CN1282580A - Release-controlling coating of antineoplastic leurocristine - Google Patents
Release-controlling coating of antineoplastic leurocristine Download PDFInfo
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- CN1282580A CN1282580A CN 00121098 CN00121098A CN1282580A CN 1282580 A CN1282580 A CN 1282580A CN 00121098 CN00121098 CN 00121098 CN 00121098 A CN00121098 A CN 00121098A CN 1282580 A CN1282580 A CN 1282580A
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- leurocristine
- vincristine
- microsphere
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Abstract
A release-controlled medicinal membrane of antineoplastic leurocristine is prepared from leurocristine 1-3 portions, copolymerized lactic acid-glycelic acid 10-30 portions and surfactant (Span-85) 1-3 portions through drying in oil to obtain microballs of leurocristine, adding to collogen solution 24000-72000 portions and freeze-drying. Its advantages include constant-speed release, high antinooplastic effect, low poison and low cost.
Description
The invention belongs to the preparation of sustained release medicine film.
The product of antitumor drug vincristine (VCR) existing marketization is slow-release medicine-membrane, the oral sustained release sheet that transdermal test in vitro absorbs, and the former pharmaceutical carrier can not be by the body degraded and absorbed, and the latter belongs to the digestive tract administration, and the uncontrollable medicine constant release that makes.
The purpose of this invention is to provide a kind of antitumor drug vincristine (VCR) sustained release medicine film, can overcome the shortcoming of prior art, in the local postoperative heeling-in of tumor focus, reduce the whole body toxic and side effects that tumor patient tradition administering mode brings, increase the partial drug level of tumor focus.
Technology of the present invention constitutes: vincristine 1-3 part, RH502H 10-30 part, surfactant (sorbester p37) 1-3 part prepares the vincristine microsphere by seasoning in the oil, add film forming collagen swelling solution 24000-72000 part, lyophilization prepares the medicine film.
Implementing concrete steps of the present invention is: get RH502H and be dissolved in the acetone soln, with the vincristine mixing in wherein; Measure liquid paraffin, add an amount of sorbester p37, stir evenly; Liquid paraffin places 10 ℃ water-bath, and RH502H solution is added in the liquid paraffin, and 4h (400rpm) under 35 ℃ of temperature is warming up to 53 ℃, stirs 1h; Sucking filtration gets slick and sly hard microsphere, and with a small amount of normal hexane washing microsphere, decompression is done then.Get the collagen swelling solution, add the dissolving of malonic acid solution, get the collagen swelling solution.Get the microsphere of above-mentioned preparation, add the collagen swelling solution, mixing.Then liquid freezing (60 ℃) drying is become the medicine film.After crosslinked 2 hours, formaldehyde is removed in washing with formalin.The liquid film after drying is promptly got vincristine controlled release medicine film.
Antitumor drug vincristine of the present invention (VCR) sustained release medicine film discharges constant speed; Medicine film physicochemical property is stable, and good reproducibility is adapted at the requirement that in-vivo embed uses; Show the chmice acute toxicity test blood of medicine film and nervus centralis toxicity reduce (comparing P＜0.01 with the intravenous injection group); The medicine film has obvious suppression effect (MTT colorimetric) to tumor cell; Tumor killing effect remarkable (with the comparison of blank group, P＜0.01, tumor is heavy) in the body of medicine film.The present invention can reach constant release in vivo and in vitro, and tumor killing effect is higher than oral administration, and low toxicity is efficient, and cost is low, the easy easy repetition of method, is expected to produce huge economic benefit.
Outstanding substantial characteristics of the present invention and good effect can be embodied from following embodiment, but they are not that the present invention is imposed any restrictions.
Embodiment 1:
Get RH502H 0.011g and be dissolved in the 2.8ml acetone soln, vincristine 1.11mg mixing is in wherein; Measure the 20ml liquid paraffin, add sorbester p37, stir evenly; Liquid paraffin places 10 ℃ water-bath, and RH502H solution is added in the liquid paraffin, stirs (400rpm); Heat to 35 ℃, insulated and stirred 4h under this temperature is warming up to 53 ℃, stirs 1h; Sucking filtration gets microsphere, and with a small amount of normal hexane washing microsphere, decompression is done then.Thus obtained microsphere should be slick and sly hard.Get collagen swelling solution 25g (1.39%), add 0.3% (w/v) malonic acid solution and dissolve to 1000ml, 0.35% collagen swelling solution.Get the microsphere of above-mentioned preparation, add the collagen swelling solution, mixing.Then liquid freezing (60 ℃) drying is become the medicine film that area is 10cm * 10cm.After crosslinked 2 hours, formaldehyde is removed in washing with 0.25% formalin (not having the medicine film).After drying promptly gets vincristine controlled release medicine film.
