CN102335130A - Preparation method of anti-tumor medicinal n-methylcantharidimide injection - Google Patents
Preparation method of anti-tumor medicinal n-methylcantharidimide injection Download PDFInfo
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- CN102335130A CN102335130A CN2011103058725A CN201110305872A CN102335130A CN 102335130 A CN102335130 A CN 102335130A CN 2011103058725 A CN2011103058725 A CN 2011103058725A CN 201110305872 A CN201110305872 A CN 201110305872A CN 102335130 A CN102335130 A CN 102335130A
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Abstract
The invention relates to a preparation method of anti-tumor medicinal n-methylcantharidimide injection. The method is characterized in that: the injection comprises n-methylcantharidimide, solubilizing agent and water, wherein the solubilizing agent is a mixed solution of tween-80 and propylene glycol, the mass ratio of the tween-80 to the propylene glycol is 1:20-10:1, and the sum of the mass concentration of the tween-80 and the propylene glycol in the injection is 0.2 to 3.0 percent; and the mass concentration of the n-methylcantharidimide in the injection is 5 to 20 percent. By the method, the dissolubility of the n-methylcantharidimide is improved, solute hydrolysis can be prevented, the stability of the preparation is improved, and the risk of hemolysis caused by tween-80 is reduced.
Description
Technical field
The present invention relates to a kind of method for preparing of antineoplastic agent N-methylcantharidimide injection.
Background technology
N-methylcantharidimide (Methyleatharidinimide) is the derivant of cantharidin, aspect anticancer and the liter white two very big effect being arranged all, cancerous cell is had directly kill and inhibitory action; Stimulate medulla hematopoietic system, the elevating blood leukocyte.
Before more than 2,000 years, the Chinese medicine of China is just brought into use cantharis treatment tumor.This property of medicine acrid in the mouth is cold, and is poisonous, but the counteracting toxic substances phagedenoma, and the removing blood stasis eliminating stagnation is to act on significantly attacking by a type Chinese medicine.But toxic and side effects is very big, takes oral cavity, back, pharyngeal mucosa hyperemia, nausea and vomiting, loss of appetite, diarrhoea, dysurea, frequent micturition, hematuria etc.And can not control the dosage of medicine, be difficult to clinically use.The effective ingredient of Mylabris treatment tumor is a cantharidin.Though the cantharidin taking convenience that extracts through science, and pharmaceutical quantities also is easy to grasp, toxic and side effects is still very big, and the effective dose of cantharidin and toxicity dose are very approaching.
The natural resources of cantharis is very deficient, 10 tons of China's annual production less thaies.Wild cantharis mainly is grown in the South China Tropical humid region, is main with the food leguminous plant, and the conservation of natural environment of life requires very high.Natural environment polluted in recent years, and the output of wild cantharis is significantly reduced, and the artificial cultivation cantharis does not also have successful experience.
Though antineoplastic N-methylcantharidimide sheet determined curative effect, taking convenience on the market are oral through gastro-intestinal digestion, medicine gets into blood circulation through distributing, spread, absorbing, and arrives affected area then.By enzyme hydrolysis, the analyte of generation has stimulation to gastrointestinal tract to medicine, causes gastrointestinal upset in the gastrointestinal tract part, and particularly patients with advanced cancer more can be refused to take because of not taking food.Medicine is in transport process, and the part medicine decomposes, and blood drug level is on the low side relatively.Influence therapeutic effect.
The objective of the invention is to overcome existing pharmaceutical preparation and the existing defective of route of administration thereof; Provide a kind of and can make full use of the cantharis resource, with the form of medication of intravenous injection or input, effect directly, fast; Avoid causing gastrointestinal upset; Solve the difficulty that patients with advanced cancer can not be oral, increase drug effect, reduce side effect.Can be long-term, the medicine of the clinical treatment tumour of safe handling, it is the digestive tract reaction of antitumor drug as none both, the urinary system reaction of not having cantharidin again and being caused.And can utilize existing drug resource more fully.
