CN1868471A - Methyl cantharis amine injection and its prepn. method - Google Patents
Methyl cantharis amine injection and its prepn. method Download PDFInfo
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- CN1868471A CN1868471A CNA2006100857439A CN200610085743A CN1868471A CN 1868471 A CN1868471 A CN 1868471A CN A2006100857439 A CNA2006100857439 A CN A2006100857439A CN 200610085743 A CN200610085743 A CN 200610085743A CN 1868471 A CN1868471 A CN 1868471A
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- methylcantharidimide
- injection
- additive
- cyclodextrin
- weight ratio
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Abstract
An injection of methyl cantharidamine is prepared from methyl cantharidamine, phosphatide, cyclodextrin, Pulangnike, polyvinyl pyrrolidone and urea. Its preparing process is also disclosed.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, be specifically related to a kind of N-methylcantharidimide ejection preparation and preparation method thereof.
Background technology
N-methylcantharidimide (Methylcantharidimide) is a kind of derivant by the isolated anticancer active ingredient cantharidin of coleoptera Herba Sonerilae cantonensis section insecticide Mylabris.N-methylcantharidimide has the anabolic effect of anticancer protein nucleic acid, tumor cell is had suppress and lethal effect, is mainly used in the treatment primary hepatocarcinoma, and pulmonary carcinoma, the esophageal carcinoma, colon cancer and breast carcinoma etc. are also had better curative effect.In addition, N-methylcantharidimide has good inhibition effect to hbv replication, thereby has the effect of improving liver function; In addition, raise in addition leukocyte and stimulate the synthetic effect of medullary cell DNA of N-methylcantharidimide, this is rare in cancer therapy drug.At present, only there is the oral tablet of N-methylcantharidimide to sell on the market, also do not have the preparation of other administration route such as injection to go on the market.But dissolubility is little in the N-methylcantharidimide water, and the oral drugs bioavailability is low, and the patient uses individual variation very big, influences clinical therapeutic efficacy.
CN1679543A discloses a kind of ejection preparation of N-methylcantharidimide, increase the dissolubility of N-methylcantharidimide by the mode that adds ethanol, PEG, acid, alkali, thereby development N-methylcantharidimide injection, but contain ethanol in the injection, during injection, local irritation is big, patient's medication poor compliance: the PEG intravenous injection has certain hemolytic, clinical application risk is big, after N-methylcantharidimide is regulated acid, alkali, changed its original molecular structure, and then changed its internal metabolism behavior, had to be assessed the influence of therapeutic effect.And adjusting is sour, alkali is not greatly improved to the dissolubility that increases N-methylcantharidimide.
Summary of the invention
The present invention is by adding the water solublity that additive has increased N-methylcantharidimide in N-methylcantharidimide, make N-methylcantharidimide can be prepared into ejection preparation, and additive therefor of the present invention meets the requirement of domestic and international injection adjuvant, zest is little, injection safety is good, clinical practice is safe, and patient's medication compliance is good.
The dissolubility of N-methylcantharidimide in water is little, about 25mg/ml, and deficiency makes injection so that it directly is dissolved in the water, and therefore needs to add a certain amount of additives, increases the dissolubility of N-methylcantharidimide, just can make the N-methylcantharidimide preparation that injectable is used.
The present invention finds under study for action, adds the water solublity that following one or more additives can effectively improve N-methylcantharidimide: phospholipid, cyclodextrin, general youth Buddhist nun's gram, polyvinylpyrrolidone, carbamide, dextran, NaTDC, tween, polyoxyethylene castor oil, propylene glycol, benzyl benzoate, dimethyl formamide, dimethyl acetylamide or dimethyl sulfoxide.The weight ratio (following ratio is weight ratio) that preferred ratio is N-methylcantharidimide and additive is 1: 0.3～50.
