CN109833312A - A kind of cannabidiol and the inclusion compound of alkaline cyclodextrin and preparation method thereof - Google Patents
A kind of cannabidiol and the inclusion compound of alkaline cyclodextrin and preparation method thereof Download PDFInfo
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- CN109833312A CN109833312A CN201910279834.3A CN201910279834A CN109833312A CN 109833312 A CN109833312 A CN 109833312A CN 201910279834 A CN201910279834 A CN 201910279834A CN 109833312 A CN109833312 A CN 109833312A
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- cyclodextrin
- cannabidiol
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Abstract
The invention discloses a kind of cannabidiols and the inclusion compound of alkaline cyclodextrin and preparation method thereof, invention neutral and alkali cyclodextrin is the cyclodextrin that amido replaces, the amido of cyclodextrin replaces, other than the clathration of cyclodextrin cavity and cannabidiol, due to forming alkaline environment in aqueous solution, ionic interaction is formed with the hydroxyl on cannabidiol, to make cannabidiol form solution in water in very wide concentration range, convenient for the formation of cannabidiol liquid preparation, inclusion compound stability provided by the invention is high, bioavilability is high, preparation method is simple, it is easy to operate, mild condition, suitable for industrialized production.
Description
Technical field
Invention is related to pharmaceutical technology field, particularly relate to a kind of cannabidiol and alkaline cyclodextrin object inclusion compound and its
Preparation method.
Background technique
Hemp (Cannabis sativaIt L.) is a kind of ancient serike with medicinal Development volue, hemp two
Phenol (Cannabidiol, abbreviation CBD) is the monomer extracted from hemp, is first cannabinoids drug of FDA approval, CBD
It is the non-additive ingredient in hemp, there are the pharmacological actions such as anti-spasm, antianxiety, anti-inflammatory, anti-oxidant, antirheumatic, antitumor；
CBD is based primarily upon its protective effect to nervous system in the application of medical field；CBD passes through to cyclooxygenase and lipoxygenase
Double inhibition play analgesic and anti-inflammatory effect, and effect is better than that people are known and the aspirin of extensive utilization；The mankind
GABA neurotransmitter in brain has sedation effect, inhibits the excitability of brain centres, and CBD, which can help to control GABA nerve, to be passed
The consumption of matter inhibits brain excitement, reduces epileptic attack, may also help in the curative effect for improving other antiepileptics；It is endogenous
Property cannboid be to aid in depressive patients and reduce a kind of important substance of anxiety, be present in human body, in CBD can help
Property cannboid in source maintains a reasonable level, allows patient body to feel good, is pleasant；CBD can not only act on a variety of
The treatment of difficult diseases can also effectively eliminate the hallucinogenic action that tetrahydrocannabinol (THC) generates human body, referred to as " anti-
Narcotics compounds ".
But cannabidiol is more sensitive to high temperature, and its is not soluble in water, limits the medicine preparation as liquid preparation
(such as oral solution and injection), and for most of oral preparation, generally molecularity can only be formed in gastric juice or intestinal juice
State by gastrointestinal mucosa wall and could absorb, and make it that curative effect occur into blood circulation.Therefore, the drug dissolution is poor, leads to it
Assimilation effect is bad in human body, and bioavilability is low,.
Summary of the invention
It is good that the purpose of the present invention is to provide a kind of dissolubilities, the packet of stability high cannabidiol and alkaline cyclodextrin object
Object and preparation method thereof is closed, inclusion compound stability provided by the invention is high, and bioavilability is high, and preparation method is simple, and it is easy to operate,
Mild condition is suitable for industrialized production.
A kind of cannabidiol and alkaline cyclodextrin object inclusion compound and preparation method thereof, which contains cannabidiol and alkali
Property cyclodextrin, wherein the weight ratio of cannabidiol and alkaline cyclodextrin be 1:3 ~ 1:98.
Heretofore described cyclodextrin (Cyclodextrin, abbreviation CD) is that amylose is generated by bacillus
A series of general name of the lower cyclic oligosaccharides generated of cyclodextrin glycosyltransferase effect, wherein studying more and having
Important practical usage is to be referred to as α-, β-and gamma-cyclodextrin containing the molecule of 6,7,8 glucose units.
Alkaline cyclodextrin is D (+)-glucopyranose C for constituting cyclodextrin molecular2、C3And/or C6Hydroxyl by amido
Replace and generate alkaline cyclodextrin, there is preferable solubilizing effect to compound containing acidic groups.
Wherein, preferably, the alkaline cyclodextrin is with structure shown in formula I
Ⅰ
Wherein m be 0 to 7, n be 1 to 8 and m+n=6,7 or 8 in one；
R1、R2And R3For-OH or-RNH2And R1、R2And R3In at least one be-RNH2；
R is (CH2)x、NH(CH2)x 、NH(CH2)xNH(CH2)x、CO(CH2) x or O (CH2) x, x is whole more than or equal to 0
Number.
