CN111346103A - Pharmaceutical composition and application thereof - Google Patents
Pharmaceutical composition and application thereof Download PDFInfo
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- CN111346103A CN111346103A CN202010292318.7A CN202010292318A CN111346103A CN 111346103 A CN111346103 A CN 111346103A CN 202010292318 A CN202010292318 A CN 202010292318A CN 111346103 A CN111346103 A CN 111346103A
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- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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Abstract
The scheme discloses a pharmaceutical composition in the technical field of medicines, which comprises (6aR,11aR) -3-hydroxy-9, 10-dimethoxy rosenane and (6aR,11aR)9, 10-dimethoxy rosenane-3-O- β -D-glucoside in a molar ratio of 1: 4-9.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a pharmaceutical composition and application thereof.
Background
Alzheimer's Disease (AD), commonly known as senile dementia, is a progressive degenerative disease of the Central Nervous System (CNS) with hidden onset, with neuritic plaques (senile plaques, SP), neurofibrillary tangles (NFT), neuronal loss, gliosis and β -amyloid (A β) deposition as its typical pathological features.
Currently, the study and search of biomarkers for the diagnosis and treatment evaluation of AD has become a hotspot. In the brain tissue of AD patients, there are found phenomena such as imbalance of neurotransmitters, mainly acetylcholine, monoamines, amino acids, etc., which are involved in learning and memory. Acetylcholine (ACh), a species of cholinergic neurotransmitters, is one of the important chemical components in brain tissue. The cholinergic components of the AD patients, such as synthesis, storage and release reduction of the Ach in the brain, are observed and found to be obviously changed in the cortex and hippocampus of the brain. At present, acetylcholinesterase (AChE) inhibitors such as tacrine and rivastigmine are commonly used for treating AD in clinic, and generally, the dosage of tacrine is 20 mu M and the dosage of rivastigmine is 50 mu M; and acetylcholinesterase (AChE) inhibitors such as tacrine and rivastigmine have certain toxicity, and are not good for the health of patients after long-term use.
Therefore, the finding of a substitute drug which can effectively enhance the AChE target inhibition effect, reduce the dosage and toxicity of the drug and improve the treatment effect of AD has important significance.
Disclosure of Invention
The invention aims to provide a medicine capable of enhancing the inhibition effect on acetylcholinesterase, and provides a new medicine source for preventing and treating AD.
The pharmaceutical composition comprises (6aR,11aR) -3-hydroxy-9, 10-dimethoxy santaline and (6aR,11aR)9, 10-dimethoxy santaline-3-O- β -D-glucoside in a molar ratio of 1: 4-9.
The scheme has the beneficial effects that through the combination of ((6aR,11aR) -3-hydroxy-9, 10-dimethoxy rosenane and (6aR,11aR)9, 10-dimethoxy rosenane-3-O- β -D-glucoside), a new drug candidate source is provided for preventing and treating AD, the acetylcholinesterase inhibition effect can be obviously enhanced, and the drug dosage and toxicity are reduced.
Further, the pharmaceutical composition comprises (6aR,11aR) -3-hydroxy-9, 10-dimethoxy santaline and (6aR,11aR)9, 10-dimethoxy santaline-3-O- β -D-glucoside, wherein the molar ratio of the (6aR,11aR) -3-hydroxy-9, 10-dimethoxy santaline to the (6aR,11aR) -9, 10-dimethoxy santaline-3-O- β -D-glucoside.
Furthermore, the pharmaceutical composition can be applied to preparation of medicines or health products for inhibiting the activity of acetylcholinesterase.
Further, the pharmaceutical composition can be applied to preparation of medicines or health products for preventing or treating neurodegenerative diseases.
Furthermore, the pharmaceutical composition can be applied to preparation of medicines or health products for preventing or treating Alzheimer's disease.
Furthermore, the dosage form of the medicine or the health care product is powder, tablets, granules, capsules or oral liquid. The selection of a suitable pharmaceutically acceptable carrier, depending on the dosage form, is routine in the art and will not be described in detail herein.
