CN1272002C - Supermolecular intercalation-structure slow-release captopril and its preparing method - Google Patents

Supermolecular intercalation-structure slow-release captopril and its preparing method Download PDF

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CN1272002C
CN1272002C CNB2004100003078A CN200410000307A CN1272002C CN 1272002 C CN1272002 C CN 1272002C CN B2004100003078 A CNB2004100003078 A CN B2004100003078A CN 200410000307 A CN200410000307 A CN 200410000307A CN 1272002 C CN1272002 C CN 1272002C
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captopril
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catopril
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CN1640395A (en
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段雪
张慧
徐向宇
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Beijing University of Chemical Technology
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Abstract

The present invention relates to supermolecular intercalation structure slow release captopril and an assembly method thereof. The present invention uses anion layer-shaped material LDH as a main body; captopril is used as an intercalation object; mixed salt solution prepared from two kinds of soluble metal salt and alkali solution of the captopril are assembled in an intercalation mode, supermolecular structure Cpl-LDHs is obtained, and a chemical formula is (M<2+>)1-x(M<3+>)x(OH)2(Cpl<->)a1(Cpl<2->)a2(B<n->)b*mH2O. In a slow release agent, the percentage content of the mass of the captopril is from 20 to 50%, and the percentage content of the mass of water is from 5 to 20%. The slow release captopril has the good slow release effect, and the slow release effective time can be from 0.5h to 12h.

