CN103550156A - Preparation method of supermolecule globular micelle based on antidepressant medicament chlorpromazine - Google Patents
Preparation method of supermolecule globular micelle based on antidepressant medicament chlorpromazine Download PDFInfo
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- CN103550156A CN103550156A CN201310579324.0A CN201310579324A CN103550156A CN 103550156 A CN103550156 A CN 103550156A CN 201310579324 A CN201310579324 A CN 201310579324A CN 103550156 A CN103550156 A CN 103550156A
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Abstract
The invention discloses a preparation method of a supermolecule globular micelle based on an antidepressant medicament chlorpromazine. The method comprises the following steps: constructing a medicament carrier through the supermolecule interaction of amphiphilic sulfonated calix [4] arene and an antidepressant medicament chlorpromazine hydrochloride, dissolving the amphiphilic sulfonated calix [4] arene and the antidepressant medicament chlorpromazine hydrochloride in water, and uniformly mixing to obtain a nano supermolecule globular micelle solution; and non-covalently modifying a targeting agent trimethyl chitosan through a bonding site of the calix arene on the surface of the micelle to obtain the supermolecule micelle loaded with trimethyl chitosan on the surface. The preparation method has the advantages that the preparation method is simple and convenient, and fewer subjective and objective raw materials are used; the medicament load rate is high since the medicament molecules are the constructing units of the medicament carrier and the medicament molecules are immobilized; the micelle can be used for non-covalently modifying the targeting agent trimethyl chitosan through the bonding site of the surface calix arene so that the micelle has a wide application prospect in the field of targeted medicament delivery.
Description
[technical field]
The invention belongs to nano-supermolecule pharmaceutical carrier preparation, particularly a kind of preparation method of the supermolecule globular micelle based on antidepressant drug chlorpromazine.
[background technology]
Self-assembled nanometer carrier all has a wide range of applications in a lot of fields especially drug delivery.Multiple assembly has been used as pharmaceutical carrier, as phospholipid, polymer, dendrimer and inorganic nano-particle etc., referring to: 1) Vladimir, P.T.Nat.Rev.Drug Discovery2005,4,145-160; 2) Vasant, V.R.J.Clin.Pharmacol.1990,30,10-23; 3) Samad, A.; Alam, M.I.; Saxena, K.Curr.Pharm.Des.2009,15,2958-2969; 4) Liong, M.; Lu, J.; Kovochich, M.; Xia, T.; Ruehm, S.G.; Nel, A.E.; Tamanoi, F.; Zink, J.I.ACS Nano2008,2,889-896.Conventional pharmaceutical carrier is first by nano material, to form assembly, then drug molecule is encapsulated in wherein, referring to: Mary, E.C.; William, B.L.; Nicholas, A.P.Acc.Chem.Res.2011,44,1061-1070.But the weak point of the method is the load factor of medicine not high (not higher than 10%).Relative with the method, by drug molecule by under specific physiological condition easily destroyed covalent bond modify on the nano-carrier being formed by macromolecule and can greatly improve drug loading rate.Yet the method synthetic route is tediously long and connect drug molecule and high molecular covalent bond can not disconnect and then affect the release efficiency of medicine completely under specific physiological condition, referring to: Ruth, D.Nat.Rev.Cancer2006,6,688-701.Therefore drug molecule and nano material are pharmaceutical carrier by the non-covalent formation of assembling altogether pharmaceutical carrier, and the new approach that provides is provided.Thereby drug molecule self participates in the drug loading rate that improved of constructing of carrier as construction unit, also avoided complicated synthesizing simultaneously, referring to: Jeremy, P.K.T.; Sung, H.K.; Fredrik, N.; Eric, A.A.; Robert, M.W.; Zhang, Y.; James, L.H.; Yang, Y.Y.Small2009,5,1504-1507.Yet the current report about this respect also seldom, be mainly because most drug molecule does not have the characteristic of self assembly.