Preferred additive is selected from one or more in phospholipid, cyclodextrin, general youth Buddhist nun's gram, polyvinylpyrrolidone, the carbamide.A kind of or several additive more than can in N-methylcantharidimide, directly adding, the weight ratio of N-methylcantharidimide and these additives is 1: 1～30 o'clock, the dissolubility of N-methylcantharidimide in water can significantly improve, and reaches as high as 80mg/ml.Also these additives and N-methylcantharidimide can be prepared into solid dispersion, when being prepared into solid dispersion, and the weight ratio of N-methylcantharidimide and additive is 1: 1～20 o'clock, and the dissolubility of N-methylcantharidimide in water can significantly improve, and reaches as high as 100mg/ml.
Further preferred additives is general youth Buddhist nun's gram and polyvinylpyrrolidone, and N-methylcantharidimide restrains with general youth Buddhist nun or the weight ratio of polyvinylpyrrolidone is preferably 1: 2～1: 12.When N-methylcantharidimide and general youth Buddhist nun gram or polyvinylpyrrolidone by 1: 2～1: 12 when being prepared into solid dispersion, the dissolubility of N-methylcantharidimide in water can significantly improve, and reaches as high as 80mg/ml.
The preparation method of solid dispersion can prepare with fusion method commonly used, solvent method, solvent-fusion method, spray drying method, freeze-drying, polishing.
The present invention also preferred additives is a cyclodextrin, can be cyclodextrin derivative such as HP-, methyl-beta-schardinger dextrin-or ethyl-beta-schardinger dextrin-.The injection of N-methylcantharidimide can directly add the cyclodextrin solubilising in preparation, when the weight ratio of N-methylcantharidimide and cyclodextrin was 1: 2～20, the dissolubility of N-methylcantharidimide in water can significantly improve, and reaches as high as 100mg/ml.More preferably N-methylcantharidimide and cyclodextrin are prepared into the cyclodextrin embedding complex, evidence, when the weight ratio of N-methylcantharidimide and cyclodextrin is: during 1: 5～10 enclose, the clathrate good stability, solubilizing effect is good, the dissolubility of N-methylcantharidimide in water can significantly improve, and reaches as high as 120mg/ml.
Preparation methods of cyclodextrin inclusion complexes can with medicament go up conventional method preparation, comprises saturated water solution method, polishing, freeze-drying, spray drying method etc.
Other several additives have also shown certain property of solubilizing, as surface active agent solubilizations such as NaTDC, polyoxyethylene castor oil, tweens, when N-methylcantharidimide and surfactant weight are: in the time of 1: 1～30, the dissolubility of N-methylcantharidimide can significantly improve, and reaches as high as 120mg/ml.Polyoxyethylene castor oil most preferably wherein, the weight ratio of N-methylcantharidimide and polyoxyethylene castor oil is 1: 1～10 o'clock, the dissolubility of N-methylcantharidimide in water can significantly improve, and reaches as high as 120mg/ml.
The also preferred following cosolvent of the injection of N-methylcantharidimide: propylene glycol, benzyl benzoate, dimethyl formamide, dimethyl acetylamide or dimethyl sulfoxide.
The cosolvent of N-methylcantharidimide dissolubility maximum is a dimethyl formamide, the ratio of solvent N-methylcantharidimide and dimethyl formamide most preferably 1: 0.3～10.The dissolubility of N-methylcantharidimide can be brought up to 500mg/ml from 25mg/ml.
Consider that from injection safety N-methylcantharidimide injection most preferred solvent is a propylene glycol, the ratio of N-methylcantharidimide and propylene glycol is preferably: 1: 1～20, and the dissolubility of N-methylcantharidimide can be brought up to 70mg/ml from 25mg/ml.
The preparation method of the injection of N-methylcantharidimide of the present invention, the method for injection that can be routinely makes, comprise N-methylcantharidimide and additive soluble in water, packing, N-methylcantharidimide injection or transfusion or sterilized powder are made in sterilization.