One in formula I in m+n=6,7 or 8, indicate that cyclodextrin of the present invention can be α-, β-or γ-ring paste
Essence, wherein n is at least at least one D (+)-glucopyranose parent hydroxy in the 1 expression alkaline cyclodextrin molecule
It is modified by amido, m is 5,6 or 7 at this time；And m is each D that the 0 expression alkaline cyclodextrin constitutes cyclodextrin molecular
(+)-glucopyranose is modified by amido.
R in formula I1、R2And R3In at least one be-RNH2Indicate that the alkaline cyclodextrin modifies D (+)-by amido
Glucopyranose molecules are at least the modification of monoamine base, can be at 2,3 or 6, or the modification of diamine base or R1, R2
It is modified with R3.
Amido-the RNH of modification cyclodextrin is also defined in formula I2In R, R is (CH2)x、NH(CH2)x 、NH(CH2)
XNH (CH2) x, CO (CH2) x or O (CH2) x indicates that the amido of modification cyclodextrin can be ammonia, methylamine, ethamine, ethylenediamine, second
The organic amino groups such as hydramine, acetamide and diethylenetriamine, wherein x is integer more than or equal to 0, preferably 0 to 10, it is more excellent
It is selected as 0,1,2,3 or 4.
Preferably, the alkaline cyclodextrin has structure shown in Formula II,
II
Wherein n be 1 and m+n=6,7 or 8 in one；
R1, R2 or R3 are-RNH2；
R is (CH2)x、NH(CH2)x、NH(CH2)xNH(CH2)x、CO(CH2) x or O (CH2) x, x 0,1,2,3 or 4.
It is further preferred that the alkaline cyclodextrin be mono- [6- (ethylenediamine base) -6- deoxidation]-beta-cyclodextrin,
Mono- [6- (Diethylenetriamine base) -6- deoxidation]-β-cyclodextrin, mono- [3- (amino) -6- deoxidation]-β-cyclodextrin,
One of mono- [6- (ethyl alcohol amido) -6- deoxidation]-gamma-cyclodextrin.
Another object of the present invention provides the preparation method of a kind of cannabidiol and alkaline cyclodextrin inclusion compound, and this method will
Alkaline cyclodextrin is dissolved in the water in the ratio that volumetric concentration is 0.02 ~ 0.05g/mL, and alkaline cyclodextrin aqueous solution is made；It presses
The volumetric concentration of cannabidiol and organic solvent is the ratio of 0.03 ~ 0.5g/mL, and cannabidiol is dissolved in organic solvent；
Then cannabidiol organic solvent solution is added in alkaline cyclodextrin aqueous solution, is stirred to react 2 ~ 18h under the conditions of 20 ~ 60 DEG C
Afterwards, filter, be concentrated under reduced pressure at 40 DEG C, it is dry after to get cannabidiol and alkaline cyclodextrin inclusion compound, wherein alkaline cyclodextrin and
The weight ratio of cannabidiol is 1:3 ~ 1:98.
Organic solvent employed in preparation method of the present invention is ethyl alcohol, methanol, dimethyl sulfoxide, N, N- diformazan
One of base formamide, acetone, isopropanol, chloroform or tetrahydrofuran.Using ethyl alcohol, methanol, dimethyl sulfoxide, N, N- bis-
One of methylformamide, acetone, isopropanol, chloroform or tetrahydrofuran.There is preferable dissolubility to cannabidiol, it can be with
Disperse cannabidiol preferably in inclusion reaction dicyandiamide solution, improves inclusion efficiency, shorten the inclusion reaction time.
The method of the present invention compared with the existing technology the advantages of and technical effect:
1, the present invention is the cyclodextrin that amido replaces for the water-soluble relatively low status of cannabidiol, the alkaline cyclodextrin of synthesis,
The amido of cyclodextrin replaces, other than the clathration of cyclodextrin cavity and cannabidiol molecule, due to being formed in aqueous solution
Hydroxyl on alkaline environment, with cannabidiol forms ionic interaction, thus make cannabidiol very wide concentration range in
Solution is formed in water, convenient for the formation of cannabidiol liquid preparation；
2, cannabidiol provided by the invention and solubility of the alkaline cyclodextrin inclusion compound in 25 DEG C of Shi Shuizhong exist
Between 10-240mg/mL, therefore, inclusion compound disclosed by the invention can be formed in water molten in very wide concentration range
Liquid, convenient for the formation of cannabidiol liquid preparation；
3, inclusion compound preparation method of the present invention is simple, easy to operate, and reaction condition is mild, is suitable for industrialized production；
4, inclusion compound produced by the present invention gives pharmacological property with good to straight caecum target spot, and highly-safe, and stability is good, dissolution
Property it is good, it is easy to use, avoid cannabidiol from being released and destroy in alimentary canal, the bioavilability for improving drug increases drug
Solubility improves the dissolution of drug.
