CN101530621A - Oxidation resisting dipeptide medicament intercalated houghite and preparation method thereof - Google Patents
Oxidation resisting dipeptide medicament intercalated houghite and preparation method thereof Download PDFInfo
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- CN101530621A CN101530621A CN200910080441A CN200910080441A CN101530621A CN 101530621 A CN101530621 A CN 101530621A CN 200910080441 A CN200910080441 A CN 200910080441A CN 200910080441 A CN200910080441 A CN 200910080441A CN 101530621 A CN101530621 A CN 101530621A
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- 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
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- 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
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- 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
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Abstract
The invention discloses an oxidation resisting dipeptide medicament intercalated houghite and a preparation method thereof, belonging to the technical field of dipeptide medicaments. The chemical formula thereof is: (Mg<2+>)1-x(Al<3+>)x(OH)a(L-Carnosine)b.mH2O. The preparation method thereof comprises the coprecipitation method and the ion exchange method; wherein the crystallization phase of the coprecipitation method and the reaction process of the ion exchange method both adopt the microwave-hydrothermal method. The invention has the advantages that: the microwave-hydrothermal method is adopted in the preparation process of the carnosine intercalated houghite, thus greatly shortening the crystallization period of the coprecipitation method and the reaction period of ion exchange method; the prepared dipeptide medicaments--- carnosine intercalated houghite composite material uses the space limited domain action of the houghite and the interaction between the subject and the object, thus having better thermal stability and certain slow release performance under normal conditions and being favorable for the storage thereof and the development of new dosing route.
Description
Technical field
The invention belongs to the dipeptide technical field of pharmaceuticals, particularly a kind of oxidation resisting dipeptide medicament-carnosine intercalated houghite and preparation method thereof.Adopt the method for microwave hydrothermal in the preparation process, shortened the crystallization time of coprecipitation and the response time of ion exchange greatly.
Background technology
Carnosine is a kind of natural water solublity two peptide materials that are present in the vertebrate skeletal muscle, and it is Beta-alanine-L-histidine that its structure is formed, and molecular weight is 226.24.The physiological property that carnosine has, as resiliency, non-oxidizability, neuron transmits the activity of substrate, and the effects such as regulon of some enzymes have obtained very extensive studies.Carnosine has had application preferably in food additive and cosmetic industry at present.
Yet because chemistry and enzyme sensitivity, dipeptides is very limited as the application of medicine in clinical treatment.In recent years, carnosine is to because anti-oxidation function low caused chronic disease has had breakthrough, as cataract, gastric ulcer etc.Harbin Medical University reported once that carnosine all had therapeutical effect (effective percentage reaches 80%) to polytype cataract.Reported several possible dipeptides route of administration, as oral, lung suction, mucosa or through approach such as subcutaneous administrations, these route of administration need usually specific transporter and (or) penetration enhancer helps medicine to enter systemic circulation from point of release.These improved main targets are not only the deficiency that overcomes oral artifact utilization rate, but also can avoid the relatively poor subcutaneous injection of patient's compliance.
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, and LDHs laminate species of metal ion and adjustable ratio become, and interlayer anion has interchangeability.Utilize this kind performance to form the supramolecular structure system with the dipeptides that has hydrophilic side group COO-by between the ion exchange interposed layer, this structural system can effectively improve the stability of dipeptides.Brucite with making it become the novel carriers that dipeptide medicament is stored and discharged, helps to develop the new effective route of administration of dipeptide medicament as the function of " molecule container " simultaneously.Still have nothing to do both at home and abroad at present in hydrotalcite stratified material and bonded document of carnosine and patent report.