Drawings
FIG. 1 is a graph showing the dose-effect relationship between (6aR,11aR) -3-hydroxy-9, 10-dimethoxypterocarpan and (6aR,11aR)9, 10-dimethoxypterocarpan-3-O- β -D-glucoside, and their combinations, in inhibiting acetylcholinesterase activity;
FIG. 2 is a Fa-C graph of the compatibility of (6aR,11aR) -3-hydroxy-9, 10-dimethoxypterocarpan and (6aR,11aR)9, 10-dimethoxypterocarpan-3-O- β -D-glucoside in a molar ratio of 1: 5.
Detailed Description
The following is further detailed by way of specific embodiments:
example (6aR,11aR) -3-hydroxy-9, 10-dimethoxypterane and (6aR,11aR)9, 10-dimethoxypterane-3-O- β -D-glucoside and combination thereof (1: 5) Studies on the anti-acetylcholinesterase Activity
1 materials and reagents
1.1 drugs and reagents
(6aR,11aR) -3-hydroxy-9, 10-dimethoxypterane and (6aR,11aR)9, 10-dimethoxypterane-3-O- β -D-glucoside are available from Kyorman Biotech, Inc. DTNB (Lot 16262), acetylcholine iodide (ATCH, Lot BCBV4822), tetraisopropyl pyrophosphate (iso-OMPA, Lot BCBW4257) from Sigma Aldrich (USA), NP-40(Lot C10297258), leupeptin (Lot C10079991), aprotinin (LotC10060365), pepsin inhibitors (Lot B10084382), 4-hydroxyethylpiperazine ethanesulfonic acid (HEPES, LotB10094032), benzamidine hydrochloride (Lot C10089171) and other analytical reagents are available from Mecanol, McMaxim Biotech, Inc.
1.2 preparation of animal brain lysate
A C57BL/6 male mouse (Zunyi university of medicine, center for animal experiments) was selected, and after the mouse was necrosed, the brain of the mouse was divided and dehydrated at-80 ℃ for 4 h. Mouse brains were carefully weighed and tissue homogenated by grinding brain tissue with low salt lysate for 15min on ice (1:10w/v containing 10mM HEPES, 1mM EDTA, 1mM ethyleneglycol bis (2-aminoethyl ether) tetraacetic acid, 150mM sodium chloride, 0.5% polyethylene glycol octylphenyl ether, 10. mu.g/mL leupeptin, 10. mu.g/mL aprotinin, 10. mu.g/mL pepstatin, and 50. mu.g/mL benzamidine hydrochloride). Centrifuging the homogenate at 16000g for 15min at 4 deg.C, and collecting supernatant to obtain mouse brain lysate containing acetylcholinesterase, and storing at-80 deg.C.
2 method of experiment
2.1 pharmaceutical formulation
A proper amount of (6aR,11aR) -3-hydroxy-9, 10-dimethoxy rosenane and (6aR,11aR)9, 10-dimethoxy rosenane-3-O- β -D-glucoside reference substances are precisely weighed and dissolved in DMSO to 50mM and 25mM respectively.
Taking a proper amount of (6aR,11aR) -3-hydroxy-9, 10-dimethoxypteridine mother liquor, diluting with DMSO, and continuously diluting to 7 gradients from a 0.8mM initial concentration 2-fold gradient, (6aR,11aR)9, 10-dimethoxypteridine-3-O- β -D-glucoside mother liquor, diluting with DMSO, and continuously diluting to 7 gradients from a 4mM initial concentration 2-fold gradient, (6aR,11aR) -3-hydroxy-9, 10-dimethoxypteridine and (6aR,11aR)9, 10-dimethoxypteridine-3-O- β -D-glucoside mother liquor are respectively taken and mixed in proper volumes to obtain a composition of (6aR,11aR) -3-hydroxy-9, 10-dimethoxypteridine and (6aR,11aR)9, 10-dimethoxypteridine-3-O- β in a molar ratio of 1: 5, and diluting with DMSO.
