CN1269487C - Arsenic trioxide oral liquid and its preparation process - Google Patents
Arsenic trioxide oral liquid and its preparation process Download PDFInfo
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- CN1269487C CN1269487C CN 200310118274 CN200310118274A CN1269487C CN 1269487 C CN1269487 C CN 1269487C CN 200310118274 CN200310118274 CN 200310118274 CN 200310118274 A CN200310118274 A CN 200310118274A CN 1269487 C CN1269487 C CN 1269487C
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- Prior art keywords
- arsenic trioxide
- oral liquid
- suspension
- injection
- solution
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- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- HJTAZXHBEBIQQX-UHFFFAOYSA-N 1,5-bis(chloromethyl)naphthalene Chemical compound C1=CC=C2C(CCl)=CC=CC2=C1CCl HJTAZXHBEBIQQX-UHFFFAOYSA-N 0.000 title claims abstract description 27
- GOLCXWYRSKYTSP-UHFFFAOYSA-N arsenic trioxide Inorganic materials O1[As]2O[As]1O2 GOLCXWYRSKYTSP-UHFFFAOYSA-N 0.000 title claims abstract description 27
- 239000007788 liquid Substances 0.000 title claims abstract description 18
- 238000002360 preparation method Methods 0.000 title description 2
- 238000004519 manufacturing process Methods 0.000 claims abstract description 9
- 235000020374 simple syrup Nutrition 0.000 claims abstract description 8
- 239000008227 sterile water for injection Substances 0.000 claims abstract description 8
- 239000000725 suspension Substances 0.000 claims abstract description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000000243 solution Substances 0.000 claims abstract description 7
- 235000002710 Ilex cornuta Nutrition 0.000 claims description 5
- 241001310146 Ilex cornuta Species 0.000 claims description 5
- 235000010326 Osmanthus heterophyllus Nutrition 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 5
- 238000012856 packing Methods 0.000 claims description 5
- 230000001954 sterilising effect Effects 0.000 claims description 5
- 238000004659 sterilization and disinfection Methods 0.000 claims description 5
- 238000005303 weighing Methods 0.000 claims description 2
- GCPXMJHSNVMWNM-UHFFFAOYSA-N arsenous acid Chemical compound O[As](O)O GCPXMJHSNVMWNM-UHFFFAOYSA-N 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 abstract 3
- 210000003462 vein Anatomy 0.000 abstract 1
- 231100000111 LD50 Toxicity 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 208000036762 Acute promyelocytic leukaemia Diseases 0.000 description 5
- 206010028980 Neoplasm Diseases 0.000 description 5
- 208000033826 Promyelocytic Acute Leukemia Diseases 0.000 description 5
- 229910052785 arsenic Inorganic materials 0.000 description 4
- RQNWIZPPADIBDY-UHFFFAOYSA-N arsenic atom Chemical compound [As] RQNWIZPPADIBDY-UHFFFAOYSA-N 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000012467 final product Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 229940090044 injection Drugs 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- 230000001186 cumulative effect Effects 0.000 description 2
- 208000032839 leukemia Diseases 0.000 description 2
- 231100000614 poison Toxicity 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 1
- 101100372758 Danio rerio vegfaa gene Proteins 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 108010017842 Telomerase Proteins 0.000 description 1
- 101150030763 Vegfa gene Proteins 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 229940030689 arsenic trioxide injection Drugs 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 238000009395 breeding Methods 0.000 description 1
- 230000001488 breeding effect Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 241000411851 herbal medicine Species 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 231100000636 lethal dose Toxicity 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000021332 multicellular organism growth Effects 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 230000007096 poisonous effect Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention provides a production method for arsenic trioxide oral medicinal liquid. The present invention comprises the procedures that 1, arsenic trioxide is weighed and is arranged in a sterile container, and proper sterile water for injection is added in sterile container so as to prepare suspension; 2, the suspension is heated, stirred and dissolved, and proper simple syrup is subsequently added so as to prepare a solution; 3, the pH value of the solution is adjusted to 3 to 5 by citric acid, and the solution is charged via split and sterilized. The present invention also provides arsenic trioxide oral medicinal liquid prepared by the method, and the safety of the arsenic trioxide oral medicinal liquid is superior to that of vein administration.
Description
Technical field
The present invention relates to medicine preparation, especially a kind of arsenic trioxide oral liquid.