Description

A kind of supermolecular intercalation structure slow-release catopril and preparation method thereof
Technical field:
The present invention relates to a kind of medicinal slow release agent and preparation method thereof, be specifically related to a kind of supermolecular intercalation structure slow-release catopril and assemble method thereof.
Background technology:
At present, at developing safety, efficient, economic, the requirement of slow releasing pharmaceutical easily, with conventional medicament initiative novel form, realize that the controlled controlled drug delivery system of drug release quantity, release time and Free up Memory is in medically research with use and be subject to people's attention day by day.When using, can keep a particular concentration for a long time on an application point and side effect is less based on the medical slow release formulation of conventional medicament development, therefore have the following advantages: (1) discharges drug slow, prolongs to hold effect; (2) reduce toxicity; (3) reduce side effect; (4) strengthen selectivity, improve drug effect; (5) easy to use etc.
Existing medicinal slow release agent mainly is to utilize natural or synthetic macromolecular compound as pharmaceutical carrier or medium.And use the defective that macromolecular material also has it to overcome, for example the final processing of wall material/polymer and its catabolite can not be ignored the influence of health, and according to its mechanism of action, though the medicine active component can correspondingly one by one with the reactive group on the macromolecular material main chain interact theoretically, but be subjected to factor affecting such as sterically hindered, the supported quantity of active component is not high.
Captopril belongs to the angiotensin-convertion enzyme inhibitor (ACE-1) in the vasodilator, resisting hypertension class medicine, and captopril has become clinician's first-selection.Indication is: hypertension, congestive heart failure, acute myocardial infarction, treatment diabetic nephropathy also have the effect of treatment rheumatoid arthritis.But this medicine ordinary preparation stripping is fast, eliminate the half-life weak point in the body, and peak valley concentration difference is bigger.Therefore the research about the captopril slow release formulation is one of focus always, and the report of this respect also has a lot.
Document (Hisu-O Ho, Han-Yen Wang, Ming-ThauSheu, J.Control.Release49 (1997) 243-251) cover type agent lactose, dicalcium phosphate and ethyl cellulose with granule and prepared the captopril slow releasing agent, but the rate of release of captopril is very fast in the slow releasing agent of gained as host material.
Document (Abubakr O.Nur, Jun S.Zhang, Int.J.Pharm.194 (2000) 139-146) summarized the progress aspect the captopril sustained release in recent years, but the inorganic material brucite that seeps water with porous is that preparing carriers captopril slow releasing agent is not seen relevant report.
Summary of the invention:
The objective of the invention is: based on anion laminated material LDHs, captopril is the intercalation object, by the intercalation assembling hydrophilic captopril is assembled into the LDHs interlayer, prepares a kind of captopril slow release formulation Cpl-LDHs that can effectively control the rate of release of captopril and discharge the lasting period.
Captopril slow release formulation Cpl-LDHs of the present invention is a supramolecular structure, and its crystal structure is the crystal structure of houghite material, and its chemical formula is:
(M 2+) 1-x(M 3+) x(OH) 2(Cpl -) a1(Cpl 2-) a2(B n-)b·mH 2O
M wherein 2+Can be Zn 2+, Mg 2+, Ni 2+, Cu 2+, Fe 2+, Co 2+, Ca 2+, Mn 2+In any;
M 3+Can be Al 3+, Fe 3+, Cr 3+, V 3+, Co 3+, Ga 3+, Ti 3+In any;
Cpl -, Cpl 2-Represent interlayer monovalence, bivalence captopril anion respectively;
B N-For carrying capacity is the inorganic anion of n, B in the Cpl-LDHs chemical formula N-Can not exist or for CO 3 2-, NO 3 -, Cl -, Br -, I -, OH -, H 2PO 4 -Any, two kinds or three kinds;
0.1＜X＜0.8; A1, a2, b are respectively Cpl -, Cpl 2-, B N-Quantity, a1+2 * a2+n * b=X; M is a water of crystallization quantity, 0.01＜m＜4.
Captopril quality percentage composition is 20-50% in this slow releasing agent, and that preferable is 20-40%; The quality percentage composition of water is 5-20%, and that preferable is 5-15%; The slow release lasting period can reach 0.5h-12h, more excellent reached 0.5h-4h.
The present invention can realize Cpl-LDHs structure, composition, burst size and the control of release lasting period by adjusting the synthesis condition of Cpl-LDHs.
The concrete preparation process of captopril slow releasing agent of the present invention is as follows:
Step 1: solubility divalent metal salt and trivalent metal salt are pressed M 2+/ M 3+=1-9: 1 mol ratio is made into mixing salt solution A with the carbon dioxide removal deionized water, in addition NaOH and the former medicine of captopril is pressed 2-9: 1 mol ratio carbon dioxide removal deionized water proportionaling alkali-forming solution B;