The concentration gradient of each experimental drug is set as follows, (6aR,11aR) -3-hydroxy-9, 10-dimethoxy rosenane concentration is 0.8, 0.4, 0.2, 0.1, 0.05, 0.025, 0.0125mM, (6aR,11aR)9, 10-dimethoxy rosenane-3-O- β -D-glucoside concentration is 4, 2, 1, 0.5, 0.25, 0.125, 0.0625 mM.
2.2Ellman method for testing the activity of (6aR,11aR) -3-hydroxy-9, 10-dimethoxypterocarpan and (6aR,11aR)9, 10-dimethoxypterocarpan-3-O- β -D-glucoside and the combination of the two on acetylcholinesterase
Determining the acetylcholinesterase inhibition activity of (6aR,11aR) -3-hydroxy-9, 10-dimethoxypterocarpan and (6aR,11aR)9, 10-dimethoxypterocarpan-3-O- β -D-glucoside and the combination of the two by adopting a modified Ellman method, setting 3 multiple holes for each drug concentration, selecting a 96-hole cell culture plate for carrying out Ellman reaction, wherein the final system volume of the reaction liquid is 200 mu L, and the reaction liquid contains 80mM Na2HPO4(pH 7.4)、0.1mM iso-OMPA、0.625mM ATCh、0.5mM DTNB。
After the drug, the animal brain lysate and the reaction solution are incubated for 15 minutes at 37 ℃, substrates of 10 mu L ATCH (12.5mM) and 10 mu L DTNB (12.5mM) are added, the incubation is carried out for 30 minutes at 37 ℃, the absorbance of each group of drugs (deducting background and color interference of the drugs) is measured at 405nm by using a BioTek EPOCH2 enzyme-labeled reader, and the inhibition rate of the drugs on the acetylcholinesterase activity is calculated.
The inhibition rate calculation formula is as follows:
the inhibition rate (1-addition drug OD value/blank control group OD value) is × 100%.
Analysis of the synergistic inhibition of Acetylcholinesterase Activity by 3- (6aR,11aR) -3-hydroxy-9, 10-dimethoxypterocarpan and (6aR,11aR)9, 10-dimethoxypterocarpan-3-O- β -D-glucoside compositions
The synergistic inhibition effect of the (6aR,11aR) -3-hydroxy-9, 10-dimethoxy rosenane and (6aR,11aR)9, 10-dimethoxy rosenane-3-O- β -D-glucoside composition on the activity of acetylcholinesterase is measured by adopting an intermediate effect principle and a Chou-Talalay combined index method, and the intermediate effect equation F is useda/Fu＝(D/Dm)mThe dosage used at a single or at two drug-specific inhibition rates was calculated. Converting the middle effect equation into a linear equation log (F)a/Fu)＝mlogD-mlogDmD represents the drug dose, FaRepresents the fractional inhibition, Fu＝1-Fa，DmThe concentration of the drug at 50% of the effect is represented by the median effect concentration, and m is the slope of the linear equation line.
According to the Chou-Talalay equation (CI ═ c: (C ═ c:)D)1/(Dx)1+(Dx)2/(Dx)2) Calculating the Combination Index (CI), D of (6aR,11aR) -3-hydroxy-9, 10-dimethoxypterocarpan and (6aR,11aR)9, 10-dimethoxypterocarpan-3-O- β -D-glucoside1、D2The concentrations of (6aR,11aR) -3-hydroxy-9, 10-dimethoxypterane and (6aR,11aR)9, 10-dimethoxypterane-3-O- β -D-glucoside compositions in the X drug effect (acetylcholinesterase activity inhibition rate) are respectively (D)x)1、(Dx)2To achieve the above X drug effect, the concentrations of (6aR,11aR) -3-hydroxy-9, 10-dimethoxypterocarpan and (6aR,11aR)9, 10-dimethoxypterocarpan-3-O- β -D-glucoside when used alone were evaluated for their synergistic inhibitory effects on acetylcholinesterase<1, the combined effect of the two medicines is a synergistic effect; when CI is 1, the effect of combining the two medicines is additive effect; when CI is present>1, the effect of the two drugs is antagonistic effect.
