CN1264501C - Process for preparing white arsenic nano particles - Google Patents
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- CN1264501C CN1264501C CN 200410041822 CN200410041822A CN1264501C CN 1264501 C CN1264501 C CN 1264501C CN 200410041822 CN200410041822 CN 200410041822 CN 200410041822 A CN200410041822 A CN 200410041822A CN 1264501 C CN1264501 C CN 1264501C
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- 239000002105 nanoparticle Substances 0.000 title claims abstract description 33
- GOLCXWYRSKYTSP-UHFFFAOYSA-N arsenic trioxide Inorganic materials O1[As]2O[As]1O2 GOLCXWYRSKYTSP-UHFFFAOYSA-N 0.000 title description 24
- 238000004519 manufacturing process Methods 0.000 title description 2
- 229960002594 arsenic trioxide Drugs 0.000 title 1
- KTTMEOWBIWLMSE-UHFFFAOYSA-N diarsenic trioxide Chemical compound O1[As](O2)O[As]3O[As]1O[As]2O3 KTTMEOWBIWLMSE-UHFFFAOYSA-N 0.000 title 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 30
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000003814 drug Substances 0.000 claims abstract description 21
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 12
- RQNWIZPPADIBDY-UHFFFAOYSA-N arsenic atom Chemical compound [As] RQNWIZPPADIBDY-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229940079593 drug Drugs 0.000 claims abstract description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 11
- 229910052785 arsenic Inorganic materials 0.000 claims abstract description 10
- 239000012153 distilled water Substances 0.000 claims abstract description 9
- 238000002360 preparation method Methods 0.000 claims abstract description 9
- 238000003756 stirring Methods 0.000 claims abstract description 8
- 238000001914 filtration Methods 0.000 claims abstract description 4
- 238000009210 therapy by ultrasound Methods 0.000 claims abstract 2
- 230000001954 sterilising effect Effects 0.000 claims description 3
- 238000004659 sterilization and disinfection Methods 0.000 claims description 3
- 239000002245 particle Substances 0.000 abstract description 18
- IXCSERBJSXMMFS-UHFFFAOYSA-N hcl hcl Chemical compound Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 abstract description 3
- 238000002156 mixing Methods 0.000 abstract description 3
- 239000007788 liquid Substances 0.000 abstract description 2
- 238000000034 method Methods 0.000 abstract description 2
- 230000008569 process Effects 0.000 abstract description 2
- 238000003760 magnetic stirring Methods 0.000 abstract 1
- 230000000694 effects Effects 0.000 description 8
- 239000000203 mixture Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 5
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 4
- 229910052802 copper Inorganic materials 0.000 description 4
- 239000010949 copper Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 230000000259 anti-tumor effect Effects 0.000 description 3
- GCPXMJHSNVMWNM-UHFFFAOYSA-N arsenous acid Chemical compound O[As](O)O GCPXMJHSNVMWNM-UHFFFAOYSA-N 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 238000005054 agglomeration Methods 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 235000013372 meat Nutrition 0.000 description 2
- 239000002088 nanocapsule Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052957 realgar Inorganic materials 0.000 description 2
- 238000010183 spectrum analysis Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- HJTAZXHBEBIQQX-UHFFFAOYSA-N 1,5-bis(chloromethyl)naphthalene Chemical compound C1=CC=C2C(CCl)=CC=CC2=C1CCl HJTAZXHBEBIQQX-UHFFFAOYSA-N 0.000 description 1
- 206010003445 Ascites Diseases 0.000 description 1
- 206010013786 Dry skin Diseases 0.000 description 1
- 206010048612 Hydrothorax Diseases 0.000 description 1
- 206010029240 Neuritis Diseases 0.000 description 1
- 208000012641 Pigmentation disease Diseases 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- -1 compound compounds Chemical class 0.000 description 1
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- 238000000635 electron micrograph Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000011841 epidemiological investigation Methods 0.000 description 1
- 238000000684 flow cytometry Methods 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
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- 201000001119 neuropathy Diseases 0.000 description 1
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- 210000002381 plasma Anatomy 0.000 description 1
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- 239000002994 raw material Substances 0.000 description 1
- 230000008085 renal dysfunction Effects 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 238000004626 scanning electron microscopy Methods 0.000 description 1
