CN105884852A - Eutectic crystal of oleanolic acid and choline and preparation method and pharmaceutical composition of eutectic crystal - Google Patents
Eutectic crystal of oleanolic acid and choline and preparation method and pharmaceutical composition of eutectic crystal Download PDFInfo
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- CN105884852A CN105884852A CN201510014403.6A CN201510014403A CN105884852A CN 105884852 A CN105884852 A CN 105884852A CN 201510014403 A CN201510014403 A CN 201510014403A CN 105884852 A CN105884852 A CN 105884852A
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- choline
- oleanolic acid
- eutectic
- isopropanol
- pharmaceutical composition
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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 119
- 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 119
- 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 119
- 229940100243 oleanolic acid Drugs 0.000 title claims abstract description 119
- 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 119
- 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 117
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 title claims abstract description 107
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- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical class NCCN PIICEJLVQHRZGT-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
- IZVFFXVYBHFIHY-SKCNUYALSA-N 5alpha-cholest-7-en-3beta-ol Chemical compound C1[C@@H](O)CC[C@]2(C)[C@@H](CC[C@@]3([C@@H]([C@H](C)CCCC(C)C)CC[C@H]33)C)C3=CC[C@H]21 IZVFFXVYBHFIHY-SKCNUYALSA-N 0.000 description 1
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Abstract
The invention relates to a eutectic crystal of oleanolic acid and choline, in particular to a eutectic crystal B formed by oleanolic acid and choline according to the ratio of 2:1. The eutectic crystal B has the solubility property and medicinal treatment effect which are superior to those of oleanolic acid itself. The invention further provides a preparation method of the eutectic crystal containing oleanolic acid and choline and a pharmaceutical composition containing the eutectic crystal.
Description
Technical field
The present invention relates to the novel crystal compound comprising oleanolic acid, especially relate to eutectic that oleanolic acid and choline formed, its preparation method and the pharmaceutical composition comprising it.
Background technology
Oleanolic acid tablet is an OTC (over-the-counter) hepatoprotective, and it is used clinically for the auxiliary treatment of acute hepatitis, chronic hepatitis, has certain protective effect to hepatic injury.On the other hand, substantial amounts of research work shows, oleanolic acid also has the effects (Natural Product Reports 2011,28,543-593) such as blood fat reducing, blood sugar lowering, antitumor, immunomodulating, neuroprotective and resisting cardiovascular disease.Of particular concern is, inventors demonstrated that oleanolic acid embodies extremely significantly effect for reducing blood fat (201210454865.6) on high fat animal model.At present, oleanolic acid, except protecting the liver in addition to aspect has clinical practice, there is no otherwise clinical practice.
Oleanolic acid is a pentacyclic triterpenoid, for white powder crystalline material, it is extremely difficult to be dissolved in water.Due to its water solublity extreme difference, oleanolic acid oral administration biaavailability extremely low (bioavailability is less than 1%), therefore, take medicine the most day by day three times for reaching to protect the liver curative effect, and taking dose is bigger.
In order to improve the bioavailability of oleanolic acid, have and oleanolic acid is made oral cavity disintegration tablet (200710068005.8), phosphatide complexes (200510081273.4), drop pill (200510013611.0) and dispersible tablet (200810302500.5) etc..But, improve drug solubility by above-mentioned preparation means and often lead to medicine cost height, and the substantially drug quality poor controllability due to medicament preparation process complexity.On the other hand, if improved the water solublity of oleanolic acid by structural modification, its major drawbacks is that the safety of drug also brings the biggest uncertainty, and protecting the liver or fat-reducing medicament especially as long-term taking is high to its security requirement.
On the premise of not changing medicines structure, the method improving drug solubility also has salt form to screen.Existing oleanolic acid salt includes powder ofSodium Oleanlic Acid (99113945.3), oleanolic acid piperazine salt (200910055705.2) and oleanolic acid ethylenediamine salt (201010171882.X).Although powder ofSodium Oleanlic Acid to some extent solves dissolubility and the dissolution problem of medicine, but research shows, powder ofSodium Oleanlic Acid continues moisture absorption in the range of 5～95%, thus affects the stability of medicine, is unsuitable for industrialized production.Although oleanolic acid piperazine salt and ethylenediamine salt have the advantages that hygroscopicity is low and stability is high, but piperazine or ethylenediamine are only responsible for base as organic amine becomes the function of salt, itself and inefficacy, taking the medicine containing this type of organic amine in a large number can bring potential safety risks especially for a long time.
