CN101935319A - Berberine organic acid salt, berberine organic acid salt inclusion compound and preparation methods thereof - Google Patents
Berberine organic acid salt, berberine organic acid salt inclusion compound and preparation methods thereof Download PDFInfo
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- CN101935319A CN101935319A CN2010102772766A CN201010277276A CN101935319A CN 101935319 A CN101935319 A CN 101935319A CN 2010102772766 A CN2010102772766 A CN 2010102772766A CN 201010277276 A CN201010277276 A CN 201010277276A CN 101935319 A CN101935319 A CN 101935319A
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Abstract
The invention provides a berberine organic acid salt, a berberine organic acid salt inclusion compound and preparations method thereof. The berberine organic acid salt consists of an alkali base and a salt ligand, wherein the alkali base is a jamaicin alkali base; the salt ligand is an acid radical of organic acid; the mole ratio of the alkali base to the acid radical of organic acid is 1:1; and the berberine organic acid salt inclusion compound consists of an inclusion base material and the berberine organic acid salt. The method for preparing the berberine organic acid salt comprises the following steps of: neutralizing solution of jamaicin and solution of organic acid into salt; crystallizing the salt; and filtering, leaching and drying the crystallized salt so as to obtain the berberine organic acid salt. The method for preparing the berberine organic acid salt inclusion compound comprises the following steps of: dissolving the inclusion base material; adding the berberine organic acid salt into the dissolved inclusion base material for dissolving and inclusion; cooling and standing reaction liquid to separate coprecipitate out; leaching the coprecipitate with acetone; and drying a filter cake so as to obtain the berberine organic acid salt inclusion compound. The berberine organic acid salt and the berberine organic acid salt inclusion compound provided by the invention have the advantages of high bioactivity, small dosage and high dissolubility. The preparation methods have the advantages of simple process, high product purity, easy operation control, simple equipment and easy realization of industrialized production.
Description
Technical field
The invention belongs to field of medicaments, particularly a kind of berberine organic acid salt and berberine organic acid salt inclusion compound and preparation method thereof.
Background technology
The coptis have the branch of berberine alkali and berberine salt, usually said berberine is the hydrochloride of berberine, it is that a kind of curative effect is antibiotic reliably, antiphlogistic drug, identical to pneumococcal inhibition strength with penicillin, antibacterial ability to streptococcus aureus is stronger than penicillin, is used for diseases such as enteritis, dysentery clinically; In recent years, discover that it has pharmacological actions such as hypoglycemic, reducing blood-fat, anti-arrhythmia, make this medicine come into one's own day by day, have a extensive future at field of medicaments.
At present, the berberine preparation of Shi Yonging clinically, its bulk drug is the hydrochloride or the vitriol of berberine, is inorganic salt.Its main deficiency has two: one, and biological activity is low, and dose is big, and actual clinical dosage is up to 1.2～1.5g/d; The 2nd, solubleness is little, absorption difference in the body, and bioavailability is low.
In view of above defective, be necessary to provide a kind of biological activity height in fact, using dosage is little, and solvability is good, and the berberine goods of being convenient to absorption of human body are to meet clinical needs.
Summary of the invention
Technical problem to be solved by this invention provides a kind of berberine organic acid salt and berberine organic acid salt inclusion compound and preparation method thereof, and biological activity height, the using dosage of this berberine organic acid salt and berberine organic acid salt inclusion compound is little, solvability good; The operational path of its preparation method is short, product purity is high, easy operation control, equipment are simple, is easy to realize industrial production requirement.
For achieving the above object, the invention provides a kind of berberine organic acid salt, be made up of base and salt aglucon, wherein, base is the Berberine base, and the salt aglucon is the organic acid acid group, and the mol ratio of described base and organic acid acid group is 1: 1.
As the preferred embodiments of the present invention, described organic acid is selected from one of them of styracin, Whitfield's ointment, succsinic acid, L-glutamic acid, citric acid or oxysuccinic acid.
For achieving the above object, the invention provides a kind of berberine organic acid salt inclusion compound, comprise inclusion base material and berberine organic acid salt, wherein, the weight ratio of inclusion base material and berberine organic acid salt is: (4～10): 1.
As the preferred embodiments of the present invention, described inclusion base material is selected from beta-cyclodextrin or hydroxypropyl-beta-cyclodextrin.