Summary of the invention
The object of the present invention is to provide a kind of oxidation resisting dipeptide medicament intercalated houghite system and preparation method thereof.Its chemical formula is: (Mg
2+)
1-x(Al
3+)
x(OH)
a(L-Carnosine)
bMH
2O, 0.2≤x≤0.33 wherein, m=3-6 is an interlayer water of crystallization molecular number.Its technical scheme is to utilize the tradable character of LDHs interlayer anion, employing coprecipitation or ion exchange to the LDHs interlayer, synthesize the anionic supermolecule stratified material that the carnosine anion accounts for hydrotalcite layers anion molal quantity sum 20%～80% with the carnosine intercalation.Dipeptide medicament intercalated houghite of the present invention keeps the Stability Analysis of Structures of dipeptide medicament by the space confinement effect of hydrotalcite layers in its storage process, play the effect of drug effect slow release by the host-guest interaction of brucite laminar composite, brucite also plays the effect of pharmaceutical carrier and control drug release simultaneously.
It is as follows that method one, coprecipitation prepare carnosine intercalated houghite concrete steps:
A. prepare the mixing salt solution of magnesium nitrate and aluminum nitrate, wherein magnesium ion concentration is 0.1-1.6M, and magnesium, aluminum metal ion molar ratio range are 2-3;
B. prepare the mixed solution of carnosine and NaOH, the mol ratio of carnosine and aluminum nitrate is 1-3, and the molal quantity of NaOH is magnesium nitrate and aluminum nitrate mole summation 2-4 a times;
C. the nitrate mixed solution that steps A is prepared is at N
2Slowly be added drop-wise under the condition of protection in the mixed solution of step B preparation, stir, the NaOH that utilizes 1-5mol/L with the pH value range regulation of solution to 7-10;
D. the serosity that step C is obtained 60 ℃-70 ℃ crystallization 12-48 hour, or serosity transferred in the quick counteracting tank of microwave, at 80-100 ℃ of microwave heating temperature control reaction 0.5-1h;
E. product is adopted and remove CO
2Deionization hot water centrifuge washing to neutral, 50-70 ℃ dry 12-24 hour, obtain the carnosine intercalated houghite.
It is as follows that method two, ion exchange prepare carnosine intercalated houghite concrete steps:
A. prepare the mixed solution of magnesium nitrate and aluminum nitrate, wherein magnesium ion concentration is 0.1-1.6M, and magnesium, aluminum metal ion molar ratio range are 2-3;
B. prepare the NaOH aqueous slkali, the molal quantity of NaOH is magnesium nitrate and aluminum nitrate mole summation 2-2.5 a times;
C. the nitrate mixed solution that steps A is prepared is at N
2Slowly be added drop-wise under the condition of protection in the alkali liquor of step B preparation, stir, the NaOH that utilizes 1-5mol/L with the pH value range regulation of solution to 8-10,60 ℃-100 ℃ crystallization 12-48 hour, adopt and remove CO
2Deionization hot water centrifuge washing to neutral, obtain nitrate anion brucite precursor;
D. it is soluble in water to get carnosine, adds undried nitrate anion brucite precursor, and carnosine and aluminum ions mol ratio are 1-3, and adjusting pH is 7-9, at 40-60 ℃ of water-bath and N
2Under the condition of protection ion exchange 12-24 hour, perhaps transfer in the quick counteracting tank of microwave, at 80-100 ℃ of microwave heating temperature control 0.5h, product adopt to remove CO
2Deionization hot water centrifuge washing to neutral, 50-70 ℃ dry 12-24 hour, obtain the intercalated houghite that the interlayer material is a carnosine.
Method three, concrete steps are as follows:
A. prepare the mixed solution of magnesium nitrate and aluminum nitrate, wherein magnesium ion concentration is 0.1-1.6M, and magnesium, aluminum metal ion molar ratio range are 2-3;
B. prepare the NaOH aqueous slkali, the molal quantity of NaOH is magnesium nitrate and aluminum nitrate mole summation 2-2.5 a times;
C: the mixing salt solution in the steps A is added in the aqueous slkali of step B preparation under the condition of high-speed stirred fast, stir after 10-30 minute, the product that obtains spends CO
2, deionized water wash centrifugalize 3～6 times;
D: get precipitation and the carnosine that step C obtains and be dissolved in CO
2, in the deionized water, carnosine and aluminum ions mol ratio are 1-3, accent pH is 7-9;
E: the serosity of step D is transferred in the autoclave, constant temperature 70-90 ℃ of reaction 6-30h, product spends CO
2, deionized water wash centrifugalize 3～6 times, will precipitate drying at room temperature in a vacuum, can obtain interlayer and contain the anionic laminar composite of carnosine.
