CN101279995A - Tripterine salt, preparation and use thereof - Google Patents
Tripterine salt, preparation and use thereof Download PDFInfo
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- CN101279995A CN101279995A CNA2007100141546A CN200710014154A CN101279995A CN 101279995 A CN101279995 A CN 101279995A CN A2007100141546 A CNA2007100141546 A CN A2007100141546A CN 200710014154 A CN200710014154 A CN 200710014154A CN 101279995 A CN101279995 A CN 101279995A
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Abstract
The invention provides a tripterine salt, in particular to a salt which is a product from the reaction of tripterine and medically acceptable basic amino acid(such as arginine, lysine, etc.) or organic amine(such as meglumine) or inorganic base(such as sodium hydroxide, potassium hydroxide,etc). The salt solves the problem in solubility of tripterine and can be made into a stable aqueous preparation with improved peroral biological availability. The general structural formula is as above, wherein R is basic amino acid, organic amine or inorganic base.
Description
Technical field:
The present invention relates to a kind of tripterine salt and preparation method thereof and purposes.
Background technology:
Trypterygine is the medicine of treatment autoimmune disease, and it contains plurality of active ingredients, as triptolide, Triptodiolide, Tripterine (Celastrol) etc.These effective constituents have complicated influence to the panimmunity cell, comprise suppressing propagation, apoptosis-induced and change cytokine secretion etc.Tripterine is one of main component in the trypterygine, and its chemical structure is as follows:
The bibliographical information Tripterine has anti-inflammatory (comprising aspects such as suppressing COX2 activity, NF-kB, NO, leukotriene), antitumor, anti-oxidant, antimycotic, anti-hepatitis, desinsection, antimalarial, contraception, inhibition dandruff, treatment nephropathy, central nervous system disease pharmacologically actives such as (as alzheimer's diseases).
But because of Tripterine belongs to insoluble drug, its bioavailability is lower, and is very limited on the route of administration of medicine, thereby influences its exploitation as new drug.
Summary of the invention:
The purpose of this invention is to provide the tripterine salt that a class Tripterine and different organic or inorganic alkali form, this tripterine salt not only solvability is good, and can be made into stable is the preparation of carrier with water, and oral administration biaavailability also obtains to improve.
The invention provides a kind of water-soluble tripterine salt, it is characterized in that the salt or the corresponding isomer of following array structure formula (I) expression, wherein the R in the structural formula is basic aminoacids, organic amine, mineral alkali.
The present invention also provides a kind of preparation method of tripterine salt: promptly add Tripterine, basic aminoacids or organic amine or mineral alkali and aqueous ethanolic solution, stirring reaction under the room temperature, reclaim under reduced pressure in reaction flask successively, place crystallization, filter, drying, promptly.
The mole proportioning of Tripterine and basic aminoacids or organic amine or mineral alkali is 1: 0.5～3 among the above-mentioned preparation method, wherein preferred 1: 1.
Basic aminoacids described in the above-mentioned preparation method can be selected from L-arginine, D-arginine, D, L-arginine, Methionin, ornithine, Histidine etc.; Described organic amine can be selected from meglumine, TERTIARY BUTYL AMINE etc.; Described mineral alkali can be selected from oxyhydroxide such as sodium hydroxide, the potassium hydroxide etc. of alkali-metal oxyhydroxide, alkaline-earth metal, wherein preferred arginine.
The invention provides tripterine salt can make up with pharmaceutical carriers, makes the various formulations of pharmacy acceptable, comprises injection, oral solid formulation such as tablet, capsule, granule etc.
The present invention also provides the purposes of tripterine salt aspect the preparation anti-tumor medicine.
The present invention also provides the purposes of tripterine salt aspect the preparation anti-inflammatory drug.
The dosage range of Tripterine salts for treating tumour is everyone 5-15mg every day, intravenous injection.The anti-inflammatory agent weight range is everyone 10-40mg every day, and usage is oral.Because this dosage is to calculate according to animal pharmacological test to get that in view of the otherness of animals and human beings body, the clinical consumption in historical facts or anecdotes border can allow to adjust to some extent.In addition the tripterine salt good water solubility that obtains because of the present invention can be made into injection, and bioavailability is higher, so antitumor and anti-inflammatory all can adopt oral, injection system administration.This section argumentation to route of administration only is representative the argumentation.
Following embodiment is not limited to this in order to explain the present invention.
Embodiment:
Tripterine obtains by buying commercially available product, produces as Paipai Tech Co., Ltd., Shenzhen City, and purity reaches more than 98%.
Embodiment 1: the preparation of Tripterine arginic acid salt
In reaction flask, add Tripterine 0.45g (0.001mol), L-arginine 0.174g (0.001mol) and 100ml 62.5% aqueous ethanolic solution successively, stirring reaction 6h under the room temperature, reclaim under reduced pressure is to 20ml, place crystallization for 4 ℃, filter, drying promptly gets red powder shape solid 0.49g, yield 78.5%.
