CN105884852B - The eutectic of oleanolic acid and choline, preparation method and its pharmaceutical composition - Google Patents
The eutectic of oleanolic acid and choline, preparation method and its pharmaceutical composition Download PDFInfo
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- CN105884852B CN105884852B CN201510014403.6A CN201510014403A CN105884852B CN 105884852 B CN105884852 B CN 105884852B CN 201510014403 A CN201510014403 A CN 201510014403A CN 105884852 B CN105884852 B CN 105884852B
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- China
- Prior art keywords
- choline
- eutectic
- oleanolic acid
- acid
- isopropanol
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- JKLISIRFYWXLQG-UHFFFAOYSA-N Epioleonolsaeure Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C(O)=O)CCC(C)(C)CC5C4CCC3C21C JKLISIRFYWXLQG-UHFFFAOYSA-N 0.000 title claims abstract description 104
- YBRJHZPWOMJYKQ-UHFFFAOYSA-N Oleanolic acid Natural products CC1(C)CC2C3=CCC4C5(C)CCC(O)C(C)(C)C5CCC4(C)C3(C)CCC2(C1)C(=O)O YBRJHZPWOMJYKQ-UHFFFAOYSA-N 0.000 title claims abstract description 104
- MIJYXULNPSFWEK-UHFFFAOYSA-N Oleanolinsaeure Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C(O)=O)CCC(C)(C)CC5C4=CCC3C21C MIJYXULNPSFWEK-UHFFFAOYSA-N 0.000 title claims abstract description 104
- 229940100243 oleanolic acid Drugs 0.000 title claims abstract description 104
- HZLWUYJLOIAQFC-UHFFFAOYSA-N prosapogenin PS-A Natural products C12CC(C)(C)CCC2(C(O)=O)CCC(C2(CCC3C4(C)C)C)(C)C1=CCC2C3(C)CCC4OC1OCC(O)C(O)C1O HZLWUYJLOIAQFC-UHFFFAOYSA-N 0.000 title claims abstract description 104
- MIJYXULNPSFWEK-GTOFXWBISA-N 3beta-hydroxyolean-12-en-28-oic acid Chemical compound C1C[C@H](O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CCC(C)(C)C[C@H]5C4=CC[C@@H]3[C@]21C MIJYXULNPSFWEK-GTOFXWBISA-N 0.000 title claims abstract description 102
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 title claims abstract description 99
- 229960001231 choline Drugs 0.000 title claims abstract description 99
- 230000005496 eutectics Effects 0.000 title claims abstract description 89
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 14
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 62
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- 239000002253 acid Substances 0.000 claims description 7
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
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- 108010023302 HDL Cholesterol Proteins 0.000 description 3
- 238000004566 IR spectroscopy Methods 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
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- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical class NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 2
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- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
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- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- 102000015427 Angiotensins Human genes 0.000 description 1
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
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Abstract
The present invention relates to the eutectic B that the eutectic that oleanolic acid and choline are formed, especially oleanolic acid and choline are formed according to 2: 1 ratio, eutectic B has the solubility properties and curative effect of medication better than oleanolic acid itself.The present invention also provides the preparation method containing oleanolic acid and the eutectic of choline and include its pharmaceutical composition.
Description
Technical field
The present invention relates to the novel crystal compounds comprising oleanolic acid, are formed more particularly, to oleanolic acid and choline
Eutectic, preparation method and the pharmaceutical composition comprising it.
Background technique
Oleanolic acid tablet is an over the counter hepatoprotective agent, the adjuvant treatment of acute hepatitis, chronic hepatitis is used clinically for, to liver
Damage has certain protective effect.On the other hand, a large amount of research work, which shows oleanolic acid also, has lipid-loweringing, hypoglycemic, resists and swell
The effects of tumor, immunological regulation, neuroprotection and resisting cardiovascular disease (Natural Product Reports 2011,28,
543-593).Of particular concern is, inventors demonstrated that oleanolic acid embody on animal model high in fat it is extremely significant
Effect for reducing blood fat (201210454865.6).Currently, oleanolic acid is in addition to there is no it other than having clinical application in terms of liver protection
Clinical application in terms of him.
