CN100496613C - Magnetic target slow-release catopril and its preparing method - Google Patents

Magnetic target slow-release catopril and its preparing method Download PDF

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CN100496613C
CN100496613C CNB2004100908179A CN200410090817A CN100496613C CN 100496613 C CN100496613 C CN 100496613C CN B2004100908179 A CNB2004100908179 A CN B2004100908179A CN 200410090817 A CN200410090817 A CN 200410090817A CN 100496613 C CN100496613 C CN 100496613C
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cpl
captopril
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slow
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CN1775209A (en
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段雪
张慧
孙辉
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Beijing University of Chemical Technology
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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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5094—Microcapsules containing magnetic carrier material, e.g. ferrite for drug targeting
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/401—Proline; Derivatives thereof, e.g. captopril
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

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Abstract

The present invention relates to a magnetic target slowly-released captopril and its preparation method. Said invention uses spinel type ferrite and tri-iron tetroxide as magnetic material seed, uses anionic lamellar material LDHs as main body and uses captopril as intercalation guest, and utilizes self-assembling method to implement structure design of Cpl-LDHs/MP. Said magnetic captopril slow-release agent is shell-kernel structure, namely, the exterior of magnetic nano granule is covered with lamellar material Cpl-LDHs, specific saturated magnetization is 1.0-6.0 emu/g, its granular grain distribution is 20-200 nm, its captopril content in said slow-release preparation is 10-50%, and its slowly-released effective time can be up to 0.4h-13h.