The productive rate that vincristine prepares microsphere is 59.3%; Behind the in-vivo embed of controlled release medicine film, drug release reaches constant speed substantially in 30 days and sees Fig. 1; Medicine film physicochemical property (contact angle, configuration of surface, water absorption, differential thermal analysis, tensile strength) is stable, and good reproducibility is adapted at the requirement that in-vivo embed uses; Behind the normal Kunming mouse in-vivo embed medicine film 14 days, carry out the chmice acute toxicity test and detect, show that the medicine film obviously reduces the blood of mice and the more traditional oral administration of nervus centralis toxicity to see Table 1 Fig. 2; In vitro culture K562 tumor cell adds and is used as medicine film culture fluid co-cultivation after 14 days, measures the medicine film to K562 cell inhibiting rate with mtt assay, and the result shows that the medicine film has the obvious suppression effect to see Table 2 to this tumor cell; At tumor-bearing mice in-vivo tumour position heeling-in medicine film, investigate the tumour inhibiting rate of medicine film, experimental result shows that the tumor killing effect of medicine film is higher than or sees Table 3 near oral administration.
Embodiment 2:
Get RH502H 0.11g and be dissolved in the 28ml acetone soln, vincristine 11.1mg mixing is in wherein; Measure the 200ml liquid paraffin, add sorbester p37, stir evenly; Liquid paraffin places 10 ℃ water-bath, and RH502H solution is added in the liquid paraffin, stirs (400rpm); Insulated and stirred 4h (400rpm) under 35 ℃ of temperature is warming up to 53 ℃, continues to stir 1h; Sucking filtration gets microsphere, and with a small amount of normal hexane washing microsphere, decompression is done then.Thus obtained microsphere should be slick and sly hard.Get collagen swelling solution 250g (1.39%), add 0.3% (w/v) malonic acid solution and dissolve to 100ml, 0.35% collagen swelling solution.Get the vincristine microsphere of above-mentioned preparation, add the collagen swelling solution then, mixing.Then liquid dried is become the medicine film that area is 40cm * 25cm.After crosslinked 2 hours, formaldehyde is removed in washing with 0.25% formalin (not having the medicine film).After drying promptly gets vincristine controlled release medicine film.
Embodiment 3:
Get RH502H 0.0055g and be dissolved in the 1.4ml acetone soln, vincristine 0.555mg mixing is in wherein; Measure the 10ml liquid paraffin, add sorbester p37, stir evenly; Liquid paraffin places 10 ℃ water-bath, and RH502H solution is added in the liquid paraffin, stirs (400rpm); Stir 4h (400rpm) under 35 ℃ of temperature, be warming up to 53 ℃, keep former rotating speed insulated and stirred 1h; Sucking filtration gets microsphere, and with a small amount of normal hexane washing microsphere, decompression is done then.Thus obtained microsphere should be slick and sly hard.Get collagen swelling solution 12.5g (1.39%), add 0.3% (w/v) malonic acid solution and dissolve to 50ml, 0.35% collagen swelling solution.Get the vincristine microsphere of above-mentioned preparation, add the collagen swelling solution then, mixing.Then liquid dried is become the medicine film that area is 5cm * 10cm.After crosslinked 2 hours, formaldehyde is removed in washing with 0.25% formalin (not having the medicine film).After drying promptly gets vincristine controlled release medicine film.