Oleanolic acid is a pentacyclic triterpenoid, is white powder crystalline material, it is extremely difficult to be dissolved in water.Due to its water
Dissolubility is very poor, and oleanolic acid oral administration biaavailability is extremely low (bioavilability is less than 1%), therefore, every to reach liver protection curative effect
It takes medicine three times day by day, and taking dose is larger.
In order to improve the bioavilability of oleanolic acid, has and oral disnitegration tablet is made in oleanolic acid
(200710068005.8), phosphatide complexes (200510081273.4), dripping pill (200510013611.0) and dispersible tablet
(200810302500.5) etc..However, improving drug solubility by above-mentioned preparation means, to often lead to drug at high cost, and by
And substantially drug quality poor controllability complicated in medicament preparation process.On the other hand, if improved by structural modification
The water solubility of oleanolic acid, major drawbacks are also to bring very big uncertainty to Drug safety, especially as
The liver protection of long-term use or fat-reducing medicament, it is high to its security requirement.
Under the premise of not changing medicines structure, improving the method for drug solubility, there are also salt form screenings.Existing neat pier
Tartaric acid salt includes powder ofSodium Oleanlic Acid (99113945.3), oleanolic acid piperazine salt (200910055705.2) and oleanolic acid second
Diamine salts (201010171882.X).Although powder ofSodium Oleanlic Acid solves the solubility and dissolution rate of drug to a certain extent
Problem, but studies have shown that powder ofSodium Oleanlic Acid continues moisture absorption, thus the stability of influence drug in the range of 5~95%, no
Suitable for industrialized production.Although oleanolic acid piperazine salt and ethylenediamine salt have the characteristics that hygroscopicity is low and stability is high, piperazine
Piperazine or ethylenediamine are only responsible for base as organic amine into the function of salt, itself and inefficacy, especially largely take for a long time
Drug containing such organic amine can bring potential safety risks.
Under the premise of not changing medicines structure, another method for improving physical and chemical properties of drugs is to form pharmaceutical co-crystals.
So-called pharmaceutical co-crystals refer to will be active pharmaceutical ingredient (active pharmaceutical ingredients, API) and suitable
Eutectic formation (cocrystal former, CCF) is by H-bonding self-assembly, or by non-with saturability and directionality
A kind of new structure that covalent bond (such as Van der Waals force) assembling is formed, i.e. pharmaceutical co-crystals.Pharmaceutical co-crystals research is also drug crystal forms
One important component of research.Why pharmaceutical co-crystals have very big attraction to be that it provides one kind pharmaceuticals industry
It does not need to destroy and generate the chance that covalent bond can reach the physicochemical property of improvement active pharmaceutical ingredient (API).Drug is total
Brilliant majority is formed based on hydrogen bond, is generally formed by the connection of hydrogen bond receptor and hydrogen bond donor.Pass through hydrogen bond
The pharmaceutical co-crystals of formation neither need to form new covalent bond, also do not need to destroy existing covalent bond；Retaining drug itself
Pharmacological properties while, achieved the purpose that improve drug physicochemical property, this point be pharmaceutical co-crystals in pharmaceuticals industry side
The application in face provides more extensive development space.In the case where not changing medicines structure and pharmacological properties itself, shape
At new crystal dissolubility, dissolution rate, bioavilability, the stability of drug can be improved, reduction is drawn moist and is improved mechanical
Performance etc..Therefore, obtaining more there are novel, practical and creative pharmaceutical co-crystals to have important practical significance, especially
Some water-insoluble drugs.