Description

A kind of magnetic target slow-release catopril and preparation method thereof
Technical field:
The present invention relates to a kind of magnetic target slow-release catopril and preparation method thereof.
Background technology:
In the process of clinical treating disease, often need to improve the targeting of medicine, in the hope of strengthening the curative effect of medicine to greatest extent, it is minimum that the untoward reaction of medicine is reduced to, so targeting drug delivery system (targeteddrug delivery system) has become the important content of modern medicinal agents.The target administration system refers to that medicine combines with carrier or the suppressed by vector parcel can directly be positioned the target area with medicine, or medicine is assembled in the target area after the administration, makes the target area drug level be higher than the drug delivery system of normal structure.Target administration can reduce dosage, improves curative effect of medication, reduces the toxic and side effects of medicine, strengthens the specificity of medicine to target tissue.The common type of target administration has: 1. passive targeted preparation, as liposome, nanocapsule etc.; 2. active target preparation.As the prodrug targeting preparation, contain the pharmaceutical carrier of monoclonal antibody; 3. physical chemistry targeting preparation.Targeting preparation, thromboembolism targeting preparation, heat sensitive target preparation as magnetic preparation, pH sensitivity.In various targeting preparations, the magnetic microsphere preparation belong to the 4th generation targeting drug delivery system.The characteristics of this dosage form are that medicine and suitable magnetic components (as Fe3O4) are formulated in the medicine stabilisation systems, under enough strong external magnetic field effect, gradually carrier is oriented to target position, makes its contained drug be located release, play a role and reach new formulation efficient, quick-acting, low toxicity thereby concentrate on diseased region.Because the nano-magnetic powder that it wrapped up has superparamagnetism, it can carry out fast enriching by the effect of external magnetic field, and after external magnetic field is cancelled, can finish demagnetization again, again disperseed, blocked the serious consequence that blood capillary causes thereby avoided assembling the back because of rigid microspheres.
Captopril (Cpl) is first generation Angiotensin-Converting (ACE) inhibitor, it acts on renin-angiotensin system, thereby the balance of blood pressure regulation, electrolyte and body fluid, in recent years treatment hypertension, improve aspect cardiac function and the renal function effect day by day and certainly by clinical understanding, become a line medicine of treatment hypertension and heart failure.The clinical manifestation of this medicine is that the 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 captopril target slow-release dosage form is one of focus always, yet still belongs to blank about the research of magnetic targeting captopril slow releasing agent.
Document (Yoichi Ikeda, Kenya Kimura, Fumitoshi Hirayama, Hidetoshi Arima, Kaneto Uekama, Journal of Controlled Release 66 (2000) 271-280) with 2-hyroxypropyl-β-cyclodextrin (β-CyD) and hydrophobic perbutanoyl-β-cyclodextrin (TB-β-CyD) prepare 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) has carried out comprehensive argumentation to the progress of captopril sustained release, in the literary composition and not mentionedly improve medication effect by adding magnetisable material; Be that preparing carriers captopril slow releasing agent is not seen explanation yet with acid soluble inorganic material brucite simultaneously.
Summary of the invention:
The present invention seeks to prepare a kind of slow-release catopril with magnetic target effect.Another purpose provides a kind of preparation method of magnetic target slow-release catopril.
Magnetic captopril slow release formulation Cpl-LDHs/MP of the present invention (wherein MP is a magnetic-particle), its chemical formula is:
(M 2+) 1-x(M 3+) x(OH) 2(Cpl -) a(Cpl 2-) b(B n-) c·mH 2O/(MP) y
M wherein 2+Be Zn 2+, Mg 2+, Ni 2+, Cu 2+, Fe 2+, Co 2+, Ca 2+, Mn 2+In any, that more excellent is Zn 2+Or Mg 2+M 3+Be Al 3+, Fe 3+, Cr 3+, V 3+, Co 3+, Ga 3+, Ti 3+In any, that more excellent is Al 3+
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;
0.1＜X＜0.8; A, b, c are respectively Cpl -, Cpl 2-, B N-Quantity, and a+2 * b+n * c=X; M is a water of crystallization quantity, 0.01＜m＜4; Y is the quantity of MP, 0.001＜y＜1;