Tripterine arginic acid salt chemical structure confirms that data are as follows:
ESI-MS?m/z(100％)：624([M-H]
+，2.61)，448([Cel-H]
+，100)，173([Arg-H]
+，8.38)；
13C-NMRδ(Hz)：184.2，178.5，173.5，171.5，165.3，157.4，146.4，135.1，127.1，119.1，118.7，118.2，55.6，45.0，44.0，43.0，41.9，40.5，39.5，38.5，36.6，34.7，33.5，32.8，31.6，31.0，30.7，29.9，29.8，29.3，28.4，25.9，20.8，18.1，8.9。
Embodiment 2: the preparation of Tripterine arginic acid salt
In reaction flask, add Tripterine 0.45g (0.001mol), L-arginine 0.087g (0.0005mol) and 100ml 62.5% aqueous ethanolic solution successively, stirring reaction 6h under the room temperature, reclaim under reduced pressure is to 20ml, place crystallization for 4 ℃, filter, drying promptly gets red powder shape solid 0.61g, yield 76.4%.
Embodiment 3: the preparation of Tripterine arginic acid salt
In reaction flask, add Tripterine 0.45g (0.001mol), L-arginine 0.522g (0.003mol) and 100ml 62.5% aqueous ethanolic solution successively, stirring reaction 6h under the room temperature, reclaim under reduced pressure is to 20ml, place crystallization for 4 ℃, filter, drying promptly gets red powder shape solid 0.41g, yield 76.3%.
Embodiment 4: the preparation of Tripterine lysine salt
In reaction flask, add Tripterine 0.45g (0.001mol), Methionin 0.146g (0.001mol) and 100ml 62.5% aqueous ethanolic solution successively, stirring reaction 6h under the room temperature, reclaim under reduced pressure is to 20ml, place crystallization for 4 ℃, filter, drying gets red powder shape solid 0.45g, yield 75.5%.
Embodiment 5: the preparation of Tripterine meglumine salt
In reaction flask, add Tripterine 0.45g (0.001mol), meglumine 0.195g (0.001mol) and 100ml 62.5% aqueous ethanolic solution successively, stirring reaction 6h under the room temperature, reclaim under reduced pressure is to 20ml, place crystallization for 4 ℃, filter, drying promptly gets red powder shape solid 0.42g, yield 65.1%.
Embodiment 6: the preparation of Tripterine sodium salt
In reaction flask, add Tripterine 0.45g (0.001mol), sodium hydroxide 0.04g (0.001mol) and 3000ml dehydrated alcohol successively, stirring reaction is to clear liquor, filter, reclaim under reduced pressure is to 10ml, place crystallization for 4 ℃, filter drying, get red powder shape solid 0.36g, yield 73.5%.
Embodiment 8: the preparation of Tripterine sylvite
Add Tripterine 0.45g (0.001mol), potassium hydroxide 0.056g (0.001mol), methyl alcohol 1000ml in reaction flask successively, stirring reaction filters to clear liquor, reclaim under reduced pressure is placed crystallization for 4 ℃ to 10ml, filters, drying gets red powder shape solid 0.35g, yield 70%.
Embodiment 9: the preparation of Tripterine arginic acid salt tablet
Take by weighing Tripterine arginic acid salt 10g (pressing embodiment 1 preparation), mixing is crossed 80 mesh sieves, add Microcrystalline Cellulose 90g, starch 100g and form pharmaceutical formulation as thinner, mixing, spraying into 75% ethanol is tackiness agent system softwood, granulate with 24 mesh sieves, the whole grain in dry back, mixing, compressing tablet, make 1000, dressing, that is, every contains Tripterine arginic acid salt 10mg.
Embodiment 10; The preparation of Tripterine arginic acid salt injection liquid
Take by weighing Tripterine arginic acid salt 0.5g (pressing embodiment 1 preparation), water for injection to 900ml, is stirred and makes dissolving, filter, get filtrate, 0.1mol/lNaOH solution adjust pH is to 8-9, add the injection water to 1000ml, after assay meets the requirements, filter just, it is qualified that essence is filtered to clarity test, embedding, sterilization, that is, and 0.5mg/ml.
Embodiment 11: the preparation of Tripterine meglumine salt capsule
Take by weighing Tripterine meglumine salt 10g (pressing embodiment 5 preparations), mixing is crossed 80 mesh sieves, add pregelatinized Starch 190g and form pharmaceutical formulation as thinner, mixing, spraying into 75% ethanol is tackiness agent system softwood, granulates with 24 mesh sieves, the whole grain in dry back, mixing, encapsulated, make 1000, that is, every contains Tripterine meglumine salt 10mg.