On the premise of not changing medicines structure, the another kind of method improving physical and chemical properties of drugs is to form pharmaceutical co-crystals.So-called pharmaceutical co-crystals refers to active constituents of medicine (active pharmaceutical ingredients, API) with suitable eutectic formation (cocrystal former, CCF) H-bonding self-assembly is passed through, or assemble a kind of new structure formed, i.e. pharmaceutical co-crystals by the non-covalent bond (such as Van der Waals force) with saturability and directivity.Pharmaceutical co-crystals research is also an important component part of drug crystal forms research.Why pharmaceuticals industry is had the biggest captivation to be to it provide one to need not destroy and produce covalent bond and just can reach to improve the chance of the physicochemical property of active constituents of medicine (API) by pharmaceutical co-crystals.Pharmaceutical co-crystals majority is formed based on hydrogen bond, is typically formed by the connection of hydrogen bond receptor and hydrogen-bond donating body.The pharmaceutical co-crystals formed by hydrogen bond both need not form new covalent bond, it is not required that destroys existing covalent bond；While retaining the pharmacological properties of medicine itself, having reached the purpose of the physicochemical property improving medicine, this point is that pharmaceutical co-crystals application in terms of pharmaceuticals industry provides the most wide development space.In the case of not changing medicines structure and the pharmacological properties of itself, the new crystal of formation can improve the dissolubility of medicine, dissolution, bioavailability, stability, reduces and draws moist and improve mechanical performance etc..Therefore, it is thus achieved that more have novelty, practical and creative pharmaceutical co-crystals has important practical significance, particularly some water-insoluble drugs.
Choline is to be separated from Fel Sus domestica in 1894 by Streker first, has become additive conventional in human food.Choline is classified as the product of " it is generally acknowledged safety " by " the federal code " of the U.S.；Choline is classified as the product allowing to make an addition to baby food by the regulation that European Union is promulgated for 1991.Choline is a kind of strong organic base, is the constituent of lecithin, exists among sphingomyelin, is that of the variable methyl of body originates and acts on the product of synthesizing methyl, is again the precursor of acetylcholine simultaneously.Human body also can synthesize choline, so not easily causing deficiency disease.Choline is heat-resisting, and the loss in processing and gastronomical process is little, under dry environment, also has almost no change even if storing content of choline in food for a long time.Of particular concern is, choline also has extraordinary health care and disease prevention effect.Such as, choline can promote lipid metabolism, and application choline can treat liver cirrhosis, hepatitis and other hepatopathys clinically, respond well.Choline has good emulsification property, and cholesterol can be stoped in the deposition of blood vessel and to remove Parts of deposits, improves absorption and the utilization of fat simultaneously, therefore has the effect of prevention cardiovascular disease.
Up to now, there is not yet any report and describe salt or the eutectic that oleanolic acid is formed with choline.
Summary of the invention
The physicochemical properties such as an object of the present invention is to provide the eutectic that novel oleanolic acid is formed with choline, its dissolubility are better than oleanolic acid self.The eutectic of the present invention includes: oleanolic acid/choline/isopropanol 2: 1: 1 eutectic A or oleanolic acid/choline 2: 1 eutectic B.
The invention provides the eutectic comprising oleanolic acid and choline, it has the feature that
1. powder X-ray diffraction:
Instrument: D8Advance X-ray diffractometer (Germany Bruker)
Target: Cu-K α
Wavelength: 1.5406A °
Pipe pressure: 40KV
Pipe flow: 40mA
Step-length: 0.02 °
The powder X-ray diffraction feature of table 1, oleanolic acid/choline/isopropanol 2: 1: 1 eutectic A
Table 2, the powder X-ray diffraction feature of oleanolic acid/choline 2: 1 eutectic B
2. differential scanning calorimetry (DSC):
Instrument: NETZSCH DSC 204 differential scanning calorimeter instrument
Scope: 40～300 DEG C
Programming rate: 10 DEG C/min
The endothermic transition of oleanolic acid/choline/isopropanol 2: 1: 1 eutectic A about at 116.3 DEG C and 254.6 DEG C, has highly endothermic peak herein.
