CN1299668C - Nanometer realgar solid dispersion and its preparation method - Google Patents
Nanometer realgar solid dispersion and its preparation method Download PDFInfo
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- CN1299668C CN1299668C CNB031282911A CN03128291A CN1299668C CN 1299668 C CN1299668 C CN 1299668C CN B031282911 A CNB031282911 A CN B031282911A CN 03128291 A CN03128291 A CN 03128291A CN 1299668 C CN1299668 C CN 1299668C
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Abstract
Nanometer realgar predominantly enhances the biological availability and the antitumous effect of realgar, but the problem that a main component As2S2 of the nanometer realgar can be oxidized and agglomerated in use influences the pharmacodynamic exertion of the nanometer realgar. Aiming at the problem, nanometer realgar solid dispersion of the present invention uses nanometer realgar as an active component, uses high molecular polymer as a carrier, and is also added with an antioxidant and a surface active agent. A measurement result indicates that the present invention solves the problem of the oxidization and the agglomeration of nanometer realgar. Simultaneously, the present invention also discloses two methods for preparing the nanometer realgar solid dispersion, namely a melting method and a solvent volatilization method.
Description
Invention field
The present invention relates to a kind of nanometer-size realgar solid dispersion that prevents nanometer-size realgar oxidation and reunion, and the preparation method of this solid dispersion.
Background of invention
Realgar is traditional mineral Chinese medicine, and its main component is As
2S
2, Xin Wen is poisonous, goes into liver stomach warp.Has the effect that detoxifcation parasite killing, dampness are removed wind, transforming phlegm and dispersing accumulations.The Realgar that studies show that in recent years can pass through inducing apoptosis of tumour cell, suppress mechanism performance antitumor actions such as cell DNA is synthetic, enhancing body's immunological function, demonstrates wide application prospect.Clinically at present, Realgar also is used for treating other malignant hematologic disease such as chronic myelocytic leukemia, myelodysplastic syndrome etc. widely except being used for the treatment of acute promyelocytic leukemia.
As mineral Chinese medicine, the main effective ingredient As of Realgar
2S
2Be insoluble in water, bioavailability is low, and using dosage is big, influences therapeutic effect.Adopt nanotechnology that the Chinese medicine Realgar is prepared into nanoparticle, significantly improved bioavailability and antitumous effect (referring to patent CN1288723A).
But in use nanometer-size realgar exists following two subject matters: the 1. main constituent As of Realgar
2S
2Can be oxidized when in air and under the sunlight, exposing and be transformed into As
2S
3And As
2O
3Mixture.As
2O
3, being commonly called as arsenicum, severe toxicity is the main component of poisoning when causing the Realgar constant to use.2. because nanoparticle has very high surface energy, and there is agglomeration in nanometer-size realgar, this has influenced the performance of its nano effect.
About the problem of oxidation, doctor family just takes much count of the process of preparing Chinese medicine detoxification of Realgar since ancient times, promptly flies by water or dried traditional method such as grind is removed As in the Realgar
2O
3, but the problem of oxidation of Realgar in storage process after concocting often paid attention to inadequately.Compare with plain particles, because skin effect, nanoparticle has very high chemism, and for nanometer-size realgar, its As
2S
2The easier As that is oxidized to
2O
3So, prevent that the oxidation of nanometer-size realgar when storing is very important.
At present the carrier that solid dispersion is commonly used mainly contains following several: 1. high molecular polymer be a crystalline high polymer as polyethylene glycols (PEG), and chemical property is stablized, and is heat-resisting; 2. sugar, organic acid, ureas, can with multiple medicine with hydrogen bond association; 3. fat-soluble carrier can delay drug release, as cholesterol, cupreol etc.; 4. Hydroxypropyl Methylcellulose Phathalate, Cellulose ethyl hydroxypropyl ether, cellulose acetate-phthalate etc.According to existing disclosed solid dispersion, still to be difficult nanometer-size realgar be active component and prevent to be reported by the technology of the solid dispersion of dispersion medicine oxidation and reunion.
Summary of the invention
The invention provides a kind of nanometer-size realgar solid dispersion and preparation method thereof, solved the oxidation and the agglomeration traits of nanometer-size realgar.