M wherein 2+Can be Zn 2+, Mg 2+, Ni 2+, Cu 2+, Fe 2+, Co 2+, Ca 2+, Mn 2+In any; M 3+Can be Al 3+, Fe 3+, Cr 3+, V 3+, Co 3+, Ti 3+In any, M 2+/ M 3+More excellent mol ratio is 1.5-4: 1; Soluble M 2+, M 3+The anion of salt can be NO 3 -, Cl -, Br -, I -, OH -, H 2PO 4 -, CO 3 2-
Step 2: with the reaction vessel that solution B places band to stir, be under the 0.001-1ml/s condition mixing salt solution A slowly to be added in titration speed, to the pH of gained serosity be that 6-10 stops, changing in the crystallizing kettle;
Step 3: in crystallizing kettle, use N 2The protection, make serosity crystallization 12-50h under 25-70 ℃ of temperature, again through sucking filtration, be washed to neutrality, at 15-70 ℃ of dry 25-60h, obtain Cpl-LDHs.
Above-mentioned institute water is the carbon dioxide removal deionized water.
The Cpl-LDHs that obtains is carried out X-ray powder diffraction and IR characterize, the result shows Cpl between interposed layer, and has an effect by hydrogen bond and laminate, and this Cpl-LDHs has the crystal structure of hydrotalcite-like material.
Because Cpl-LDHs body layer board memory is in strong covalent bond effect, interlayer is a kind of weak interaction force, interlayer species (as phosphate radical anion) are had molecule distinguishability to its layer structure and its veneer structure is relatively stable, so this slow releasing agent is used under the phosphate radical anion effect of back in intestinal, the interlayer captopril can progressively be displaced, therefore, Cpl-LDHs can reach the purpose of sustained release.
Cpl-LDHs release test 1: get Cpl-LDHs 0.5g, be scattered in the phosphate buffer solution in the conical flask, then conical flask is put into the continuous oscillation of constant temperature water bath agitator, by the certain hour suspension that takes a morsel at interval, institute's suspension of getting is after centrifugalize, according to Chinese Pharmacopoeia, with the metric measurement concentration of captopril wherein, record the result and be plotted in Fig. 3, wherein a is the release profiles of embodiment 1, and b is the release profiles of embodiment 5.
Cpl-LDHs release test 2: get 2 parts of Cpl-LDHs and be scattered in two respectively and pH value solution is housed is respectively in 4.6,7.4 the conical flask, measuring it according to the method for release test 1 discharges the result and is plotted in Fig. 4 in two kinds of pH value buffer solution, find out that by Fig. 4 the slow release effect of Cpl-LDHs is influenced significantly by pH, and in different pH environment, all have certain capacity of slow release.
Material of main part LDH of the present invention has polytype, and for example: Zn, Al, Mg, Al or Zn, Fe are the Cpl-LDHs of laminate element, and different body layer plate elements has different Nutritions to human body.Therefore, can make Cpl-LDHs of the present invention be applied to different diseases by the kind that changes body layer sheetmetal element.
Advantage of the present invention is:
(1) prepares a kind of new supermolecular intercalation structure slow-release catopril, and had better slow release effect.Owing to medicament intercalated in hydrotalcite layers, suppressed the abnormal flavour of medicine itself effectively, more can not bring the abnormal flavour of polymer into, thereby have better mouthfeel.
(2) at first the supermolecular intercalation assemble method is used to prepare slow-release catopril.
(3) by adjusting the assembling condition of Cpl-LDHs, as changing M 2+/ M 3+Type and the pH value of mol ratio, building-up process, synthesis temperature, generated time etc., can realize Cpl-LDHs structure, composition, burst size and discharge the control of lasting period.
Description of drawings:
Fig. 1 is the X-ray powder diffraction figure of Cpl-LDHs under embodiment 1 assembling condition.
Fig. 2 is the IR spectrogram of Cpl-LDHs under embodiment 1 assembling condition.
Fig. 3 is that the Cpl-LDHs of embodiment 1, embodiment 5 preparations discharges the rate curve of captopril in phosphate radical buffer solution.
Fig. 4 is the rate diagram that Cpl-LDHs discharges captopril under embodiment 1 assembling condition in different pH buffer solution.
The specific embodiment:
Embodiment 1
1. with Zn (NO 3) 26H 2O (5.3545g) and Al (NO 3) 39H 2O (2.2508g) is made into the mixing salt solution A that the Zn/Al mol ratio equals 3 with 80ml water; In addition NaOH (2.5000g)/former medicine of captopril (3.9114g) is made into the mixed ammonium/alkali solutions B that mol ratio equals 3 with 120ml water;
2. at N 2Protection slowly splashes into mixing salt solution A among the mixed ammonium/alkali solutions B of vigorous stirring down, dropwises, and be 8.5 with the NaOH accent pH of 0.1M;