The endothermic transition of oleanolic acid/choline 2: 1 eutectic B about at 255.5 DEG C, has highly endothermic peak herein.
3. fusing point:
Instrument: RY-1 melting point apparatus (Tianjin analytical tool factory)
The fusing point of oleanolic acid/choline/isopropanol 2: 1: 1 eutectic A is: 255～258 DEG C.
The fusing point of oleanolic acid/choline 2: 1 eutectic B is: 258～262 DEG C.
4. infrared spectrum:
Instrument: Shimadzu Corporation IR Affinity-1
Infrared spectrum wave number (the cm of oleanolic acid/choline/isopropanol 2: 1: 1 eutectic A-1) it is about: 3421,2972,2941,2926,2858,1681,1548,1465,1384,1373.
Infrared spectrum wave number (the cm of oleanolic acid/choline 2: 1 eutectic B-1) it is about: 3458,2941,2862,1703,1556,1462,1388,1361.
The eutectic A of the oleanolic acid of the present invention, choline and isopropanol, it is characterised in that eutectic A is to be formed according to the ratio combination of 2: 1: 1 by oleanolic acid, choline and isopropanol；Use Cu-K α radiation, its X-ray powder diffraction figure, diffraction maximum is had in 14.3 ± 0.2 and 15.5 ± 0.2 with 2 θ that degree represents, particularly, 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 more (in any combination, including two or more, or all) diffraction maximum, see Fig. 1；The endothermic transition of the DSC scanning of eutectic A, mainly at 116.3 DEG C and about 254.6 DEG C, is shown in Fig. 3；The infrared absorption spectroscopy that eutectic A KBr tabletting records about exists: 3421cm-1、2972cm-1、2941cm-1、2926cm-1、2858cm-1、1681cm-1、1548cm-1、1465cm-1、1384cm-1And 1373cm-1There is absworption peak at place, sees Fig. 7.
The oleanolic acid of the present invention and the eutectic B of choline, it is characterised in that eutectic B is to be formed according to the ratio combination of 2: 1 by oleanolic acid and choline；Use Cu-K α radiation, its X-ray powder diffraction figure, diffraction maximum is had in 13.2 ± 0.2 and 15.1 ± 0.2 with 2 θ that degree represents, particularly, 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 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, about at about 255.5 DEG C, is shown in Fig. 4；The infrared absorption spectroscopy that eutectic B KBr tabletting records about exists: 3458cm-1、2941cm-1、2862cm-1、1703cm-1、1556cm-1、1462cm-1、1388cm-1、1361cm-1There is absworption peak at place, sees Fig. 8.
It is a further object of the present invention to provide the method preparing oleanolic acid/choline eutectic.
The preparation method of oleanolic acid/choline/isopropanol 2: 1: 1 eutectic A that the present invention provides is as follows:
Preparation method 1, step as follows:
The most in a heated condition, oleanolic acid is dissolved in appropriate suitable solvents, described solvent is selected from water, methanol, ethanol, acetone, isopropanol, n-butyl alcohol, dichloromethane, chloroform, ethyl acetate, acetonitrile, oxolane or N, a kind of solvent in N-dimethylformamide or more than one mixed solvent, preferred solvent is isopropanol, ethyl acetate or acetone；
2. choline solution is slowly added drop-wise in the solution of step 1 gained, separates out a large amount of solid；The amount of the choline added is preferably 0.5～5 equivalents；
3. filter, wash with appropriate above-mentioned suitable solvents or insoluble solvent, obtain solid；
4. solid recrystallisation from isopropanol collection obtained i.e. obtains oleanolic acid/choline/isopropanol 2: 1: 1 eutectic A.
Preparation method 2, step as follows:
1. choline being dissolved in isopropanol, the amount of the choline added is preferably 0.5～5 equivalents；
The most in a heated condition, in above-mentioned solution, add oleanolic acid, stir to obtain settled solution；
3. above-mentioned solution is slowly cooled to room temperature, stands and separate out white crystal, volatilize solvent after sucking filtration, obtain oleanolic acid/choline/isopropanol 2: 1: 1 eutectic A.