Nanometer-size realgar solid dispersion of the present invention is an active component with the nanometer-size realgar, is carrier with the high molecular polymer, also is added with antioxidant and surfactant.
The composition of nanometer-size realgar solid dispersion of the present invention is based on the nanometer-size realgar powder of 1 weight portion, 1～1000nm particle diameter; 0.1～50 weight portion carriers; 0.01～10 weight portion antioxidants and 0～20 weight portion surfactant.
Carrier comprises one of following polyphosphazene polymer and thing: polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), crospolyvinylpyrrolidone (PVPP), vinyl pyrrolidone-vinyl acetate copolymer (PVP/VA), ethylene-vinyl acetate copolymer (EVA), Polyethylene Glycol (PEG), poloxamer.
The antioxidant that adopts comprises one of following chemical compound: vitamin C, sodium pyrosulfate, sodium sulfite, sodium thiosulfate, 1-Thiosorbitol, disodium edetate, mercaptosuccinic acid., L-arginine, L-tryptophan.
Surfactant is selected from nonionic, anion, cation or amphiphilic surfactant, comprises one of following chemical compound: polysorbas20, polysorbate60, Tween 80, Myrij 35, sodium laurylsulfate, dodecyl sodium sulfate, lecithin.
The preparation method of nanometer-size realgar solid dispersion of the present invention is: (1) fusion method: under nitrogen protection; with fusing point is that 30～150 ℃ macromolecule carrier substrate is heated to molten state; stir and add nanometer-size realgar, antioxidant and surfactant down; stir after 10～40 minutes; be transferred to the ice bath cooling rapidly; put into exsiccator ageing certain hour, grinding is sieved, and gets the light yellow solid powdered product.(2) solvent evaporation method: under nitrogen protection; the high-melting-point or the labile macromolecule carrier that is heated are added organic solvent; such as dehydrated alcohol, methanol, dichloromethane, chloroform, ethyl acetate; until dissolving; add nanometer-size realgar, antioxidant and surfactant then, stir, make organic solvent evaporation to most (as spray drying or rotary evaporation etc.) get solid again; grinding is sieved, and gets the light yellow solid powdered product.
Nanometer-size realgar solid dispersion of the present invention, the adding of antioxidant has solved the problem of oxidation of nanometer-size realgar.The adding of surfactant makes that then the dispersion of nanometer-size realgar is even, more stable when depositing more.Measurement result shows that the present invention has well solved the oxidation and the agglomeration traits of nanometer-size realgar, lays a good foundation for further preparing ideal nanometer-size realgar preparation.
The product that has provided nanometer-size realgar and each embodiment in the following table 1 was preserved 30 days As under room temperature in dry environment
2O
3The changing value of content and particle diameter.As
2O
3Content is measured by 2000 editions pharmacopeia appendix arsenic salt detection methods, and particle diameter is measured by laser light scattering method.
As when table 1. nanometer-size realgar stores
2O
3The situation of change of content and particle diameter
| Sample | As 2O 3Content | Particle diameter | ||
| Before depositing | After 30 days | Before depositing | After 30 days | |
| Nanometer-size realgar embodiment 1 embodiment 2 embodiment 3 embodiment 4 embodiment 5 embodiment 6 embodiment 7 | 3.043mg/g 3.043mg/g 3.043mg/g 3.043mg/g 3.043mg/g 3.043mg/g 3.043mg/g 3.043mg/g | 13.681mg/g 3.109mg/g 3.162mg/g 3.113mg/g 3.088mg/g 3.076mg/g 3.069mg/g 3.107mg/g | 303.4nm 303.4nm 303.4nm 303.4nm 303.4nm 303.4nm 303.4nm 303.4nm | 678.5nm 311.3nm 307.8nm 306.5nm 321.6nm 318.7nm 305.3nm 322.3nm |
Description of drawings
Accompanying drawing 1: arsenic trioxide content change curve in time among nanometer-size realgar and the embodiment 2
Series 1 expression nanometer-size realgar, the product of series 2 expression embodiment 2.
Accompanying drawing 2: the scanning electron microscope of nanometer-size realgar and embodiment 2 (JSM-5510LV type) photo
A is the nanometer-size realgar powder body, and B is the product of embodiment 2.
