CN102921017A - Nano hybrid of cytarabine/layered double-metal hydroxides and preparation process of nano hybrid - Google Patents
Nano hybrid of cytarabine/layered double-metal hydroxides and preparation process of nano hybrid Download PDFInfo
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- CN102921017A CN102921017A CN2012104439979A CN201210443997A CN102921017A CN 102921017 A CN102921017 A CN 102921017A CN 2012104439979 A CN2012104439979 A CN 2012104439979A CN 201210443997 A CN201210443997 A CN 201210443997A CN 102921017 A CN102921017 A CN 102921017A
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- ldhs
- cytosine arabinoside
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- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 title claims abstract description 102
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- 229910000000 metal hydroxide Inorganic materials 0.000 title abstract description 6
- 229960000684 cytarabine Drugs 0.000 title abstract 8
- 239000000203 mixture Substances 0.000 claims abstract description 11
- 239000000243 solution Substances 0.000 claims description 42
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 34
- 239000008367 deionised water Substances 0.000 claims description 27
- 229910021641 deionized water Inorganic materials 0.000 claims description 27
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- 238000006243 chemical reaction Methods 0.000 claims description 20
- 239000011229 interlayer Substances 0.000 claims description 18
- 238000003756 stirring Methods 0.000 claims description 18
- 150000001450 anions Chemical class 0.000 claims description 17
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 16
- 229910021645 metal ion Inorganic materials 0.000 claims description 14
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 14
- 239000012265 solid product Substances 0.000 claims description 12
- 239000000047 product Substances 0.000 claims description 10
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 238000001354 calcination Methods 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 6
- 239000012065 filter cake Substances 0.000 claims description 6
- 230000007935 neutral effect Effects 0.000 claims description 6
- 238000001935 peptisation Methods 0.000 claims description 6
- 239000007787 solid Substances 0.000 claims description 6
- 239000004094 surface-active agent Substances 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 5
- 230000004044 response Effects 0.000 claims description 4
- 239000004141 Sodium laurylsulphate Substances 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 150000007942 carboxylates Chemical class 0.000 claims description 2
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- JHJUUEHSAZXEEO-UHFFFAOYSA-M sodium;4-dodecylbenzenesulfonate Chemical compound [Na+].CCCCCCCCCCCCC1=CC=C(S([O-])(=O)=O)C=C1 JHJUUEHSAZXEEO-UHFFFAOYSA-M 0.000 claims description 2
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 18
- 238000000034 method Methods 0.000 abstract description 16
- 229940079593 drug Drugs 0.000 abstract description 8
- 230000000694 effects Effects 0.000 abstract description 7
- 230000008569 process Effects 0.000 abstract description 5
- 230000003578 releasing effect Effects 0.000 abstract description 4
- 231100000331 toxic Toxicity 0.000 abstract description 4
- 230000002588 toxic effect Effects 0.000 abstract description 4
- 238000010189 synthetic method Methods 0.000 abstract description 3
- 230000032683 aging Effects 0.000 abstract description 2
- 230000000857 drug effect Effects 0.000 abstract description 2
- 238000011068 loading method Methods 0.000 abstract description 2
- 239000002246 antineoplastic agent Substances 0.000 abstract 1
- 229940041181 antineoplastic drug Drugs 0.000 abstract 1
- 239000000969 carrier Substances 0.000 abstract 1
- 230000004048 modification Effects 0.000 description 8
- 238000012986 modification Methods 0.000 description 8
- 238000002798 spectrophotometry method Methods 0.000 description 8
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 6
- 238000010276 construction Methods 0.000 description 5
- 238000002441 X-ray diffraction Methods 0.000 description 4
- 150000004692 metal hydroxides Chemical class 0.000 description 4
- 238000000634 powder X-ray diffraction Methods 0.000 description 4
- 238000007634 remodeling Methods 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- 229940104302 cytosine Drugs 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 238000000643 oven drying Methods 0.000 description 3
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 2