As to adopt N-methylcantharidimide be to be prepared into solid dispersion or cyclodextrin clathrate, then is prepared into solid dispersion or cyclodextrin clathrate earlier, again solid dispersion or cyclodextrin clathrate is prepared into injection according to a conventional method.
Injection of the present invention can be to be the liquid infusion agent of solvent with water, also can be lyophilized formulations.Wherein freeze drying protectant can be selected from: one or more in sorbitol, mannitol, glucose, lactose, galactose, fructose, maltose, sucrose, xylose, mannose, sodium chloride, low molecular dextran, glycine, carbamide or the gelatin.
N-methylcantharidimide injection of the present invention has high bioavailability than N-methylcantharidimide oral formulations, is the contrast test and the data of bioavailability below:
Laboratory animal: 6 of SD rats, male and female half and half, body weight 200～300g
Dosage: N-methylcantharidimide sheet 30mg/kg
The injection 30mg/5ml/kg (embodiment 1 makes) of the present invention's development
Experimental technique: adopt binary cycle intersection dose regimen, according to body surface area method conversion dosage, the rat oral gavage administration is got blood in 10,30,60,120,180,240,360 minutes eyeground veins; One week was cleaned after date, and the tail vein injection administration is got blood in 5,10,30,60,120,180,240,360 minutes eyeground veins.Separated plasma with the drug level in the RP-HPLC method detection blood plasma, is asked calculation area under curve AUC with moment method
0～∞, and calculate absolute bioavailability:
F＝AUCpo/AUCiv*100％
| No.1 | No.2 | No.3 | No.4 | No.5 | No.6 | |
| AUCpo AUCiv F(％) | 5142 10983 46.82 | 4056 8231 49.28 | 5188 13951 37.18 | 5508 8338 66.06 | 5242 9244 56.71 | 5021 8467 59.30 |
| Average F SD (F) RSD (F) | 52.56％ 10.25％ 19.50％ | |||||
The result as seen, behind the oral N-methylcantharidimide of rat, the area under curve of blood plasma Chinese medicine concentration only is quiet 52.56% of the back plasma drug level area under curve of annotating.Have the medicine of a nearly half-value dose not to be absorbed behind the N-methylcantharidimide oral administration, visible N-methylcantharidimide oral administration can not be given full play to drug effect.
Advantage of the present invention is: by the injecting and administering preparations of N-methylcantharidimide that added nontoxic non-irritating additive preparation, injection need not pass through absorption process, good effect, onset is rapid, individual variation is little, make things convenient for the doctor to carry out clinical treatment monitoring, and can satisfy the needs of the critically ill patient that some can not be oral.The experiment proved that bioavailability oral in the rat body is low, absolute bioavailability only is 52.56 ± 10.25%.The injection of N-methylcantharidimide can reduce dosage when reaching with the same curative effect of oral administration, reduce the medicine material cost, reduces poisonous side effect of medicine.The injection of N-methylcantharidimide is a kind of novel form that is better than oral tablet, also meets the needs of present clinical cancer patient treatment.
The specific embodiment
Embodiment 1
With N-methylcantharidimide 0.3g and 1g beta-schardinger dextrin-, under the room temperature, ground 1 hour, and promptly prepared the Benexate Hydrochloride of N-methylcantharidimide, the gained clathrate is dissolved in the 5ml water for injection by the every 0.3g of N-methylcantharidimide, filter, fill is sealed, sterilization, promptly get the injection of N-methylcantharidimide, every ampoule props up by N-methylcantharidimide 0.3g/.
Embodiment 2
N-methylcantharidimide 0.3g and propylene glycol 5ml are dissolved in the 250ml normal saline, filter, fill is sealed, sterilization, the transfusion that promptly gets N-methylcantharidimide.