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- 208000024891 symptom Diseases 0.000 description 1
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- 210000004881 tumor cell Anatomy 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
一种作为治疗肿瘤药物的砒霜纳米粒的制备工艺，将As2O3和盐酸(HCl)按每毫克质量与每毫升体积之比为1∶(0.02-0.2)的比例混和并磁力搅拌10-20分钟使其充分混和溶解，再按盐酸与乙醇体积比为1∶(5-10)的比例加入乙醇，继续搅拌10-20分钟，50℃-60℃超声处理10-20分钟，按乙醇与蒸馏水体积比1∶(4-5)加入蒸馏水并充分搅拌10-20分钟，分装，微孔过滤除菌后即得无菌可用于肿瘤治疗的As2O3纳米粒。采用本发明所述工艺制造的As2O3纳米粒肉眼见为无色液体状，电镜下可见其密度较均匀一致，形态呈圆形或椭圆形，分散性好，粒径约80nm和40nm。
A preparation process of arsenic nanoparticles as a drug for treating tumors, mixing As 2 O 3 and hydrochloric acid (HCl) at a ratio of 1: (0.02-0.2) per milligram of mass to per milliliter volume and magnetic stirring for 10- Make it fully mix and dissolve for 20 minutes, then add ethanol according to the ratio of hydrochloric acid and ethanol volume ratio of 1: (5-10), continue to stir for 10-20 minutes, 50 ℃ -60 ℃ ultrasonic treatment for 10-20 minutes, press ethanol and ethanol The volume ratio of distilled water is 1: (4-5). Distilled water is added and fully stirred for 10-20 minutes, subpackaged, sterilized by microporous filtration to obtain sterile As 2 O 3 nanoparticles that can be used for tumor treatment. The As 2 O 3 nanoparticles produced by the process described in the present invention are colorless liquid with naked eyes, uniform in density, round or elliptical in shape, good in dispersibility, and about 80nm and 40nm in particle size under an electron microscope.
Description
Technical Field
The present invention relates to a new medicine preparation of traditional medicine arsenic for curing tumor, namely a preparation process of nano granules.
Background
Arsenic trioxide (As)2O3) Has a long history of being used for treating leukemia, As in 19992O3The medicine is approved by the national drug administration, passes the FDA approval in 25.9.2000 months, is widely applied to clinic and achieves remarkable effect. A large number of studies have shown that As2O3The mechanisms of antitumor are mainly growth inhibition, differentiation induction and apoptosis. As2O3The powder is insoluble in water and produces significant toxic side effects if administered orally. The dosage form used clinically is As2O3The injection mainly contains arsenous acid, and after intravenous administration, due to the fact that the arsenic concentration in blood plasma is rapidly increased and rapidly diffused to surrounding tissues, the injection can cause patients to have digestive tract symptoms, peripheral neuritis, dryskin, pigmentation, even toxic and side effects such as renal dysfunction or hydrothorax and ascites, and particularly epidemiological investigation finds that the occurrence of certain tumors is related to the accumulation amount of arsenic. We are therefore seeing As2O3The clinical application value of the composition is realized, and simultaneously, the composition can be used for preparing a new medicament form, so that the dosage is reduced, the curative effect is improved, and the composition has important clinical significance. Nanotechnology is considered to be one of the most promising fields in the 21 st century, and in the field of drug research, due to the continuous penetration and influence of nanotechnology, a profound revolution in the field of drugs is initiated, and a new term of nano drugs appears. The nano-drug is nano-particles (NP) orNanospheres (NS), Nanocapsules (NC), etc. are carriers that are combined with drugs in a manner to produce drugs that may have particle sizes in excess of 100nm, but are typically less than 500 nm. The nano-drug can also be a nano-particle prepared by directly processing the raw material drug. The National Science and Technology Committee (NSTC) proposed nanotechnology development report forecast in 2000: about 50% of the drugs in the market sales will be applied by nanotechnology in the whole world in the next 10 years. In recent years, nanotechnology has begun to be widely regarded in traditional Chinese medicine research and application in China, and a new concept of nano traditional Chinese medicine is created, so that certain progress has been made in the aspects of traditional Chinese medicine effective components, effective parts, raw medicines, compound compounds, novel preparations and the like manufactured by adopting nanotechnology. Xuhuibi and the like prepare nano abalone shell and realgar particles, and research shows that the nano abalone shell and realgar particles have good anti-tumor effect.
