CN1282578A - Release-controlling coating of antineoplastic lomustine - Google Patents
Release-controlling coating of antineoplastic lomustine Download PDFInfo
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- CN1282578A CN1282578A CN 00121099 CN00121099A CN1282578A CN 1282578 A CN1282578 A CN 1282578A CN 00121099 CN00121099 CN 00121099 CN 00121099 A CN00121099 A CN 00121099A CN 1282578 A CN1282578 A CN 1282578A
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- lomustine
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Abstract
A release-controlled medicinal membrane of antineoplastic lomustine is prepared from lomustine 1-3 portions, gelatin. and arabic gum 300-900 portionseach, and surfactant (Tween-60) 2-6 portions through recoagulation to prepare microcapsule of lomustine, adding to collogen solution 2000-6000 portions and freeze-drying. Its advantage constant-speed release, high antineoplastic effect, low poison, and low cost.
Description
The invention belongs to the preparation of sustained release medicine film.
The product of antitumor drug lomustine (CCNU) 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 lomustine (CCNU) 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: lomustine 1-3 part, and gelatin, each 300-900 part of arabic gum, surfactant (polysorbate60) 2-6 part prepare the lomustine microcapsule by complex coacervation, add collagen swelling solution 2000-6000 part, and lyophilization prepares the medicine film.
Implementing concrete steps of the present invention is: lomustine is dissolved in ether, adds polysorbate60 then and grinds mixing; Add the arabic gum aqueous solution, stir under (400rpm) 50 ℃ solution is made the CCNU-arabic gum Emulsion that oily microdroplet is homogeneous state; Get aqueous gelatin solution and add in the Emulsion, stir; Regulate its pH value near 7 with 10% NaOH solution, continue to stir, mixing time is exceeded (40min) with the non-foaming foam of Emulsion, adds 5% HAc solution regulator solution pH value to 4.06 then, and oily microdroplet is enclosed in the transparent complex coacervation somatocyst sheath fully, be spheroidal, continue to stir (60rpm) 5min, add the entry dilution then, be cooled to 28 ℃, in ice bath, cool to again below 10 ℃, stir.Then, add formalin and be cured, regulate pH value to 7-8 with 10% NaOH solution behind the 30min, stir 4h (60rpm), leave standstill, microcapsule sinks.The sucking filtration suspension discards filtrate, keeps filtering residue and is microcapsule.Wash and remove formaldehyde 3-4 time.With microcapsule drying 50 ℃ the time; Cross 200 mesh sieves, sieve microgranule down promptly is a microcapsule.Get the collagen swelling solution, add malonic acid solution dissolve the collagen swelling solution.Get the lomustine microcapsule 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.After drying promptly gets lomustine controlled release medicine film.
Lomustine controlled release medicine film of the present invention 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.Low toxicity of the present invention is the kill tumor cell efficiently, 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:
Take by weighing lomustine 12.2mg, be dissolved in a small amount of ether, add a little polysorbate60 then and grind mixing; The arabic gum aqueous solution that adds 10ml 3% stirs (400rpm) down at 50 ℃, and solution is made the CCNU-arabic gum Emulsion that general oily microdroplet is homogeneous state; Get 3% aqueous gelatin solution 10ml and add in the Emulsion, regulate its pH value near 7, keep former speed to continue stirring 40min with 10% NaOH solution.The HAc solution regulator solution pH value to 4.06 of adding 5%, examine under a microscope this moment, and oily microdroplet should be enclosed in the transparent complex coacervation somatocyst sheath fully, is spheroidal (above operation is all carried out in water-bath).Continue to stir (60rpm) 5min, add the dilution of 20ml water, be cooled to 28 ℃, in ice bath, cool to rapidly again below 10 ℃, stir.Then, after adding 37% formalin and being cured 30min, the NaOH solution with 10% is regulated pH value to 7-8, stirs 4h (60rpm), leaves standstill, and microcapsule sinks.The sucking filtration suspension discards filtrate, keeps filtering residue and is microcapsule.Wash and remove formaldehyde 3-4 time, with microcapsule drying 50 ℃ the time; Cross 200 mesh sieves then, sieve microgranule down promptly is a microcapsule.Get collagen swelling solution 25g (1.39%), add 0.3% (w/v) malonic acid solution 100ml and get collagen solution.Get above-mentioned microcapsule, add the collagen swelling solution, mixing.Then liquid freezing drying (60 ℃) is become the medicine film that area is 10cm * 10cm.After not having the medicine film to carry out crosslinked 2 hours with 0.25% formalin, formaldehyde is removed in washing.Lyophilization once more (60 ℃) promptly gets lomustine controlled release medicine film.