Phenothiazine compound is the important amphipathic drug molecule of a class, is used as clinically antidepressant drug.Wherein research is chlorpromazine the most widely, and its structure is that a hydrophobic nitrogen heterocyclic ring connects a charged amido by short alkyl chain.Chlorpromazine can be self-assembled into the structure of similar micelle at critical aggregate concentration, referring to: 1) Parkanyi, C.; Boniface, C.; Aaron, J.J.; Maafi, M.Spectrochim.Acta1993,12,1715-1720; 2) Ford, J.M.; Hait, W.N.Pharmacol.Rev.1990,42,155-199; 3) Fowler, G.J.S.; Rees, R.C.; Devonshire, R.Photochem.Photobiol.1990,52,489-494; 4) Ramu, A.; Ramu, N.; Cancer Chemother.Pharmacol.1992,30,165-173; 5) Attwood, D.Adv.Colloid Interface Sci.1995,55,271-303.Therefore the ideal medicament model that, chlorpromazine can be assembled altogether as medicine.
Calixarenes is the class macro ring oligomer being formed by the phenol of para-orientation and formaldehyde condensation, referring to: Asfari, M.-Z.;
v.; Harrowfield, J.; Vicens, J.Calixarenes, Kluwer Academic Publishers, Dordrecht, 2001.By simple modification, can obtain multiple derivant.The research of calixarenes is that the host molecule that has an evident characteristics by design starts.Yet the characteristic of calixarenes is not limited to this.Through certain modification, calixarenes can also be applied to constructing of assembly, referring to: 1) Mulder, A.; Auletta, T.; Sartori, A.; Ciotto, S.D.; Casnati, A.; Ungaro, R.; Huskens, J.; Reinhoudt, D.N.J.Am.Chem.Soc.2004,126,6627-6636; 2) Arduini, A.; Demuru, D.; Pochini, A.; Secchi, A.Chem.Commun.2005,645-647; 3) Arduini, A.; Ciesa, F.; Fragassi, M.; Pochini, A.; Secchi, A.Angew.Chem.Int.Ed.2005,44,278-281; 4) Rudkevich, D.M.Bull.Chem.Soc.Jpn.2002,75,393-413; 5) Helttunena, K.; Shahgaldian, P.New J.Chem.2010,34,2704-2714.By modifying respectively hydrophilic group at calixarenes two ends and lipophilic group can obtain amphipathic calixarene, its rigidity bevel-type configuration is the ideal structure that forms globular micelle, referring to: 1) Shinkai, S.; Mori, S.; Koreishi, H.; Tsubake, T.; Manabe, O.J.Am.Chem.Soc.1986,108,2409-2416; 2) Shinkai, S.; Kawabata, H.; Arimura, T.; Matsuda, T.; Satoh, H.; Manabe, O.J.Chem.Soc., Perkin Trans.11989,1073-1074; 3) Shinkai, S.; Arimura, T.; Araki, K.; Kawabata, H.; Satoh, H.; Tsubaki, T.; Manabe, O.; Sunamoto, J.J.Chem.Soc., Perkin Trans.11989,2039-2045; 4) Arimori, S.; Nagasaki, T.; Shinkai, S.J.Chem.Soc., Perkin Trans.21995,679-683; 5) Bas í lio, N.; Garc í a-R í o, L.; Martin-Pastor, M.J.Phys.Chem.B2010,114,4816-4820; 6) Bas í lio, N.; Garc í a-R í o, L.ChemPhysChem2012,13,2368-2376; 7) Bas í lio, N.; Garc í a-R í o, L.; Martin-Pastor, M.Langmuir2012,28,2404-2414; 8) Sansone, F.; Dudic, M.; Donofrio, G.; Rivelli, C.; Baldini, L.; Casnati, A.; Cellai, S.; Ungaro, R.J.Am.Chem.Soc.2006,128,14528-14536; 9) Consoli, G.M.L.; Granata, G.; Nigro, R.L.; Malandrino, G.; Geraci, C.Langmuir2008,24,6194-6200.
