CN101543472B - Method for preparing oxaliplatin sustained release suppository - Google Patents

Method for preparing oxaliplatin sustained release suppository Download PDF

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CN101543472B
CN101543472B CN2009100618588A CN200910061858A CN101543472B CN 101543472 B CN101543472 B CN 101543472B CN 2009100618588 A CN2009100618588 A CN 2009100618588A CN 200910061858 A CN200910061858 A CN 200910061858A CN 101543472 B CN101543472 B CN 101543472B
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oxaliplatin
sustained release
mixture
suppository
microsphere
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CN101543472A (en
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刘小平
耿丹清
吴霞
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Wuhan University of Technology WUT
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Abstract

The invention discloses a method for preparing an oxaliplatin sustained release suppository, which comprises the following steps of: using an acetic acid solution with a mass concentration of between 0.5 and 5 percent to prepare an oxaliplatin solution with a concentration of between 0.5 and 5 mg/mL, taking chitosan, using an oxaliplatin acetic acid solution to dissolve the chitosan, adding span-80 or tween-80 and liquid paraffin, stirring and emulsifying the mixture, adding glutaric dialdehyde into the emulsified mixture, adding NaOH or ammonia water to adjust to ensure that the pH value is more than or equal to 9, stirring the mixture, crosslinking the mixture, centrifugally separating microspheres, and drying to obtain oxaliplatin microspheres; mixing polyethyleneglycol 4000 and polyethyleneglycol 6000 according to the mass ratio of 1-7: 1, and carrying out hot melting on the mixture in water bath with constant temperature; and adding the oxaliplatin microspheres which account for 0.01 to 0.5 times of the total mass of the polyethyleneglycol 4000 and the polyethyleneglycol 6000 into the mixture after the hot melting is finished, and obtaining the oxaliplatin sustained release suppository after the model filling and cooling. The preparation method is simple, and the prepared oxaliplatin sustained release suppository has no burst effect; and the medicament has sustained release characteristics, is slowly released and has sustained release effect. The oxaliplatin sustained release suppository can well play the antitumor effect of oxaliplatin, improve the antitumor activity of the oxaliplatin, and furthest reduce the toxic side effect of the oxaliplatin at the same time.

