CN101273977B - Preparation technique of tryptanthrin preparations and uses thereof - Google Patents
Preparation technique of tryptanthrin preparations and uses thereof Download PDFInfo
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- CN101273977B CN101273977B CN2008100173950A CN200810017395A CN101273977B CN 101273977 B CN101273977 B CN 101273977B CN 2008100173950 A CN2008100173950 A CN 2008100173950A CN 200810017395 A CN200810017395 A CN 200810017395A CN 101273977 B CN101273977 B CN 101273977B
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- couroupitine
- tryptanthrin
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- colitis
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Abstract
The invention proposes drugs for the treatment of leukemia and other tumors, colitis and fungal infection, which are a series of tryptanthrin preparations and a preparation process thereof, pertaining to the fields of pharmaceutical preparation process and clinical application. The invention is characterized in that the tryptanthrin has killing and inhibiting effects on tumor cells, animal transplantable tumors, various fungi and bacteria, inhibiting effect on inflammation, the regulation of the immune function of a body structure and other pharmacological activities. The tryptanthrin is prepared into tryptanthrin sustained-release tablets, tryptanthrin sustained-release capsules and tryptanthrin injections for the treatment of leukemia and other tumors, colitis and fungal infection, thus being used for the treatment of leukemia and other tumors, colitis, fungal infection and other diseases. The series of tryptanthrin drug preparations have stable drug content, controllable quality, high bioavailability, small drug dosage, accurate efficacy, low side effects, abundant sources of raw materials and low production cost.
Description
Affiliated technical field
Couroupitine A preparation series of the present invention relates to slow releasing tablet, slow releasing capsule and the injection preparation series for the treatment of tumor, colitis, fungal infection.
Background technology
Couroupitine A (tryptanthrin) produces in blue plant such as Acanthaceous indigo, polygonum tinctorium ait., Isatis indigotica Fort. etc. and the part microorganism and can separation and Extraction obtain at some.That couroupitine A mainly contains is anticancer, anti-inflammatory, antifungal isoreactivity.Couroupitine A is yellow acicular crystal, 267～369 ℃ of molten points, and molecular formula is C
15H
8N
2O
2But, existing synthetic, industrial products content is up to 97～99%.
Tumor, colitis and fungal infection are common clinical and frequently-occurring disease.Tumor particularly, whole world every year, new cases surpassed 8,000,000, and sickness rate is also increasing year by year because of cancer mortality number nearly 6,000,000; And the serious health that is endangering people of colitis and fungal infection, and there is not the specific treatment medicine.Therefore, antitumor and effective treatment colitis, fungal infection medicine have great market.At present, domestic and foreign literature and wes' studies confirm that couroupitine A has obvious therapeutic action to diseases such as tumors such as leukemia, colitis and fungal infections.The present invention is intended to adopt modern preparation process and technology initiative new drug, for tumors such as vast leukemia, colitis and fungal infection patient provide efficiently, low toxicity, preparation series easy to use, for removing patient's sufferings and ensureing that people's health has important and realistic meaning.
Summary of the invention
The objective of the invention is: a kind of slow releasing tablet, slow releasing capsule and injection of doing tumor such as main raw material treatment leukemia, colitis, fungal infection with couroupitine A is provided, and its production cost is low, and stable content, quality controllable has a extensive future.