Choline is to be separated from pig's bile by Streker in 1894 for the first time, has become in human food and has commonly used
Additive.Choline is classified as the product of " it is generally acknowledged that safety " by " the federal code " in the U.S.；What European Union was promulgated for 1991
Choline is classified as the product for allowing to make an addition to baby food by regulation.Choline is a kind of strong organic base, is the constituent of lecithin,
It exists among sphingomyelin, is that body can be changed a source of methyl and act on the product of synthesizing methyl, while again
It is the precursor of acetylcholine.Human body can also synthesize choline, so not easily causing deficiency disease.Choline is heat-resisting, processing and it is cooked
Loss in journey is seldom, under dry environment, has almost no change content of choline in some time storage food.Especially it is worth
It must be concerned with, choline also has extraordinary health care and disease prevention effect.For example, choline can promote fat metabolism, it is clinical
Upper application choline can treat cirrhosis, hepatitis and other liver diseases, work well.Choline has good emulsification property, can hinder
Only cholesterol the deposition of wall and removes Parts of deposits in the blood vessels, while improving the absorption and utilization of fat, therefore has pre-
The effect of anti-cardiovascular disease.
So far, there is not yet salt or eutectic that any report description oleanolic acid and choline are formed.
Summary of the invention
An object of the present invention is to provide the eutectic that novel oleanolic acid and choline are formed, the physics and chemistry such as solubility
Matter is better than oleanolic acid itself.Eutectic of the invention includes: 2: 1: 1 eutectic A of oleanolic acid/choline/isopropanol or olive
2: 1 eutectic B of acid/choline.
The present invention provides the eutectics comprising oleanolic acid and choline, have the feature that
1. powder x-ray diffraction:
Instrument: D8Advance X-ray diffractometer (German Bruker)
Target: Cu-K α
Wavelength: 1.5406A °
Pipe pressure: 40KV
Guan Liu: 40mA
Step-length: 0.02 °
The powder x-ray diffraction feature of table 1,2: 1: 1 eutectic A of oleanolic acid/choline/isopropanol
The powder x-ray diffraction feature of table 2,2: 1 eutectic B of oleanolic acid/choline
2. differential scanning calorimetry (DSC):
Instrument: 204 differential scanning calorimeter instrument of NETZSCH DSC
Range: 40~300 DEG C
Heating rate: 10 DEG C/min
The endothermic transition of 2: 1: 1 eutectic A of oleanolic acid/choline/isopropanol has strong herein about in 116.3 DEG C and 254.6 DEG C
Endothermic peak.
The endothermic transition of 2: 1 eutectic B of oleanolic acid/choline has highly endothermic peak about at 255.5 DEG C herein.
3. fusing point:
Instrument: RY-1 melting point apparatus (Tianjin analysis instrument factory)
The fusing point of 2: 1: 1 eutectic A of oleanolic acid/choline/isopropanol are as follows: 255~258 DEG C.
The fusing point of 2: 1 eutectic B of oleanolic acid/choline are as follows: 258~262 DEG C.
4. infrared spectroscopy:
Instrument: Shimadzu Corporation IR Affinity-1
Infrared spectroscopy wave number (the cm of 2: 1: 1 eutectic A of oleanolic acid/choline/isopropanol-1) about are as follows: 3421,2972,2941,
2926、2858、1681、1548、1465、1384、1373。
Infrared spectroscopy wave number (the cm of 2: 1 eutectic B of oleanolic acid/choline-1) about are as follows: 3458,2941,2862,1703,
1556、1462、1388、1361。
The eutectic A of oleanolic acid of the invention, choline and isopropanol, which is characterized in that eutectic A is by oleanolic acid, gallbladder
Alkali and isopropanol are combined according to 2: 1: 1 ratio to be formed；It is radiated using Cu-K α, X-ray powder diffraction figure, 2 be expressed in degrees
θ has diffraction maximum in 14.3 ± 0.2 and 15.5 ± 0.2, in particular, 3.1 ± 0.2,5.4 ± 0.2,6.3 ± 0.2,6.6 ± 0.2,
11.5 ± 0.2,11.7 ± 0.2,13.3 ± 0.2,14.3 ± 0.2,15.5 ± 0.2,15.8 ± 0.2,20.3 ± 0.2 have one or
Multiple (in any combination, including two or more, or all) diffraction maximums, are shown in Fig. 1；The endothermic transition master of the DSC scanning of eutectic A
Fig. 3 is seen at 116.3 DEG C and 254.6 DEG C or so；The infrared absorption spectrum that eutectic A is measured with KBr tabletting about exists: 3421cm-1、
2972cm-1、2941cm-1、2926cm-1、2858cm-1、1681cm-1、1548cm-1、1465cm-1、1384cm-1And 1373cm-1Place
There is absorption peak, sees Fig. 7.