The specific embodiment
Embodiment one
Take by weighing 1 weight portion PEG4000, under nitrogen protection, be heated to fusion, stir adding 1 weight portion nanometer-size realgar and 1 weight portion sodium pyrosulfate down, stir 20min, be transferred to the ice bath cooling rapidly, put into exsiccator ageing certain hour, ground 100 mesh sieves promptly.
Embodiment two
Take by weighing 9 weight portion PEG4000, under nitrogen protection, be heated to fusion; stir adding 1 weight portion nanometer-size realgar, 3 weight portion sodium sulfite and 3 weight portion Tween 80s down, stir 20min, be transferred to the ice bath cooling rapidly; put into exsiccator ageing certain hour, ground 100 mesh sieves promptly.
Product was deposited under room temperature 30 days in dry environment, and arsenic trioxide content is constant substantially in the holding time, and obvious agglomeration does not take place; And arsenic trioxide content sharply increase with the prolongation of resting period in the nanometer-size realgar under the same terms, it is serious to reunite, and sees attached Fig. 1 and 2.
Embodiment three
Take by weighing 5 weight portion PEG6000, under nitrogen protection, be heated to fusion; stir adding 1 weight portion nanometer-size realgar, 1 weight portion mercaptosuccinic acid. and 5 weight portion Myrij 35 down, stir 30min, be transferred to the ice bath cooling rapidly; put into exsiccator ageing certain hour, ground 100 mesh sieves promptly.
Embodiment four
Take by weighing 10 weight portion PEG20000, under nitrogen protection, be heated to fusion; stir adding 1 weight portion nanometer-size realgar, 5 weight portion vitamin Cs and 6 weight portion disodium edetate down, stir 30min, be transferred to the ice bath cooling rapidly; put into exsiccator ageing certain hour, ground 100 mesh sieves promptly.
Embodiment five
Take by weighing 10 weight portion PVP k15, under nitrogen protection, use an amount of anhydrous alcohol solution, add 1 weight portion nanometer-size realgar, 7 weight portion sodium sulfite stir, rotary evaporation is removed dehydrated alcohol, solid, ground 100 mesh sieves promptly.
Embodiment six
Take by weighing 1 weight portion PVP k15, under nitrogen protection, use an amount of anhydrous alcohol solution, add 1 weight portion nanometer-size realgar, 3 weight portion sodium sulfite and 10 weight portion Tween 80s and stir, rotary evaporation is removed dehydrated alcohol, gets solid, grinds 100 mesh sieves promptly.
Embodiment seven
Take by weighing 1 weight portion PVP k30, under nitrogen protection, use an amount of anhydrous alcohol solution; adding 1 weight portion nanometer-size realgar, 3 weight portion sodium thiosulfate and 15 weight portion Tween 80s stirs; rotary evaporation is removed dehydrated alcohol, gets solid, grinds 100 mesh sieves promptly.
Claims (7)
1. nanometer-size realgar solid dispersion, it is characterized in that: be made up of following component and weight portion thereof: with 1～1000nm particle diameter, the nanometer-size realgar of 1 weight portion is an active component; 0.1 the high molecular polymer of～50 weight portions is a carrier; Be added with the antioxidant of 0.01～10 weight portion and the surfactant of 0～20 weight portion.
2. according to the nanometer-size realgar solid dispersion of claim 1, described carrier comprises one of following chemical compound: polyvinyl alcohol, polyvinylpyrrolidone, crospolyvinylpyrrolidone, vinyl pyrrolidone-vinyl acetate copolymer, ethylene-vinyl acetate copolymer, Polyethylene Glycol, poloxamer.
3. according to the nanometer-size realgar solid dispersion of claim 1, described antioxidant comprises one of following chemical compound: vitamin C, sodium pyrosulfate, sodium sulfite, sodium thiosulfate, 1-Thiosorbitol, disodium edetate, mercaptosuccinic acid., L-arginine, L-tryptophan.
4. according to the nanometer-size realgar solid dispersion of claim 1, described surfactant comprises one of following compounds: polysorbas20, polysorbate60, Tween 80, Myrij 35, sodium laurylsulfate, dodecyl sodium sulfate, lecithin.