[summary of the invention]
The object of the invention is for above-mentioned technical Analysis, a kind of preparation method of the supermolecule globular micelle based on antidepressant drug chlorpromazine is provided, the common assembling of this nano-supermolecule globular micelle based on amphipathic sulfonation cup [4] aromatic hydrocarbons and chlorpromazine, the existence of sulfonation cup [4] aromatic hydrocarbons can make chlorpromazine group dress up large-sized globular micelle, in addition the Host-guest Recognition site due to calixarenes is positioned at micelle outer surface and unoccupied, therefore can some targeting agent be modified in micellar surface it is transmitted for specific targeted drug by supermolecule noncovalent interaction.
Technical scheme of the present invention:
A kind of preparation method of the nano-supermolecule globular micelle based on antidepressant drug chlorpromazine, by amphiphilic sulfonation cup [4] aromatic hydrocarbons (SC4AH), interact and construct pharmaceutical carrier with antidepressant drug chlorpromazine hydrochloride (CPZ) supermolecule, described amphiphilic sulfonation cup [4] aromatic hydrocarbons is amphiphilic sulfonation cup [4] aromatic hydrocarbons (SC4AH) that the full heptyl in lower edge is modified, amphiphilic sulfonation cup [4] aromatic hydrocarbons and chlorpromazine hydrochloride are dissolved in the water, after evenly mixing, obtain nano-supermolecule globular micelle solution; Binding site non-covalent modification targeting agent N-trimethyl chitosan TMC (TMC) by micellar surface calixarenes, obtains the supermolecule micelle that area load has N-trimethyl chitosan TMC.
In described nano-supermolecule globular micelle solution, the concentration of amphiphilic sulfonation cup [4] aromatic hydrocarbons and chlorpromazine hydrochloride is respectively 25 μ M and 75 μ M.
Advantage of the present invention is: 1) preparation method is easy, raw material consumption is few, cost is low; 2) drug loading rate is high, and this is due to drug molecule, to be the construction unit of pharmaceutical carrier, and drug molecule has been played to fixing effect; 3) supermolecule globular micelle solution can, by the binding site non-covalent modification targeting agent of surperficial calixarenes, make it in targeted drug transmission field, have broad application prospects.
[accompanying drawing explanation]
Fig. 1 is for constructing super-molecule assembling body schematic diagram by non-covalent assembling altogether.
Fig. 2 is the critical aggregate concentration figure of amphiphilic sulfonation cup [4] aromatic hydrocarbons.
Fig. 3 is the critical aggregate concentration figure of chlorpromazine hydrochloride.
Fig. 4 is amphiphilic sulfonation cup [4] aromatic hydrocarbons and the critical aggregate concentration figure of chlorpromazine hydrochloride under mol ratio 1:3.
Fig. 5 is the dynamic light scattering figure of the globular micelle of amphiphilic sulfonation cup [4] aromatic hydrocarbons and chlorpromazine hydrochloride Supramolecular Assembling.
Fig. 6 is the high resolution transmission electron microscopy image of the globular micelle of amphiphilic sulfonation cup [4] aromatic hydrocarbons and chlorpromazine hydrochloride Z Supramolecular Assembling.
[specific embodiment]
Embodiment:
A preparation method for the supermolecule globular micelle of antidepressant drug chlorpromazine, is dissolved in the water SC4AH and CPZ, after evenly mixing, obtains supermolecule micelle, and in described supermolecule micellar solution, the concentration of SC4AH and CPZ is respectively 25 μ M and 75 μ M.
Fig. 1 is for constructing supermolecule globular micelle schematic diagram by non-covalent assembling altogether.
SC4AH and CPZ all have amphipathic, and as shown in Figure 2, the critical aggregate concentration of SC4AH is 210 μ M; As shown in Figure 3, the critical aggregate concentration of CPZ is 140 μ M; When as shown in Figure 4, fixedly SC4AH and CPZ mol ratio are 1:3, the critical aggregate concentration of SC4AH+CPZ is 12 μ M.
The particle diameter of this supermolecule micelle and pattern characterize by dynamic light scattering and high resolution transmission electron microscopy respectively, and Fig. 5 is the dynamic light scattering figure of the globular micelle of SC4AH and CPZ Supramolecular Assembling; Fig. 6 is the high resolution transmission electron microscopy image of the globular micelle of SC4AH and CPZ Supramolecular Assembling.