To achieve these goals, the technical scheme that the present invention takes is: couroupitine A is selected the industrial products of plant purification thing or synthetic, C for use
15H
8N
2O
2Content is 97～99%, wherein the preparation technology of couroupitine A slow releasing tablet be with the 2-HP-with the couroupitine A enclose, sieve back and other adjuvant mix homogeneously, direct compression is put label in the coating pan, with sustained release coating liquid spray coating, gets patent medicine; The preparation technology of couroupitine A capsule slow releasing agent is with the resulting loose shape white powder of 2-HP-enclose couroupitine A and microcrystalline Cellulose powder mixing in proportion, with the pelletize of K-30 povidone solution, extrude through extruder, balling-up in spheronizator, get coated micropill, drying is carried out coating with sustained release coating liquid, and the hard capsule of packing into of the micropill behind the coating namely gets patent medicine; The preparation technology of couroupitine A freeze-dried powder injection adds the physiological saline solution heated and stirred with vitamin C to make its dissolving, add activated carbon decolorizing, filtered while hot goes the charcoal degerming standby, 2-HP-normal saline solution is heated to 90 ℃, slowly splash into the inferior wind solution stirring of couroupitine A dimethyl, add said vitamin C solution after the degerming again, mixing, add physiological saline solution and adjust mixed liquor to 1000mL, be sub-packed in 500～1000 sterilization glass tube vials lyophilization 20～24h in freeze dryer, towards nitrogen, gland, sealing gets couroupitine A freeze-dried powder injection finished product; The preparation technology of couroupitine A injectable emulsion is with couroupitine A, soybean lecithin and cholesterol mixing, add an amount of chloroform dissolving back film forming on Rotary Evaporators, drain chloroform, dry film places that phosphate buffer is ultrasonic to dissolve it fully, adds phosphate buffer to 1000 milliliter again, the overanxious degerming of super worry film, be sub-packed in 200～500 sterilization glass tube vials gland, sealing, get the couroupitine A injectable emulsion, get product.
It is reported the effect that couroupitine A has induced apoptosis in leukemia cell lines in the knotweed Huang, its clinical practice still under study for action.Kimoto etc. also find the composition of a kind of biologically active in the arsesmart polygonum tinctorium ait., be in the Indigo Naturalis plant family-member, and external multiple human leukaemia cell is had lethal effect, its effect may can cause leukaemia's mitochondrion significantly to expand with couroupitine A and destroy relevant; Result of study shows, but the couroupitine A of the difference high concentration that the couroupitine A of low concentration can the inducing leukemia cell will utilize apoptosis to kill the leukaemia, may be by-bar caspasse-3/Fas antigen approach.Results of study such as calendar year 2001 Koya Miyata show that couroupitine A has preventive effect to the intestinal canal tumour that azoxymethane causes.The nearest couroupitine A that studies show that has inhibitory action to the cancerous cell of multidrug resistance, and the drug resistance of amycin being treated breast cancer cell has reverse effect.
People once cured athletic feet wound with the fresh juice of Acanthaceous indigo in the past, and people separated from Acanthaceous indigo and obtain couroupitine A afterwards, and found that it has the activity that suppresses dermatophytes.Through the antifungal experiment, find that couroupitine A has stronger bacteriostasis to the sick fungus of various skin, its minimal inhibitory concentration is 5ug/ml.
Nitric oxide and prostaglandin are the virulence factors of several inflammation diseases.They are that macrophage is enzyme-added at two kinds of synthetic multiple-effect mediators of inflammation part by nitric oxide synthetase and epoxy.It is nitric oxide production synthetic that discovery couroupitine As such as Tatsuya in 2000 etc. and Danz can suppress in range of doses, and couroupitine A is to reach by the gene expression that suppresses inducible nitric oxide synthase to suppress the synthetic purpose of nitric oxide.And the generation mechanism of couroupitine A inhibition prostaglandin is nitric oxide production synthetic different with inhibition, and it is the generation that suppresses prostaglandin by the inhibition cyclooxygenase activity, thereby the performance antiinflammatory action.
Specific embodiments
The couroupitine A preparation series is selected plant purification thing or the synthetic main medicinal raw material of couroupitine A conduct of industry for use, is prepared into various preparations, and its concrete preparation technology is described below respectively.
