CN104984356A - Satraplatin cyclodextrin compound and preparation method - Google Patents
Satraplatin cyclodextrin compound and preparation method Download PDFInfo
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- CN104984356A CN104984356A CN201510250273.6A CN201510250273A CN104984356A CN 104984356 A CN104984356 A CN 104984356A CN 201510250273 A CN201510250273 A CN 201510250273A CN 104984356 A CN104984356 A CN 104984356A
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Abstract
The invention discloses a satraplatin cyclodextrin compound and a preparation method, and belongs to a platinum-based antitumor drug. A specific method and a specific type of cyclodextrin are adopted to obtain the satraplatin cyclodextrin compound. The compound is formed by compounding satraplatin and cyclodextrin according to the stoichiometric ratio being 1:1. Satraplatin is partially or wholly embedded into a cyclodextrin cavity to form the stable compound, so that the water solubility and stability of satraplatin are improved, and the in-vivo or in-vitro anti-tumor activity of satraplatin is kept or improved. The preparation method for the compound comprises the steps that satraplatin and cyclodextrin are dissolved into a good solvent according to a certain ratio, insoluble substance is filtered out after stirring is performed for a period of time, and then vacuum concentration or freeze drying is performed on a filtrate, thereby obtaining the satraplatin cyclodextrin compound.
Description
Technical field
The present invention relates to cyclodextrin complexes and the preparation method of platinum series antineoplastic medicament Satraplatin JM216 BMS 182751, belong to antitumor drug and formulation art thereof.
Background technology
Satraplatin JM216 BMS 182751 (Satraplatin) code name JM216, chemical name is suitable, instead, cis-two chloro-oxalic acid-ammonia, cyclohexylamine closes platinum (IV), and English name is bis (acetato) amminedichloro (cyclohexylamine) platinum (IV).The dissolubility of Satraplatin JM216 BMS 182751 in water is very little, lower than 0.5mg/ml.
Satraplatin JM216 BMS 182751 is first platinum series antineoplastic medicament with Orally active entering clinical research, has entered the clinical research of III phase at present.
Satraplatin JM216 BMS 182751 is the mixed amine complex of monokaryon Pt (IV), and structural formula is:
Cyclodextrin (CDs) is by the cyclic oligosaccharide be made up of α (Isosorbide-5-Nitrae)-glucoside unit after glucose unit cyclization.Common are α-, β-, gamma-cyclodextrin and replace obtain cyclodextrin, as HP-β-CD etc., wherein alpha-cyclodextrin cavity is minimum, and gamma-cyclodextrin cavity is maximum, and beta-schardinger dextrin-is considered suitable for the enclose of most of Common drugs.
Cyclodextrin is a kind of annular cones mesa-shaped molecule, and have the outer surface of polar hydrophilic and a hydrophobic non-polar cavity, due to this special structure, the hydrophobic cavity of cyclodextrin can hold suitable enclosed molecule, forms complex by Non-covalent binding.Be combineding with each other of this master/enclosed molecule is based on hydrophobic intermolecular interaction force, and the complex of formation can improve the dissolution characteristics of insoluble medicine, stability and biological activity.
The dissolution characteristics of a lot of medicine can be wrapped up by cyclodextrin and improve, and therefore, the present invention has prepared the cyclodextrin complexes of Satraplatin JM216 BMS 182751, can improve water solublity and the stability of Satraplatin JM216 BMS 182751, retains simultaneously or improve the anti-tumor activity of Satraplatin JM216 BMS 182751.
Summary of the invention
The invention discloses a kind of space structure and preparation method of Satraplatin JM216 BMS 182751 cyclodextrin complexes, the structure of this complex is confirmed by means such as nuclear magnetic resonance, NMR (NMR), fourier conversion infrared spectrum analysis instrument (FTIR), thermogravimetric analyzer (TGA), X-ray diffraction (XRD), scanning electron microscope (SEM) and Quantum chemical calculation.
Above-mentioned Satraplatin JM216 BMS 182751 cyclodextrin complexes preparation method is: by the Satraplatin JM216 BMS 182751 of certain proportioning and cyclodextrin in good solvent, stir to cross after a period of time and filter insoluble matter, then filtrate is carried out vacuum concentration or lyophilization can obtain Satraplatin JM216 BMS 182751 cyclodextrin complexes.