Table 1 vincristine medicine film is to the influence of mice blood cell count
Compare?with?i．v．group，**P＜0．01，*P＜0．05
| Group | WBC／10 9．L -1 | RBC／10 12．L -1 | HGB／g．L -1 | PLT／10 11．L -1 |
| ????VCR60μg ????120μg ????240μg ????480μg ????i．v50μg | 8．37±2．01** 8．04±1．37** 7．79±2．44** 5．89±2．74 3．94±2．10 | ?9．94±3．33* ?8．36±2．73 ?8．41±3．14 ?7．64±2．27 ?7．33±1．94 | ?162．11±34．12** ?152．70±29．31** ?149．05±31．21* ?131．84±31．25 ?117．40±27．13 | ?12．71±4．72* ?12．14±3．40* ?11．71±4．14 ?10．29±3．97 ??9．06±2．27 |
Table 2 vincristine medicine film is to the effect of K562 cell inhibiting
| Group | 1 | Tumour inhibiting rate 2 | 3 |
| The low positive control of VCR among the high VCR of negative control VCR | --- 63.4％ 60.7％ 10.2％ 74.8％ | --- 69.2％ 55.2％ 15.2％ 77.6％ | --- 72.5％ 65.3％ 15.9％ 79.2％ |
Table 3 VCR medicine film to the inhibitory action of Emhorn solid tumor (± sD)
| Group | Number of animals (only) 1 | Heavy (g) 2 of tumor | 3 |
| The low positive controls of VCR among the high VCR of negative control group VCR | 20 0.7406±0.1941 10 0.4044±0.1923** 10 0.4991±0.1625** 10 0.6719±0.2137* 10 0.5385±0.1741** | 0.7333±0.2046 0.3726±0.1463** 0.5101±0.2244** 0.6187±0.2086* 0.4894±0.2012** | 0.7562±0.2135 0.4897±0.2011** 0.5490±0.1947* 0.6395±0.2274* 0.5004±0.2122** |
Compare?with?control?group,?*?P〈0.05,?**?P〈0.01
Claims (4)
1. release-controlling coating of antineoplastic leurocristine, the weight that it is characterized in that it are formed:
Vincristine 1-3 part
RH502H 10-30 part
Sorbester p37 1-3 part
2. the said release-controlling coating of antineoplastic leurocristine preparation method of claim 1 is characterized in that it comprises the steps:
(1) get RH502H and be dissolved in acetone soln to dissolving fully, with the vincristine mixing in wherein;
(2) get liquid paraffin 15-45 part, add sorbester p37 and stir, liquid paraffin places 10 ℃ water-bath, in the acetone soln adding liquid paraffin with RH502H, stirs 4h with 400rpm under 35 ℃ of temperature;
(3) system is warming up to 53 ℃, stirs 1h with 400rpm, has this moment the vincristine microsphere to generate in the solution; Sucking filtration gets slick and sly hard microsphere, removes surface liquid paraffin, drying under reduced pressure then with normal hexane washing microsphere;
(4) get the collagen swelling solution, add the malonic acid solution dilution, get the microsphere of above-mentioned preparation, add the collagen swelling solution after diluting, mixing is then with liquid-60 a ℃ lyophilization becoming medicine film;
(5) with formalin after crosslinked 2 hours, formaldehyde is removed in washing, with liquid film once more-60 ℃ lyophilization promptly get vincristine controlled release medicine film.
3. according to the said release-controlling coating of antineoplastic leurocristine preparation method of claim 2, the span that it is characterized in that the collagen swelling solution of said patent medicine film is 24000-72000 part.
4. according to the said release-controlling coating of antineoplastic leurocristine preparation method of claim 2, the quality ratio that it is characterized in that said collagen and its solvent malonic acid is 1.2: 1, and the concentration of the malonic acid solution of dissolving collagen is 0.3%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CNB00121098XA CN1133430C (en) | 2000-07-20 | 2000-07-20 | Release-controlling coating of antineoplastic leurocristine |
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| Application Number | Priority Date | Filing Date | Title |
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| CNB00121098XA CN1133430C (en) | 2000-07-20 | 2000-07-20 | Release-controlling coating of antineoplastic leurocristine |
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| CN1282580A true CN1282580A (en) | 2001-02-07 |
| CN1133430C CN1133430C (en) | 2004-01-07 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100340296C (en) * | 2005-02-03 | 2007-10-03 | 山东蓝金生物工程有限公司 | Anticarcinogenic internal implant agent |
| CN1511510B (en) * | 2002-12-30 | 2010-04-28 | 沈阳药科大学 | High oil-coating type solid micro pill for preparing liquid oily medicine in liquid phase and is preparing method |
-
2000
- 2000-07-20 CN CNB00121098XA patent/CN1133430C/en not_active Expired - Fee Related
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1511510B (en) * | 2002-12-30 | 2010-04-28 | 沈阳药科大学 | High oil-coating type solid micro pill for preparing liquid oily medicine in liquid phase and is preparing method |
| CN100340296C (en) * | 2005-02-03 | 2007-10-03 | 山东蓝金生物工程有限公司 | Anticarcinogenic internal implant agent |
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| CN1133430C (en) | 2004-01-07 |
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