3 results of the experiment
3.1. FIG. 1 is a dose-response relationship curve of the inhibition of acetylcholinesterase activity by (6aR,11aR) -3-hydroxy-9, 10-dimethoxypterane and (6aR,11aR)9, 10-dimethoxypterane-3-O- β -D-glucoside and their combinations, (6aR,11aR) -3-hydroxy-9, 10-dimethoxypterane and (6aR,11aR)9, 10-dimethoxypterane-3-O- β -D-glucoside in combination at a molar concentration ratio of 1: 5. the results show that the inhibition of acetylcholinesterase activity by (6aR,11aR) -3-hydroxy-9, 10-dimethoxypterane and (6aR,11aR)9, 10-dimethoxypterane-3-O- β -D-glucoside is concentration-dependent and obviously reduced compared with the inhibition of the activity by (6aR,11aR) -3-hydroxy-9, 10-dimethoxypterane-O- β -D-glucoside by (6aR,11aR) -3-hydroxy-9, 10-dimethoxypterane-O- β -D-glucoside alone.
Analysis of the synergistic inhibitory Effect of 2- (6aR,11aR) -3-hydroxy-9, 10-dimethoxypterocarpan and (6aR,11aR)9, 10-dimethoxypterocarpan-3-O- β -D-glucoside compositions on Acetylcholinesterase Activity
The synergistic compatibility effect of (6aR,11aR) -3-hydroxy-9, 10-dimethoxypterocarpan and (6aR,11aR)9, 10-dimethoxypterocarpan-3-O- β -D-glucoside under the condition of the molar concentration ratio of 1: 5 is evaluated according to the mesogenic principle and the Chou-Talalay combined index method, the combined use index (Fa-C curve) of (6aR,11aR) -3-hydroxy-9, 10-dimethoxypterocarpan and (6aR,11aR)9, 10-dimethoxypterocarpan-3-O- β -D-glucoside is drawn according to the calculation result, and the combined use effect and the combined use index curve graph are used for evaluating the synergistic compatibility effect of (6aR,11aR) -3-hydroxy-9, 10-dimethoxypterocarpan-3-O- β -D-glucoside.
FIG. 2 is a Fa-C graph of (6aR,11aR) -3-hydroxy-9, 10-dimethoxypterane and (6aR,11aR)9, 10-dimethoxypterane-3-O- β -D-glucoside in a molar ratio of 1: 5 compatibility, the results show that (6aR,11aR) -3-hydroxy-9, 10-dimethoxypterane and (6aR,11aR)9, 10-dimethoxypterane-3-O- β -D-glucoside can exert a significant synergistic effect of inhibiting acetylcholinesterase activity when combined in a molar ratio of 1: 5, and Table 1 shows that when Fa is 0.5, (6aR,11aR) -3-hydroxy-9, 10-dimethoxypterane and (6aR,11aR)9, 10-dimethoxypterane-3-O- β -D-glucoside can be used in a significantly reduced dosage after combined in a molar ratio of 1: 5.
The conclusion is that the influence of (6aR,11aR) -3-hydroxy-9, 10-dimethoxypterocarpan and (6aR,11aR)9, 10-dimethoxypterocarpan-3-O- β -D-glucoside and the combination of the two on the activity of acetylcholinesterase is measured by adopting a modified Ellman method, and when the molar ratio is 1: 5, the combination of (6aR,11aR) -3-hydroxy-9, 10-dimethoxypterocarpan and (6aR,11aR)9, 10-dimethoxypterocarpan-3-O- β -D-glucoside has obvious synergistic inhibition effect on the activity of acetylcholinesterase.
In addition, the inventor also adopts the method to test the AchE inhibition ratio of different compatibility ratios of (6aR,11aR) -3-hydroxy-9, 10-dimethoxypterocarpan and (6aR,11aR)9, 10-dimethoxypterocarpan-3-O- β -D-glucoside, and the specific parameters are shown in the following table:
the data show that the compatibility ratio of (6aR,11aR) -3-hydroxy-9, 10-dimethoxy rosenane to (6aR,11aR)9, 10-dimethoxy rosenane-3-O- β -D-glucoside is 1: 4-1: 9, and the effect of inhibiting acetylcholinesterase is better.