The present invention also provides a kind of preparation method of berberine organic acid salt, at first, the purified water that Berberine and Berberine is weighed 10～30 times adds in the reactor, heating while stirring, when temperature was increased to 40～60 ℃, adding mass concentration in it was 0.5～15% organic acid soln, the add-on of described organic acid soln is counted in molar ratio, for 1～1.25 times of Berberine, then, regulate the pH value to the salifiable pH value of organic acid; Then 50～80 ℃ of insulations 30～60 minutes; Subsequently, be cooled to 10～30 ℃, the berberine organic acid salt is separated out; At last, suction filtration, drip washing crystallization, filter cake is dry under 60～70 ℃, promptly gets the berberine organic acid salt.
As the preferred embodiments of the present invention, adopt Berberine to weigh 3～8 times cold purified water drip washing during the drip washing crystallization.
The present invention also provides a kind of preparation method of berberine organic acid salt inclusion compound, and at first, be (4～10) according to weight ratio: 1 ratio takes by weighing inclusion base material and berberine organic acid salt respectively; Then the inclusion base material is poured in the reactor, added the inclusion base material then and weigh 18～30 times purified water, heating when temperature is increased to 50～90 ℃, promptly gets substrate solution while stirring; Follow again, in substrate solution, add aforementioned berberine organic acid salt, treat that the berberine organic acid salt dissolves fully after, continue to stir 3～5 hours, last, be cooled to room temperature; Follow again, reaction solution is changed in the crystallization kettle, make it be cooled to 1～10 ℃, left standstill crystallization 24～32 hours; At last, leach throw out, drip washing, be drying to obtain.
As the preferred embodiments of the present invention, adopt the heavy 3-8 of inclusion base material acetone drip washing doubly during drip washing.
Berberine organic acid salt of the present invention and berberine organic acid salt inclusion compound and preparation method thereof have the following advantages at least: berberine organic acid salt of the present invention is 1.33 times of berberine hydrochloride to the bacteriostasis of streptococcus aureus, its inclusion compound is 1.44 times of berberine hydrochloride, and is suitable substantially therewith to the increasing degree of other bacterium such as intestinal bacteria; The solubleness of berberine organic acid salt of the present invention is 1.54 times of berberine hydrochloride, and its inclusion compound is 21.8 times of berberine hydrochloride; The security of berberine organic acid salt of the present invention is 1.06 times of berberine hydrochloride, and its inclusion compound is 1.11 times of berberine hydrochloride.
Embodiment
Berberine organic acid salt of the present invention and preparation method thereof is as follows:
Embodiment 1:
The purified water that Berberine and Berberine is weighed 10～30 times adds in the reactor, heating while stirring, when temperature is increased to 60 ℃, adding mass concentration in it is 1～5% salicylic acid solution, the add-on of salicylic acid solution is according to molar ratio computing, be 1～1.15 times of Berberine, then the pH value 2.4～3.4 of regulator solution; Then be incubated 60 minutes; Subsequently, be cooled to 30 ℃, the berberine salicylate is separated out; Then, suction filtration makes solid-liquid separation, weighs 6 times cold purified water drip washing crystallization at last with Berberine, and filter cake is dry under 60 ℃, promptly gets the berberine salicylate, and fusing point is 205.7～206.5 ℃.
Embodiment 2:
The purified water that Berberine and Berberine is weighed 10～30 times adds in the reactor, heating while stirring, when temperature is increased to 50 ℃, adding mass concentration is 5% succinic acid solution, the add-on of succinic acid solution is counted in molar ratio, be 1～1.25 times of Berberine, then pH value to 2.0～5.3 of regulator solution; Then 80 ℃ of insulations 30 minutes; Subsequently, be cooled to 10 ℃, the berberine succinate is separated out; Then, suction filtration makes solid-liquid separation, weighs 3 times cold purified water drip washing crystallization at last with Berberine, and filter cake is dry under 70 ℃, promptly gets the berberine succinate, and fusing point is 204.5～206.5 ℃.
Embodiment 3:
The purified water that Berberine and Berberine is weighed 10～30 times adds in the reactor, heating while stirring, when temperature is increased to 40 ℃, adding mass concentration is 0.5% styracin solution, the add-on of styracin solution is counted in molar ratio, be 1～1.25 times of Berberine, then pH value to 2.3～4.9 of regulator solution; Then 70 ℃ of insulations 40 minutes; Subsequently, be cooled to 30 ℃, the berberine cinnamate is separated out; Then, suction filtration makes solid-liquid separation, weighs 8 times cold purified water drip washing crystallization at last with Berberine, and filter cake is dry under 60 ℃, promptly gets the berberine cinnamate, and fusing point is 130.7～132.3 ℃.