3. the gained serosity is in 25 ℃ of crystallization 48h, sucking filtration, washing, and room temperature vacuum drying 72h obtains captopril intercalation zinc-aluminium LDH.Institute's water is the carbon dioxide removal deionized water in the process.
The Cpl-LDHs that obtains is carried out X-ray powder diffraction characterize, the results are shown in Figure 1, this Cpl-LDHs has the crystal structure of hydrotalcite-like material as seen from Figure 1.
The Cpl-LDHs that obtains is carried out IR characterize, the results are shown in Figure 2, Cpl between interposed layer as seen from Figure 2, and have an effect by hydrogen bond and laminate.
Adopt TG/DTA, ICP and elemental analysis method that product is analyzed, characterized, determine its chemical formula/consist of: [Zn 0.687Al 0.313(OH) 2] (C 9H 14NO 3S -) 0.255(CO 3 2-) 0.0290.8H 2O, captopril content are 34.8%, and water content is 9.1%.
Embodiment 2
According to the building-up process of embodiment 1, step 2 changed into mixing salt solution A and mixed ammonium/alkali solutions B are added drop-wise in the deionized water simultaneously powerful the stirring, control pH is 9, and the gained serosity is in 25 ℃ of crystallization 48h, sucking filtration, washing, room temperature vacuum drying 72h obtains captopril intercalation zinc-aluminium LDH.Institute's water is the carbon dioxide removal deionized water in the process.
Adopt the method for embodiment 1 that product is analyzed, obtain its chemical formula/consist of: [Zn 0.732Al 0.268(OH) 2] (C 9H 14NO 3S -) 0.2680.9H 2O, captopril content are 33.2%, and water content is 9.3%.
Embodiment 3
With Zn (NO 3) 26H 2O (35.6815g), Al (NO 3) 39H 2O (22.6103g), NaNO 3(9.0712g) being made into the Zn/Al mol ratio with 160ml water is 3 mixing salt solution A, in addition with NaOH (12.0282g) with 100ml water proportionaling alkali-forming solution B, N 2Protection slowly splashes into aqueous slkali B among the mixing salt solution A down, and powerful the stirring is to stop to drip in 6.5 o'clock to pH.In 70 ℃ of crystallization 24h, sucking filtration, washing, 70 ℃ of dry 18h obtain zinc-aluminium nitrate anion brucite then with pulpous state liquid.
With former medicine of captopril (4.0000g) and prepared zinc-aluminium nitrate anion brucite (3.0000g) is 4 to be mixed in the 100ml water in molar ratio, NaOH accent pH with 0.1M is 6.5, the gained serosity is in 25 ℃ of crystallization 48h, sucking filtration, washing, room temperature vacuum drying 72h obtains captopril intercalation zinc-aluminium LDH.Institute's water is the carbon dioxide removal deionized water in the process.
Adopt the method for embodiment 1 that product is analyzed, obtain its chemical formula/consist of: Zn 0.6076Al 0.3924(OH) 2(C 9H 14NO 3S -) 0.2867(CO 3 2-) 0.0454(NO 3 -) 0.06030.9H 2O, captopril content are 36.7%, and water content is 9.6%.
Embodiment 4
With Mg (NO 3) 26H 2O (6.1536g) and Al (NO 3) 39H 2O (4.5016g) is made into the mixing salt solution A that the Mg/Al mol ratio equals 2 with 50ml water, in addition NaOH (3.1389g)/former medicine of captopril (5.2152g) is made into mixed ammonium/alkali solutions B, N with 150ml water 2Protection slowly splashes into mixing salt solution A among the alkali liquor B down, and powerful the stirring dropwises, and it is 10 that the NaOH of reuse 0.1M transfers pH.Serosity is in 25 ℃ of crystallization 48h, sucking filtration, washing, and room temperature vacuum drying 72h obtains captopril intercalation magnalium LDH.Institute's water is the carbon dioxide removal deionized water in the process.
Adopt the method for embodiment 1 that product is analyzed, obtain its chemical formula/consist of: Mg 0.6833Al 0.3167(OH) 2(C 9H 13NO 3S 2-) 0.1100(CO 3 2-) 0.04840.6H 2O, captopril content are 24.2%, and water content is 11.0%.
Embodiment 5
Press embodiment 1 building-up process, changing the Zn/Al mol ratio is 2, and all the other conditions get captopril intercalation zinc-aluminium LDH, its chemical formula/consist of: Zn with embodiment 1 0.6563Al 0.3454(OH) 2(C 9H 13NO 3S -) 0.2884(CO 3 2-) 0.0260.7H 2O, captopril content are 37.75%, and water content is 12.0%.
Embodiment 6
With Mg (NO 3) 26H 2O (6.1536g) and Fe (NO 3) 39H 2O (4.8480g) is made into the Mg/Fe mol ratio with 50ml water and equals 2 mixing salt solution A, in addition NaOH (6.2516g)/former medicine of captopril (5.2124g) is made into mixed ammonium/alkali solutions B, N with 150ml water 2Protection slowly splashes into mixing salt solution A among the aqueous slkali B down, and powerful the stirring dropwises, and is 10 with the NaOH accent pH of 0.1M.Serosity is in 25 ℃ of crystallization 48h, sucking filtration, washing, and room temperature vacuum drying 72h obtains captopril intercalation magnesium ferrum LDH.Institute's water is the carbon dioxide removal deionized water in the process.
Adopt the method for embodiment 1 that product is analyzed, record the chemical formula of this product/consist of: Mg 0.6748Fe 0.3252(OH) 2(C 9H 13NO 3S 2-) 0.16260.7H 2O, captopril content wherein is 30.2%, water content is 10.9%.