The preparation method of oleanolic acid/choline 2: 1 eutectic B that the present invention provides is as follows:
Preparation method 1, step as follows:
At room temperature being suspended in appropriate solvent by oleanolic acid/choline/isopropanol 2: 1: 1 eutectic A, quickly after stirring a period of time, sucking filtration obtains white solid, is drying to obtain oleanolic acid/choline 2: 1 eutectic B；The mixed solvent of described solvent one or more than one in ethyl acetate, acetone, acetonitrile, n-butyl alcohol, dichloromethane, chloroform, oxolane or DMF, preferred solvent is ethyl acetate or acetone.
Preparation method 2, step as follows:
After oleanolic acid/choline/isopropanol 2: 1: 1 eutectic A is heated a period of time under normal pressure or reduced pressure, obtain oleanolic acid/choline 2: 1 eutectic B；The heating-up temperature used is 50～200 DEG C, preferably 100～150 DEG C.
Present invention also offers a kind of prevention or treatment hyperlipidemia, atherosclerosis, coronary heart disease, myocardial infarction, diabetes, tumor, hepatitis, liver cirrhosis, senile dementia, cerebral ischemia, apoplexy, nephropathy or the pharmaceutical composition of rheumatoid arthritis, it comprises oleanolic acid/choline/isopropanol 2: 1: 1 eutectic A or oleanolic acid/choline 2: 1 eutectic B for the treatment of effective dose as active component and pharmaceutically acceptable carrier.This pharmaceutical composition can be formulated for specific route of administration, the most Orally administered, parenteral administration and rectal administration etc..Additionally, the pharmaceutical composition of the present invention can also be prepared in solid form, including capsule, tablet, pill, granule, powder or suppository, or liquid form, including solution, suspensoid or Emulsion.The pharmaceutical composition of the present invention can pass through conventional pharmaceutical practice such as sterilizing and/or can contain conventional inert diluent, lubricant or buffer agent, and adjuvant such as preservative, stabilizer, wetting agent, emulsifying agent and buffer agent etc..
Additionally, the pharmaceutical composition of the present invention can be used in combination with other class medicine that can be used for preventing or treating hyperlipidemia, atherosclerosis, coronary heart disease, myocardial infarction, diabetes, tumor, hepatitis, liver cirrhosis, senile dementia, cerebral ischemia, apoplexy, nephropathy or rheumatoid arthritis.Such as, the pharmaceutical composition of the present invention can be used in combination in case curing hyperlipemia with agents: cholesterol synthetic inhibitor, such as HMG-CoA reductase inhibitor；Cholesterol absorption inhibitor, such as Ezetimibe；Reduce triglyceride medicine, such as bezafibrate or fenofibrate；Antihypertensive, such as ACE inhibitor, angiotensin receptor blocker, calcium antagonist or Beta receptor blockers；Lose weight fat medicine, such as maincenter anorexigenic, esterase inhibitor, CB1R antagonist or DGAT inhibitor；Antidiabetic medicine, such as euglycemic agent, D2 agonist, sulfonylurea, metformin, alpha-glucosidase inhibitor, SGLT inhibitor or DPP-IV inhibitor, or other cholesterol-lowering agent, such as ACAT inhibitor.
Accompanying drawing explanation
Fig. 1 is the x-ray diffractogram of powder of oleanolic acid/choline/isopropanol 2: 1: 1 eutectic A；
Fig. 2 is the x-ray diffractogram of powder of oleanolic acid/choline 2: 1 eutectic B；
Fig. 3 is the DSC figure of oleanolic acid/choline/isopropanol 2: 1: 1 eutectic A；
Fig. 4 is the DSC figure of oleanolic acid/choline 2: 1 eutectic B；
Fig. 5 is the TGA figure of oleanolic acid/choline/isopropanol 2: 1: 1 eutectic A；
Fig. 6 is the TGA figure of oleanolic acid/choline 2: 1 eutectic B；
Fig. 7 is the infrared spectrogram of oleanolic acid/choline/isopropanol 2: 1: 1 eutectic A；
Fig. 8 is the infrared spectrogram of oleanolic acid/choline 2: 1 eutectic B；
Fig. 9 is oleanolic acid/choline/isopropanol 2: 1: 1 eutectic A1H-NMR collection of illustrative plates；
Figure 10 is oleanolic acid/choline 2: 1 eutectic B1H-NMR collection of illustrative plates；
Figure 11 is oleanolic acid/choline 2: 1 eutectic B and oleanolic acid dissolubility test result in artificial simulation gastric juices；
Figure 12 is oleanolic acid/choline 2: 1 eutectic B and oleanolic acid dissolubility test result in artificial simulation intestinal juice.