- 239000006069 physical mixture Substances 0.000 description 2
- 230000006820 DNA synthesis Effects 0.000 description 1
- 102000016928 DNA-directed DNA polymerase Human genes 0.000 description 1
- 108010014303 DNA-directed DNA polymerase Proteins 0.000 description 1
- 206010013786 Dry skin Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 125000000089 arabinosyl group Chemical group C1([C@@H](O)[C@H](O)[C@H](O)CO1)* 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000009615 deamination Effects 0.000 description 1
- 238000006481 deamination reaction Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- GDVKFRBCXAPAQJ-UHFFFAOYSA-A dialuminum;hexamagnesium;carbonate;hexadecahydroxide Chemical compound [OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Al+3].[Al+3].[O-]C([O-])=O GDVKFRBCXAPAQJ-UHFFFAOYSA-A 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- -1 glycoside compounds Chemical class 0.000 description 1
- 229960001545 hydrotalcite Drugs 0.000 description 1
- 229910001701 hydrotalcite Inorganic materials 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000009830 intercalation Methods 0.000 description 1
- 230000002687 intercalation Effects 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000012982 microporous membrane Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
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- 239000000843 powder Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 125000000548 ribosyl group Chemical class C1([C@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
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- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 229940035893 uracil Drugs 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a nano hybrid of an anti-cancer drug of cytarabine/layered double-metal hydroxides (LDHs) and a preparation process of the nano hybrid. The process comprises the steps of preparing the nano hybrid of the cytarabine/LDHs for slow releasing of the cytarabine with LDHs serving as carriers, so that the drug effect is improved, and the toxic side effect of the drug is reduced. The process comprises that LDHs serve as main bodies, the cytarabine serves as an intercalated object, and the cytarabine is assembled between layers of LDHs through a secondary assembling method or a structure reconstruction method to prepare the nano hybrid of the cytarabine/LDHs. The process has the advantages that the drug loading capacity of nano hybrids obtained through two methods is large, and the good slow releasing effect can be achieved; the adopted preparation process is simple and conditions are mild; and the structure, the composition and the releasing speed of the nano hybrid of the cytarabine/LDHs can be controlled by adjustment of the synthetic method or synthetic conditions or by changing of the concentration of the drug and factors such as the pH, the temperature and the ageing time of the synthetic process.
Description
Technical field
The invention belongs to new material and pharmaceutical preparations technology field, relate to a kind of cytosine arabinoside/layered double hydroxide (LDHs) nano hybrid and preparation method thereof.
Background technology
Along with the progress of the reach of science and science and technology, people improve day by day to the therapeutic effect of disease and the requirement for the treatment of means.The toxic and side effects that how to improve curative effect, simplification application method, reduction medicine is scientific worker's research emphasis.Especially the very large medicine of toxicity is taken in order to make things convenient for the patient, when guaranteeing effectively to treat concentration, reduces the toxic and side effects of medicine, avoids chemical sproof generation, adopts effective conveying and the slow release of medicine to be undoubtedly a kind of effective approach.In this effective way, the development of pharmaceutical carrier is one of its key issue.
The hydroxide with hydrotalcite layered structure that layered double hydroxide (Layered double hydroxide, LDHs) is comprised of bivalent metal ion and trivalent metal ion.LDHs has unique construction features: one has layered crystal structure, synusia band structure positive charge; It two is that interlayer exists tradable anion.Special structure is given its special performance, studies have shown that the interlayer of LDHs can be used as miniature reservoir, drug molecule is inserted form nano hybrid therebetween, because of the interaction between drug molecule and laminate and space steric effect, can realize effective slow release of medicine.