The Satraplatin JM216 BMS 182751 of above-mentioned certain proportioning and cyclodextrin refer to the ratio of the amount of substance of Satraplatin JM216 BMS 182751 and the amount of substance of cyclodextrin, can equal, are less than or are greater than 1:1, wherein preferred 2:1.
Above-mentioned good solvent, can refer to the single or mixed solvents such as water, methanol, ethanol, glycerol, 1,2-PD, isopropyl alcohol and Polyethylene Glycol, wherein preferred alcohol aqueous solution, but be not limited to this.
Above-mentioned ethanol water preferred volume ratio is ethanol: water (v:v)=1:5.
Above-mentioned filter operation refers to that employing 0.45 μm of microporous film filter filters, and can obtain the Satraplatin JM216 BMS 182751 cyclodextrin complexes that particle diameter is less than 0.5 μm, but be not limited to this.
Adopt said method can prepare Satraplatin JM216 BMS 182751 cyclodextrin complexes, the physicochemical properties of this complex are different from the physical mixture of Satraplatin JM216 BMS 182751 and cyclodextrin.
Above-mentioned cyclodextrin comprise modified or not natural α-, β-, gamma-cyclodextrin, and by the cyclodextrin that chemical modification obtains, wherein preferred beta-schardinger dextrin-.
Above-mentioned physical mixture forms by a certain amount of pulverous Satraplatin JM216 BMS 182751 and solid ring dextrin being mixed, the wherein preferred 1:1 of ratio.
The physicochemical properties of above-mentioned complex refer to spectral quality, thermally-stabilised etc.
In above-mentioned Satraplatin JM216 BMS 182751 cyclodextrin complexes, Satraplatin JM216 BMS 182751 and cyclodextrin are combined into by 1:1.
Above-mentioned Satraplatin JM216 BMS 182751 cyclodextrin complexes, the some or all of group of Satraplatin JM216 BMS 182751 is embedded in cyclodextrin hydrophobic pocket, forms stable complex, wherein embeds by the cyclohexane moiety of Satraplatin JM216 BMS 182751 the complex formed more stable.
In above-mentioned Satraplatin JM216 BMS 182751 cyclodextrin complexes, Satraplatin JM216 BMS 182751 remains original structure.
The result of study such as nuclear magnetic resonance, NMR (NMR), fourier conversion infrared spectrum analysis instrument (FTIR), X-ray diffraction (XRD), scanning electron microscope (SEM) shows, adopt above-mentioned preparation method, Satraplatin JM216 BMS 182751 and cyclodextrin define complex really, are different from general physical mixture.
Thermal gravimetric analysis results shows that above-mentioned preparation method can obtain Satraplatin JM216 BMS 182751 cyclodextrin complexes further, and the complex heat stability of formation changes.
Above-mentioned Satraplatin JM216 BMS 182751 cyclodextrin complexes can improve the dissolution characteristics of Satraplatin JM216 BMS 182751, and under room temperature, complex is compared with Satraplatin JM216 BMS 182751, and the dissolubility in water significantly promotes.
Above-mentioned Satraplatin JM216 BMS 182751 cyclodextrin complexes can improve the stability of Satraplatin JM216 BMS 182751, is included in the stability in acidity or alkaline solution.
Above-mentioned Satraplatin JM216 BMS 182751 cyclodextrin complexes can improve or retain the anti-tumor activity of Satraplatin JM216 BMS 182751.
Above-mentioned anti-tumor activity refers to the external or anti-cancer activity in vivo to the JEG-3 such as pulmonary carcinoma, breast carcinoma or xenograft tumor, such as A549 and MCF-7 cell strain.
Above-mentioned Satraplatin JM216 BMS 182751 cyclodextrin complexes can be used for preparing Satraplatin JM216 BMS 182751 injection, oral formulations etc., comprises the multiple dosage forms such as dry powder, lyophilized powder, aqueous injection, suspensoid, solid oral agent.
Accompanying drawing explanation
Accompanying drawing 1: the more stable composite structure that Satraplatin JM216 BMS 182751 and cyclodextrin are formed.
The physical mixture of accompanying drawing 2:XRD image (a) Satraplatin JM216 BMS 182751, (b) beta-schardinger dextrin-, (c) Satraplatin JM216 BMS 182751 and beta-schardinger dextrin-complex, (d) Satraplatin JM216 BMS 182751 and beta-schardinger dextrin-.