Detailed description of the invention
Present disclosure is illustrated below by embodiment.In the present invention, embodiments discussed below is to preferably illustrate the present invention rather than for limiting the scope of the present invention.
Embodiment 1
The preparation of oleanolic acid/choline/isopropanol 2: 1: 1 eutectic A
The aqueous choline base solution (49%, content of choline 0.27g) of 0.54g being dissolved in the isopropanol of 50mL, solution is light yellow.Under the conditions of heating (80 DEG C), add the oleanolic acid of 2.0g, stir and clarify to solution, continue stir about 0.5h.Stop heating, be slowly cooled to room temperature, stand.Separate out white, needle-shaped crystals, sucking filtration, dried 1.58g white solid, be oleanolic acid/choline/isopropanol 2: 1: 1 eutectic A: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 oleanolic acid/choline/isopropanol 2: 1: 1 eutectic A
Under the conditions of heating (80 DEG C), being dissolved in 85mL ethyl acetate by 1.20g oleanolic acid, solution is clarified.The most slowly dripping the aqueous choline base solution (49%, content of choline 0.32g) of 0.65g, reactant liquor gradually becomes cloudy, and ultimately forms milky and poises liquid.Stopping heating, be cooled to room temperature, sucking filtration obtains white solid.Gained white solid recrystallisation from isopropanol is obtained oleanolic acid/choline/isopropanol 2: 1: 1 eutectic A (1.25g).
Embodiment 3
The preparation of oleanolic acid/choline 2: 1 eutectic B
Oleanolic acid/choline/the isopropanol 2: 1: 1 eutectic A (1.52g) prepared in embodiment 1 heat at ambient pressure (150 DEG C) drying 1 hour, obtains oleanolic acid/choline 2: 1 eutectic B (1.40g):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 oleanolic acid/choline 2: 1 eutectic B
At room temperature, oleanolic acid/choline/isopropanol 2: 1: 1 eutectic A (1.00g) the making beating half an hour in ethyl acetate (50mL) that will prepare in embodiment 1, sucking filtration obtains oleanolic acid/choline 2: 1 eutectic B (0.82g).
Embodiment 5
Oleanolic acid/choline 2: 1 eutectic B solubility test in artificial simulation gastric juices
Oleanolic acid/choline 2: 1 eutectic B of preparation in embodiment 3 is carried out solubility test, detecting step and condition are specific as follows: precision weighs oleanolic acid/choline 2: 1 eutectic B and each 20mg of oleanolic acid in different bottles respectively, it is separately added into artificial simulation gastric juices, balance to dissolubility no longer changes, HPLC measures drug level, and testing result is shown in Figure 11.As can be seen from Fig. 11: oleanolic acid dissolubility in artificial simulation gastric juices is 0.06809mg/mL；Oleanolic acid/choline 2: 1 eutectic B dissolubility in artificial simulation gastric juices is 0.7615mg/mL.As can be seen here, oleanolic acid/choline 2: 1 eutectic B dissolubility oleanolic acid to be significantly better than in artificial simulation gastric juices self.
Embodiment 6
Oleanolic acid/choline 2: 1 eutectic B solubility test in artificial simulation intestinal juice
Oleanolic acid/choline 2: 1 eutectic B of preparation in embodiment 3 is carried out solubility test, detecting step and condition are specific as follows: precision weighs oleanolic acid/choline 2: 1 eutectic B and each 20mg of oleanolic acid in different bottles respectively, it is separately added into artificial simulation intestinal juice, balance to dissolubility no longer changes, HPLC measures drug level, and testing result is shown in Figure 12.As can be seen from Fig. 12: oleanolic acid dissolubility in artificial simulation intestinal juice is 0.01692mg/mL；Oleanolic acid/choline 2: 1 eutectic B dissolubility in artificial simulation intestinal juice is 0.1814mg/mL.As can be seen here, oleanolic acid/choline 2: 1 eutectic B dissolubility oleanolic acid to be significantly better than in artificial simulation intestinal juice self.