The productive rate that lomustine prepares microcapsule is 65.7%; 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:
Take by weighing lomustine 122mg, be dissolved in a small amount of ether, add a little polysorbate60 then and grind mixing; The arabic gum aqueous solution that adds 100ml3% stirs (400rpm), solution is made general CCNU-arabic gum Emulsion under 50 ℃; Use microscopic examination, the oily microdroplet in the Emulsion is homogeneous state.Get 3% aqueous gelatin solution 100ml and add in the Emulsion, (400rpm) stirs; Regulate its pH value near 7 with 10% NaOH solution, continue to stir 40min, mixing time is exceeded with the non-foaming foam of Emulsion.The HAc solution regulator solution pH value to 4.06 of adding 5%, examine under a microscope this moment, and oily microdroplet should be enclosed in the transparent complex coacervation somatocyst sheath fully, is spheroidal (above operation is all carried out in water-bath, constantly stirs).Continue to stir (60rpm) 5min, add the dilution of 200ml water then, be cooled to about 28 ℃, in ice bath, cool to rapidly again below 10 ℃, stir.Then, add a certain amount of 37% formalin and be cured, regulate pH value to 7-8 with 10% NaOH solution behind the 30min, continue to stir 4h (60rpm), leave standstill, microcapsule sinks.The sucking filtration suspension discards filtrate, keeps filtering residue and is microcapsule.Wash and remove formaldehyde 3-4 time, with microcapsule 50 ℃ of dryings; Cross 200 mesh sieves then, promptly get microcapsule.Get collagen swelling solution 250g (1.39%), add 0.3% (w/v) malonic acid solution and get the collagen swelling solution.Get the lomustine microcapsule of above-mentioned preparation, add the collagen swelling solution, mixing.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.After drying promptly gets lomustine controlled release medicine film.
Embodiment 3:
Take by weighing lomustine 6.1mg, be dissolved in a small amount of ether, add a little polysorbate60 then and grind mixing; The arabic gum aqueous solution that adds 5ml 3% stirs (400rpm), solution is made CCNU-arabic gum Emulsion under 50 ℃; Use microscopic examination, the oily microdroplet in the Emulsion is homogeneous state.Get 3% aqueous gelatin solution 5ml and add in the Emulsion, (400rpm) stirs; Regulate its pH value near 7 with 10% NaOH solution, continue to stir, mixing time is exceeded with the non-foaming foam of Emulsion, about 40min.The HAc solution regulator solution pH value to 4.06 of adding 5%, examine under a microscope this moment, and oily microdroplet should be enclosed in the transparent complex coacervation somatocyst sheath fully, is spheroidal.Continue to stir (60rpm) 5min, add the dilution of 10ml water then, be cooled to 28 ℃, in ice bath, cool to rapidly again below IO ℃, in the process of cooling, stir at a slow speed with Glass rod.Then, add 37% formalin and be cured, regulate pH value to 7-8 with 10% NaOH solution behind the 30min, continue to stir 4h (60rpm), leave standstill, microcapsule sinks.The sucking filtration suspension discards filtrate, keeps filtering residue and is microcapsule.Wash and remove formaldehyde 3-4 time, with microcapsule drying 50 ℃ the time: sieve then, sieve microgranule down promptly is the microcapsule that this experiment obtains.Get collagen swelling solution 12.59 (1.39%), add 0.3% (w/v) malonic acid solution and get the collagen swelling solution.Get the lomustine microcapsule 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.After drying promptly gets lomustine controlled release medicine film.