Embodiment 3
The general youth Buddhist nun who makes N-methylcantharidimide through fusion method who N-methylcantharidimide and general youth Buddhist nun is restrained F-68 restrains the F-68 solid dispersion: N-methylcantharidimide 0.3g and the general youth Buddhist nun of 2g are restrained F-68 weighing respectively, and at room temperature be mixed, be heated to 85 ℃, constant temperature stirred 30 minutes for 85 ℃, cool to room temperature, comminution by gas stream obtains the general youth Buddhist nun of N-methylcantharidimide and restrains the solid dispersion powder, through the aseptic subpackaged powder pin that obtains N-methylcantharidimide, dissolves in normal saline or the glucose infusion liquid.
Embodiment 4
N-methylcantharidimide 0.3g and phosphatidase 10 .5g are dissolved in the oxolane, 40 ℃ of spray dryinges, obtain N-methylcantharidimide-phospholipid solid dispersion powder, 40 ℃ are dissolved among the water for injection 5ml, add mannitol 2g, be stirred in the dissolving fully, sterilize with 0.22 μ m filtering with microporous membrane, obtain the powder pin of N-methylcantharidimide through lyophilization or spray drying, dissolve in normal saline or the glucose infusion liquid.
Claims (10)
1, a kind of N-methylcantharidimide injection, it is characterized in that containing N-methylcantharidimide and additive, described additive is selected from one or more in phospholipid, cyclodextrin, general youth Buddhist nun's gram, polyvinylpyrrolidone, carbamide, dextran, NaTDC, tween, polyoxyethylene castor oil, propylene glycol, benzyl benzoate, dimethyl formamide, dimethyl acetylamide, the dimethyl sulfoxide.
2, the N-methylcantharidimide injection of claim 1, wherein the weight ratio of N-methylcantharidimide and additive is: 1: 0.3～50.
3, the N-methylcantharidimide injection of claim 1, wherein additive is selected from one or more in phospholipid, cyclodextrin, general youth Buddhist nun's gram, polyvinylpyrrolidone, the carbamide.
4, the N-methylcantharidimide injection of claim 3, wherein the weight ratio of N-methylcantharidimide and additive is: 1: 1～30.
5, the N-methylcantharidimide injection of claim 3, wherein additive is general youth Buddhist nun's gram or polyvinylpyrrolidone, the weight ratio of N-methylcantharidimide and general youth Buddhist nun gram or polyvinylpyrrolidone is: 1: 2～12.
6, the preparation method of claim 3,4 or 5 N-methylcantharidimide injection comprises: N-methylcantharidimide and additive are made solid dispersion earlier, and then be prepared into injection according to a conventional method.
7, the N-methylcantharidimide injection of claim 1, wherein additive is polyoxyethylene castor oil or NaTDC, the weight ratio of N-methylcantharidimide and polyoxyethylene castor oil or NaTDC is 1: 1～10.
8, the N-methylcantharidimide injection of claim 1, wherein additive is a propylene glycol, the weight ratio of N-methylcantharidimide and propylene glycol is 1: 1～20.
9, the N-methylcantharidimide injection of claim 1, wherein additive is a cyclodextrin, the weight ratio of N-methylcantharidimide and cyclodextrin is 1: 2～20.
10, the N-methylcantharidimide injection of claim 9, wherein N-methylcantharidimide and cyclodextrin exist with the form of clathrate.
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| Application Number | Priority Date | Filing Date | Title |
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| CNA2006100857439A CN1868471A (en) | 2006-06-28 | 2006-06-28 | Methyl cantharis amine injection and its prepn. method |
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| CNA2006100857439A CN1868471A (en) | 2006-06-28 | 2006-06-28 | Methyl cantharis amine injection and its prepn. method |
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Cited By (2)
| 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 |
| CN101926786B (en) * | 2009-06-22 | 2013-02-06 | 中国医学科学院药用植物研究所 | Sustained release preparation for cantharidin and cantharidin extract |
-
2006
- 2006-06-28 CN CNA2006100857439A patent/CN1868471A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101926786B (en) * | 2009-06-22 | 2013-02-06 | 中国医学科学院药用植物研究所 | Sustained release preparation for cantharidin and cantharidin extract |
| 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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