The physical mixture of accompanying drawing 3:FTIR image (a) Satraplatin JM216 BMS 182751, (b) beta-schardinger dextrin-, (c) Satraplatin JM216 BMS 182751 and beta-schardinger dextrin-complex, (d) Satraplatin JM216 BMS 182751 and beta-schardinger dextrin-.
Accompanying drawing 4:SEM schemes the physical mixture of (a) Satraplatin JM216 BMS 182751, (b) beta-schardinger dextrin-, (c) Satraplatin JM216 BMS 182751 and beta-schardinger dextrin-complex, (d) Satraplatin JM216 BMS 182751 and beta-schardinger dextrin-.
Detailed description of the invention
The present embodiment is the feasibility that the invention is described, and unrestricted the present invention.Under the prerequisite of the inventive method, all the scope of protection of present invention is belonged to any change of invention.
Embodiment 1
The preparation of Satraplatin JM216 BMS 182751 cyclodextrin complexes and confirmation
Second alcohol and water presses 1:5 (v/v) mixed preparing 7ml ethanol water, 0.02mM Satraplatin JM216 BMS 182751 and 0.01Mm beta-schardinger dextrin-are dissolved in wherein, stirring at room temperature is evaporating ethanol after 5 days, adopt 0.45 μm of microporous film filter to cross and filter insoluble matter, filter vacuum is concentrated and drying obtains Satraplatin JM216 BMS 182751 cyclodextrin complexes.
According to phased soln characteristic and etc. molar concentration method of changing can determine, Satraplatin JM216 BMS 182751 and beta-schardinger dextrin-are combined into by 1:1.
In the nuclear magnetic resoance spectrum of contrast Satraplatin JM216 BMS 182751, beta-schardinger dextrin-, physical mixture and complex (
1h-NMR) hydrogen chemical shifts can be determined, Satraplatin JM216 BMS 182751 and beta-schardinger dextrin-define complex really, is different from simple physical mixture.
The infrared spectrogram of contrast Satraplatin JM216 BMS 182751, beta-schardinger dextrin-, physical mixture and complex can be determined, Satraplatin JM216 BMS 182751 and beta-schardinger dextrin-form the complex being different from physical mixture really.
The scanning electron microscope image of contrast Satraplatin JM216 BMS 182751, beta-schardinger dextrin-, physical mixture and complex can be determined, Satraplatin JM216 BMS 182751 is irregular crystal, beta-schardinger dextrin-is irregular granular texture, both physical mixtures present both forms simultaneously, complex then shows as compact uniform laminated structure, and Satraplatin JM216 BMS 182751 and beta-schardinger dextrin-crystalline state separately all disappears.
The X-ray diffraction image of contrast Satraplatin JM216 BMS 182751, beta-schardinger dextrin-, physical mixture and complex, can determine that this preparation method obtains both complex really, its XRD figure picture is different from the XRD figure picture of physical mixture.
Thermal gravimetric analysis results shows, and Satraplatin JM216 BMS 182751, beta-schardinger dextrin-, physical mixture are all not identical with the heat decomposition temperature of complex, illustrates that after forming complex, heat stability changes.
Embodiment 2
The preparation of Satraplatin JM216 BMS 182751 cyclodextrin complexes and confirmation
Second alcohol and water presses 1:5 (v/v) mixed preparing 7ml ethanol water, 0.02mM Satraplatin JM216 BMS 182751 and 0.01Mm HP-β-CD are dissolved in wherein, stirring at room temperature is evaporating ethanol after 5 days, adopt 0.45 μm of microporous film filter to cross and filter insoluble matter, filter vacuum is concentrated and drying obtains Satraplatin JM216 BMS 182751 cyclodextrin complexes.
According to phased soln characteristic and etc. molar concentration method of changing can determine, Satraplatin JM216 BMS 182751 and HP-β-CD are combined into by 1:1.
In the nuclear magnetic resoance spectrum of contrast Satraplatin JM216 BMS 182751, HP-β-CD, physical mixture and complex (
1h-NMR) hydrogen chemical shifts can be determined, Satraplatin JM216 BMS 182751 and HP-β-CD define complex really, is different from simple physical mixture.
The infrared spectrogram of contrast Satraplatin JM216 BMS 182751, HP-β-CD, physical mixture and complex can be determined, Satraplatin JM216 BMS 182751 and beta-schardinger dextrin-form the complex being different from physical mixture really.
The X-ray diffraction image of contrast Satraplatin JM216 BMS 182751, HP-β-CD, physical mixture and complex, can determine that this preparation method obtains both complex really, its XRD figure picture is different from the XRD figure picture of physical mixture.