The eutectic B of oleanolic acid and choline of the invention, which is characterized in that eutectic B is by oleanolic acid and choline according to 2
: 1 ratio is combined and is formed；It is radiated using Cu-K α, X-ray powder diffraction figure, 2 θ being expressed in degrees are in 13.2 ± 0.2 Hes
15.1 ± 0.2 have diffraction maximum, in particular, 7.3 ± 0.2,9.8 ± 0.2,12.1 ± 0.2,13.2 ± 0.2,14.1 ± 0.2,
15.1 ± 0.2,15.9 ± 0.2,19.8 ± 0.2,21.0 ± 0.2 have it is one or more (in any combination, including two or more,
Or all) diffraction maximum, see Fig. 2；The maximum endothermic transition of the DSC scanning of eutectic B is shown in Fig. 4 about at 255.5 DEG C or so；Eutectic B
The infrared absorption spectrum measured with KBr tabletting about exists: 3458cm-1、2941cm-1、2862cm-1、1703cm-1、1556cm-1、
1462cm-1、1388cm-1、1361cm-1There is absorption peak at place, sees Fig. 8.
It is a further object of the present invention to provide prepare oleanolic acid/choline eutectic method.
Oleanolic acid provided by the invention/2: 1: 1 eutectic of choline/isopropanol A's the preparation method is as follows:
Preparation method 1, steps are as follows:
1. in a heated condition, oleanolic acid is dissolved in suitable suitable solvents, the solvent be selected from water, methanol,
Ethyl alcohol, acetone, isopropanol, n-butanol, methylene chloride, chloroform, ethyl acetate, acetonitrile, tetrahydrofuran or N, N- dimethyl
One of formamide solvent or more than one mixed solvent, preferred solvent are isopropanol, ethyl acetate or acetone；
2. choline solution is slowly added drop-wise in the resulting solution of step 1, a large amount of solids are precipitated；The amount for the choline being added
Preferably 0.5~5 equivalent；
3. filtering, is washed with suitable above-mentioned suitable solvents or insoluble solvent, obtains solid；
4. obtained solid recrystallisation from isopropanol will be collected up to 2: 1: 1 eutectic A of oleanolic acid/choline/isopropanol.
Preparation method 2, steps are as follows:
1. choline is dissolved in isopropanol, the amount for the choline being added is preferably 0.5~5 equivalent；
2. oleanolic acid in a heated condition, is added in Xiang Shangshu solution, clear solution is stirred to obtain；
3. above-mentioned solution is slowly cooled to room temperature, stands and white crystal is precipitated, volatilize solvent after suction filtration to get olive
2: 1: 1 eutectic A of acid/choline/isopropanol.
2: 1 eutectic of oleanolic acid/choline provided by the invention B's the preparation method is as follows:
Preparation method 1, steps are as follows:
2: 1: 1 eutectic A of oleanolic acid/choline/isopropanol is suspended in suitable solvent at room temperature, quickly stirs one
After the section time, white solid is filtered to obtain, 2: 1 eutectic B of oleanolic acid/choline is drying to obtain；The solvent is selected from ethyl acetate, third
One of ketone, acetonitrile, n-butanol, methylene chloride, chloroform, tetrahydrofuran or n,N-Dimethylformamide or it is a kind of with
On mixed solvent, preferred solvent be ethyl acetate or acetone.