1, the preparation technology of couroupitine A slow releasing tablet
The preparation technology of couroupitine A slow releasing tablet divides three parts, the one, enclose; The 2nd, the preparation label; The 3rd, coating.Wherein the raw-material formula proportion of enclose and tabletting is: couroupitine A 1.0～6.0%, dehydrated alcohol 1.0～3.0%, vitamin C 2.0～3.0%, 2-HP-20.0～24.0%, 5%Eudragit RS acetone soln 0.5～1.0%, Aluminium Hydroxide 0.5～1.0%, magnesium stearate 0.5～1.0%, Pulvis Talci 0.5～1.0%, distilled water 74.0～60.0%.The material of traditional sustained release coating liquid is Eudragit RS12.5, Eudragit RL12.5, dibutyl phthalate (DBP), isobutanol/acetone, Pulvis Talci, magnesium stearate, coloring agent, PEG6000, distilled water, isopropyl alcohol.
The preparation technology of couroupitine A slow releasing tablet adds the 2-HP-in 90 ℃ of distilled water earlier to stir, make saturated solution, under 1800 rev/mins of conditions, slowly add couroupitine A dehydrated alcohol suspension solution, stirred 25 minutes, centrifugal 20 minutes with 3000 rev/mins with the freezing centrifuge, abandoning supernatant is tiled in last paste in the pallet, pulverizes after 60 ℃ of oven dry in-20 hours, cross 80 mesh sieves, get clathrate; Adopt wet granule compression tablet then, 2-HP--couroupitine A clathrate is mixed with vitamin C, add 5%Eudragit RS acetone soln, be warming up to 60 ℃ gradually after in High Speed Stirring Machine, making wet grain, dry 14 hours, cross 20 mesh sieves, with Pulvis Talci, magnesium stearate, Aluminium Hydroxide mixing in blender with the rotary tablet machine tabletting, gets 500～1000 labels; Using the buried tube type coating method at last, is 65～75% at relative humidity, and less than 50 ℃ temperature, compressed air pressure is 2～3kg/cm
2Under the condition label is put in the coating pan, used sustained release coating liquid, spray coating, coating film forming thickness are 100～105 μ m, and coated tablet is put in 50 ℃ of baking ovens and is incubated 24 hours, gets the couroupitine A slow releasing tablet, gets product.
2, the preparation technology of couroupitine A slow releasing capsule
The preparation technology of couroupitine A slow releasing capsule divides three parts, the one, enclose; The 2nd, preparation ball core; The 3rd, coating.Wherein the raw-material formula proportion of enclose and pill is: couroupitine A 0.5～3.0%, 2-HP-5.0～8.0%, dehydrated alcohol 0.5～2.0%, distilled water 12.0～16.0%, K-30 polyvidone 8.0～10.0%, microcrystalline Cellulose 74.0～61.0%.The material of traditional sustained release coating liquid is Eudragit RS12.5, Eudragit RL12.5, dibutyl phthalate (DBP), isobutanol/acetone, Pulvis Talci, magnesium stearate, coloring agent, PEG6000, distilled water, isopropyl alcohol.
The preparation technology of couroupitine A slow releasing capsule is: the 2-HP-is added in 90 ℃ of distilled water stir, make saturated solution, under 1800 rev/mins of conditions, slowly splash into couroupitine A dehydrated alcohol suspension solution, stirred 25 minutes, centrifugal 20 minutes with 3000 rev/mins with the freezing centrifuge, after the abandoning supernatant with last paste through 60 ℃-20 hours the oven dry, pulverize, cross 80 mesh sieves, get clathrate; Adopt wet granulation method then, fine powder mixing with 2-HP--couroupitine A clathrate and microcrystalline Cellulose, with the pelletize of K-30 povidone solution, use 23 rev/mins of rotating speeds and sieve aperture to extrude as the extruder of 0.8mm, extrudate places to roll in the spheronizator of 950 rev/mins of rotating speeds made wet ball in 8 minutes, through 50 ℃ of dryings 4 hours, get coated micropill ball core; Take by weighing quantitative ball core at last and put in the coating pan, roll, spray into coating solution after the blowing hot-air preheating, get the slow-release micro-pill that granularity is diameter 1mm, 400～1000 hard capsules of packing into namely get the couroupitine A slow releasing capsule.