Specific embodiment
The present invention is further illustrated below, but the present invention is limited in any way, based on the present invention
It is any made by introduction to transform or replace, it all belongs to the scope of protection of the present invention.
Embodiment 1: the inclusion compound of this cannabidiol and alkaline cyclodextrin, cannabidiol and mono- [6- (divinyl
Three amidos) -6- deoxidation]-β-cyclodextrin, cannabidiol and mono- [6- (diethylenetriamine base) -6- deoxidation]-β-ring
The weight ratio of dextrin is 1:45.
1g cannabidiol is dissolved in 40mL ethyl alcohol, solution is formed；By mono- [6- (diethylenetriamine the base) -6- of 45g
Deoxidation]-β-cyclodextrin is dissolved in 200mL water, and preparing becomes solution；Above two solution is mixed under agitation,
9h is stirred at 40 DEG C, acquired solution filters, and is concentrated under reduced pressure at 40 DEG C, after dry, obtains cannabidiol inclusion compound, inclusion compound is 25
The solubility of DEG C Shi Shuizhong is 36mg/mL.
Embodiment 2: the inclusion compound of this cannabidiol and alkaline cyclodextrin, cannabidiol and mono- [6- (ethanol amine
Base) -6- deoxidation]-gamma-cyclodextrin weight ratio be 1:98.
1g cannabidiol is dissolved in 30mL ethyl alcohol, solution is formed；By 98g, mono- [6- (ethylenediamine base) -6- is de-
Oxygen]-β-cyclodextrin is dissolved in 500mL water, and preparing becomes solution；Above two solution is mixed under agitation, 20
18h is stirred at DEG C, acquired solution filters, and is concentrated under reduced pressure at 40 DEG C, after dry, obtains cannabidiol inclusion compound, inclusion compound is 25
The solubility of DEG C Shi Shuizhong is 240mg/mL.
The above description of the embodiment is only used to help understand the method for the present invention and its core ideas.It should be pointed out that pair
For those skilled in the art, without departing from the principle of the present invention, the present invention can also be carried out
Some improvements and modifications, these improvements and modifications also fall within the scope of protection of the claims of the present invention.
Claims (6)
1. the inclusion compound of a kind of cannabidiol and alkaline cyclodextrin, it is characterised in that: it includes cannabidiol and alkaline cyclodextrin,
Wherein the weight ratio of cannabidiol and alkaline cyclodextrin is 1:3 ~ 1:98.
2. the inclusion compound of the cannabidiol and alkaline cyclodextrin according to claim 1, it is characterised in that alkaline cyclodextrin has
Structure shown in Formulas I:
I
Wherein m be 0 to 7, n be 1 to 8 and m+n=6,7 or 8 in one；
R1、R2And R3For-OH or-RNH2And R1、R2And R3In at least one be-RNH2；
R is (CH2)x、NH(CH2)x、NH(CH2)xNH(CH2)x、CO(CH2) x or O (CH2) x, x is whole more than or equal to 0
Number.
3. the inclusion compound of the cannabidiol and alkaline cyclodextrin according to claim 1, it is characterised in that alkaline cyclodextrin has
Structure shown in formula II:
Ⅱ
Wherein n be 1 and m+n=6,7 or 8 in one；
R1、R2Or R3For-RNH2；R is (CH2)x、NH(CH2)x、NH(CH2)xNH(CH2)x、CO(CH2) x or O (CH2) x, x
It is 0,1,2,3 or 4.
4. the inclusion compound of the cannabidiol according to any one of Claims 2 or 3 and alkaline cyclodextrin, feature exist
In: alkaline cyclodextrin includes mono- [6- (ethylenediamine base) -6- deoxidation]-beta-cyclodextrin, mono- [6- (diethylenetriamine base) -6-
Deoxidation]-beta-cyclodextrin, mono- [6- (amino) -6- deoxidation]-beta-cyclodextrin, mono- [6- (ethyl alcohol amido) -6- deoxidation]-γ -
One of cyclodextrin.
5. the preparation method of a kind of cannabidiol and alkaline cyclodextrin inclusion compound, it is characterised in that: alkaline cyclodextrin is pressed volume
Concentration is that the ratio of 0.03 ~ 0.5g/mL is dissolved in the water, and alkaline cyclodextrin aqueous solution is made；By cannabidiol and organic solvent
Volumetric concentration be 0.02 ~ 0.05g/mL ratio, cannabidiol is dissolved in organic solvent；Then cannabidiol is had
Solvent solution is added in alkaline cyclodextrin aqueous solution, and after being stirred to react 2 ~ 18h under the conditions of 20 ~ 60 DEG C, filtering is depressurized dense
Contracting, it is dry after to get cannabidiol and alkaline cyclodextrin inclusion compound, the wherein weight of alkaline cyclodextrin and cannabidiol series matter
Than for 1:3 ~ 1:98.