Cytosine arabinoside (be amino-2 (the 1H)-pyrimidones of 1-beta-D-arabinofuranosyl base-4-, molecular formula: C
9H
13N
3O
5, molecular weight: 243.22), claim again cytosine (ribose) nucleotide, the glycoside compounds that cytosine and arabinose form is the competitive inhibitor of archaeal dna polymerase, suppresses DNA biosynthesis in the body, be used as antitumor, especially treat leukemic medicine.But the deoxidation cytosine enzyme in the normal structure can make its rapid deamination become the uracil cytosine arabinoside and lose the antineoplastic activity, must be repeatedly and continuous use in order to keep its effective blood concentration.
Summary of the invention
The present invention is directed to the deficiencies in the prior art, take LDHs as carrier, prepare cytosine arabinoside/LDHs nano hybrid, can be used for the slow release of cytosine arabinoside, to improve drug effect, reduce poisonous side effect of medicine etc.
Content of the present invention is: take LDHs as main body, take cytosine arabinoside as the intercalation object, by secondary construction from part or structural remodeling method cytosine arabinoside is assembled into the LDHs interlayer, prepare a kind of cytosine arabinoside/LDHs nano hybrid, the slow release that can be used for cytosine arabinoside effectively reduces its toxic and side effects.The present invention can by adjusting synthetic method or the condition of cytosine arabinoside/LDHs nano hybrid, realize the control to cytosine arabinoside/LDHs nano hybrid structure, composition and rate of release.
Concrete technical scheme of the present invention is: a kind of cytosine arabinoside/layered duplex metal hydroxide nanometer hybrid, the hybrid synusia contains bivalent metal ion (M
II) and trivalent metal ion (M
III), interlayer contains anion, wherein M
IIBe Mg
2+, Mn
2+, Fe
2+, Co
2+, Ni
2+, Cu
2+, Zn
2+In a kind of; M
IIIBe Al
3+, Cr
3+, Mn
3+, Fe
3+, Co
3+, Ni
3+In a kind of; Interlayer anion is OH
-, CO
3 2-, SO
4 2-, Cl
-, NO
3 -In one or both.
Cytosine arabinoside quality percentage composition is 1%～50% in the described hybrid.
The secondary construction from part is adopted in the preparation of cytosine arabinoside/layered duplex metal hydroxide nanometer hybrid, comprises the following steps:
A. compound concentration is the solubility bivalent metal ion (M of 0.2～1.0mol/L
II) and trivalent metal ion (M
III) mixed-salt aqueous solution, both mol ratio M
II/ M
III=1～3: 1;
M wherein
IIBe Mg
2+, Mn
2+, Fe
2+, Co
2+, Ni
2+, Cu
2+, Zn
2+In one or both; M
IIIBe Al
3+, Cr
3+, Fe
3+In one or both; The anion of soluble-salt is SO
4 2-, Cl
-, NO
3 -In one or both;
B. compound concentration is the aqueous surfactant solution of 0.01～0.5mol/L; Described surfactant is any in sodium lauryl sulphate, dodecyl sodium sulfate, dodecylbenzene sodium sulfonate, the carboxylate;
C. compound concentration is the aqueous slkali of 0.3～3mol/L; Described aqueous slkali is NH
4OH, NaOH and Na
2CO
3In one or both;
D, preparation cytosine arabinoside aqueous solution
E. step a solution and step c solution are joined in the step b solution simultaneously, stirring and controlling pH is 9～12, and reaction temperature is 20～80 ℃, and the response time is 20～48 hours; Filter, water washing is to neutral, and 80 ℃ of lower peptizations of filter cake 24 hours obtain surfactant-modified LDHs;
F, get the surfactant-modified LDHs solid that step e obtains and be distributed in the steps d solution, fully mix, 20～80 ℃ of lower reactions 1～4 day obtain cytosine arabinoside/LDHs nano hybrid.