MP is magnetisable material MgFe 2O 4, NiFe 2O 4, CoFe 2O 4, ZnFe 2O 4, MnFe 2O 4And Fe 3O 4In any, preferred MgFe 2O 4, NiFe 2O 4And Fe 3O 4
The chemical constitution of this magnetic slow releasing agent is a core-shell type, and promptly at magnetic nanoparticle external coating shape material C pl-LDHs, its specific saturation magnetization is 1.0-6.0emu/g, and particle size distribution is at 20-200nm.
Captopril quality percentage composition is 10-50% in this magnetic slow releasing agent, and that preferable is 20-40%; The slow release lasting period can reach 0.4h-13h, more excellent reached 0.5h-4h.
The concrete preparation process of magnetic captopril slow releasing agent of the present invention is as follows:
Step 1: with solubility divalent metal salt M 2+Y 1With solubility trivalent metal salt M 3+Y 2Press M 2+/ M 3+The mol ratio of=1-8:1 is made into mixing salt solution A, wherein [M with the carbon dioxide removal deionized water 2+] be 0.01～1mol/l; The mol ratio carbon dioxide removal deionized water proportionaling alkali-forming solution B that other presses 2-9:1 with NaOH and the former medicine of captopril, wherein [captopril]/[M 2+]=1-4/1; Again magnetisable material MP is pressed M 2+The mass ratio of/MP=1-10:1 is put in the solution B, and vigorous stirring makes its homodisperse;
M wherein 2+Be Zn 2+, Mg 2+, Ni 2+, Cu 2+, Fe 2+, Co 2+, Ca 2+, Mn 2+In any,
That more excellent is Zn 2+Or Mg 2+M 3+Be Al 3+, Fe 3+, Cr 3+, V 3+, Co 3+, Ga 3+, Ti 3+In any, that more excellent is Al 3+[M 2+]/[M 3+] more excellent mol ratio is 1-4:1; Y 1, Y 2Represent soluble M 2+, M 3+The anion N O of salt 3 -, Cl -, Br -, I -, H 2PO 4 -, CO 3 2-In any one, Y 1, Y 2Can be the same or different, that preferable is NO 3 -, Cl -, CO 3 2-MP is MgFe 2O 4, NiFe 2O 4, CoFe 2O 4, ZnFe 2O 4, MnFe 2O 4And Fe 3O 4In any, preferred MgFe 2O 4, NiFe 2O 4And Fe 3O 4
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 reaction system be that 6-10 stops, changing in the crystallizing kettle;
Step 3: at N 2Under the protection, make crystallizing kettle internal reaction serosity crystallization 12-64h under 25-70 ℃ of temperature, again through sucking filtration, be washed till neutrality,, obtain Cpl-LDHs/MP at 15-70 ℃ of dry 25-60h with the carbon dioxide removal deionized water.
The Cpl-LDHs/MP that obtains is carried out X-ray powder diffraction and IR characterize, the result shows Cpl between interposed layer, and has an effect and have the crystal structure of hydrotalcite-like material by hydrogen bond and laminate; Characterize to confirm that by XPS Cpl-LDHs connects with the Lattice Oxygen form between biphase with MP; Vibrating specimen magnetometer demonstrates Cpl-LDHs/MP and has tangible magnetic.
Targeting Performance characterizes: product C pl-LDHs/MP is evenly spread in the alcoholic solution, getting a suspension places on the sheet glass, be sidelong at one of drop and put Magnet, can examine under a microscope the solid insoluble particles immediately and promptly move, and assemble in a side near Magnet to the Magnet direction.After a few minutes, almost total solids all accumulates in a side of Magnet, illustrates that solid particle has good magnetic.Strengthen if will contain the drop of solid particle and the distance of Magnet, because the suffered magnetic force of solid particle reduces, movement velocity obviously slows down, and arranges but still visible solid particle is beading along magnetic line of force direction.This is because under the effect in magnetic field, solid particle self is magnetized and becomes small magnet, forms the beading gathering because of connecting before and after attracting each other.
Cpl-LDHs release experiment: the Cpl-LDHs/MP that gets two parts of 0.5g, place two conical flasks that fill pH buffer solution (4.6 and 7.4) respectively, 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.Find out that by Fig. 3 the slow release effect of Cpl-LDHs/MP is influenced significantly by pH, and in different pH value environment, all have certain capacity of slow release.
Advantage of the present invention is: make medicine carrying magnetic, but targeted drug is to lesions position down in the guiding of magnetic outside, the minimizing dosage improves curative effect of medication, reduces the toxic and side effects of medicine, strengthens the specificity of medicine to target tissue.Because the hydrotalcite stratified material can be with phosphate radical anion generation ion exchange in the intestinal, and then discharges the effect that interlayer Cpl reaches sustained release, therefore can be used as the sustained-release matrix material.