Experiments on the inhibition rate of AchE were carried out on different compatibility ratios of (6aR,11aR)9, 10-dimethoxypterane-3-O- β -D-glucoside and (6aR,11aR) -3-hydroxy-9, 10-dimethoxypterane, and the specific parameters are shown in the following table:
| drug concentration (nM) | 1:1 | 1:2 | 1:3 | 1:4 | 1:5 | 1:6 | 1:7 | 1:8 | 1:9 | 1:10 |
| 30 | 13.6％ | 8.0％ | 6.9％ | 7.8％ | 16.2％ | 12.2％ | 13.5％ | 6.0％ | 15.6％ | 8.5％ |
| 100 | 16.9％ | 10.6％ | 7.1％ | 12.2％ | 15.9％ | 15.0％ | 16.9％ | 6.9％ | 15.3％ | 16.9％ |
| 300 | 22.3％ | 15.2％ | 8.3％ | 14.2％ | 26.1％ | 16.2％ | 19.2％ | 6.9％ | 21.4％ | 14.8％ |
| 1000 | 29.9％ | 19.7％ | 14.2％ | 10.9％ | 22.3％ | 17.7％ | 20.8％ | 5.9％ | 26.5％ | 23.6％ |
| 3000 | 41.6％ | 23.6％ | 16.3％ | 18.7％ | 18.9％ | 20.6％ | 21.6％ | 26.8％ | 31.1％ | 27.4％ |
| 10000 | 52.9％ | 20.8％ | 23.1％ | 23.3％ | 18.4％ | 23.4％ | 22.3％ | 25.9％ | 30.9％ | 35.3％ |
The data show that when the content of (6aR,11aR)9, 10-dimethoxypterane-3-O- β -D-glucoside is higher than that of (6aR,11aR) -3-hydroxy-9, 10-dimethoxypterane, the inhibition effect of the drug mixture consisting of the two on acetylcholinesterase is poor.
While the present invention has been described with reference to the embodiments shown in the drawings, the present invention is not limited to the embodiments, which are illustrative and not restrictive, and it will be apparent to those skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope of the invention as defined in the appended claims.
Claims (6)
1. The pharmaceutical composition is characterized by comprising (6aR,11aR) -3-hydroxy-9, 10-dimethoxy santaline and (6aR,11aR)9, 10-dimethoxy santaline-3-O- β -D-glucoside in a molar ratio of 1: 4-9.
2. The pharmaceutical composition according to claim 1, which comprises (6aR,11aR) -3-hydroxy-9, 10-dimethoxypterocarpan and (6aR,11aR)9, 10-dimethoxypterocarpan-3-O- β -D-glucoside in a molar ratio of 1: 4-6.
3. Use of a pharmaceutical composition according to claim 1 or 2 for the preparation of a medicament or health product for inhibiting acetylcholinesterase activity.
4. Use of a pharmaceutical composition according to claim 1 or 2 for the preparation of a medicament or health product for the prevention or treatment of neurodegenerative diseases.
5. Use of a pharmaceutical composition according to claim 1 or 2 for the preparation of a medicament or health product for the prevention or treatment of alzheimer's disease.
6. The use of a pharmaceutical composition according to claim 3, wherein: the dosage form of the medicine or the health-care product is powder, tablets, granules, capsules or oral liquid.
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| CN111972405A (en) * | 2020-07-27 | 2020-11-24 | 南京太化化工有限公司 | Auxiliary agent for suspending agent and isoxaflutole suspending agent |
| CN114533722A (en) * | 2022-03-14 | 2022-05-27 | 遵义医科大学珠海校区 | Pharmaceutical composition for treating depression |
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| CN114533722A (en) * | 2022-03-14 | 2022-05-27 | 遵义医科大学珠海校区 | Pharmaceutical composition for treating depression |
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