The described mixed-salt aqueous solution concentration of above-mentioned steps a is preferably 0.5mol/L, wherein M
II/ M
IIIMol ratio be
2: 1; The anion of soluble-salt is preferably Cl
-And NO
3 -
The preferred lauryl sulphate acid of the described surfactant of above-mentioned steps b, the concentration of solution is 0.2mol/L.
The preferred NaOH solution of the described aqueous slkali of above-mentioned steps c, concentration is 0.5mol/L.
The described pH value of above-mentioned steps e is 11; Reaction temperature is 45 ℃; The stirring reaction time is 24 hours.
The described reaction temperature of above-mentioned steps f is 45 ℃; Response time is 3 days.
The structural remodeling method is adopted in the preparation of cytosine arabinoside/layered duplex metal hydroxide nanometer hybrid, comprises the following steps:
A. cytosine arabinoside is dissolved in the deionized water that to form concentration be the cytosine arabinoside solution of 100～10000mg/L;
B. LDHs was calcined 2～8 hours under 400～600 ℃; Among the described LDHs, bivalent metal ion (M
II) be Mg
2+, Mn
2+, Fe
2+, Co
2+, Ni
2+, Cu
2+, Zn
2+In one or both; Trivalent metal ion (M
III) be Al
3+, Cr
3+, Mn
3+, Fe
3+, Co
3+, Ni
3+In one or both; Both mol ratio M
II/ M
III=1～3: 1; Interlayer anion is OH
-, CO
3 2-, SO
4 2-, Cl
-, NO
3 -In any or two kinds;
C. under 20～80 ℃, the LDHs calcined product is scattered in the cytosine arabinoside solution; The mass ratio of cytosine arabinoside is 1～10: 1 in the calcined product of LDHs and the solution;
D. 20～80 ℃ of lower stirrings 12～72 hours, then that serosity is centrifugal, with deionized water wash gained solid product;
E. steps d gained solid product is dry under 40～100 ℃, obtain cytosine arabinoside/LDHs nano hybrid.
The preferred Cl of the described interlayer anion of above-mentioned steps b
-And NO
3 -Calcining heat is preferably 500 ℃.
The mass ratio of cytosine arabinoside is preferably 2: 1 in the calcined product of the described LDHs of above-mentioned steps c and the solution.
The described temperature of above-mentioned steps d is preferably 65 ℃, and the described time is preferably 24h; The described baking temperature of step e is preferably 80 ℃.
The cytosine arabinoside of the present invention preparation/LDHs nano hybrid is carried out XRD, IR and characterizes, and the result shows that cytosine arabinoside has inserted the LDHs interlayer.
Cytosine arabinoside/LDHs release experiment: get 0.02g cytosine arabinoside/LDHs nano hybrid, be scattered in the there-necked flask that the pH=7.2 phosphate buffer is housed, 37 ℃ of continuous magnetic agitation, get the suspension of certain volume by the certain hour interval, use immediately filtering with microporous membrane, with the concentration of the cytosine arabinoside in the spectrophotometer measurement filtrate, can draw release rate.
The invention has the beneficial effects as follows:
1, adopt respectively two kinds of methods to prepare cytosine arabinoside/LDHs nano hybrid, the drug loading of two kinds of method gained nano hybrids is all larger, has good slow release effect;
2, the preparation method that adopts is simple, mild condition;
3, the present invention is by adjusting synthetic method or the synthesis condition of cytosine arabinoside/LDHs nano hybrid, as adopt secondary construction from part or structural remodeling method, perhaps change the factor such as pH, temperature, ageing time of concentration, the building-up process of medicine, can realize the control to cytosine arabinoside/LDHs structure, composition and rate of release.