5. the preparation method of claim 1 nanometer-size realgar solid dispersion; it is characterized in that; under nitrogen protection; with fusing point is that 30～150 ℃ macromolecule carrier substrate is heated to molten state, stirs to add nanometer-size realgar, antioxidant and surfactant down, stirs after 10～40 minutes; be transferred to the ice bath cooling rapidly; put into exsiccator ageing certain hour, grinding is sieved, and gets the light yellow solid powdered product.
6. the preparation method of claim 1 nanometer-size realgar solid dispersion; it is characterized in that; under nitrogen protection; macromolecule carrier is added organic solvent until dissolving, add nanometer-size realgar, antioxidant and surfactant then, stir; make organic solvent evaporation to most again; get solid, grinding is sieved, and gets the light yellow solid powdered product.
7. according to the preparation method of the said nanometer-size realgar solid dispersion of claim 6, it is characterized in that said organic solvent is one of following solvent: dehydrated alcohol, methanol, dichloromethane, chloroform, ethyl acetate.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB031282911A CN1299668C (en) | 2003-07-08 | 2003-07-08 | Nanometer realgar solid dispersion and its preparation method |
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|---|---|---|---|
| CNB031282911A CN1299668C (en) | 2003-07-08 | 2003-07-08 | Nanometer realgar solid dispersion and its preparation method |
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|---|---|
| CN1478486A CN1478486A (en) | 2004-03-03 |
| CN1299668C true CN1299668C (en) | 2007-02-14 |
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|---|---|---|---|
| CNB031282911A Expired - Lifetime CN1299668C (en) | 2003-07-08 | 2003-07-08 | Nanometer realgar solid dispersion and its preparation method |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20210155901A1 (en) * | 2018-04-11 | 2021-05-27 | Institute Of Basic Medical Sciences Chinese Academy Of Medical Sciences | Use of water-soluble realgar solid dispersion in preparation of erythroid differentiation inducer for bone marrow hematopoietic stem cells and/or bone marrow hematopoietic progenitor cells |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100374463C (en) * | 2005-03-05 | 2008-03-12 | 广西师范大学 | Method for preparing nanometer realgar gel and nanometer realgar with biomacromolecule template to regulate shape and particle thereof |
| CN105079814B (en) * | 2014-05-12 | 2018-07-24 | 中国药科大学 | A kind of realgar of modified with folic acid-mesoporous monox nanometer combination drug |
| CN106236773B (en) * | 2015-06-12 | 2021-04-02 | 中国医学科学院基础医学研究所 | Water-soluble realgar solid dispersion and preparation method and application thereof |
| CN107320489A (en) * | 2017-04-15 | 2017-11-07 | 安徽天康(集团)股份有限公司 | The application of a kind of nanometer-size realgar medically and preparation method thereof |
| CN106890191A (en) * | 2017-04-27 | 2017-06-27 | 兰州大学 | A kind of biological concocting method of nanometer-size realgar |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1288723A (en) * | 2000-09-25 | 2001-03-28 | 华中科技大学 | Nanometer-size realgar and its preparation |
-
2003
- 2003-07-08 CN CNB031282911A patent/CN1299668C/en not_active Expired - Lifetime
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1288723A (en) * | 2000-09-25 | 2001-03-28 | 华中科技大学 | Nanometer-size realgar and its preparation |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20210155901A1 (en) * | 2018-04-11 | 2021-05-27 | Institute Of Basic Medical Sciences Chinese Academy Of Medical Sciences | Use of water-soluble realgar solid dispersion in preparation of erythroid differentiation inducer for bone marrow hematopoietic stem cells and/or bone marrow hematopoietic progenitor cells |
| US11976300B2 (en) * | 2018-04-11 | 2024-05-07 | Institute Of Basic Medical Sciences Chinese Academy Of Medical Sciences | Use of water-soluble realgar solid dispersion in preparation of erythroid differentiation inducer for bone marrow hematopoietic stem cells and/or bone marrow hematopoietic progenitor cells |
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| Publication number | Publication date |
|---|---|
| CN1478486A (en) | 2004-03-03 |
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