Description

A kind of method for preparing of oxaliplatin slow release suppository
Technical field
The present invention relates to a kind of method for preparing that contains the suppository of treatment colon, rectal cancer medicine microspheres; Especially the method for preparing of oxaliplatin slow release suppository.
Background technology
According to American Cancer Society's statistics, among all cancer patients, colorectal cancer patients accounts for 10%-15%, has become the second largest malignant disease that causes death of the U.S., has every year 150000 Americans to suffer from colorectal cancer approximately, has 5.6 ten thousand people to die from this disease simultaneously approximately.
Colon cancer is one of gastral common tumor, and postoperative chemotherapy is an important step of treatment of colon cancer, to the prolongation of patient life cycle and the improvement of quality of life, important effect is arranged, but the effective percentage of chemotherapeutics is all lower at present.Seeking the chemotherapeutics of good effect, few side effects, is clinical requirement place.Because oxaliplatin has curative effect preferably to it, and is more to its research in recent years.
Oxaliplatin is the third generation cancer therapy drug behind carboplatin and cisplatin, and it has not only improved the toxic and side effects of cisplatin and carboplatin, and has enlarged their activity profile, and the cell strain or the tumor strain of many anti-cisplatin or carboplatin had activity.Oxaliplatin is mainly used in the patient that the colorectal cancer after fluorouracil treatment failure shifts clinically, can separately or unite fluorouracil and use.
Oxaliplatin (Oxaliplatin) be a kind ofly contain 1, the new platinum-based chemotherapy medicine of 2-diamino cyclohexane extraction (DACH) group; It has overcome first; The main toxicity of second filial generation platinum class; There is not crossing drug resistant with the drug-fast tumor line of second filial generation platinum medicine cisplatin (Cisplatin), as a kind of cancer therapy drug paid more and more attention with applications well prospect.Introduce clinically since first generation platinum medicine cisplatin, platinum medicine develops along the direction of two broads, and the one, improve the toxic and side effects of cisplatin, the 2nd, overcome it at the intravital drug resistance of tumor.Oxaliplatin is the third generation platinum class broad-spectrum anti-cancer drug after cisplatin and carboplatin; Be mainly used in treatment colon cancer, rectal cancer, ovarian cancer, germinoma, mastocarcinoma, gastric cancer, head and neck cancer, pulmonary carcinoma, lymphatic cancer, carcinoma mesothelial, cancer of pancreas, carcinoma of prostate etc., but best to the therapeutic effect of colon cancer and rectal cancer.
Oxaliplatin all has good therapeutic effect to various cancers, has also brought sizable side effect just because of this.
Summary of the invention
The object of the present invention is to provide the method for preparing of oxaliplatin slow release suppository, this method can obtain to have the oxaliplatin suppository of medicament slow release function; Thereby can reduce the toxic and side effects of oxaliplatin greatly.
To achieve these goals, technical scheme of the present invention is: a kind of method for preparing of oxaliplatin slow release suppository comprises the steps:
1) preparation of microsphere: using mass concentration is the oxaliplatin acetum of acetum preparation 0.5~5mg/mL of 0.5%~5%; Get 1~10 times of chitosan,, add emulsifying agent and liquid paraffin with above-mentioned oxaliplatin acetum dissolving to the oxaliplatin quality; Stir emulsifying 0.5~2h; Regulate pH >=9 after adding glutaraldehyde, stir crosslinked 0.5~2h; The centrifugalize microsphere is drying to obtain the oxaliplatin microsphere; Wherein the consumption volume ratio of oxaliplatin acetum, emulsifying agent, liquid paraffin and glutaraldehyde is 5~15mL: 0.5~5mL: 10~50mL: 0.1~1mL;
2) Macrogol 4000 and polyethylene glycol 6000 are pressed mass ratio and mixed in 1: 1~7: 1, under 50~100 ℃ of waters bath with thermostatic control, make its hot melt; Melt the oxaliplatin microsphere of 0.01~0.5 times of back adding Macrogol 4000 and polyethylene glycol 6000 gross mass, promptly got oxaliplatin slow release suppository after filling mould, the cooling.
Mentioned emulsifier is Arlacel-80 or tween 80.
Regulating the used material of pH behind the adding glutaraldehyde according to the invention is NaOH or ammonia.
The concentration of said NaOH is 0.5~3mol/L; The concentration of ammonia is 8~25g/100mL.
The invention has the beneficial effects as follows: method for preparing is simple, carries oxaliplatin with the chitosan bag and is prepared into microsphere, and medicine carrying microballoons is processed suppository; Thereby prepare oxaliplatin slow releasing pharmaceutical novel form, have slow-releasing and controlled-releasing action preferably, but prolong drug action time in vivo; Can well bring into play the antitumor action of oxaliplatin; Improve its anti-tumor activity, reduce its toxic and side effects to greatest extent simultaneously, make it become antineoplastic target drug-supplying system novel form.
The present invention adopts the anum administration form, and dosage and usage and dosage are each 20mg (in oxaliplatin content).
The oxaliplatin slow release suppository of the present invention's preparation is used for the treatment of colon, rectal cancer.
1), the medicine destruction that do not receive gastrointestinal tract pH or enzyme the present invention is designed to rectal suppository with oxaliplatin and also has the following advantages:; 2), medicine absorbs from rectum, receives the first-pass effect of liver in the time of can avoiding oral and destroys, and can also reduce toxicity and the side effect of medicine to liver; 3), the general oral tablet of the time ratio of its effect is long.
The applicant finds, processes suppository again after oxaliplatin is wrapped into microsphere, can make it have slow release effect.Solve the too fast characteristic of its drug release of ordinary suppository, thereby can reduce the toxic and side effects of oxaliplatin greatly.
Description of drawings
Accompanying drawing is the releasing curve diagram of oxaliplatin slow release suppository.
The specific embodiment
In order to understand the present invention better, further illustrate content of the present invention below in conjunction with embodiment, but content of the present invention not only is confined to following embodiment.
Embodiment 1:
The method for preparing of oxaliplatin slow release suppository, it comprises the steps:
1. the preparation of oxaliplatin microsphere
