymer for, weighing 0.15-0.60 g amounts is dissolved in 300 ml deionized water, obtains the solution that concentration is 0.5-2.0 g/1；(b) Bo Nisong for, weighing 0.01-0.05g is dissolved in 20 ml acetone, is then transferred to step with 1 ml/s-3 ml/s speed（A) in；(c) nitrate mixed solution of soluble magnesium nitrate and soluble aluminum nitrate, is prepared, the wherein ion concentration of divalent metal magnesium is 0.02-0.05 M;(d) NaOH solution, is prepared；(e), by step（C) nitrate mixed solution and step prepared（D) NaOH solution prepared is added drop-wise to step under conditions of shield with 1 ml/s-3 ml/s speed（A) in, stirring is adjusted the pH value range of the solution of gained to 10-11 using 1-5 mol/L NaOH, is used in 40 °C of -60 °C of crystallization after 12-48 hour and is eliminated C02Deionization hot water centrifuge washing to neutrality, under 70 °C -100 °C dry 12-24 hours, obtain body class medicament intercalated houghite；B, target product release：(a2), take the body class medicament intercalated houghite of 0.05-0.10 g amounts to add in the cushioning liquid, be slowly stirred,(b), every the ml's of decimation in time 2 of 0.5-4 hours（A2 its Bo Nisong absorption intensity is detected after the solution filtering in) by UV-vis.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009801029894A CN101854954B (en) | 2008-09-05 | 2009-06-08 | A methods for preparing the clathrate compound of steroid medicines utilizing hydrotalcite as carrier |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008101196803A CN101366947A (en) | 2008-09-05 | 2008-09-05 | Method for inclusion of steroid medicament with hydrotalcite as carrier |
| CN200810119680.3 | 2008-09-05 | ||
| CN2009801029894A CN101854954B (en) | 2008-09-05 | 2009-06-08 | A methods for preparing the clathrate compound of steroid medicines utilizing hydrotalcite as carrier |
| PCT/CN2009/072173 WO2010025632A1 (en) | 2008-09-05 | 2009-06-08 | A methods for preparing the clathrate compound of steroid medicines utilizing hydrotalcite as carrier |
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| Publication Number | Publication Date |
|---|---|
| CN101854954A true CN101854954A (en) | 2010-10-06 |
| CN101854954B CN101854954B (en) | 2012-10-17 |
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| CNA2008101196803A Pending CN101366947A (en) | 2008-09-05 | 2008-09-05 | Method for inclusion of steroid medicament with hydrotalcite as carrier |
| CN2009801029894A Expired - Fee Related CN101854954B (en) | 2008-09-05 | 2009-06-08 | A methods for preparing the clathrate compound of steroid medicines utilizing hydrotalcite as carrier |
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| CNA2008101196803A Pending CN101366947A (en) | 2008-09-05 | 2008-09-05 | Method for inclusion of steroid medicament with hydrotalcite as carrier |
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| WO (1) | WO2010025632A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101366947A (en) * | 2008-09-05 | 2009-02-18 | 北京化工大学 | Method for inclusion of steroid medicament with hydrotalcite as carrier |
| CN110522732A (en) * | 2019-09-04 | 2019-12-03 | 中国科学院上海硅酸盐研究所 | A kind of extra small nano hydrotalcite-peptide nucleic acid composite material and preparation method and application |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JP3278631B2 (en) * | 1999-04-06 | 2002-04-30 | 科学技術振興事業団 | Process for producing anion-layered double hydroxide intercalation compound and product thereof |
| GB0030460D0 (en) * | 2000-12-14 | 2001-01-24 | Isis Innovation | Drug delivery system |
| CN1272002C (en) * | 2004-01-07 | 2006-08-30 | 北京化工大学 | Supermolecular intercalation-structure slow-release captopril and its preparing method |
| CN1561963A (en) * | 2004-03-26 | 2005-01-12 | 北京化工大学 | Enteric coatel material coated anti-inflammation agent insert layer hydrotalcite and its preparing method |
| US20050244439A1 (en) * | 2004-04-30 | 2005-11-03 | Eastman Kodak Company | Composition comprising anionic clay layered host material with intercalated functional-active organic compound |
| CN1850275A (en) * | 2006-02-28 | 2006-10-25 | 北京化工大学 | Chiral drug intercalation hydrotalcite and its preparing method |
| CN100998872B (en) * | 2007-01-16 | 2010-12-08 | 北京化工大学 | Polypeptide medicine intercalation hydrotalcite and its preparation method |
| CN101366947A (en) * | 2008-09-05 | 2009-02-18 | 北京化工大学 | Method for inclusion of steroid medicament with hydrotalcite as carrier |
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- 2008-09-05 CN CNA2008101196803A patent/CN101366947A/en active Pending
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2009
- 2009-06-08 CN CN2009801029894A patent/CN101854954B/en not_active Expired - Fee Related
- 2009-06-08 WO PCT/CN2009/072173 patent/WO2010025632A1/en active Application Filing
Also Published As
| Publication number | Publication date |
|---|---|
| CN101366947A (en) | 2009-02-18 |
| WO2010025632A1 (en) | 2010-03-11 |
| CN101854954B (en) | 2012-10-17 |
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Granted publication date: 20121017 Termination date: 20130608 |