Background technology
At present, arsenic trioxide is used for treating the effect of leukemia and other entity tumors extensively to be approved in the world, thereby arsenic trioxide becomes a big focus of leukemia and treatment of solid tumor research.
Studies show that, a small amount of arsenic (lethal dose is 70～180mg/ time) for oral administration can promote the synthetic of protein in body, stimulate bone marrow hematogenesis, help body growth and breeding, and may pass through protoplasmic poison kill tumor cell (referring to Guo Xiaozhuan, poisonous Chinese herbal medicine voluminous dictionary, Tianjin Scientific English Translation publishing house, 1992).
Arsenic trioxide all has significant curative effect to the acute promyelocytic leukemia (APL) with refractory that just control, recurrence, its complete remission rate (CR) is respectively 87.9%, 88.4% and 48.7%, 5 years and 7 probabilities of living in a year reach 90% and 70% respectively (referring to Zhang Peng, Chinese Journal of Hematology, 2000,2).
U.S. FDA official approval arsenic trioxide is used for the treatment of AML, MM, MDS, CML and five indications of APL.Aspect entity tumor, China and all have big quantity research document to prove that it is by following several mechanism of action treatment tumors abroad:
(1) cell death inducing;
(2) suppress the tumor cell vegf expression;
(3) antitumor cell signal conduction;
(4) expression of rise neoplasm metastasis inhibitive factor;
(5) suppress the tumor cell telomerase activation;
(6) artitumor multi-medicine-resistant factor expression etc.
But the production dosage form of the China and the U.S. is the liquid drugs injection type all at present, and it has the following disadvantages:
(1) breakage rate height all has higher breakage rate in producing, transport, store, using;
(2) present arsenic trioxide injection especially below 5 degrees centigrade the time, is easily separated out crystallization when temperature is lower than 16 degrees centigrade, not only cause the character instability, and affect the treatment;
(3) in case liquid drugs injection peace bottle opening just must once be used up, easily cause waste sometimes, the patient considers for economic aspect, uses preserving after once exhaustless liquid drugs injection breaks a seal sometimes, has increased the incidence rate of side effect such as infusion reaction;
The most important thing is that (4) no matter arsenic trioxide is treatment APL or entity tumor, the general treatment method all is once a day, and continuous 30～60 days, certain interval of time carried out next one course of treatment.APL will keep medication 5 years, and other indication administration times also were not less than 1 year, long-time a large amount of intravenously administrable, patient's misery and financial burden (intravenously administrable must be in hospital) have been strengthened, especially for rural patient, go to hospital and abandon keeping treatment owing to inconvenience, cause recurrence and delay treatment.
So the exploitation oral liquid will bring to the patient and greatly facilitate and interests.
Summary of the invention
The invention provides a kind of production method of arsenic trioxide oral liquid, it may further comprise the steps:
(1) takes by weighing arsenic trioxide, place sterile chamber, add an amount of sterile water for injection, make suspension;
(2) with the extremely dissolving of suspension heated and stirred, add an amount of simple syrup again, make solution;
(3) pH value to 3～5 of transferring solution with the acid of Chinese holly edge, the packing sterilization.
In the production method of above-mentioned arsenic trioxide oral liquid, in described step (1), the preferable ratio of using arsenic trioxide and sterile water for injection is 1mg: 1.6ml.
In the production method of above-mentioned arsenic trioxide oral liquid, in described step (2), the simple syrup of preferable adding and the volume ratio of suspension are 0.4: 1.6.
The present invention also provides the arsenic trioxide that is made by aforementioned production method oral liquid.
The specific embodiment
The following examples will be further explained the present invention, but the present invention is not limited only to these embodiment, the scope that these embodiment do not limit the present invention in any way.Some change that those skilled in the art is made within the scope of the claims and adjust also should be thought and belongs to scope of the present invention.
Embodiment 1
The 1000mg arsenic trioxide adds the 1600ml sterile water for injection, and heating for dissolving adds the 400ml simple syrup again, and with Chinese holly edge acid adjust pH to 3.5, the packing sterilization gets final product every bottle of 10ml trioxygen-containingization two arsenic 5mg.
Embodiment 2
The 2000mg arsenic trioxide adds the 3150ml sterile water for injection, and heating for dissolving adds the 850ml simple syrup again, and with Chinese holly edge acid adjust pH to 3.0, the packing sterilization gets final product every bottle of 10ml trioxygen-containingization two arsenic 5mg.