Description of drawings:
Fig. 1 is the X-ray powder diffraction figure of Cpl-LDHs/MP under embodiment 1 condition.
Fig. 2 is the IR spectrogram of Cpl-LDHs/MP under embodiment 1 condition.
Fig. 3 is the release profiles of Cpl-LDHs/MP captopril in phosphate radical buffer solution (pH4.6 and pH7.4) under embodiment 1 condition.
Fig. 4 is the electromicroscopic photograph of Cpl-LDHs/MP under embodiment 1 condition.
The specific embodiment:
Embodiment 1
1. with the Mg (NO of 3.0795g 3) 26H 2Al (the NO of O and 2.2507g 3) 39H 2O is made into the mixing salt solution A that the Mg/Al mol ratio equals 2 with 50ml water; In addition the NaOH of 1.5g and the former medicinal 150ml water of captopril of 2.6097g are made into mixed ammonium/alkali solutions B, again with the MgFe of 0.0576g 2O 4Put into wherein;
2. at N 2Protection slowly splashes into mixing salt solution A among the mixed ammonium/alkali solutions B of vigorous stirring down, stops to add when pH value is 10 left and right sides;
3. the gained serosity is in 25 ℃ of crystallization 48h, sucking filtration, washing, and room temperature vacuum drying 72h obtains magnetic captopril slow releasing agent.Institute's water is the carbon dioxide removal deionized water in the process.
Fig. 1 is Cpl-LDHs/MgFe 2O 4The X-ray powder diffraction characterization result, have the crystal structure of hydrotalcite-like material.
Fig. 2 is Cpl-LDHs/MgFe 2O 4The IR characterization result, confirm Cpl between interposed layer, and have an effect, and can observe MgFe by hydrogen bond and laminate 2O 4Characteristic absorption peak.
Fig. 3 is Cpl-LDHs/MgFe 2O 4The release profiles of captopril in phosphate radical buffer solution (pH4.6 and pH7.4).
Adopt TG/DTA, ICP and elemental analysis method that product is analyzed, characterized, determine that its empirical formula is: [Mg 0.636Al 0.364(OH) 2] (C 9H 14NO 3S 2-) 0.0618(CO 3 2-) 0.12020.7H 2O/ (MgFe 2O 4) 0.0186, captopril content is 19.65%, specific saturation magnetization is 1.04emu/g.
Embodiment 2
With MgFe in embodiment 1 step 1 2O 4Use NiFe 2O 4Substitute, other parts are with embodiment 1.
Adopt the method identical with embodiment 1 to analyze in the sample that obtains, its empirical formula is: [Mg 0.632Al 0.368(OH) 2] (C 9H 14NO 3S 2-) 0.0736(CO 3 2-) 0.11040.6H 2O/ (NiFe 2O 4) 0.0152, captopril content is 20.40%, specific saturation magnetization is 1.30emu/g.
Embodiment 3
With MgFe in embodiment 1 step 1 2O 4Use Fe 3O 4Substitute, other parts are with embodiment 1.
Adopt the method identical with embodiment 1 to analyze in the sample that obtains, its empirical formula is: [Mg 0.642Al 0.358(OH) 2] (C 9H 14NO 3S 2-) 0.0667(CO 3 2-) 0.11230.8H 2O/ (Fe 3O 4) 0.0194, captopril content is 21.72%, specific saturation magnetization is 3.64emu/g.
Embodiment 4
1. with the Zn (NO of 4.2241g 3) 26H 2Al (the NO of O and 1.3317g 3) 39H 2O is made into the mixing salt solution A that the Zn/Al mol ratio equals 4 with 30ml water, in addition the NaOH of 1.988g and the former medicinal 30ml water of captopril of 3.0854g is made into mixed ammonium/alkali solutions B;
2. at N 2Protection is added drop-wise to the MgFe that contains 100ml deionized water and 0.073g simultaneously with mixing salt solution A and mixed ammonium/alkali solutions B down 2O 4In, the powerful stirring maintains about 9 the pH value of reaction system.
3. serosity is in 25 ℃ of crystallization 48h, sucking filtration, washing, and room temperature vacuum drying 72h obtains magnetic captopril slow releasing agent.
Institute's water is the carbon dioxide removal deionized water in the process.
Adopt the method identical to analyze in the sample that obtains, obtain its empirical formula and be: [Zn with embodiment 1 0.608Al 0.392(OH) 2] (C 9H 13NO 3S 2-) 0.1960.9H 2O/ (MgFe 2O 4) 0.0165, captopril content is 28.61%, specific saturation magnetization is 1.23emu/g.
Embodiment 5
With MgFe in embodiment 4 steps 1 2O 4Use NiFe 2O 4Substitute, other parts are with embodiment 4.
Adopt the method identical with embodiment 1 to analyze in the sample that obtains, its empirical formula is: [Zn 0.606Al 0.394(OH) 2] (C 9H 13NO 3S 2-) 0.3030.7H 2O/ (NiFe 2O 4) 0.0174, captopril content is 28.60%, specific saturation magnetization is 1.42emu/g.
Embodiment 6
With MgFe in embodiment 4 steps 1 2O 4Use Fe 3O 4Substitute, other parts are with embodiment 4.Adopt the method identical with embodiment 1 to analyze in the sample that obtains, its empirical formula is: [Zn 0.618Al 0.382(OH) 2] (C 9H 13NO 3S 2-) 0.1960.9H 2O/ (Fe 3O 4) 0.0194, captopril content wherein is 30.23%, specific saturation magnetization is 4.68emu/g.