Embodiment 4:
The purified water that Berberine and Berberine is weighed 10～30 times adds in the reactor, heating while stirring, when temperature is increased to 40 ℃, the adding mass concentration is 15% citric acid solution in it, the add-on of citric acid solution is counted in molar ratio, be 1～1.05 times of Berberine, then pH value to 2.3～4.0 of regulator solution; Then 50 ℃ of insulations 40 minutes; Subsequently, be cooled to 30 ℃, the berberine Citrate trianion is separated out; Then, suction filtration makes solid-liquid separation, weighs 5 times cold purified water drip washing crystallization at last with Berberine, and filter cake is dry under 60 ℃, promptly gets the berberine Citrate trianion, and fusing point is 203.8～204.9 ℃.
Embodiment 5:
The purified water that Berberine and Berberine is weighed 10～30 times adds in the reactor, heating while stirring, when temperature is increased to 40 ℃, adding mass concentration in it is 5% malic acid solution, the add-on of malic acid solution is counted in molar ratio, be 1～1.15 times of Berberine, then pH value to 2.4～4.1 of regulator solution; Then 80 ℃ of insulations 60 minutes; Subsequently, be cooled to 30 ℃, the berberine malate is separated out; Then, suction filtration makes solid-liquid separation, weighs 6 times cold purified water drip washing crystallization at last with Berberine, and filter cake is dry under 60 ℃, promptly gets the berberine malate, and fusing point is 201.1～204.4 ℃.
Embodiment 6:
The purified water that Berberine and Berberine is weighed 10～30 times adds in the reactor, heating while stirring, when temperature is increased to 40 ℃, adding mass concentration in it is 10% glutamic acid solution, the add-on of glutamic acid solution is calculated in molar ratio as 1～1.15 times of Berberine, then pH value to 3.2～4.1 of regulator solution; Then 70 ℃ of insulations 40 minutes; Subsequently, be cooled to 30 ℃, the berberine glutaminate is separated out; Then, suction filtration makes solid-liquid separation, weighs 6 times cold purified water drip washing crystallization at last with Berberine, and filter cake is dry under 60 ℃, promptly gets the berberine glutaminate, and fusing point is 197.1～198.7 ℃.
The preparation method of berberine organic acid salt inclusion compound of the present invention is as follows:
Embodiment 1:
At first beta-cyclodextrin is joined in the stirred autoclave, then, add beta-cyclodextrin and weigh 30 times purified water in reactor, heating when temperature is increased to 60 ℃, promptly gets the inclusion substrate solution, i.e. beta-cyclodextrin solution while stirring; Then, under agitation, in aforementioned inclusion substrate solution, add beta-cyclodextrin and weigh 0.1 times berberine cinnamate, after treating to dissolve fully, continue to stir 3 hours; Follow again, be cooled to room temperature; Subsequently, take out reaction solution, make it to be cooled to 1～10 ℃, left standstill crystallization 24 hours; Then, leach throw out, weigh 6 times acetone drip washing throw out with beta-cyclodextrin, the subsequent drying filter cake promptly gets berberine cinnamate inclusion compound.
Embodiment 2:
At first hydroxypropyl-beta-cyclodextrin is added in the stirred autoclave, then, add hydroxypropyl-beta-cyclodextrin and weigh 18 times purified water in reactor, heating when temperature is increased to 50-90 ℃, promptly gets the inclusion substrate solution, i.e. beta-cyclodextrin solution while stirring; Then, under agitation, in aforementioned inclusion substrate solution, add hydroxypropyl-beta-cyclodextrin and weigh 0.25 times berberine succinate, after treating to dissolve fully, continue to stir 5 hours; Follow again, be cooled to room temperature; Subsequently, take out reaction solution, make it to be cooled to 1～10 ℃, left standstill crystallization 32 hours; Then, leach throw out, weigh 8 times acetone drip washing throw out with hydroxypropyl-beta-cyclodextrin, the subsequent drying filter cake promptly gets the coptis and have the succinate inclusion compound.
With streptococcus aureus, intestinal bacteria, subtilis is subjects, adopt plate to cultivate the method for measuring antibacterial figure diameter, berberine organic acid salt and inclusion compound thereof and berberine hydrochloride have been carried out the test contrast, experimental results show that: berberine organic acid salt of the present invention is 1.33 times of berberine hydrochloride to the bacteriostasis of streptococcus aureus, its inclusion compound is 1.44 times of berberine hydrochloride, and is suitable substantially therewith to the increasing degree of other bacterium such as intestinal bacteria.
Adopting saturated solution method that berberine organic acid salt and inclusion compound thereof have been carried out test with berberine hydrochloride contrasts, experimental results show that: the solubleness of berberine organic acid salt of the present invention is 1.54 times of berberine hydrochloride, and its inclusion compound is 21.8 times of berberine hydrochloride.