Embodiment 3
The 1000mg arsenic trioxide adds the 1600ml sterile water for injection, and heating for dissolving adds the 400ml simple syrup again, and with Chinese holly edge acid adjust pH to 5.0, the packing sterilization gets final product every bottle of 10ml trioxygen-containingization two arsenic 5mg.
Embodiment 4
The result of animal experiment study shows, the arsenic trioxide oral administration, and the median lethal dose(LD 50) of mice is 23mg/kg, the median lethal dose(LD 50) of the mice of intravenously administrable is 12mg/kg, illustrates that the oral administration safety exceeds one times of intravenously administrable.Suppose that the clinical treatment amount is 10mg/ people's every day, body weight for humans is pressed 60kg and is calculated, i.e. 0.17mg/kg, this amount be about mice median lethal dose(LD 50) 1/135, the safety of visible arsenic trioxide oral liquid is than intravenously administrable height.
The subacute cumulative toxicity of oral administration is measured, and the KC value is greater than 5, and is consistent with intravenously administrable KC value, and prompting does not have marked difference with intravenously administrable aspect cumulative toxicity.
Above experimental result explanation, the safety of arsenic trioxide oral liquid is better than intravenously administrable.
Claims (2)
1. the production method of an arsenic trioxide oral liquid, it may further comprise the steps:
(1) take by weighing arsenous acid, place sterile chamber, add an amount of sterile water for injection, make suspension, the ratio of use therein arsenic trioxide and sterile water for injection is 1mg: 1.6ml;
(2) with the extremely dissolving of suspension heated and stirred, add an amount of simple syrup again, make solution, wherein the volume ratio of simple syrup of Jia Ruing and suspension is 0.4: 1.6;
(3) pH value to 3～5 of transferring solution with the acid of Chinese holly edge, the packing sterilization.
2. the arsenic trioxide oral liquid that makes by the described production method of claim 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200310118274 CN1269487C (en) | 2003-12-09 | 2003-12-09 | Arsenic trioxide oral liquid and its preparation process |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200310118274 CN1269487C (en) | 2003-12-09 | 2003-12-09 | Arsenic trioxide oral liquid and its preparation process |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1546059A CN1546059A (en) | 2004-11-17 |
| CN1269487C true CN1269487C (en) | 2006-08-16 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200310118274 Expired - Fee Related CN1269487C (en) | 2003-12-09 | 2003-12-09 | Arsenic trioxide oral liquid and its preparation process |
Country Status (1)
| Country | Link |
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| CN (1) | CN1269487C (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8906422B2 (en) | 2002-10-09 | 2014-12-09 | The University Of Hong Kong | Method for inhibiting cancer using arsenic trioxide |
| US20080089949A1 (en) * | 2006-10-13 | 2008-04-17 | Yok-Lam Kwong | Method for treating cancer using oral arsenic trioxide |
| CN103393719B (en) * | 2013-08-07 | 2014-07-23 | 骆红宇 | Production method of arsenic trioxide oral liquid |
| CN104784228A (en) * | 2014-01-20 | 2015-07-22 | 中国中医科学院中药研究所 | Traditional Chinese medicine for alleviating toxicity of arsenic trioxide, and effective component thereof |
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2003
- 2003-12-09 CN CN 200310118274 patent/CN1269487C/en not_active Expired - Fee Related
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| Publication number | Publication date |
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| CN1546059A (en) | 2004-11-17 |
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Owner name: SHANGHAI YAOJIAN MEDICAL TECHNOLOGY CO., LTD. Free format text: FORMER OWNER: CHONGQING WEITERUI MEDICINE DEVELOPMENT CO., LTD. Effective date: 20111212 |
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Free format text: CORRECT: ADDRESS; FROM: 400047 YUBEI, CHONGQING TO: 200063 PUTUO, SHANGHAI |
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Effective date of registration: 20111212 Address after: 200063, room 603, D District, 137 Lanxi Road, Shanghai, Putuo District Patentee after: Shanghai tele Medical Technology Co., Ltd. Address before: 400047, No. 29, West Flower Road, Longxi Town, Chongqing, Yubei District, 24-1 Patentee before: Chongqing Weiterui Medicine Development Co., Ltd. |
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Granted publication date: 20060816 Termination date: 20201209 |
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