In this supermolecule micelle, the load factor of CPZ is determined as 46% by nuclear-magnetism.
By the supermolecule globular micelle of above-mentioned preparation, the binding site non-covalent modification targeting agent N-trimethyl chitosan TMC (TMC) by common assembling micellar surface calixarenes, obtains the supermolecule micelle that area load has TMC, and method is as follows:
1) SC4AH and CPZ are dissolved in the water, after evenly mixing, obtain supermolecule micellar solution object.Add TMC solution, after evenly mixing, obtain the supermolecule micellar solution object that area load has TMC.In described supermolecule micellar solution, the concentration of SC4AH, CPZ and TMC is respectively 25 μ M, 75 μ M and 20 μ g/mL.
2) micelle before and after load TMC is carried out to the mensuration of zeta current potential, before load TMC, the zeta current potential of micelle is-16.18mV, and after load, the zeta current potential of micelle is-7.28mV.By the variation of zeta current potential, can prove that TMC is interacted and is supported on the surface of micelle by supermolecule by quaternary ammonium cations and calixarenes.
Claims (2)
1. the preparation method of the nano-supermolecule globular micelle based on antidepressant drug chlorpromazine, it is characterized in that: by amphiphilic sulfonation cup [4] aromatic hydrocarbons and antidepressant drug chlorpromazine hydrochloride supermolecule, interact and construct pharmaceutical carrier, described amphiphilic sulfonation cup [4] aromatic hydrocarbons is amphiphilic sulfonation cup [4] aromatic hydrocarbons that the full heptyl in lower edge is modified, amphiphilic sulfonation cup [4] aromatic hydrocarbons and chlorpromazine hydrochloride are dissolved in the water, after evenly mixing, obtain nano-supermolecule globular micelle solution; Binding site non-covalent modification targeting agent N-trimethyl chitosan TMC by micellar surface calixarenes, obtains the supermolecule micelle that area load has N-trimethyl chitosan TMC.
2. the preparation method of the nano-supermolecule globular micelle based on antidepressant drug chlorpromazine according to claim 1, is characterized in that: in described nano-supermolecule globular micelle solution, the concentration of amphiphilic sulfonation cup [4] aromatic hydrocarbons and chlorpromazine hydrochloride is respectively 25 μ M and 75 μ M.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104174026A (en) * | 2014-08-28 | 2014-12-03 | 南开大学 | Preparation method and applications of irinotecan hydrochloride based anti-cancer nanoparticles |
| CN104922693A (en) * | 2015-06-19 | 2015-09-23 | 南开大学 | Anionic-type cyclodextrin and anti-cancer drug clathrate compound and preparation method |
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| KR100741160B1 (en) * | 2006-10-11 | 2007-07-20 | 충북대학교 산학협력단 | High-throughput analysis of protein-protein interaction on protein nanoarray |
| CN102405215A (en) * | 2008-05-12 | 2012-04-04 | 圣保罗研究支持基金会-Fapesp | Stabilization processes of cation radicals of phenothiazinic compounds, cosmeceutical formulations and methods for skin diseases and disturbances prevention |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO1999016734A1 (en) * | 1997-10-01 | 1999-04-08 | Macgillivray Leonard R | Spherical molecular assembly |
| KR100741160B1 (en) * | 2006-10-11 | 2007-07-20 | 충북대학교 산학협력단 | High-throughput analysis of protein-protein interaction on protein nanoarray |
| CN102405215A (en) * | 2008-05-12 | 2012-04-04 | 圣保罗研究支持基金会-Fapesp | Stabilization processes of cation radicals of phenothiazinic compounds, cosmeceutical formulations and methods for skin diseases and disturbances prevention |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104174026A (en) * | 2014-08-28 | 2014-12-03 | 南开大学 | Preparation method and applications of irinotecan hydrochloride based anti-cancer nanoparticles |
| CN104922693A (en) * | 2015-06-19 | 2015-09-23 | 南开大学 | Anionic-type cyclodextrin and anti-cancer drug clathrate compound and preparation method |
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