6. the preparation method of cannabidiol and alkaline cyclodextrin inclusion compound according to claim 5, it is characterised in that: organic
Solvent includes ethyl alcohol, methanol, dimethyl sulfoxide, N, in N- dimethylformamide, acetone, isopropanol, chloroform or tetrahydrofuran
It is a kind of.
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Cited By (9)
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| CN110151825A (en) * | 2019-06-26 | 2019-08-23 | 云南绿新生物药业有限公司 | A kind of water solubility industrial hemp composes the preparation method of oily inclusion compound entirely |
| CN110179862A (en) * | 2019-06-26 | 2019-08-30 | 云南绿新生物药业有限公司 | A kind of preparation method of water solubility cannabidiol inclusion compound (Nano capsule) |
| CN110204426A (en) * | 2019-07-02 | 2019-09-06 | 黑龙江康源生物科技有限公司 | A kind of preparation method and water solubility CBD of water solubility CBD |
| CN111000827A (en) * | 2019-12-31 | 2020-04-14 | 云南省农业科学院经济作物研究所 | Water-soluble cannabidiol nano preparation based on cyclodextrin carrier and preparation method thereof |
| CN112094364A (en) * | 2020-09-28 | 2020-12-18 | 沐荷永康生物科技(云南)有限公司 | Clathrate compound of bridged cyclodextrin and cannabidiol, preparation method and application thereof |
| CN112111025A (en) * | 2020-09-28 | 2020-12-22 | 沐荷永康生物科技(云南)有限公司 | Cannabidiol cyclodextrin conjugate and preparation method thereof |
| CN112441952A (en) * | 2019-08-28 | 2021-03-05 | 烟台汉麻生物技术有限公司 | Cannabidiol-3-sulfonic acid, preparation method and application thereof, and cannabidiol derivative |
| CN113101281A (en) * | 2021-04-12 | 2021-07-13 | 云南汉盟制药有限公司 | Preparation method and application of water-soluble cannabidiol clathrate compound |
| CN114667155A (en) * | 2019-11-04 | 2022-06-24 | 成长生物科技有限公司 | Method for selectively recovering hydrophobic compound |
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Cited By (11)
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| CN110151825A (en) * | 2019-06-26 | 2019-08-23 | 云南绿新生物药业有限公司 | A kind of water solubility industrial hemp composes the preparation method of oily inclusion compound entirely |
| CN110179862A (en) * | 2019-06-26 | 2019-08-30 | 云南绿新生物药业有限公司 | A kind of preparation method of water solubility cannabidiol inclusion compound (Nano capsule) |
| CN110204426A (en) * | 2019-07-02 | 2019-09-06 | 黑龙江康源生物科技有限公司 | A kind of preparation method and water solubility CBD of water solubility CBD |
| CN110204426B (en) * | 2019-07-02 | 2023-05-30 | 梁志全 | Preparation method of water-soluble CBD and water-soluble CBD |
| CN112441952A (en) * | 2019-08-28 | 2021-03-05 | 烟台汉麻生物技术有限公司 | Cannabidiol-3-sulfonic acid, preparation method and application thereof, and cannabidiol derivative |
| CN114667155A (en) * | 2019-11-04 | 2022-06-24 | 成长生物科技有限公司 | Method for selectively recovering hydrophobic compound |
| CN111000827A (en) * | 2019-12-31 | 2020-04-14 | 云南省农业科学院经济作物研究所 | Water-soluble cannabidiol nano preparation based on cyclodextrin carrier and preparation method thereof |
| CN112094364A (en) * | 2020-09-28 | 2020-12-18 | 沐荷永康生物科技(云南)有限公司 | Clathrate compound of bridged cyclodextrin and cannabidiol, preparation method and application thereof |
| CN112111025A (en) * | 2020-09-28 | 2020-12-22 | 沐荷永康生物科技(云南)有限公司 | Cannabidiol cyclodextrin conjugate and preparation method thereof |
| CN112111025B (en) * | 2020-09-28 | 2022-08-16 | 云南佩林科技有限公司 | Cannabidiol cyclodextrin conjugate and preparation method thereof |
| CN113101281A (en) * | 2021-04-12 | 2021-07-13 | 云南汉盟制药有限公司 | Preparation method and application of water-soluble cannabidiol clathrate compound |
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Application publication date: 20190604 |