Embodiment 7
Oleanolic acid/choline 2: 1 eutectic B impact on guinea pig blood lipid level
Method: (Qinglongshan animal reproduction field, Jiangning county provides to male Hartley guinea pigs, regular grade, 7-8 week old, body weight 240g-260g, the quality certification number: SCXK revives 2012-0008) after adaptability feeds 1 week, be randomly divided into 2 groups: be respectively 10 feed the Normal group with standard mouse food and 30 feed the model group with high lipid food.High lipid food formula is: 1% cholesterol, and 10% Adeps Sus domestica and 89% normal diet uniformly mix composition.Model group gives high lipid food nursing every day, and Normal group does not apply intervention factor.After high fat modeling 4 weeks, the Cavia porcellus of model group is randomly divided into hyperlipidemia model group (10) (feeding with solvent), oleanolic acid/choline 2: 1 eutectic B group (10) and oleanolic acid group (10), adds that Normal group is 4 groups altogether.Wherein oleanolic acid/choline 2: 1 eutectic B group is fed with oleanolic acid/choline 2: 1 eutectic B (20mg/kg/d)；Oleanolic acid group is fed with oleanolic acid (20mg/kg/d).The solvent of all test medicine is 0.5%CMC sodium solution.Oral administration 2 weeks, every day 1 time.Being administered the fasting day before yesterday the last time, last day, eye socket took blood, collected blood, and centrifuging and taking serum, for the mensuration of serum lipid level.Reference reagent box description measures T-CHOL (TC) in serum, triglyceride (TG), HDL-C (HDL-C), low-density lipoprotein cholesterol (LDL-C) level on automatic clinical chemistry analyzer.TC uses CHOD-PAP method, and TG uses GPO-PAP method, LDL-C and HDL-C uses direct enzymatic assays.
Result: test medicine the results are shown in Table 1 to the impact of Cavia porcellus hyperlipidemia model blood lipid level.
The impact on Cavia porcellus hyperlipidemia model blood lipid level of table 1, test medicine
* P ＜ 0.05, * * P ＜ 0.01 is (t inspection) compared with Normal group；
#P ＜ 0.05, ##P ＜ 0.01 is (t inspection) compared with model group.
Above-mentioned active testing result shows: on Cavia porcellus hyperlipidemia model, and blood fat reducing (TG, TC and LDL-C) activity of oleanolic acid/choline 2: 1 eutectic B of Isodose is significantly better than oleanolic acid；Two compounds on HDL-C level all without impact.
Above solubility experiment and the prompting of pharmacodynamic study result: oleanolic acid/choline 2: 1 eutectic B of the present invention is more suitable for preparation prevention or the medicine for the treatment of dyslipidemia relevant disease than oleanolic acid itself.
Embodiment 8
The preparation of Pharmaceutical composition: tablet
Oleanolic acid/the choline 2: 1 eutectic B (1g) of preparation in embodiment 3 is mixed with mixer with lactose (23g) and microcrystalline Cellulose (5.7g).With roller bearing compacting machine by compressing for gained mixture, it is worth flake sheeted product.With beater grinder, described flake sheeted product is pulverized, make gained granular material by 20 mesh sieve.Portion light silicon dioxide (0.3g) and magnesium stearate (0.3g) are joined in screened material, and mix.Gained mix products pelleter tabletting, prepares tablet.
Embodiment 9
The preparation of Pharmaceutical composition: gelatine capsule agent
Oleanolic acid/the choline 2: 1 eutectic B (1g) of preparation in embodiment 3 is pelletized with microcrystalline Cellulose (0.35g) and lactose (0.15g) water, then this granule is mixed with hinge sodium carboxymethyl cellulose (0.04g) and magnesium stearate (0.01g).Gained mix products fills gelatine capsule, prepares gelatine capsule agent.(gelatine capsule used in the present invention is produced by Suzhou Capsule Co., Ltd of China, and this gelatine capsule meets medicinal standard).