Measure 36% (mass percent) acetic acid 8.33mL; Be diluted to the acetum that 100mL gets 3% (mass percent); Take by weighing oxaliplatin 0.300g and be dissolved in the above-mentioned acetum, ultrasonic it is fully dissolved, promptly get 3% (mass percent) acetic acid oxaliplatin solution of 3.00mg/mL.Accurately measure 10mL oxaliplatin acetum, take by weighing the 0.3g chitosan and be dissolved in the above-mentioned solution, and ultrasonic making it dissolved.Get a beaker; To wherein adding the 30mL liquid paraffin; On magnetic stirring apparatus, stir, and add the about 2.4ml of Arlacel-80 while stirring, to be mixedly add the above-mentioned oxaliplatin acetum that contains chitosan again after evenly; The glutaraldehyde that adds 0.5ml behind the emulsifying 1.5h again, regulating pH value with 20% (g/mL) ammonia is 9.After beginning crosslinked 1.5h, stop to stir.This moment, microsphere formed, and the centrifugalize microsphere promptly gets the oxaliplatin microsphere after the drying.
Oxaliplatin microsphere drug loading, entrapment efficiency determination:
Take by weighing oxaliplatin microsphere 0.252g, add the 20mL distilled water, ultrasonic 45min fully destroys microsphere, discharges Ao Lili platinum.The envelop rate that records oxaliplatin is 36.8%.
2. the preparation of suppository
Take by weighing 14g PEG4000 and 2g PEG6000, in 60 ℃ thermostat water bath, make its hot melt.Melted the microsphere 8g that the back adds above-mentioned preparation, stirred.And will take out at the bolt mould of 50 ℃ of preheatings, be coated with the last layer liquid paraffin, the mould that closes again, and the mixture of hot melt irritated mould.The liquid height of irritating mould needs high depanning outer surface 1~2mm.After treating fully cooling, take out suppository.
The weight differential of suppository:
(1) pure substrate bolt
Do four groups of experiments, get for every group and contain 10 on pure substrate bolt, the accurate title, decided weight, and the result sees table 1.
The pure substrate bolt of table 1 weight differential check result
Figure G2009100618588D00031
(2) oxaliplatin slow-release suppository
Do four groups of experiments, get 10 of medicated bougies for every group, the accurate title, decided weight, and the result sees table 2
Table 2 oxaliplatin slow-release suppository weight differential check result
Through the displacement value that calculates suppository is 1.03.
Melt the change overtime check:
By " 2005 editions (two ones) appendix XB of Chinese pharmacopoeia melt and become the time limit item inspection, are placed on respectively on lower floor's plectane of 3 metal rack, in separately the sleeve of packing into, and fix with hook.Said apparatus immersed respectively to fill temperature be in 37 ± 0.5 ℃ the container, end distance water surface 90mm on it.Every separated this device of 10min upset once.3 pieces of the suppositorys of fat-soluble substrate all should all melt in 30min, softening or do not have hard-core when pressing.3 pieces of suppositorys of experimental result are all softening in 60min.
Limit test of microbe:
With reference to " 2005 editions (two ones) appendix XI of Chinese pharmacopoeia J microbial limit test inspection.Bacterial population<1000/g, mycete and yeast count<100/g, every 1g does not detect staphylococcus aureus, Pseudomonas aeruginosa.
The drug release rate experiment:
The release profiles of oxaliplatin slow release suppository:
Measure down with reference to Chinese Pharmacopoeia version appendix in 2005 XIX D vitro drug release degree test item; Get 3 pieces of oxaliplatin slow release suppositorys, put in the drug dissolution appearance (RCZ-6C type, Shanghai); Get 5mL solution respectively at 0.5,1,2,4,6,8, and timely supplementing solvent; Measure oxaliplatin content at wavelength 250nm place with ultraviolet spectrophotometer (760 CRT, Shanghai), the result sees table 3; And draw release profiles according to measuring the result, see Fig. 1; The result shows that oxaliplatin slow release suppository is slow release.
Table 3 oxaliplatin slow release suppository discharges percentage rate
Can know that by table 3 and Fig. 1 medicine is 7.89% at the drug release percentage rate of 0.5h,, therefore not have burst effect well below 40%.And medicine is to be the slow release release characteristics, and the slow release medicine has slow releasing function.
Embodiment 2:
The method for preparing of oxaliplatin slow release suppository, it comprises the steps:
1. the preparation of oxaliplatin microsphere
Measure 36% (mass percent) acetic acid 5.56mL; Be diluted to the acetum that 100mL gets 2% (mass percent); Take by weighing oxaliplatin 0.200g and be dissolved in the above-mentioned acetum, ultrasonic it is fully dissolved, promptly get 2% (mass percent) acetic acid oxaliplatin solution of 2.00mg/mL.Accurately measure 10mL oxaliplatin acetum, take by weighing the 0.1g chitosan and be dissolved in the above-mentioned solution, and ultrasonic making it dissolved.Get a beaker; To wherein adding the 20mL liquid paraffin; On magnetic stirring apparatus, stir, and add the about 1.6ml of Arlacel-80 while stirring, to be mixedly add the above-mentioned oxaliplatin acetum that contains chitosan again after evenly; The glutaraldehyde that adds 0.3ml behind the emulsifying 1.0h again, regulating pH value with 20% (g/mL) ammonia is 10.After beginning crosslinked 1.0h, stop to stir.This moment, microsphere formed, and the centrifugalize microsphere promptly gets the oxaliplatin microsphere after the drying.
2. the preparation of suppository
Take by weighing 10g PEG4000 and 6g PEG6000, in 80 ℃ thermostat water bath, make its hot melt.Melted the microsphere 8g that the back adds above-mentioned preparation, stirred.And will take out at the bolt mould of 50 ℃ of preheatings, be coated with the last layer liquid paraffin, the mould that closes again, and the mixture of hot melt irritated mould.The liquid height of irritating mould needs high depanning outer surface 1~2mm.After treating fully cooling, take out suppository.
Embodiment 3:
1. the preparation of oxaliplatin microsphere
Measure 36% (mass percent) acetic acid 13.89mL; Be diluted to the acetum that 100mL gets 5% (mass percent); Take by weighing oxaliplatin 0.500g and be dissolved in the above-mentioned acetum, ultrasonic it is fully dissolved, promptly get 5% (mass percent) acetic acid oxaliplatin solution of 5.00mg/mL.Accurately measure 10mL oxaliplatin acetum, take by weighing the 0.5g chitosan and be dissolved in the above-mentioned solution, and ultrasonic making it dissolved.Get a beaker; To wherein adding the 40mL liquid paraffin; On magnetic stirring apparatus, stir, and add the about 3ml of tween 80 while stirring, to be mixedly add the above-mentioned oxaliplatin acetum that contains chitosan again after evenly; The glutaraldehyde that adds 0.5ml behind the emulsifying 2h again, using 0.5mol/L NaOH to regulate pH value is 9.5.After beginning crosslinked 2.0h, stop to stir.This moment, microsphere formed, and the centrifugalize microsphere promptly gets the oxaliplatin microsphere after the drying.
2. the preparation of suppository
Take by weighing 12g PEG4000 and 4g PEG6000, in 90 ℃ thermostat water bath, make its hot melt.Melted the microsphere 8g that the back adds above-mentioned preparation, stirred.And will take out at the bolt mould of 50 ℃ of preheatings, be coated with the last layer liquid paraffin, the mould that closes again, and the mixture of hot melt irritated mould.The liquid height of irritating mould needs high depanning outer surface 1~2mm.After treating fully cooling, take out suppository.