Description of drawings
Fig. 1 is X-ray powder diffraction (XRD) figure of the cytosine arabinoside/LDHs nano hybrid of embodiment 1 preparation, and the XRD spectra of having drawn simultaneously SDS-LDHs and Mg-Al-LDHs compares;
Fig. 2 is x-ray powder (XRD) diffraction pattern of the cytosine arabinoside/LDHs nano hybrid of embodiment 5 preparation, and the XRD spectra of having drawn simultaneously Mg-Al-LDHs compares;
Fig. 3 is the FT-IR figure of the cytosine arabinoside/LDHs nano hybrid of embodiment 5 preparation, and the infared spectrum of having drawn simultaneously LDHs and cytosine arabinoside crude drug compares;
Fig. 4 is that the cytosine arabinoside/LDHs nano hybrid of embodiment 5 preparation discharges respectively the rate curve of cytosine arabinoside in the phosphate buffer solution of pH=7.2, have in addition simultaneously LDHs and cytosine arabinoside physical mixture release rate profile as a comparison.
The specific embodiment
Embodiment described herein is some preferred implementation methods, is used for further describing and illustrating the present invention, is not intended to limit the invention to following definite details.
Secondary construction from part embodiment
Embodiment 1:
Step a: with 10.26g (0.040mol) Mg (NO
3)
26H
2O and 7.50g (0.020mol) Al (NO
3)
39H
2O is dissolved in the 120ml deionized water.
Step b: the SDS of 0.69g is dissolved in the 120ml deionized water.
Step c: the NaOH of 2.4g is dissolved in the 120ml deionized water.
Steps d: the 5.59g cytosine arabinoside is dissolved in the 50ml deionized water.
Step e: step a solution and step c solution are joined in the step b solution simultaneously, and stirring and controlling pH is 10, and reaction temperature is 65 ℃, stirring reaction 24 hours; Filter, water washing is to neutral, and 80 ℃ of lower peptizations of filter cake 24 hours obtain the LDHs of SDS modification;
F, the LDHs solid 0.2g that gets the SDS modification that step e obtains are distributed in the steps d solution, fully mix, and 65 ℃ of lower reactions 2 days obtain cytosine arabinoside/LDHs nano hybrid.
By XRD spectra (Fig. 1) as can be known, this cytosine arabinoside/LDHs nano hybrid has the stratiform crystalline structure, and by interlamellar spacing (d
003) as can be known cytosine arabinoside inserted the LDHs interlayer.
Adopt ultraviolet spectrophotometry that sample is analyzed, the content of determining cytosine arabinoside is 10.27%.
Embodiment 2:
Step a: with the Ni (NO of 0.030mol
3)
26H
2Fe (the NO of O and 0.010mol
3)
39H
2O is dissolved in the 40ml deionized water.
Step b: the SDS of 0.60g is dissolved in the 40ml deionized water.
Step c: the NaOH of 4.0g is dissolved in the 40ml deionized water.
Steps d: the 11.18g cytosine arabinoside is dissolved in the 50ml deionized water.
Step e: step a solution and step c solution are joined in the step b solution simultaneously, and stirring and controlling pH is 11, and reaction temperature is 45 ℃, stirring reaction 36 hours; Filter, water washing is to neutral, and 80 ℃ of lower peptizations of filter cake 24 hours obtain the LDHs of SDS modification;
F, the LDHs solid 0.2g that gets the SDS modification that step e obtains are distributed in the steps d solution, fully mix, and 45 ℃ of lower reactions 4 days obtain cytosine arabinoside/LDHs nano hybrid.
Adopt ultraviolet spectrophotometry that sample is analyzed, the content of determining cytosine arabinoside is 45.63%.
Embodiment 3:
Step a: with the ZnCl of 0.010mol
26H
2O and 0.010mol AlCl
36H
2O is dissolved in the 35ml deionized water.
Step b: the SDS of 0.11g is dissolved in the 40ml deionized water.
Step c: the NaOH of 1.6g is dissolved in the 40ml deionized water.
Steps d: the 2.79g cytosine arabinoside is dissolved in the 50ml deionized water.