Claims (4)

1. magnetic target slow-release catopril, its chemical formula is:
(M 2+) 1-x(M 3+) x(OH) 2(Cpl -) a(Cpl 2-) b(B n-) c·mH 2O/(MP) y
M wherein 2+Be bivalent metal ion Zn 2+, Mg 2+, Ni 2+, Cu 2+, Fe 2+, Co 2+, Ca 2+, Mn 2+In any; M 3+Be trivalent metal ion 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;
0.1＜X＜0.8; A, b, c are respectively Cpl -, Cpl 2-, B N-Quantity, and a+2 * b+n * c=X; M is a water of crystallization quantity, 0.01＜m＜4;
MP represents magnetisable material MgFe 2O 4, NiFe 2O 4, CoFe 2O 4, ZnFe 2O 4, MnFe 2O 4Or Fe 3O 4In any; Y is the quantity of MP, 0.001＜y＜1;
The specific saturation magnetization of this magnetic slow releasing agent is 1.0-6.0emu/g, and particle size distribution is at 20-200nm, and captopril quality percentage composition is 10-50% in the magnetic slow releasing agent; The slow release lasting period is 0.4-13h.
2. magnetic target slow-release catopril according to claim 1 is characterized in that M 2+Be Zn 2+Or Mg 2+, M 3+Be Al 3+MP is MgFe 2O 4, NiFe 2O 4Or Fe 3O 4
Captopril quality percentage composition is 20-40% in the magnetic slow releasing agent, and the slow release lasting period is 0.5h-4h.
3. the preparation method of a magnetic target slow-release catopril, preparation process is as follows:
Step 1: with solubility divalent metal salt M 2+Y 1With solubility trivalent metal salt M 3+Y 2Press M 2+/ M 3+The mol ratio of=1-8:1 is made into mixing salt solution A, wherein [M with the carbon dioxide removal deionized water 2+] be 0.01～1mol/l; The mol ratio carbon dioxide removal deionized water proportionaling alkali-forming solution B that other presses 2-9:1 with NaOH and the former medicine of captopril, wherein [captopril]/[M 2+]=1-4/1; Again magnetisable material MP is pressed M 2+The mass ratio of/MP=1-10:1 is put in the solution B, and vigorous stirring makes its homodisperse;
Step 2: with the reaction vessel that above-mentioned aqueous slkali B places band to stir, be under the 0.001-1ml/s condition mixing salt solution A slowly to be added, stop during for 6-10 to the pH of reaction system, change in the crystallizing kettle in titration speed;
Step 3: at N 2Under the protection, make crystallizing kettle internal reaction serosity crystallization 12-64h under 25-70 ℃ of temperature, again through sucking filtration, be washed till neutrality,, obtain Cpl-LDHs/MP at 15-70 ℃ of dry 25-60h with the carbon dioxide removal deionized water;
M in the step 1 2+Represent bivalent metal ion Zn 2+, Mg 2+, Ni 2+, Cu 2+, Fe 2+, Co 2+, Ca 2+, Mn 2+In any; M 3+Represent trivalent metal ion Al 3+, Fe 3+, Cr 3+, V 3+, Co 3+, Ga 3+, Ti 3+In any; Y 1, Y 2Represent soluble M 2+, M 3+The anion N O of salt 3 -, Cl -, Br -, I -, H 2PO 4 -, CO 3 2-In any one, Y 1, Y 2Can be the same or different; MP represents magnetisable material MgFe 2O 4, NiFe 2O 4, CoFe 2O 4, ZnFe 2O 4, MnFe 2O 4Or Fe 3O 4In any.
4. the preparation method of magnetic target slow-release catopril according to claim 3 is characterized in that M in the step 1 2+Be Zn 2+Or Mg 2+, M 3+Be Al 3+, Y 1, Y 2Be NO 3 -, Cl -Or CO 3 2-MP is MgFe 2O 4, NiFe 2O 4Or Fe 3O 4[M 2+]/[M 3+] mol ratio is 1-4:1;
In the step 2 when the pH of reaction system is 8-10 stopped reaction.
CNB2004100908179A 2004-11-15 2004-11-15 Magnetic target slow-release catopril and its preparing method Expired - Fee Related CN100496613C (en)

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Cited By (1)

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CN106552269A (en) * 2015-09-23 2017-04-05 南京理工大学 A kind of pH responsive types Fe3O4The Nano medication particle of@LDH load methotrexate (MTX)s, preparation method and applications

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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

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Intercalation and controlled release of pharmaceuticallyactivecompounds from a layered double hydroxide. Aamir I.Khan et al.CHEM. COMM.. 2001
Intercalation and controlled release of pharmaceuticallyactivecompounds from a layered double hydroxide. Aamir I.Khan et al.CHEM. COMM.. 2001 *
磁性纳米固体碱催化剂MgAl-OH-LDHs/NiFe2O4的合成、表征与性能研究. 张慧等.化学学报，第62卷第8期. 2004
磁性纳米固体碱催化剂MgAl-OH-LDHs/NiFe2O4的合成、表征与性能研究. 张慧等.化学学报，第62卷第8期. 2004 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106552269A (en) * 2015-09-23 2017-04-05 南京理工大学 A kind of pH responsive types Fe3O4The Nano medication particle of@LDH load methotrexate (MTX)s, preparation method and applications
CN106552269B (en) * 2015-09-23 2019-04-16 南京理工大学 A kind of pH responsive type Fe3O4@LDH loads the Nano medication particle of methotrexate (MTX), preparation method and applications

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