Preparation method 2, steps are as follows:
By 2: 1: 1 eutectic A of oleanolic acid/choline/isopropanol heated under normal pressure or reduced pressure after a period of time to get
2: 1 eutectic B of oleanolic acid/choline；Used heating temperature is 50~200 DEG C, preferably 100~150 DEG C.
The present invention also provides a kind of prevention or treatment hyperlipemias, atherosclerosis, coronary heart disease, myocardial infarction, sugar
Urinate the pharmaceutical composition of disease, tumour, hepatitis, cirrhosis, senile dementia, cerebral ischemia, apoplexy, nephrosis or rheumatoid arthritis
Object, it includes 2: the 1 eutectic B of 2: 1: 1 eutectic A of oleanolic acid/choline/isopropanol or oleanolic acid/choline for the treatment of effective dose
As active constituent and pharmaceutically acceptable carrier.The pharmaceutical composition can be formulated for specific administration method, example
Such as oral administration, parenteral administration and rectal administration.In addition, pharmaceutical composition of the invention can also be prepared in solid shape
In formula, including capsule, tablet, pill, granule, powder or suppository or liquid form, including solution, suspension or cream
Agent.Pharmaceutical composition of the invention can be by conventional pharmaceutical practice as sterilized and/or can contain conventional inert diluents
Agent, lubricant or buffer and adjuvant such as preservative, stabilizer, wetting agent, emulsifier and buffer etc..
In addition, pharmaceutical composition of the invention can with can be used for preventing or treating hyperlipemia, atherosclerosis, hat
Heart trouble, myocardial infarction, diabetes, tumour, hepatitis, cirrhosis, senile dementia, cerebral ischemia, apoplexy, nephrosis or rheumatoid close
The scorching other class drugs of section are used in combination.For example, pharmaceutical composition of the invention can be used in combination to prevent and treat with agents
Hyperlipemia: inhibitors of cholesterol synthesis, such as HMG-CoA reductase inhibitor；Cholesterol absorption inhibitor, such as according to folding wheat
Cloth；Triglycerides drug is reduced, such as Bezafibrate or fenofibrate；Antihypertensive, as Vel-Tyr-Pro-Trp-Thr-Gln-Arg-Phe, angiotensins by
Body blocking agent, calcium antagonist or Beta receptor blockers；Weight reduction medicine, as maincenter anorexigenic, esterase inhibitor, CB1R antagonist or
DGAT inhibitor；Antidiabetic medicine, such as insulin sensitizer, D2 agonist, sulfonylurea, melbine, alpha-glucosaccharase
Enzyme inhibitor, SGLT inhibitor or DPP-IV inhibitor or other cholesterol-lowering agents, such as ACAT inhibitor.
Detailed description of the invention
Fig. 1 is the x-ray diffractogram of powder of 2: 1: 1 eutectic A of oleanolic acid/choline/isopropanol；
Fig. 2 is the x-ray diffractogram of powder of 2: 1 eutectic B of oleanolic acid/choline；
Fig. 3 is the DSC figure of 2: 1: 1 eutectic A of oleanolic acid/choline/isopropanol；
Fig. 4 is the DSC figure of 2: 1 eutectic B of oleanolic acid/choline；
Fig. 5 is the TGA figure of 2: 1: 1 eutectic A of oleanolic acid/choline/isopropanol；
Fig. 6 is the TGA figure of 2: 1 eutectic B of oleanolic acid/choline；
Fig. 7 is the infrared spectrogram of 2: 1: 1 eutectic A of oleanolic acid/choline/isopropanol；
Fig. 8 is the infrared spectrogram of 2: 1 eutectic B of oleanolic acid/choline；
Fig. 9 is 2: 1: 1 eutectic A of oleanolic acid/choline/isopropanol1H-NMR map；
Figure 10 is 2: 1 eutectic B of oleanolic acid/choline1H-NMR map；
Figure 11 is the solubility test knot of 2: 1 eutectic B of oleanolic acid/choline and oleanolic acid in artificial simulation gastric juices
Fruit；
Figure 12 is the solubility test knot of 2: 1 eutectic B of oleanolic acid/choline and oleanolic acid in artificial simulation intestinal juice
Fruit.