Step e: step a solution and step c solution are joined in the step b solution simultaneously, and stirring and controlling pH is 9, and reaction temperature is 20 ℃, stirring reaction 20 hours; Filter, water washing is to neutral, and 80 ℃ of lower peptizations of filter cake 24 hours obtain the LDHs of SDS modification;
F, the LDHs solid 0.2g that gets the SDS modification that step e obtains are distributed in the steps d solution, fully mix, and 25 ℃ of lower reactions 3 days obtain cytosine arabinoside/LDHs nano hybrid.
Adopt ultraviolet spectrophotometry that sample is analyzed, the content of determining cytosine arabinoside is 1.05%.
Embodiment 4:
Step a: with the CuSO of 0.030mol
45H
2O and 0.010mol Al
2(SO
4)
318H
2O is dissolved in the 35ml water.
Step b: the SDS of 0.35g is dissolved in the 40ml deionized water.
Step c: the NaOH of 0.64g is dissolved in the 40ml deionized water.
Steps d: the 5.59g cytosine arabinoside is dissolved in the 50ml deionized water.
Step e: step a solution and step c solution are joined in the step b solution simultaneously, and stirring and controlling pH is 12, and reaction temperature is 80 ℃, stirring reaction 48 hours; Filter, water washing is to neutral, and 80 ℃ of lower peptizations of filter cake 24 hours obtain the LDHs of SDS modification;
F, the LDHs solid 0.2g that gets the SDS modification that step e obtains are distributed in the steps d solution, fully mix, and 70 ℃ of lower reactions 1 day obtain cytosine arabinoside/LDHs nano hybrid.
Adopt ultraviolet spectrophotometry that sample is analyzed, the content of determining cytosine arabinoside is 20.10%.
Structural remodeling method embodiment
Embodiment 5:
Step a: take by weighing the 0.50g cytosine arabinoside and be dissolved in the 100ml deionized water;
Step b: with Mg
2Al-NO
3LDHs is at 500 ℃ of lower calcining 4h; (Mg
2Al-NO
3LDHs: refer to M
IIBe Mg
2+, M
IIIBe Al
3+, both mol ratio M
II/ M
III=2: 1, interlayer anion is NO
3 -LDHs)
Step c: under 65 ℃ with Mg
2Al-NO
3The calcined product 0.50g of LDHs is scattered in the cytosine arabinoside solution;
Steps d: then that serosity is centrifugal 65 ℃ of lower stirrings 24 hours, with deionized water wash gained solid product;
Step e: steps d gained solid product obtains cytosine arabinoside/LDHs nano hybrid 80 ℃ of lower dryings.
By XRD spectra (Fig. 2) as can be known, this cytosine arabinoside/LDHs nano hybrid has the stratiform crystalline structure, and by interlamellar spacing (d
003) as can be known cytosine arabinoside inserted the LDHs interlayer.
Confirm further that by IR spectrogram (Fig. 3) cytosine arabinoside is between interposed layer.
Adopt ultraviolet spectrophotometry that sample is analyzed, the content of determining cytosine arabinoside is 37.90%.
The drug release experimental result is seen Fig. 4, and the visible cytosine arabinoside/rate of release of LDHs nano hybrid is starkly lower than the physical mixture of the former medicine of cytosine arabinoside and LDHs, shows that cytosine arabinoside/LDHs nano hybrid has good medicine controlled releasing effect.
Embodiment 6:
Step a: take by weighing the 1.00g cytosine arabinoside and be dissolved in the 100ml deionized water;
Step b: with Mn
2.5Ni-NO
3LDHs is at 450 ℃ of lower calcining 2h; (Mn
2.5Ni-NO
3LDHs: refer to M
IIBe Mn
2+, M
IIIBe Ni
3+, both mol ratio M
II/ M
III=2.5: 1, interlayer anion is NO
3 -LDHs)
Step c: under 20 ℃ with Mn
2.5Ni-NO
3The calcined product 1.50g of LDHs is scattered in the cytosine arabinoside solution;
Steps d: then that serosity is centrifugal 20 ℃ of lower stirrings 12 hours, with deionized water wash gained solid product;
Step e: steps d gained solid product obtains cytosine arabinoside/LDHs nano hybrid at 60 ℃ oven drying.