The drug standard of N-methylcantharidimide points out that this medicine is slightly soluble in water, and " two listed solubility test methods of Chinese pharmacopoeia are tested, and the dissolubility of N-methylcantharidimide in water is approximately 0.5% according to 2010 editions.When the water base injection of preparation, the concentration of required active component N-methylcantharidimide in water formulation approximately is 0.5%-2.0%.Can estimate, when preparation N-methylcantharidimide injection, only need to add a little solubilizing agent and just possibly make the N-methylcantharidimide solubilising to reaching required steady concentration.
Conventional method is to adopt ethanol as solubilizing agent, and its shortcoming is: big (the white mice median lethal dose(LD 50) LD of alcoholic acid drug administration by injection toxicity
50Intravenous injection is 1.973g/kg); Adopted muscle or subcutaneous injection zest bigger above 10% o'clock in concentration; And make blood red ball degeneration or haemolysis (write " pharmaceutics ", People's Health Publisher referring to pharmaceutics teaching and research group of Nanjing pharmaceutical college through the human body blood red cell membrane easily; 1984, the 435th page).In addition, also be a no small colony to ethanol crowd hypersensitive, these patients can not use contains alcoholic acid preparation.These have all limited its scope of application.
Summary of the invention:
The present invention has overcome the deficiency of prior art, provides a kind of and does not contain alcoholic acid N-methylcantharidimide injection, uses ethanol as various defectives that solubilizing agent caused thereby overcome.
The objective of the invention is to realize like this: a kind of method for preparing of antineoplastic agent N-methylcantharidimide injection; This injection mainly is made up of N-methylcantharidimide, solubilizing agent and water; Described solubilizing agent is the mixed solution of tween 80 and propylene glycol; The two mass ratio of said tween 80 and propylene glycol is 1:20 ~ 10:1, and the two mass concentration sum in injection is 0.2% ~ 3.0%.
Mass concentration in the said N-methylcantharidimide injection is 5-20%.
As preferred version, the two mass ratio of said tween 80 and propylene glycol is 1:1.
Add a certain amount of propylene glycol and can reduce the consumption of tween 80 in injection, wherein the concentration of tween 80 in injection is 0.1% ~ 1.0%; Described propylene glycol is 1, the 2-propylene glycol, and the concentration in injection is 0.1% ~ 2.0%.
During preparation, at first aqueous solution of propylene glycol is disposed in preparation by weight percentage; Then tween 80 and N-methylcantharidimide are dissolved in the above-mentioned aqueous solution of propylene glycol; PH value with gained solution is adjusted to neutrality again, and by the conventional method for preparing injection, filtration, embedding, sterilization, packing make the N-methylcantharidimide injection.
Concrete grammar is: get propylene glycol and add an amount of water for injection, when being heated with stirring to 50 ℃ ~ 60 ℃, add tween 80 earlier; Add N-methylcantharidimide again and make it dissolving; Regulate pH value to neutral, and then add the injection water to desired concn, and the conventional method of pressing the preparation injection; Filtration, embedding, sterilization, packing make the N-methylcantharidimide injection.
Injection of the present invention uses tween 80 and propylene glycol can on the basis that reaches the solubilising purpose, reduce the consumption of tween 80 as solubilizing agent simultaneously, and then reduces hemolytic risk due to the tween 80, strengthens security of products.
N-methylcantharidimide injection of the present invention can be made into the injection of required dosage; For example; Said injection can be every injection that contains the 10mg-100mg N-methylcantharidimide, and preferred, said injection is every injection that contains 10mg or 20mg or 50mg N-methylcantharidimide.
Preferably, the present invention's method of preparing the N-methylcantharidimide injection may further comprise the steps:
1. the preparation weight percent concentration is 0.1% ~ 2.0% aqueous solution of propylene glycol;
2. tween 80 and N-methylcantharidimide are dissolved in the above-mentioned aqueous solution of propylene glycol;
3. the pH value with gained solution is adjusted to neutrality, and by the conventional method for preparing injection, filtration, embedding, sterilization, packing make the N-methylcantharidimide injection.
N-methylcantharidimide is a broad-spectrum anti-cancer drug, is applicable to the treatment of primary hepatocarcinoma, pulmonary carcinoma, esophageal carcinoma, nasopharyngeal carcinoma, the kinds of tumors such as lymphoma, bladder cancer, gynecologic malignant tumor of feeling sick, and also can be used for hepatitis, liver cirrhosis and hepatitis b virus carrier.To tumour patient, the effect of obvious alleviation cancer pain is arranged after using injection of the present invention, can improve the clinical symptoms of tumour patient, improve patient's quality of life.