Specific embodiment
The contents of the present invention are illustrated below by embodiment.In the present invention, embodiments discussed below be in order to
It preferably illustrates the present invention, rather than is used to limit the scope of the invention.
Embodiment 1
The preparation of 2: 1: 1 eutectic A of oleanolic acid/choline/isopropanol
The aqueous choline base solution (49%, content of choline 0.27g) of 0.54g is dissolved in the isopropanol of 50mL, solution is in pale yellow
Color.Under the conditions of heating (80 DEG C), the oleanolic acid of 2.0g is added, stirring to solution is clarified, and stir about 0.5h is continued.Stop adding
Heat is slowly cooled to room temperature, stands.White, needle-shaped crystals are precipitated, filter, obtain 1.58g white solid, as olive after dry
2: 1: 1 eutectic A of acid/choline/isopropanol:1H NMR (DMSO, 300MHz) δ 5.07 (s, 2H), 3.84 (m, 2H), 3.77 (m,
1H), 3.41 (m, 2H), 3.12 (s, 9H), 2.99 (m, 2H), 2.78 (m, 2H), 1.70-1.85 (m, 8H), 1.20-1.60 (m,
27H), 1.00-1.10 (m, 16H), 0.80-0.95 (m, 27H), 0.65-0.75 (m, 14H)
Embodiment 2
The preparation of 2: 1: 1 eutectic A of oleanolic acid/choline/isopropanol
Under the conditions of heating (80 DEG C), 1.20g oleanolic acid is dissolved in 85mL ethyl acetate, solution clarification.It is stirring
Under the aqueous choline base solution (49%, content of choline 0.32g) of 0.65g is slowly added dropwise, reaction solution gradually becomes cloudy, and ultimately forms milky white
Color poises liquid.Stop heating, is cooled to room temperature, filters to obtain white solid.Gained white solid is obtained together with recrystallisation from isopropanol
2: 1: 1 eutectic A (1.25g) of pier tartaric acid/choline/isopropanol.
Embodiment 3
The preparation of 2: 1 eutectic B of oleanolic acid/choline
2: 1: 1 eutectic A (1.52g) of oleanolic acid/choline/isopropanol obtained in embodiment 1 is heated under normal pressure
(150 DEG C) dry 1 hour to get 2: 1 eutectic B (1.40g) of oleanolic acid/choline:1H NMR (DMSO, 300MHz) δ 5.05 (s,
2H), 3.82 (m, 2H), 3.40 (m, 2H), 3.10 (s, 9H), 2.98 (m, 2H), 2.78 (m, 2H), 1.70-1.85 (m, 8H),
1.20-1.60 (m, 27H), 1.00-1.10 (m, 9H), 0.80-0.95 (m, 26H), 0.65-0.75 (m, 13H)
Embodiment 4
The preparation of 2: 1 eutectic B of oleanolic acid/choline
At room temperature, by 2: 1: 1 eutectic A (1.00g) of oleanolic acid/choline/isopropanol obtained in embodiment 1 in acetic acid
It is beaten half an hour in ethyl ester (50mL), filters to obtain 2: 1 eutectic B (0.82g) of oleanolic acid/choline.
Embodiment 5
Solubility test of 2: the 1 eutectic B of oleanolic acid/choline in artificial simulation gastric juices
Solubility test, detecting step and condition tool are carried out to 2: the 1 eutectic B of oleanolic acid/choline prepared in embodiment 3
Body is as follows: precision weighs oleanolic acid/choline 2: 1 eutectic B and each 20mg of oleanolic acid in different bottles respectively, is separately added into
Artificial simulation gastric juices, balance to solubility are no longer changed, and HPLC measures drug concentration, and testing result is shown in Figure 11.From Figure 11
In it is visible: solubility of the oleanolic acid in artificial simulation gastric juices be 0.06809mg/mL；2: 1 eutectic B of oleanolic acid/choline exists
Solubility in artificial simulation gastric juices is 0.7615mg/mL.It can be seen that 2: 1 eutectic B of oleanolic acid/choline is in manual simulation
Solubility in gastric juice will be significantly better than oleanolic acid itself.