With above-mentioned prepared material carry out XRD, IR, NMR, elemental analysis shows that carnosine successfully inserts hydrotalcite layers; Carrying out In-situ XRD, In-situ IR, TG-DTA, TG-MAS characterizes the heat stability that shows this composite and has had and significantly improve; 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: adopted the method for microwave hydrothermal in the process of preparation carnosine intercalated houghite, shortened the crystallization time of coprecipitation and the response time of ion exchange greatly; Prepared dipeptide medicament---carnosine intercalated hydrotalcite composite material is owing to utilized the space confinement effect of brucite and the interaction between the Subjective and Objective, thereby have heat stability and certain sustained release performance preferably under normal conditions, help its storage and open up new route of administration.
Description of drawings
Fig. 1 is the XRD spectra of embodiment 3, and a is the nitrate anion intercalated houghite, and b is the carnosine intercalated houghite.
The specific embodiment
[embodiment 1]
A. with the solid Mg (NO of 0.015mol
3)
26H
2Solid Al (the NO of O and 0.0075mol
3)
39H
2O is dissolved in 50mL and removes CO
2Deionized water in the mixing salt solution of preparation magnesium nitrate and aluminum nitrate;
B. in addition 0.018mol carnosine and 0.0625molNaOH are dissolved in 50mL except that CO
2Deionized water in the mixed solution of preparation carnosine and NaOH;
C. the nitrate mixed solution that steps A is prepared is at N
2Slowly be added drop-wise under the condition of protection in the mixed solution of step B preparation, stir, utilize the pH value range regulation to 9 of the NaOH of 3mol/L solution;
D. the serosity that step C is obtained was 60 ℃ of crystallization 24 hours;
E. product is adopted and remove CO
2Deionization hot water centrifuge washing to neutral, 70 ℃ of dryings 20 hours obtain the carnosine intercalated houghite.
[embodiment 2]
The serosity that step C among the embodiment 1 obtains is transferred in the quick counteracting tank of microwave, and at 100 ℃ of microwave heating temperature control 0.5h, the product that obtains is with removing CO
2Deionization hot water centrifuge washing to neutral, 70 ℃ of dry 24h obtain the carnosine intercalated houghite.
[embodiment 3]
Steps A: take by weighing 15.384g Mg (NO
3)
26H
2O and 11.2539g Al (NO
3)
39H
2O is dissolved in 100ml and removes CO
2, deionized water preparation mixing salt solution;
Step B: other gets 7.2g NaOH and is dissolved in 100ml and removes CO
2, in the deionized water;
Step C: with the nitrate mixed solution of steps A preparation at N
2Slowly be added drop-wise under the condition of protection in the alkali liquor of step B preparation, stir, utilize the pH value range regulation to 10 of the NaOH of 3mol/L,, adopt and remove CO 70 ℃ of crystallization 40 hours with solution
2Deionization hot water centrifuge washing to neutral, obtain nitrate anion brucite precursor;
Step D: it is soluble in water to get carnosine, adds undried nitrate anion brucite precursor, and carnosine and aluminum ions mol ratio are 1-3, and regulating pH is 8;
Step e: at 60 ℃ of water-baths and N
2Ion exchange is 24 hours under the condition of protection, and the product that obtains spends CO
2, the deionized water centrifuge washing is to neutral, 70 ℃ of dryings 24 hours can obtain interlayer and contain the anionic laminar composite of carnosine.
As shown in Figure 1, carnosine successfully inserts hydrotalcite layers.
[embodiment 4]
The mixed solution that step D among the embodiment 3 obtains is transferred in the quick counteracting tank of microwave, and at 100 ℃ of microwave heating temperature control 0.5h, the product that obtains spends CO
2, the deionized water centrifuge washing is to neutral, 70 ℃ of dryings 24 hours can obtain interlayer and contain the anionic laminar composite of carnosine.