1 solubility test of test example
Precision takes by weighing and is ground into the smart amide of fine powder Tripterine 5mg and Tripterine (press embodiment 1 preparation), Tripterine meglumine salt (press embodiment 5 prepares), each 50mg of Tripterine sodium salt (pressing embodiment 6 prepares) respectively, place 25 ℃ ± 2 ℃ 50ml distilled water respectively, 30 seconds of powerful jolting every 5 minutes; Observe the dissolving situation in 30 minutes.Tripterine still has visible particles of solute, and its water solubility belongs to almost insoluble substance of water less than 0.1mg/ml; The then dissolving fully of the smart amide of Tripterine, Tripterine meglumine salt, Tripterine sodium salt.In addition precision takes by weighing and is ground into the smart amide of fine powder Tripterine, Tripterine meglumine salt, each 100mg of Tripterine sodium salt, places 25 ℃ ± 2 ℃ 50ml distilled water, 30 seconds of powerful jolting every 5 minutes; Observe the dissolving situation in 30 minutes, the smart amide of Tripterine, Tripterine meglumine salt, Tripterine sodium salt all have a small amount of visible particles of solute.Therefore the smart amide of Tripterine, Tripterine meglumine salt, Tripterine natrium brine solubleness belong to water slightly soluble material greater than 1mg/ml.
Test example 2 tripterine salts and Tripterine oral administration biaavailability are relatively
1. soup preparation
Take by weighing Tripterine arginic acid salt (pressing embodiment 1 preparation), Tripterine meglumine salt (pressing embodiment 5 preparations), Tripterine sodium salt (pressing embodiment 6 preparations) respectively in right amount, add deionized water dissolving, being made into concentration respectively is 5mg/mL solution, is sample A, B, C; It is an amount of to take by weighing Tripterine, adds 1% carboxymethylcellulose sodium solution suspendible, makes the 5mg/mL suspension, is sample D.
2. gastric infusion scheme: rat fasting 16h, freely drink water, gastric infusion sample A, B, C, D respectively, dosage is respectively 50mg/kg.Respectively at 15min, 30min after 5min before the administration and the administration, 45min, 60min, 90min, 120min, 180min, 240min, 300min,, 360min, 480min get blood, separation of serum.
3. sample preparation
The processing of plasma sample: the accurate just sample 0.2mL of blood plasma that draws, accurate 10% trichoroacetic acid(TCA), the 40 μ L that add refrigeration, vortex 3min, the centrifugal 10min of 12000r/min draws the about 120 μ L of supernatant liquor and places point end sample introduction bottle, HPLC automatic sampling.
The mensuration of 4 samples
4.1 instrument
1100 series of high efficiency liquid chromatographs (U.S. Agilent company); Comprise the G1312A binary pump, the G1313A automatic sampler.
4.2 the chromatographic condition chromatographic column that plasma sample is measured: discover ODS post (250mm * 4mm, 5 μ m); Moving phase: acetonitrile: water (87: 13); Flow velocity 1mL/min detects wavelength: 425nm.
4.3 result
The bioavailability of table 1 Tripterine arginic acid salt and Tripterine relatively
The above results shows: oral Tripterine arginic acid salt, meglumine salt, sodium salt Plasma Concentration (Cmax) show that far above oral Tripterine Plasma Concentration (Cmax) the tripterine salt bioavailability significantly improves.
Test example 3 tripterine salt antitumor actions
Observation is tried the thing intravenous injection to U14 cervical cancer, PC-3, and the antitumor activity of Lewis lung cancer.SPF level C57BL/6 mouse is selected in experiment for use.If negative control group, Tripterine group, Tripterine arginic acid salt group (pressing embodiment 1 preparation).Adopt the oxter to connect the knurl method, connect after the knurl random packet next day, intravenously administrable is 10 days continuously, and the last administration was taken off cervical vertebra and put to death mouse after 24 hours, stripped tumor tissue, weighed, and calculated tumour inhibiting rate.The result shows that Tripterine arginic acid salt intravenously administrable has significant tumor-inhibiting action, is better than Tripterine.See table 2 for details:
The tumour inhibiting rate (%) of the various knurl strains of table 2 Tripterine salt pair
The influence of test example 4 tripterine salt p-Xylol induced mice auricle edemas
1. material and animal
Tripterine arginic acid salt: press embodiment 1 preparation.
Dexamethasone: lot number 0601146, Zhengzhou Lingrui Pharmaceutical Co., Ltd. produces.
Dimethylbenzene: Hangzhou Zhong Shan chemistry company limited produces.
Kunming mouse, unming Medical College's Experimental Animal Center provides.