3, the preparation technology of couroupitine A injection
The couroupitine A freeze-dried powder injection: the raw-material prescription of couroupitine A freeze-dried powder injection is by couroupitine A 0.1～1.0%, the inferior wind 1.0～5.0% of dimethyl, vitamin C 1.0～2.0%, 2-HP-8.0～15.0%, and normal saline solution 89.9～77.0% is formed.Preparation technology is: vitamin C added the physiological saline solution heated and stirred makes its dissolving, add activated carbon decolorizing, and filtered while hot deactivation charcoal, the solution degerming is standby; The 2-HP-is with the normal saline solution dissolving and be heated to 90 ℃, slowly add the inferior wind solution of couroupitine A dimethyl, be stirred to moltenly, add vitamin c solution after the degerming again, mixing, add physiological saline solution again and adjust mixed solution to 1000mL, evenly be sub-packed in 500～1000 sterilization glass tube vials lyophilization 18～24h in freeze dryer, towards nitrogen, gland, sealing gets couroupitine A freeze-dried powder injection finished product.
The couroupitine A injectable emulsion: the raw-material prescription of couroupitine A injectable emulsion is made up of couroupitine A 0.1～1.0%, soybean lecithin 1.0～4.0%, cholesterol 1.5～4.0%, 97.4～91.0% phosphate buffers.Preparation technology is: with couroupitine A, soybean lecithin and cholesterol mixing, add an amount of chloroform dissolving back film forming on Rotary Evaporators, drain chloroform, dry film places that phosphate buffer is ultrasonic to dissolve it fully, adds phosphate buffer to 1000 milliliter again, the overanxious degerming of super worry film, be sub-packed in 200～500 sterilization glass tube vials gland, sealing, get the couroupitine A injectable emulsion, get product.
Claims (2)
1. treat the couroupitine A freeze-dried powder injection of leukemia, colitis and fungal infection, it is characterized in that: the formula for raw stock ratio in the freeze-dried powder injection prescription is made up of couroupitine A 0.1～1.0%, dimethyl sulfoxide 1.0～5.0%, vitamin C 1.0～2.0%, 2-HP-8.0～15.0%, normal saline solution 89.9～77.0%.
2. couroupitine A freeze-dried powder injection preparation technology according to claim 1 is characterized in that: vitamin C added the physiological saline solution heated and stirred makes its dissolving, add activated carbon decolorizing, and filtered while hot deactivation charcoal, the solution degerming is standby; The 2-HP-is with the normal saline solution dissolving and be heated to 90 ℃, slowly add the couroupitine A dimethyl sulphoxide solution, be stirred to moltenly, add vitamin c solution after the degerming again, mixing, add physiological saline solution again and adjust mixed solution to 1000mL, evenly be sub-packed in 500～1000 sterilization glass tube vials lyophilization 18～24h in freeze dryer, inflated with nitrogen, gland, sealing gets couroupitine A freeze-dried powder injection finished product.
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| CN2008100173950A CN101273977B (en) | 2008-01-24 | 2008-01-24 | Preparation technique of tryptanthrin preparations and uses thereof |
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|---|---|---|---|
| CN201110220858A Division CN102319211A (en) | 2008-01-24 | 2008-01-24 | Preparation process and application of tryptanthrin injection emulsion |
| CN2010101815567A Division CN101933908A (en) | 2008-01-24 | 2008-01-24 | Preparation process of tryptanthrin sustained release tablets and application thereof |
| CN2010101815478A Division CN101933912A (en) | 2008-01-24 | 2008-01-24 | Preparation technology of tryptanthrin sustained-release capsule and application thereof |
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| CN101273977A CN101273977A (en) | 2008-10-01 |
| CN101273977B true CN101273977B (en) | 2013-08-28 |
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| JP2006241080A (en) * | 2005-03-03 | 2006-09-14 | Hirosaki Univ | Iv type allergy reaction inhibitor |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2006241080A (en) * | 2005-03-03 | 2006-09-14 | Hirosaki Univ | Iv type allergy reaction inhibitor |
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