[embodiment 5]
Steps A: the mixing salt solution in embodiment 3 steps A is added in the aqueous slkali of step B preparation under the condition of high-speed stirred fast, stir after 20 minutes, the product that obtains spends CO
2, deionized water wash centrifugalize 5 times;
Step B: get precipitation and the carnosine that steps A obtains and be dissolved in CO
2, in the deionized water, carnosine and aluminum ions mol ratio are 2, transferring pH is 8;
Step C: the serosity of step B is transferred in the autoclave, 90 ℃ of reactions of constant temperature 16h, product spends CO
2, deionized water wash centrifugalize 5 times, will precipitate drying at room temperature in a vacuum, can obtain interlayer and contain the anionic laminar composite of carnosine.
Claims (4)
1. oxidation resisting dipeptide medicament intercalated houghite composite, it is characterized in that: its chemical formula is: (Mg
2+)
1-x(Al
3+)
x(OH)
a(L-Carnosine)
bMH
2O, 0.2≤x≤0.33 wherein, m=3-6 is an interlayer water of crystallization molecular number, the carnosine anion accounts for interlayer anion molal quantity sum 20～80%, this composite can make full use of the space confinement effect of its interlayer and the interaction between the Subjective and Objective, has heat stability and certain sustained release performance preferably under normal conditions.
2. the preparation method of an oxidation resisting dipeptide medicament intercalated houghite is characterized in that, it is as follows that coprecipitation prepares carnosine intercalated houghite concrete steps:
A. prepare the mixing salt solution of magnesium nitrate and aluminum nitrate, wherein magnesium ion concentration is 0.1-1.6M, and magnesium, aluminum metal ion molar ratio range are 2-3;
B. prepare the mixed solution of carnosine and NaOH, the mol ratio of carnosine and aluminum nitrate is 1-3, and the molal quantity of NaOH is magnesium nitrate and aluminum nitrate mole summation 2-4 a times;
C. the nitrate mixed solution with steps A preparation slowly is added drop-wise under the condition of N2 protection in the mixed solution of step B preparation, stirs, the NaOH that utilizes 1-5mol/L with the pH value range regulation of solution to 7-10;
D. the serosity that step C is obtained 60 ℃-70 ℃ crystallization 12-48 hour, or serosity transferred in the quick counteracting tank of microwave, at 80-100 ℃ of microwave heating temperature control reaction 0.5-1h;
E. product is adopted and remove CO
2Deionization hot water centrifuge washing to neutral, 50-70 ℃ dry 12-24 hour, obtain the carnosine intercalated houghite.
3. the preparation method of an oxidation resisting dipeptide medicament intercalated houghite is characterized in that, it is as follows that ion exchange prepares carnosine intercalated houghite concrete steps:
A. prepare the mixed solution of magnesium nitrate and aluminum nitrate, wherein magnesium ion concentration is 0.1-1.6M, and magnesium, aluminum metal ion molar ratio range are 2-3;
B. prepare the NaOH aqueous slkali, the molal quantity of NaOH is magnesium nitrate and aluminum nitrate mole summation 2-2.5 a times;
C. the nitrate mixed solution that steps A is prepared is at N
2Slowly be added drop-wise under the condition of protection in the alkali liquor of step B preparation, stir, the NaOH that utilizes 1-5mol/L with the pH value range regulation of solution to 8-10,60 ℃-100 ℃ crystallization 12-48 hour, adopt and remove CO
2Deionization hot water centrifuge washing to neutral, obtain nitrate anion brucite precursor;
D. it is soluble in water to get carnosine, adds undried nitrate anion brucite precursor, and carnosine and aluminum ions mol ratio are 1-3, and adjusting pH is 7-9, at 40-60 ℃ of water-bath and N
2Under the condition of protection ion exchange 12-24 hour, perhaps transfer in the quick counteracting tank of microwave, at 80-100 ℃ of microwave heating temperature control 0.5h, product adopt to remove CO
2Deionization hot water centrifuge washing to neutral, 50-70 ℃ dry 12-24 hour, obtain the intercalated houghite that the interlayer material is a carnosine.