Adopt ultraviolet spectrophotometry that sample is analyzed, the content of determining cytosine arabinoside is 48.89%.
Embodiment 7:
Step a: take by weighing the 0.05g cytosine arabinoside and be dissolved in the 100ml deionized water;
Step b: with Zn
2Al-Cl LDHs is at 400 ℃ of lower calcining 8h; (Zn
2Al-Cl LDHs: refer to M
IIBe Mg
2+, M
IIIBe Al
3+, both mol ratio M
II/ M
III=2: 1, interlayer anion is Cl
-LDHs)
Step c: under 45 ℃ with Mg
2The calcined product 2.00g of Al-Cl LDHs is scattered in the cytosine arabinoside solution;
Steps d: then that serosity is centrifugal 45 ℃ of lower stirrings 36 hours, with deionized water wash gained solid product;
Step e: steps d gained solid product obtains cytosine arabinoside/LDHs nano hybrid at 40 ℃ oven drying.
Adopt ultraviolet spectrophotometry that sample is analyzed, the content of determining cytosine arabinoside is 29.13%.
Embodiment 8:
Step a: take by weighing the 0.01g cytosine arabinoside and be dissolved in the 100ml deionized water;
Step b: with Fe
2.5Cr-CO
3LDHs is at 600 ℃ of lower calcining 4h; (Fe
2.5Cr-CO
3LDHs: refer to M
IIBe Fe
2+, M
IIIBe Cr
3+, both mol ratio M
II/ M
III=2.5: 1, interlayer anion is CO
3 2-LDHs)
Step c: under 80 ℃ with Fe
2.5Cr-CO
3The calcined product 0.05g of LDHs is scattered in the cytosine arabinoside solution;
Steps d: then that serosity is centrifugal 80 ℃ of lower stirrings 72 hours, with deionized water wash gained solid product;
Step e: steps d gained solid product obtains cytosine arabinoside/LDHs nano hybrid at 100 ℃ oven drying.
Adopt ultraviolet spectrophotometry that sample is analyzed, the content of determining cytosine arabinoside is 5.21%.
Claims (10)
1. a cytosine arabinoside/layered double hydroxide (LDHs) nano hybrid, it is characterized in that: described hybrid synusia contains bivalent metal ion (M
II) and trivalent metal ion (M
III), interlayer contains anion, wherein M
IIBe Mg
2+, Mn
2+, Fe
2+, Co
2+, Ni
2+, Cu
2+, Zn
2+In a kind of; M
IIIBe Al
3+, Cr
3+, Mn
3+, Fe
3+, Co
3+, Ni
3+In a kind of; Interlayer anion is OH
-, CO
3 2-, SO
4 2-, Cl
-, NO
3 -In one or both.
2. cytosine arabinoside according to claim 1/LDHs nano hybrid, it is characterized in that: cytosine arabinoside quality percentage composition is 1%～50% in the described hybrid.