Table 1 CCNU medicine film is to the influence of mice blood cell count
| Group | WBC／10 9.L -1 | RBC／10 12.L -1 | HGB／g.L -1 | PLT／10 11.L -1 |
| CCNU150μg 300μg 600μg 1200μg i.v 800μg | 8.77±2.41** 8.29±1.97** 7.90±2.21** 5.21±2.90 3.80±1.70 | 9.12±3.04 8.70±3.41 8.20±2.91 7.31±1.71 6.92±2.44 | 177.2±29** 160.7±34** 142.9±31* 129.7±39 109.0±33 | 1291±337** 1244±239** 1114±310 1047±264 894±276 |
Compare?with?i．V．group，**P〈0.01，*P〈0.05
Table 2 lomustine medicine film is to the effect of K562 cell inhibiting
Table 3 lomustine medicine film is to the inhibitory action of Emhorn solid tumor (X ± SD)
| Group | Number of animals (only) 1 | Heavy (g) 2 of tumor | 3 |
| The low CCNUi.v. of CCNU among the high CCNU of solvent control CCNU | 20 0.7333±0.2046 12 0.4750±0.2007** 12 0.5681±0.1899** 12 0.6808±0.2293 12 0.5805±0.2616* | 0.7406±0.1941 0.4717±0.2016** 0.5743±0.2124** 0.6621±0.1894 0.5921±0.2166* | 0.7562±0.2135 0.5189±0.2224** 0.5812±0.1716** 0.6687±0.1470 0.5105±0.1241** |
Compare?with?control?group，*P〈0．05，**P〈0．01
Claims (4)
1. the weight that release-controlling coating of antineoplastic lomustine, its feature are stored in it forms and content is:
Lomustine 1-3 part
Gelatin 300-900 part
Arabic gum 300-900 part
Surfactant polysorbate60 2-6 part
2. the said release-controlling coating of antineoplastic lomustine preparation method of claim 1 is characterized in that it comprises the steps:
(1) lomustine is dissolved in ether to dissolving fully, adds polysorbate60 then and grind mixing; Add the arabic gum aqueous solution, stir, solution is made lomustine-arabic gum Emulsion that oily microdroplet is homogeneous state under 50 ℃ with 400rpm;
(2) getting aqueous gelatin solution adds in lomustine-arabic gum Emulsion, stir, regulate pH=7, continue to stir 40min with 400rpm with aqueous slkali, use acetum regulator solution pH value to 4.06 then, oily microdroplet is enclosed in the transparent complex coacervation somatocyst sheath fully; Continuation is stirred 5min with 60rpm, and times water gaging dilution is cooled to 28 ℃, cools in ice bath below 10 ℃ again, adds the formalin crosslinking curing then;
(3) regulate pH value to 7-8 with aqueous slkali behind the 30min, stir 4h with 60rpm, leave standstill, microcapsule sinks, and the sucking filtration suspension discards filtrate, keeps filtering residue and is microcapsule; Wash and remove formaldehyde 3-4 time;
(4) with microcapsule drying 50 ℃ the time, cross 200 mesh sieves, sieve microgranule down promptly is a microcapsule;
(5) get the collagen swelling solution, add the malonic acid solution dilution, get the microcapsule of above-mentioned preparation, add the collagen swelling solution after diluting, mixing is then with liquid-60 a ℃ lyophilization becoming medicine film;
(6) with formalin crosslinked 2 hours, formaldehyde was removed in washing, and ℃ lyophilization promptly gets lomustine controlled release medicine film once more-60.
3. according to the said release-controlling coating of antineoplastic lomustine preparation method of claim 2, the span that it is characterized in that the collagen swelling solution of said patent medicine film is 2000-6000 part.
4. according to the said release-controlling coating of antineoplastic lomustine 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 |
|---|---|---|---|
| CNB001210998A CN1141087C (en) | 2000-07-20 | 2000-07-20 | Release-controlling coating of antineoplastic lomustine |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB001210998A CN1141087C (en) | 2000-07-20 | 2000-07-20 | Release-controlling coating of antineoplastic lomustine |
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| CN1282578A true CN1282578A (en) | 2001-02-07 |
| CN1141087C CN1141087C (en) | 2004-03-10 |
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| CNB001210998A Expired - Fee Related CN1141087C (en) | 2000-07-20 | 2000-07-20 | Release-controlling coating of antineoplastic lomustine |
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Cited By (1)
| 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 |
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2000
- 2000-07-20 CN CNB001210998A patent/CN1141087C/en not_active Expired - Fee Related
Cited By (1)
| 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 |
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