Embodiment 6
Solubility test of 2: the 1 eutectic B of oleanolic acid/choline in artificial simulation intestinal juice
Solubility test, detecting step and condition tool are carried out to 2: the 1 eutectic B of oleanolic acid/choline prepared in embodiment 3
Body is as follows: precision weighs oleanolic acid/choline 2: 1 eutectic B and each 20mg of oleanolic acid in different bottles respectively, is separately added into
Artificial simulation intestinal juice, balance to solubility are no longer changed, and HPLC measures drug concentration, and testing result is shown in Figure 12.From Figure 12
In it is visible: solubility of the oleanolic acid in artificial simulation intestinal juice be 0.01692mg/mL；2: 1 eutectic B of oleanolic acid/choline exists
Solubility in artificial simulation intestinal juice is 0.1814mg/mL.It can be seen that 2: 1 eutectic B of oleanolic acid/choline is in manual simulation
Solubility in intestinal juice will be significantly better than oleanolic acid itself.
Embodiment 7
Influence of 2: the 1 eutectic B of oleanolic acid/choline to cavy blood lipid level
Method: to male Hartley guinea pigs (Jiangning county Qinglongshan animal reproduction field provide, regular grade, 7-8 weeks
Age, weight 240g-260g, quality certification number: SCXK Soviet Union 2012-0008) after adaptable fed 1 week, it is randomly divided into 2 groups: be respectively
It feeds for 10 and is fed with the Normal group of standard mouse food and 30 with the model group of high lipid food.High lipid food formula are as follows: 1% gallbladder
Sterol, 10% lard uniformly mix composition with 89% normal diet.Model group gives high lipid food nursing, Normal group daily
Do not apply intervention factor.After modeling high in fat 4 weeks, the cavy of model group be randomly divided into hyperlipidemia model group (10) (feed with solvent),
2: 1 eutectic B group (10) of oleanolic acid/choline and oleanolic acid group (10), in addition Normal group is 4 groups altogether.It is wherein neat
2: 1 eutectic B group of pier tartaric acid/choline is fed with 2: 1 eutectic B (20mg/kg/d) of oleanolic acid/choline；Oleanolic acid group is fed with neat pier
Tartaric acid (20mg/kg/d).The solvent of all test medicines is 0.5%CMC sodium solution.Oral administration 2 weeks, 1 time a day.Last
Single administration day before yesterday fasting, last day eye socket take blood, collect blood, centrifuging and taking serum, the measurement for serum lipid level.
Referring to kit specification in measuring total cholesterol (TC) in serum, triglycerides (TG), highly dense on automatic clinical chemistry analyzer
Spend lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C) level.TC uses CHOD-PAP method, and TG is used
GPO-PAP method, LDL-C and HDL-C use direct enzymatic assays.
As a result: influence of the test medicine to cavy hyperlipidemia model blood lipid level the results are shown in Table 1.
The influence of table 1, test medicine to cavy hyperlipidemia model blood lipid level
* P < 0.05, * * P < 0.01 (t inspection) compared with Normal group；
#P < 0.05, ##P < 0.01 (t inspection) compared with model group.
Above-mentioned active testing is as the result is shown: on cavy hyperlipidemia model, the same dose of 2: 1 eutectic B of oleanolic acid/choline
Reducing blood lipid (TG, TC and LDL-C) activity be significantly better than oleanolic acid；Two compounds are on HDL-C level all without influence.
The above solubility experiment and the prompt of pharmacodynamic study result: 2: 1 eutectic B of oleanolic acid/choline of the invention is than neat
Pier tartaric acid itself is more suitable for the drug of preparation prevention or treatment dyslipidemia related disease.