Claims (7)

1. supermolecular intercalation structure slow-release catopril, its chemical formula is:
(M 2+) 1-x(M 3+) x(OH) 2(Cpl -) a1(Cpl 2-) a2(B n-) b·mH 2O
M wherein 2+Be Zn 2+, Mg 2+, Ni 2+, Cu 2+, Fe 2+, Co 2+, Ca 2+, Mn 2+In any;
M 3+Be Al 3+, Fe 3+, Cr 3+, V 3+, Co 3+, Ga 3+, Ti 3+In any;
Cpl -, Cpl 2-Represent interlayer monovalence, bivalence captopril anion respectively;
B N-For carrying capacity is the inorganic anion of n, B N-Can not exist or for CO 3 2-, NO 3 -, Cl -, Br -, I -, OH -, H 2PO 4 -In any, two kinds or three kinds;
0.1＜X＜0.8；
A1, a2, b are respectively Cpl -, Cpl 2-, B N-Quantity, and a1+2 * a2+n * b=X;
M is a water of crystallization quantity, 0.01＜m＜4.
2. a supermolecular intercalation structure slow-release catopril as claimed in claim 1 is characterized in that M 2+Be Zn 2+, Mg 2+, Cu 2+, Fe 2+, Ca 2+, Mn 2+M 3+Be Al 3+, Co 3+, Fe 3+
3. a supermolecular intercalation structure slow-release catopril as claimed in claim 1 is characterized in that captopril quality percentage composition is 20-50% in this slow releasing agent, and the quality percentage composition of water is 5-20%; Its slow release lasting period reaches 0.5h-12h.
4. a supermolecular intercalation structure slow-release catopril as claimed in claim 1 is characterized in that captopril quality percentage composition is 20-40% in this slow releasing agent, and the water quality percentage composition is 5-15%; Its slow release lasting period reaches 0.5h-4h.
5. a supermolecular intercalation structure slow-release catopril as claimed in claim 1 is characterized in that its crystal structure is the crystal structure of houghite material, is supermolecular intercalation structure.
6. the preparation method of a supermolecular intercalation structure slow-release catopril as claimed in claim 1, concrete preparation process is as follows:
Step 1: solubility divalent metal salt and trivalent metal salt are pressed M 2+/ M 3+The mol ratio of=1-9 is made into mixing salt solution A with the carbon dioxide removal deionized water, in addition NaOH and the former medicine of captopril is pressed 2-9: 1 mol ratio carbon dioxide removal deionized water proportionaling alkali-forming solution B;
M wherein 2+Be Zn 2+, Mg 2+, Ni 2+, Cu 2+, Fe 2+, Co 2+, Ca 2+, Mn 2+In any, M 3+Be Al 3+, Fe 3+, Cr 3+, V 3+, Co 3+, Ti 3+In any, the anion of solubility divalent metal salt, trivalent metal salt is NO 3 -, Cl -, Br -, I -, OH -, H 2PO 4 -Or CO 3 2-
Step 2: with the reaction vessel that solution B places band to stir, be under the 0.001-1ml/s condition mixing salt solution A slowly to be added in drop rate, to the pH of gained serosity be that 6-10 stops, changing in the crystallizing kettle;
Step 3: in crystallizing kettle, use N 2The protection, make serosity crystallization 12-50h under 25-70 ℃ of temperature, again through sucking filtration, be washed to neutrality, at 15-70 ℃ of dry 25-60h, obtain the supermolecular intercalation structure slow-release catopril.
7. the preparation method of a supermolecular intercalation structure slow-release catopril as claimed in claim 6: it is characterized in that M in the step 1 2+/ M 3+Mol ratio is 1.5-4: 1.
CNB2004100003078A 2004-01-07 2004-01-07 Supermolecular intercalation-structure slow-release captopril and its preparing method Expired - Fee Related CN1272002C (en)

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PCT/CN2004/001117 WO2005067975A1 (en) 2004-01-07 2004-09-28 Title: a sustained release captopril formulation having a supermolecular intercalation structure and the preparation process thereof

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CN1288078A (en) * 1999-09-14 2001-03-21 北京化工大学 Method for synthesis of well-dispersed and super fine anion laminated material

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1970084B (en) * 2006-12-04 2010-08-25 山东大学 Hydrotalcite-like vesicle compounds and method for preparing same

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