After the intravenous drip of this injection, most of medicine is discharged from urine.Significantly improve body's immunological function; With put, chemotherapy combined uses and to heighten the effect of a treatment; Before the surgical oncology art, postoperative uses, but the after treatment effect.
The present invention treats the N-methylcantharidimide injection intravenous drip of tumor.1 time on the one, each 2 to 10ml, dilutes the back in right amount with 0.9% sodium chloride or 5% to 10% glucose injection and instils.
Pharmacodynamic experiment of the present invention:
1. pharmacology: these article are the derivant of cantharidin, and anticancer DNA is synthetic, the splitted M phase of interference cell.Zoopery shows that these article are that rat liver cancer, ehrlich ascites carcinoma have certain inhibitory action.When 16 ~ 18.5mg/ml blood concentration, can prolong the life span 31% ~ 103% of mice.These article have certain effect to body's immunity, and the intravenous injection N-methylcantharidimide has phagocytosis that strengthens the animal body macrophage and the effect that suppresses the antibody generation.
2. toxicity: the intravenous median lethal dose(LD 50) LD of these article
50Be 375.2mg/kg, irritate the median lethal dose(LD 50) LD of stomach
50Be 813.7mg/kg.
3. pharmacokinetics: these article absorption in vivo distributes and excretory rapid speed half-life (t
1/2) be 0.72 hour.After the 3H-N-methylcantharidimide gets into human body, be distributed to each tissue of body rapidly widely, particularly the distribution of liver and bile is more, and can combine with cancerous tissue.Medicine is after metabolism, and major part is the catabolite form has urine to discharge, and only has sub-fraction to drain with original shape.
N-methylcantharidimide injection through above-mentioned prescription and preparation technology's gained has the following advantages:
1. N-methylcantharidimide injection of the present invention adopts propylene glycol and tween 80 as solubilizing agent, thereby has improved the dissolubility of N-methylcantharidimide, and can prevent the solute hydrolysis, has improved stability of formulation.
2. injection of the present invention uses tween 80 and propylene glycol can on the basis that reaches the solubilising purpose, reduce the consumption of tween 80 as solubilizing agent simultaneously, and then reduces hemolytic risk due to the tween 80.
3. the present invention is adjusted to neutrality with the pH value of prepared injection, makes the stability of injection be higher than existing patent of prior art or medicine.
The specific embodiment
Below in conjunction with embodiment prescription and the preparation technology that the present invention is used to treat the N-methylcantharidimide injection formulation of tumor further explained, but following embodiment does not limit the present invention in any way.
Embodiment 1:1ml:10mg, 2ml:20mg, 5ml:50mg, 10ml:100mg
The preparation of N-methylcantharidimide injection
Prescription:
N-methylcantharidimide: 10g
Tween 80: 1g
Propylene glycol: 1g
Water for injection adds to: 1000ml
Get propylene glycol 1g and add an amount of water for injection, when being heated with stirring to 50 ℃ ~ 60 ℃, add tween 80 1g earlier; Add N-methylcantharidimide 10g again and make it dissolving, regulate about pH value to 7.0, add the injection water to 1000ml; Add active carbon, stir decarburization; Detect qualified after-filtration to clarification, embedding, 121 ℃ of sterilizations promptly got N-methylcantharidimide injection of the present invention in 8 minutes.
The preparation of embodiment 2:1ml:20mg N-methylcantharidimide injection
Prescription:
N-methylcantharidimide: 20g
Tween 80: 2g
Propylene glycol: 2g
Water for injection adds to: 1000ml
Get propylene glycol 2g and add an amount of water for injection, when being heated with stirring to 50 ℃ ~ 60 ℃, add tween 80 2g earlier; Add N-methylcantharidimide 20g again and make it dissolving, regulate about pH value to 7.0, add the injection water to 1000ml; Add active carbon, stir decarburization; Detect qualified after-filtration to clarification, embedding, 121 ℃ of sterilizations promptly got N-methylcantharidimide injection of the present invention in 8 minutes.