Embodiment 8
The preparation of Pharmaceutical composition: tablet
By 2: the 1 eutectic B (1g) of oleanolic acid/choline prepared in embodiment 3 and lactose (23g) and microcrystalline cellulose
(5.7g) is mixed with mixing machine.With roller bearing compacting machine by gained mixture compression moulding, it is worth flake sheeted product.Use hammer
Pulverizer pulverizes the laminar sheeted product, and gained granular material is made to pass through 20 mesh sieves.By a lightweight two
Silica (0.3g) and magnesium stearate (0.3g) are added in screened material, and are mixed.Gained mix products pelleter
Tabletting prepares tablet.
Embodiment 9
The preparation of Pharmaceutical composition: gelatine capsule agent
By 2: the 1 eutectic B (1g) of oleanolic acid/choline prepared in embodiment 3 and microcrystalline cellulose (0.35g) and lactose
(0.15g) is pelletized with water, then mixes the particle with hinge sodium carboxymethylcellulose (0.04g) and magnesium stearate (0.01g).
Gained mix products fill gelatine capsule, prepare gelatine capsule agent.(gelatine capsule used in the present invention is by Chinese Suzhou capsule
Co., Ltd's production, the gelatine capsule meet medicinal standard).
Claims (5)
1. the eutectic B of oleanolic acid and choline, which is characterized in that eutectic B be by oleanolic acid and choline according to 2: 1 ratio knot
It closes and is formed, and radiated using Cu-K α, in its x-ray diffraction pattern, 2 θ being expressed in degrees are in 13.2 ± 0.2 and 15.1 ± 0.2
There is diffraction maximum.
2. the eutectic B of oleanolic acid as described in claim 1 and choline, is radiated using Cu-Ka, in its X-ray powder diffraction
In figure, 2 θ being expressed in degrees also 7.3 ± 0.2,9.8 ± 0.2,12.1 ± 0.2,14.1 ± 0.2,15.9 ± 0.2,19.8 ±
0.2,21.0 ± 0.2 have one or more diffraction maximums.
3. the eutectic B of oleanolic acid as described in claim 1 and choline, it is characterised in that: (1) have substantially with Fig. 2 institute
The identical X-ray powder diffraction figure shown；(2) there is infrared absorption spectrum scanning figure substantially same as shown in Figure 8；
(3) there is differential scanning calorimetric analysis (DSC) figure substantially same as shown in Figure 4.
4. the preparation method of the eutectic B of oleanolic acid and choline in claim 1, which is characterized in that by oleanolic acid, choline
And isopropanol combines the eutectic A formed to heat removing isopropanol under normal or reduced pressure to get olive according to 2: 1: 1 ratio
The eutectic B of acid and choline.
5. a kind of prevention or treatment hyperlipemia, atherosclerosis, coronary heart disease, myocardial infarction, diabetes, tumour, hepatitis, liver
Hardening, senile dementia, cerebral ischemia, apoplexy, the pharmaceutical composition of nephrosis or rheumatoid arthritis, which is characterized in that described
Contain the eutectic B conduct of the oleanolic acid and choline as claimed in claim 1,2 or 3 for the treatment of effective dose in pharmaceutical composition
Active constituent and pharmaceutically acceptable carrier.
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| CN1709283A (en) * | 2005-06-23 | 2005-12-21 | 马金玲 | Oleanolic acid phospholipid compound and its preparing method |
| CN102191560A (en) * | 2011-04-04 | 2011-09-21 | 南京师范大学 | 3-oxooleanolic acid monocrystal and culture method thereof |
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| CN102191560A (en) * | 2011-04-04 | 2011-09-21 | 南京师范大学 | 3-oxooleanolic acid monocrystal and culture method thereof |
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| Title |
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| 《齐墩果酸共晶的制备及热力学研究》;任天坤等;《中国医药工业杂志》;20141231;第45卷(第7期);第649-652页 |
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