2. divide into groups and method
Get 80 of Kunming kind small white mouses, be divided into 8 groups at random.Model group (physiological saline), Tripterine high dose group (ig, 2mg/kg), middle dosage group (ig, 4mg/kg), low dose group (ig, 8mg/kg), Tripterine arginic acid salt high dose group (ig, 2mg/kg), middle dosage group (ig, 4mg/kg), low dose group (ig, 8mg/kg), the dexamethasone positive controls (iv, 2mg/kg).Gastric infusion 3 days, 40min after the last administration, 50 μ l dimethylbenzene are applied to the wide two sides of mouse right ear cause inflammation, left side ear in contrast, cause the disconnected neck of scorching back 1h and put to death power, cut two ears, lay auricle at same position respectively with the punch tool of diameter 9mm along the auricle baseline, immediately weigh, calculate and respectively organize swelling degree and inhibiting rate.
Heavy (the mg)-auris dextra auricle of swelling degree (mg)=left ear auricle heavy (mg)
Inhibiting rate (%)=(the average auricle of the average auricle weight-administration of model group group is heavy)/average auricle of model group heavy * 100%
3. result
The Tripterine arginic acid salt can significantly suppress the auricle edema that dimethylbenzene causes, is better than Tripterine.See table 3 for details.
Table 3 Tripterine arginic acid salt p-Xylol cause mice auricle swelling influence (x ± s, n=10)
Annotate: compare with model group
*P＜0.05,
*P＜0.01,
* *P＜0.001.
Claims (10)
1. water-soluble tripterine salt is characterized in that: the salt of following array structure formula (I) expression or corresponding isomer, wherein the R in the structural formula is basic aminoacids, organic amine, mineral alkali.
2. the preparation method of the described tripterine salt of claim 1 is characterized in that: add Tripterine, basic aminoacids or organic amine or mineral alkali and aqueous ethanolic solution successively in reaction flask, stirring reaction under the room temperature, reclaim under reduced pressure is placed crystallization, filters, drying, promptly.
3. the preparation method of tripterine salt according to claim 2, it is characterized in that: the mole proportioning of described Tripterine and basic aminoacids or organic amine or mineral alkali is 1: 0.5～3.
4. the preparation method of tripterine salt according to claim 3, it is characterized in that: the mole proportioning of described Tripterine and basic aminoacids or organic amine or mineral alkali is 1: 1.
5. the preparation method of tripterine salt according to claim 2 is characterized in that: described basic aminoacids can be selected from any in L-arginine, D-arginine, D, L-arginine, Methionin, ornithine, the Histidine.
6. the preparation method of tripterine salt according to claim 2 is characterized in that: described organic amine can be selected from any in meglumine, the TERTIARY BUTYL AMINE.
7. the preparation method of tripterine salt according to claim 2 is characterized in that: described mineral alkali can be selected from any in the oxyhydroxide of alkali-metal oxyhydroxide, alkaline-earth metal such as sodium hydroxide, the potassium hydroxide.
8. tripterine salt according to claim 1 is characterized in that: described tripterine salt and pharmaceutical carriers combination, can be made into the various formulations of pharmacy acceptable, and comprise injection, oral solid formulation.
9. the described tripterine salt of claim 1 is in the application of preparation antitumor drug.
10. the described tripterine salt of claim 1 is in the application of preparation anti-inflammatory drug.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102796254A (en) * | 2011-05-26 | 2012-11-28 | 复旦大学 | Pegylated celastrol and preparation method and application thereof |
| CN110229210A (en) * | 2019-06-25 | 2019-09-13 | 河南中医药大学 | Amino acid eutectic object of Celastrol and its preparation method and application |
| CN111529535A (en) * | 2012-09-27 | 2020-08-14 | 儿童医学中心公司 | Compounds for the treatment of obesity and methods of their use |
| CN115368430A (en) * | 2022-09-02 | 2022-11-22 | 北京化工大学 | A kind of preparation method and application of tripterine metal complex |
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2007
- 2007-04-03 CN CNA2007100141546A patent/CN101279995A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102796254A (en) * | 2011-05-26 | 2012-11-28 | 复旦大学 | Pegylated celastrol and preparation method and application thereof |
| CN111529535A (en) * | 2012-09-27 | 2020-08-14 | 儿童医学中心公司 | Compounds for the treatment of obesity and methods of their use |
| CN110229210A (en) * | 2019-06-25 | 2019-09-13 | 河南中医药大学 | Amino acid eutectic object of Celastrol and its preparation method and application |
| CN110229210B (en) * | 2019-06-25 | 2022-07-12 | 河南中医药大学 | Amino acid eutectic compound of tripterine, preparation method and application thereof |
| CN115368430A (en) * | 2022-09-02 | 2022-11-22 | 北京化工大学 | A kind of preparation method and application of tripterine metal complex |
| CN115368430B (en) * | 2022-09-02 | 2024-02-02 | 北京化工大学 | Preparation method and application of triptolide metal complex |
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