Claims (10)
1. the eutectic A of oleanolic acid, choline and isopropanol, it is characterised in that eutectic A is by oleanolic acid, choline and isopropyl
Alcohol combines according to the ratio of 2: 1: 1 and is formed, and uses Cu-K α radiation, in its x-ray diffraction pattern, 2 θ represented with degree
Diffraction maximum is had in 14.3 ± 0.2 and 15.5 ± 0.2.
2. oleanolic acid as claimed in claim 1, choline and the eutectic A of isopropanol, uses Cu-Ka radiation, at its X-
In ray powder diffraction pattern, with 2 θ that represent of degree also 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 ± 0.2,15.8 ± 0.2,20.3 ± 0.2 have one or more diffraction maximum.
3. oleanolic acid as claimed in claim 1, choline and the eutectic A of isopropanol, it is characterised in that: (1) has base
X-ray powder diagram same as shown in Figure 1 in basis；(2) there is infrared suction the most same as shown in Figure 7
Receive spectral scan figure；(3) there is differential scanning calorimetric analysis (DSC) figure the most same as shown in Figure 3.
4. the eutectic B of oleanolic acid and choline, it is characterised in that eutectic B be by oleanolic acid and choline according to 2: 1 ratio
In conjunction with being formed, and use Cu-K α radiation, in its x-ray diffraction pattern, to spend 2 θ represented 13.2 ± 0.2 and 15.1
± 0.2 has diffraction maximum.
5. oleanolic acid as claimed in claim 4 and the eutectic B of choline, use Cu-Ka radiation, at its X-ray powder
In diffraction pattern, to spend 2 θ represented 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 maximum.
6. the eutectic B of oleanolic acid as claimed in claim 4 and choline, it is characterised in that: (1) have substantially with figure
Identical X-ray powder diagram shown in 2；(2) there is infrared absorption spectroscopy the most same as shown in Figure 8 to sweep
Tracing；(3) there is differential scanning calorimetric analysis (DSC) figure the most same as shown in Figure 4.
7. the preparation method of the eutectic A of the oleanolic acid in claim 1, choline and isopropanol, it is characterised in that by choline
It is dissolved in isopropanol, under heating stirring condition, adds oleanolic acid and obtain settled solution, be then cooled to room temperature, stand and separate out
White needle-like crystals, sucking filtration, dry, obtain eutectic A.
8. the preparation method of the eutectic B of the oleanolic acid in claim 4 and choline, it is characterised in that by claim 1 institute
The eutectic A of oleanolic acid, choline and the isopropanol stated adds heat extraction isopropanol under normal or reduced pressure, obtains oleanolic acid and gallbladder
The eutectic B of alkali.
9. one kind prevention or treatment hyperlipidemia, atherosclerosis, coronary heart disease, myocardial infarction, diabetes, tumor, hepatitis,
The pharmaceutical composition of liver cirrhosis, senile dementia, cerebral ischemia, apoplexy, nephropathy or rheumatoid arthritis, it is characterised in that
Containing oleanolic acid, choline and the isopropyl as described in claim 1,2 or 3 treating effective dose in described pharmaceutical composition
The eutectic A of alcohol is as active component and pharmaceutically acceptable carrier.
10. one kind prevention or treatment hyperlipidemia, atherosclerosis, coronary heart disease, myocardial infarction, diabetes, tumor, hepatitis,
The pharmaceutical composition of liver cirrhosis, senile dementia, cerebral ischemia, apoplexy, nephropathy or rheumatoid arthritis, it is characterised in that
The oleanolic acid as described in claim 4,5 or 6 containing treatment effective dose and the eutectic of choline in described pharmaceutical composition
B is as active component 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 |
| WO2012170546A1 (en) * | 2011-06-06 | 2012-12-13 | University Of Iowa Research Foundation | Methods of inhibiting muscle atrophy |
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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 |
| WO2012170546A1 (en) * | 2011-06-06 | 2012-12-13 | University Of Iowa Research Foundation | Methods of inhibiting muscle atrophy |
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