3. the preparation method of cytosine arabinoside as claimed in claim 1/LDHs nano hybrid is characterized in that, comprises the following steps:
A. compound concentration is the solubility bivalent metal ion (M of 0.2～1.0mol/L
II) and trivalent metal ion (M
III) mixed-salt aqueous solution, both mol ratio M
II/ M
III=1～3: 1;
M wherein
IIBe Mg
2+, Mn
2+, Fe
2+, Co
2+, Ni
2+, Cu
2+, Zn
2+In one or both; M
IIIBe Al
3+, Cr
3+, Fe
3+In one or both; The anion of soluble-salt is SO
4 2-, Cl
-, NO
3 -In one or both;
B. compound concentration is the aqueous surfactant solution of 0.01～0.5mol/L; Described surfactant is any in sodium lauryl sulphate, dodecyl sodium sulfate, dodecylbenzene sodium sulfonate, the carboxylate;
C. compound concentration is the aqueous slkali of 0.3-3mol/L; Described aqueous slkali is NH
4OH, NaOH and Na
2CO
3In one or both;
D, preparation cytosine arabinoside aqueous solution
E. step a solution and step c solution are joined in the step b solution simultaneously, stirring and controlling pH is 9～12, and reaction temperature is 20～80 ℃, and the response time is 20～48 hours; Filter, water washing is to neutral, and 80 ℃ of lower peptizations of filter cake 24 hours obtain surfactant-modified LDHs;
F, get the surfactant-modified LDHs solid that step e obtains and be distributed in the steps d solution, fully mix, 20～80 ℃ of lower reactions 1～4 day obtain cytosine arabinoside/LDHs nano hybrid.
4. the preparation method of cytosine arabinoside according to claim 3/LDHs nano hybrid, it is characterized in that: the described mixed-salt aqueous solution concentration of step a is preferably 0.5mol/L, wherein M
II/ M
IIIMol ratio be 2: 1; The anion of soluble-salt is preferably Cl
-And NO
3 -
5. the preparation method of cytosine arabinoside according to claim 3/LDHs nano hybrid is characterized in that: the preferred lauryl sulphate acid of the described surfactant of step b, and the concentration of solution is 0.2mol/L; The preferred NaOH solution of the described aqueous slkali of step c, concentration is 0.5mol/L.
6. the preparation method of cytosine arabinoside according to claim 3/LDHs nano hybrid, it is characterized in that: the described pH value of step e is 11; Described reaction temperature is 45 ℃; The stirring reaction time is 24 hours.
7. the preparation method of cytosine arabinoside according to claim 3/LDHs nano hybrid, it is characterized in that: the described reaction temperature of step f is 45 ℃; Response time is 3 days.
8. the preparation method of cytosine arabinoside as claimed in claim 1/LDHs nano hybrid is characterized in that, comprises the following steps:
A. cytosine arabinoside is dissolved in the deionized water that to form concentration be the cytosine arabinoside solution of 100～10000mg/L;
B. LDHs was calcined 2～8 hours under 400～600 ℃; Among the described LDHs, bivalent metal ion (M
II) be Mg
2+, Mn
2+, Fe
2+, Co
2+, Ni
2+, Cu
2+, Zn
2+In one or both; Trivalent metal ion (M
III) be Al
3+, Cr
3+, Mn
3+, Fe
3+, Co
3+, Ni
3+In one or both; Both mol ratio M
II/ M
III=1～3: 1; Interlayer anion is OH
-, CO
3 2-, SO
4 2-, Cl
-, NO
3 -In any or two kinds;
C. under 20～80 ℃, the LDHs calcined product is scattered in the cytosine arabinoside solution; The mass ratio of cytosine arabinoside is 1～10: 1 in the calcined product of LDHs and the solution;
D. 20～80 ℃ of lower stirrings 12～72 hours, then that serosity is centrifugal, with deionized water wash gained solid product;
E. steps d gained solid product is dry under 40～100 ℃, obtain cytosine arabinoside/LDHs nano hybrid.
9. the preparation method of cytosine arabinoside according to claim 8/LDHs nano hybrid is characterized in that: the preferred Cl of the described interlayer anion of step b
-And NO
3 -, calcining heat is preferably 500 ℃; The mass ratio of cytosine arabinoside is preferably 2: 1 in the calcined product of the described LDHs of step c and the solution.
10. the preparation method of cytosine arabinoside according to claim 8/LDHs nano hybrid, it is characterized in that: the described temperature of steps d is preferably 65 ℃, and the described time is preferably 24h; The described baking temperature of step e is preferably 80 ℃.
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