The preparation of embodiment 3:2ml:10mg N-methylcantharidimide injection
Prescription:
N-methylcantharidimide: 5g
Tween 80: 1g
Propylene glycol: 1g
Water for injection adds to: 1000ml
Get propylene glycol 1g and add an amount of water for injection, when being heated with stirring to 50 ℃ ~ 60 ℃, add tween 80 1g altogether earlier; Add N-methylcantharidimide 5g again and make it dissolving, regulate about pH value to 7.0, add the injection water to 1000ml; Add active carbon, stir decarburization; Detect qualified after-filtration to clarification, embedding, 121 ℃ of sterilizations promptly got N-methylcantharidimide injection of the present invention in 8 minutes.
Below described embodiment of the present invention in detail, can do a lot of improvement and variation obviously for a person skilled in the art and can not deviate from essence spirit of the present invention.All these variations and improvement are all within protection scope of the present invention.
Claims (5)
1. the method for preparing of an antineoplastic agent N-methylcantharidimide injection; It is characterized in that: said injection comprises N-methylcantharidimide, solubilizing agent and water; Described solubilizing agent is the mixed solution of tween 80 and propylene glycol; The two mass ratio of said tween 80 and propylene glycol is 1:20 ~ 10:1, and the two mass concentration sum in injection is 0.2% ~ 3.0%;
Mass concentration in the said N-methylcantharidimide injection is 5-20%.
2. the method for preparing of a kind of antineoplastic agent N-methylcantharidimide injection according to claim 1 is characterized in that: the two mass ratio of said tween 80 and propylene glycol is 1:1.
3. the method for preparing of a kind of antineoplastic agent N-methylcantharidimide injection according to claim 1 is characterized in that: described propylene glycol is 1, the 2-propylene glycol, and its concentration in injection is 0.1% ~ 2.0%.
4. according to the method for preparing of claim 1 or 2 or 3 described a kind of antineoplastic agent N-methylcantharidimide injection, it is characterized in that: at first aqueous solution of propylene glycol is disposed in preparation by weight percentage; Then tween 80 and N-methylcantharidimide are dissolved in the above-mentioned aqueous solution of propylene glycol; PH value with gained solution is adjusted to neutrality again, and by the conventional method for preparing injection, filtration, embedding, sterilization, packing make the N-methylcantharidimide injection.
5. according to the method for preparing of claim 1 or 2 or 3 described a kind of antineoplastic agent N-methylcantharidimide injection, it is characterized in that: get propylene glycol and add an amount of water for injection, when being heated with stirring to 50 ℃ ~ 60 ℃; Add tween 80 earlier, add N-methylcantharidimide again and make it dissolving, regulate pH value to neutral; And then add the injection water to desired concn; And by the conventional method for preparing injection, filtration, embedding, sterilization, packing make the N-methylcantharidimide injection.
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| CN2011103058725A CN102335130A (en) | 2011-10-11 | 2011-10-11 | Preparation method of anti-tumor medicinal n-methylcantharidimide injection |
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| CN2011103058725A CN102335130A (en) | 2011-10-11 | 2011-10-11 | Preparation method of anti-tumor medicinal n-methylcantharidimide injection |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102697723A (en) * | 2012-06-04 | 2012-10-03 | 重庆市中药研究院 | Methylcantharidinimde fat emulsion and preparation method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101120941A (en) * | 2006-06-09 | 2008-02-13 | 江苏四环生物股份有限公司 | Methylcantharidimide injection and freeze-dried powder injection for treating tumor and preparation method thereof |
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2011
- 2011-10-11 CN CN2011103058725A patent/CN102335130A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101120941A (en) * | 2006-06-09 | 2008-02-13 | 江苏四环生物股份有限公司 | Methylcantharidimide injection and freeze-dried powder injection for treating tumor and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 安中原等: "斑蝥素及其衍生物的抗肿瘤研究进展", 《亚太传统医药》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102697723A (en) * | 2012-06-04 | 2012-10-03 | 重庆市中药研究院 | Methylcantharidinimde fat emulsion and preparation method thereof |
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Application publication date: 20120201 |