Thermal gravimetric analysis results shows, and Satraplatin JM216 BMS 182751, HP-β-CD, physical mixture are all not identical with the heat decomposition temperature of complex, illustrates that after forming complex, heat stability changes.
Embodiment 3
Satraplatin JM216 BMS 182751/beta-schardinger dextrin-complex solubility test
Get excessive Satraplatin JM216 BMS 182751/beta-schardinger dextrin-complex in 2ml water, stir 1h, cross concentrating under reduced pressure after filtering insoluble matter dry, weigh the Weight computation dissolubility of residue.
Above-mentioned Satraplatin JM216 BMS 182751/the dissolubility of beta-schardinger dextrin-complex in water is 7.4mg/ml (room temperature).
Claims (10)
1. Satraplatin JM216 BMS 182751 cyclodextrin complexes, is characterized in that: Satraplatin JM216 BMS 182751 and cyclodextrin are combined into by the stoichiometric proportion of 1:1.
2. Satraplatin JM216 BMS 182751 cyclodextrin complexes according to claim 1, it is characterized in that: described cyclodextrin comprise modified or not natural α-, β-, gamma-cyclodextrin, and such as, by the cyclodextrin that chemical modification obtains, HP-β-CD etc., wherein preferred beta-schardinger dextrin-.
3. Satraplatin JM216 BMS 182751 cyclodextrin complexes according to claim 1, is characterized in that: Satraplatin JM216 BMS 182751 part or embed wholly, in cyclodextrin hydrophobic pocket, form stable complex, and wherein the complex of the cyclohexane moiety embedding formation of Satraplatin JM216 BMS 182751 is more stable.
4. Satraplatin JM216 BMS 182751 cyclodextrin complexes according to claim 1, is characterized in that: the anti-tumor activity retaining or improve Satraplatin JM216 BMS 182751 while improving the water solublity of Satraplatin JM216 BMS 182751 and stability.
5. the application of Satraplatin JM216 BMS 182751 cyclodextrin complexes described in claim 1 in the body preparing the JEG-3 such as anti-pulmonary carcinoma, breast carcinoma or xenograft tumor or in Anticancer Activity in vitro medicine.
6. the preparation method of Satraplatin JM216 BMS 182751 cyclodextrin complexes, it is characterized in that: by the Satraplatin JM216 BMS 182751 of certain proportioning and cyclodextrin in good solvent, stir to cross after a period of time and filter insoluble matter, then filtrate is carried out vacuum concentration or lyophilization can obtain Satraplatin JM216 BMS 182751 cyclodextrin complexes.
7. the preparation method of Satraplatin JM216 BMS 182751 cyclodextrin complexes according to claim 6, it is characterized in that: the Satraplatin JM216 BMS 182751 of described certain proportioning and cyclodextrin refer to the ratio of the amount of substance of Satraplatin JM216 BMS 182751 and the amount of substance of cyclodextrin, can equal, be less than or be greater than 1:1, wherein preferred 2:1.
8. the preparation method of Satraplatin JM216 BMS 182751 cyclodextrin complexes according to claim 6, it is characterized in that: described good solvent, can be the single or mixed solvents such as water, methanol, ethanol, glycerol, 1,2-PD, isopropyl alcohol and Polyethylene Glycol, wherein preferred alcohol aqueous solution.
9. the preparation method of claim 8 Satraplatin JM216 BMS 182751 cyclodextrin complexes, is characterized in that: described ethanol water preferred volume ratio is ethanol: water (v:v)=1:5.
10. Satraplatin JM216 BMS 182751 cyclodextrin complexes according to claim 1, can be used for preparing Satraplatin JM216 BMS 182751 injection, oral formulations etc., comprises the multiple dosage forms such as dry powder, lyophilized powder, aqueous injection, suspensoid, solid oral agent.
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CN106565859A (en) * | 2016-10-14 | 2017-04-19 | 昆明理工大学 | Chiral platinum-cyclodextrin linkage object, preparation method and application thereof |
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CN106565859A (en) * | 2016-10-14 | 2017-04-19 | 昆明理工大学 | Chiral platinum-cyclodextrin linkage object, preparation method and application thereof |
CN106565859B (en) * | 2016-10-14 | 2019-09-27 | 昆明理工大学 | Cyclodextrin-bonded object of a kind of chirality platinum-and its preparation method and application |
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