Disclosure of Invention
The invention provides a process for preparing nano-scale arsenic nanoparticles, which can improve the drug effect of arsenic on treating solid tumors and reduce the dosage, thereby effectively reducing the toxic and side effects of arsenic.
The invention adopts the following technical scheme:
a preparation method of arsenicum nanoparticle for treating tumor comprises adding As2O3Mixing with hydrochloric acid (HCl) at a ratio of 1: 0.02-0.2 in terms of mass per milligram to volume per milliliter, magnetically stirring for 10-20 minutes to fully mix and dissolve the HCl and the HCl, adding ethanol at a ratio of 1: 5-10 in terms of volume of the HCl and the ethanol, continuously stirring for 10-20 minutes, ultrasonically treating for 10-20 minutes at 50-60 ℃, adding distilled water at a ratio of 1: 4-5 in terms of volume of the ethanol and the distilled water, fully stirring for 10-20 minutes, subpackaging, and filtering for sterilization to obtain sterile As for tumor treatment2O3And (3) nanoparticles.
The preparation principle of the invention is the following equation: ； ； ； its structural features and physical characteristics: (1) form; (2) and the particle size; (3) and performing energy spectrum analysis.
Compared with the prior art, the invention has the following advantages:
as produced by the process of the present invention2O3The nano-particlemeat is in a colorless liquid state, the density of the nano-particle meat is relatively uniform under an electron microscope, the nano-particle meat is in a round or oval shape, the dispersibility is good, and the particle size is about 80nm and 40 nm. Electron microscope energy spectrum analysis, using a probe to hit on a single nanoparticle, wherein only the components of carbon, oxygen, arsenic and copper (carbon, oxygen and copper are all components of copper net, copper is removed As background in fig. 4) can be hit in the energy spectrum, which indicates that the prepared nanoparticle is indeed As2O3. When a material is processed to nanometer size (1-100 nm), it exhibits many specific properties due to its size close to the wavelength of light and its large surface area. Surface effects refer to the smaller the size of the particle, the larger the surface area. E.g. a specific surface area of 90m at a particle size of 10nm2·g-1: when the particle diameter is 5nm, the specific surface area is 180m2·g-1(ii) a When the particle diameter is as small as 2nm, the specific surface area is increased to 450m2·g-1. Such a large specific surface area results in a rapid increase in the surface energy due to the increasing number of atoms present on the surface, and thus the nanoparticles have a high chemical activity. As2O3Belongs to mineral traditional Chinese medicine, the powder of the traditional Chinese medicine is insoluble in water, has high electron density under an electron microscope, is in a square, polygonal or irregular crystal shape, and has the average diameter of about 5 mu m. The traditional arsenous acid injection for clinical use is an alkaline solution, although the particle size of the particles in the solution is small, the dispersibility is poor, the particles are easy to form agglomeration, and the particle size of the particles is increased after a plurality of particles are agglomerated. As prepared by the present invention2O3The nano-particles have very good dispersibility and little agglomeration among the particles, so the particles have very large sizeSurface energy and chemical activity to make As2O3The efficacy of the composition is enhanced.