With the Kunming mouse is experimental subjects, adopt the intraperitoneal injection mode, adopt point slope method to calculate LD50, berberine organic acid salt and inclusion compound thereof and berberine hydrochloride have been carried out the test contrast, experimental results show that: the security of berberine organic acid salt of the present invention is 1.06 times of berberine hydrochloride, and its inclusion compound is 1.11 times of berberine hydrochloride.
The above only is one embodiment of the present invention, it or not whole or unique embodiment, the conversion of any equivalence that those of ordinary skills take technical solution of the present invention by reading specification sheets of the present invention is claim of the present invention and contains.
Claims (10)
1. berberine organic acid salt, it is characterized in that: be made up of base and salt aglucon, wherein, base is the Berberine base, and the salt aglucon is the organic acid acid group, and the mol ratio of described base and organic acid acid group is 1: 1.
2. berberine organic acid salt as claimed in claim 1 is characterized in that: described organic acid is selected from one of them of styracin, Whitfield's ointment, succsinic acid, L-glutamic acid, citric acid or oxysuccinic acid.
3. berberine organic acid salt inclusion compound that includes claim 1 or 2 described berberine organic acid salts, it is characterized in that: form by inclusion base material and berberine organic acid salt, wherein, the weight ratio of inclusion base material and berberine organic acid salt is: (4～10): 1.
4. berberine organic acid salt inclusion compound as claimed in claim 3 is characterized in that: described inclusion base material is selected from beta-cyclodextrin or hydroxypropyl-beta-cyclodextrin.
5. the preparation method of the described berberine organic acid salt of claim 1, it is characterized in that: at first, the purified water that Berberine and Berberine is weighed 10～30 times adds in the reactor, heating while stirring, when temperature was increased to 40～60 ℃, adding mass concentration in it was 0.5～15% organic acid soln, the add-on of described organic acid soln is counted in molar ratio, for 1～1.25 times of Berberine, then, regulate the pH value to the salifiable pH value of organic acid; Then 50～80 ℃ of insulations 30～60 minutes; Subsequently, be cooled to 10～30 ℃, the berberine organic acid salt is separated out; At last, suction filtration, drip washing crystallization, filter cake is dry under 60～70 ℃, promptly gets the berberine organic acid salt.
6. the preparation method of berberine organic acid salt as claimed in claim 5 is characterized in that: adopt the cold purified water drip washing of 3～8 times of amounts of Berberine during the drip washing crystallization.
7. the preparation method of berberine organic acid salt as claimed in claim 5 is characterized in that: the salifiable pH value of organic acid is 2.1～5.5.
8. the preparation method of the described berberine organic acid salt of claim 3 inclusion compound, it is characterized in that: at first, be (4～10) according to weight ratio: 1 ratio takes by weighing inclusion base material and berberine organic acid salt respectively; Then the inclusion base material is poured in the reactor, added the inclusion base material then and weigh 18～30 times purified water, heating when temperature is increased to 50～90 ℃, promptly gets substrate solution while stirring; Follow again, in substrate solution, add aforementioned berberine organic acid salt, treat that the berberine organic acid salt dissolves fully after, continue to stir 3～5 hours, last, be cooled to room temperature; Follow again, reaction solution is changed in the crystallization kettle, make it be cooled to 1～10 ℃, left standstill crystallization 24～32 hours; At last, leach throw out, drip washing, be drying to obtain.
9. the preparation method of berberine organic acid salt inclusion compound as claimed in claim 8 is characterized in that: described inclusion base material is selected from beta-cyclodextrin or hydroxypropyl-beta-cyclodextrin.The berberine organic acid salt, be selected from berberine cinnamate, berberine succinate, berberine salicylate, berberine glutaminate, L-glutamic acid Citrate trianion or berberine malate.
10. the preparation method of berberine organic acid salt inclusion compound as claimed in claim 8 or 9 is characterized in that: adopt the heavy 3-8 of inclusion base material acetone drip washing doubly during drip washing.
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| WO2016015634A1 (en) | 2014-07-29 | 2016-02-04 | Shenzhen Hightide Biopharmaceutical, Ltd. | Berberine salts, ursodeoxycholic salts and combinations, methods of preparation and application thereof |
| WO2016161921A1 (en) * | 2015-04-06 | 2016-10-13 | Shenzhen Hightide Biopharmaceutical, Ltd. | Conjugate compounds of ursodeoxycholic, berberine or l-carnitine, and compositions and methods thereof |
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