4. the preparation method of an oxidation resisting dipeptide medicament intercalated houghite is characterized in that, preparation process is:
A. prepare the mixed solution of magnesium nitrate and aluminum nitrate, wherein magnesium ion concentration is 0.1-1.6M, and magnesium, aluminum metal ion molar ratio range are 2-3;
B. prepare the NaOH aqueous slkali, the molal quantity of NaOH is magnesium nitrate and aluminum nitrate mole summation 2-2.5 a times;
C: the mixing salt solution in the steps A is added in the aqueous slkali of step B preparation under the condition of high-speed stirred fast, stir after 10-30 minute, the product that obtains spends CO
2, deionized water wash centrifugalize 3～6 times;
D: get precipitation and the carnosine that step C obtains and be dissolved in CO
2, in the deionized water, carnosine and aluminum ions mol ratio are 1-3, accent pH is 7-9;
E: the serosity of step D is transferred in the autoclave, constant temperature 70-90 ℃ of reaction 6-30h, product spends CO
2, deionized water wash centrifugalize 3～6 times, will precipitate drying at room temperature in a vacuum, can obtain interlayer and contain the anionic laminar composite of carnosine.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910080441A CN101530621A (en) | 2009-03-18 | 2009-03-18 | Oxidation resisting dipeptide medicament intercalated houghite and preparation method thereof |
| PCT/CN2009/071925 WO2010105450A1 (en) | 2009-03-18 | 2009-05-22 | A layered double hydroxide complex inserted by carnosine and the preparation method thereof |
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|---|---|---|---|
| CN200910080441A CN101530621A (en) | 2009-03-18 | 2009-03-18 | Oxidation resisting dipeptide medicament intercalated houghite and preparation method thereof |
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|---|---|
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| WO (1) | WO2010105450A1 (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104017557A (en) * | 2014-06-12 | 2014-09-03 | 北京化工大学 | Preparation method and application of diphenylamine sulfonate intercalated hydrotalcite material |
| CN108873557A (en) * | 2018-07-20 | 2018-11-23 | 珠海市众澄天地科技有限公司 | A kind of optical material and preparation method thereof |
| CN109734109A (en) * | 2019-02-22 | 2019-05-10 | 华北电力大学（保定） | A method of preparing ethoxy-dithioformic acid Intercalated |
| 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 |
| CN116196222A (en) * | 2023-02-28 | 2023-06-02 | 上海沐良医疗器械有限公司 | Caries preventing additive, caries preventing material, dental diaphragm and invisible appliance |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100998872B (en) * | 2007-01-16 | 2010-12-08 | 北京化工大学 | Polypeptide medicine intercalation hydrotalcite and its preparation method |
-
2009
- 2009-03-18 CN CN200910080441A patent/CN101530621A/en active Pending
- 2009-05-22 WO PCT/CN2009/071925 patent/WO2010105450A1/en active Application Filing
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104017557A (en) * | 2014-06-12 | 2014-09-03 | 北京化工大学 | Preparation method and application of diphenylamine sulfonate intercalated hydrotalcite material |
| CN104017557B (en) * | 2014-06-12 | 2016-02-24 | 北京化工大学 | A kind of preparation method of diphenylamine sulfonic acid root intercalated houghite material and application thereof |
| CN108873557A (en) * | 2018-07-20 | 2018-11-23 | 珠海市众澄天地科技有限公司 | A kind of optical material and preparation method thereof |
| CN109734109A (en) * | 2019-02-22 | 2019-05-10 | 华北电力大学（保定） | A method of preparing ethoxy-dithioformic acid Intercalated |
| CN109734109B (en) * | 2019-02-22 | 2021-05-04 | 华北电力大学（保定） | Method for preparing ethyl xanthic acid intercalated magnesium-aluminum hydrotalcite |
| 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 |
| CN116196222A (en) * | 2023-02-28 | 2023-06-02 | 上海沐良医疗器械有限公司 | Caries preventing additive, caries preventing material, dental diaphragm and invisible appliance |
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| Publication number | Publication date |
|---|---|
| WO2010105450A1 (en) | 2010-09-23 |
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Open date: 20090916 |