As prepared by the present invention for the laboratory2O3The nanoparticles are used for carrying out in-vitro treatment experiments on human hepatoma cells SMMC-7721, and MTT and flow cytometry experiments prove that As is2O3The nanoparticles can generate obvious cytotoxic effect on tumor cells, and the cell survival rate is obviously lower than that of As with the same concentration2O3Solution treatment group. As compared with the clinical arsenous acid injection through in vitro cell experiments2O3The nanoparticles show better antitumor effect. As2O3The nano-particle is expected to become As2O3A new dosage form for treating tumor is As2O3Opens up a new way for clinical application.
Drawings
FIG. 1 is As2O3A projection electron micrograph of the powder;
FIG. 2 is As2O3The diameter of the nanoparticle is about 80nm in a transmission electron microscope picture 1 of the nanoparticle;
FIG. 3 is As2O3Transmission electron microscope photograph 2 of nanoparticles having a diameter of about 40 nm;
FIG. 4 is As2O3The nanoparticles were analyzed by scanning electron microscopy.
FIG. 5 As2O3Solution and As2O3The comparative survival rate concentration after the nanoparticles are used for treating SMMC-7721 cells is 5 mu mol/L (b) the concentration is 10 mu mol/L, and NP is the nanoparticles.
FIG. 6 As2O3Solution and As2O3After the nanoparticles are used for treating SMMC-7721 cells, a normal control group of apoptosis rate (A) is determined by a flow cytometer; (B)5 μmol/LAs2O3A solution group; (C)5 μmol/LAs2O3A set of nanoparticles; (D) 10. mu. mol/LAs2O3Solution group: (E) 10. mu. mol/LAs2O3Nano particleAnd (4) grouping.
Detailed Description
A preparation method of arsenicum nanoparticle for treating tumor comprises adding As2O3Mixing with hydrochloric acid (HCl) at a ratio of 1: 0.02-0.2 in terms of mass per milligram to volume per milliliter, magnetically stirring for 10-20 minutes to fully mix and dissolve the HCl and the HCl, adding ethanol at a ratio of 1: 5-10 in terms of volume of the HCl and the ethanol, continuously stirring for 10-20 minutes, ultrasonically treating for 10-20 minutes at 50-60 ℃, adding distilled water at a ratio of 1: 4-5 in terms of volume of the ethanol and the distilled water, fully stirring for 10-20 minutes, subpackaging, and filtering for sterilization to obtain sterile As for tumor treatment2O3Nanoparticles, in this example, As2O3The ratio of hydrochloric acid and hydrochloric acid can be selected to be 1: 0.03, 1: 0.05, 1: 0.08, 1: 0.1, 1: 0.13, 1: 0.145, 1: 0.18, 1: 0.19, the volume ratio of hydrochloric acid to ethanol can be selected to be 1: 6, 1: 7.5, 1: 9, the volume ratio of ethanol to distilled water can be selected to be 1: 4.2, 1: 4.5, 1: 4.65, 1: 4.9.
Claims (1)
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410041822 CN1264501C (en) | 2004-08-31 | 2004-08-31 | Process for preparing white arsenic nano particles |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410041822 CN1264501C (en) | 2004-08-31 | 2004-08-31 | Process for preparing white arsenic nano particles |
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| Publication Number | Publication Date |
|---|---|
| CN1615904A CN1615904A (en) | 2005-05-18 |
| CN1264501C true CN1264501C (en) | 2006-07-19 |
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| CN 200410041822 Expired - Fee Related CN1264501C (en) | 2004-08-31 | 2004-08-31 | Process for preparing white arsenic nano particles |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| GB0620335D0 (en) * | 2006-10-12 | 2006-11-22 | Rgb Res Ltd | Nanostructures |
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Granted publication date: 20060719 Termination date: 20130831 |