Claims (4)

1. the method for preparing of an oxaliplatin slow release suppository is characterized in that it comprises the steps:
1) preparation of microsphere: using mass concentration is the oxaliplatin acetum of acetum preparation 0.5~5mg/mL of 0.5%~5%; Get 1~10 times of chitosan,, add emulsifying agent and liquid paraffin with above-mentioned oxaliplatin acetum dissolving to the oxaliplatin quality; Stir emulsifying 0.5~2h; Regulate pH >=9 after adding glutaraldehyde, stir crosslinked 0.5~2h; The centrifugalize microsphere is drying to obtain the oxaliplatin microsphere; Wherein the consumption volume ratio of oxaliplatin acetum, emulsifying agent, liquid paraffin and glutaraldehyde is 5~15mL: 0.5~5mL: 10~50mL: 0.1~1mL;
2) Macrogol 4000 and polyethylene glycol 6000 are pressed mass ratio and mixed in 1: 1~7: 1, under 50~100 ℃ of waters bath with thermostatic control, make its hot melt; Melt the oxaliplatin microsphere of 0.01~0.5 times of back adding Macrogol 4000 and polyethylene glycol 6000 gross mass, promptly got oxaliplatin slow release suppository after filling mould, the cooling.
2. method for preparing according to claim 1 is characterized in that: emulsifying agent is Arlacel-80 or tween 80.
3. method for preparing according to claim 1 and 2 is characterized in that: regulating the used material of pH behind the said adding glutaraldehyde is NaOH or ammonia.
4. method for preparing according to claim 3 is characterized in that: the concentration of said NaOH is 0.5~3mol/L; The concentration of ammonia is 8~25g/100mL.
CN2009100618588A 2009-04-28 2009-04-28 Method for preparing oxaliplatin sustained release suppository Expired - Fee Related CN101543472B (en)

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CN105726475B (en) * 2016-04-12 2018-05-04 青岛市妇女儿童医院 A kind of parenteral solution for treating advanced ovarian cancer and preparation method thereof
CN105726474B (en) * 2016-04-12 2018-04-13 周英杰 It is a kind of to be used to treat parenteral solution of advanced ovarian cancer and preparation method thereof
CN115745196B (en) * 2022-11-15 2024-05-07 吉林大学 Composite medicament for carrying out slow release restoration on petroleum-polluted underground water

Non-Patent Citations (3)

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Title
张伦.铂类抗癌药物市场分析.《中国药房》.2003,第14卷(第3期),138-140. *
徐蔚等.碳铂壳聚糖缓释微球制备时的粒径控制.《昆明医学院学报》.2001,(第3期),30-34. *
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