CN108578411A - A kind of pharmaceutical composition and its preparation method and application for preventing and/or treating neurodegenerative disease - Google Patents
A kind of pharmaceutical composition and its preparation method and application for preventing and/or treating neurodegenerative disease Download PDFInfo
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- CN108578411A CN108578411A CN201810846203.0A CN201810846203A CN108578411A CN 108578411 A CN108578411 A CN 108578411A CN 201810846203 A CN201810846203 A CN 201810846203A CN 108578411 A CN108578411 A CN 108578411A
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- rutaecarpin
- chlorogenic acid
- neurodegenerative disease
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- 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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- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
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- Organic Chemistry (AREA)
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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Abstract
The invention discloses a kind of pharmaceutical compositions for preventing and/or treating neurodegenerative disease, it is that the group matched by following weight is grouped as：1~10 part of chlorogenic acid, 1~10 part of rutaecarpin.The results show, chlorogenic acid and rutaecarpin compatibility have the function of synergy.
Description
Technical field
The present invention relates to a kind of pharmaceutical compositions and preparation method thereof for preventing and/or treating neurodegenerative disease
And purposes.
Background technology
Neurodegenerative disease is caused by the central functions decline caused by nerve cell progressive degeneration necrosis
Disease, along with the aging of population in the world be in exacerbation trend, including Alzheimer disease (Alzheimer ' s disease,
AD), Parkinson's disease (Parkinson ' s disease, PD), amyotrophic lateral sclerosis (Atrophy lateral
Sclerosis, ALS) and multiple sclerosis (Multiple Sclerosis, MS) etc..The cognition of these sickness influences patient
And motor function, disable, lethality height, huge psychology and financial burden are brought to patient home and society.Most of nerve
Degenerative disease there is no the means of the healing disease of effective block nerves cell degenerative processes, clinically mainly be suited the medicine to the illness with drug
Based on treatment, symptom can only be improved.The basic method for the treatment of neurodegenerative disease can slow down or block nerves cell
Degenerative process.Therefore, the drug research for carrying out block nerves cell degeneration death has become various countries' scientific research and pharmaceutical manufacturer
Hot spot.
Invention content
The purpose of the present invention is to provide a kind of for preventing and/or treating the pharmaceutical composition of neurodegenerative disease,
It is that the group matched by following weight is grouped as：1~10 part of chlorogenic acid, 1~10 part of rutaecarpin.
Further, it is that the group matched by following weight is grouped as：1 part of chlorogenic acid, 1~10 part of rutaecarpin.
Further, it is that the group matched by following weight is grouped as：1 part of chlorogenic acid, 5~10 parts by weight of rutaecarpin.
Further, it is that the group matched by following weight is grouped as：1 part of chlorogenic acid, 5 parts of rutaecarpin.
The present invention also provides a kind of drugs for preventing and/or treating neurodegenerative disease, it is with above-mentioned
Pharmaceutical composition is active constituent, the preparation being prepared along with pharmaceutically acceptable auxiliary material.
Further, the preparation is oral preparation or ejection preparation；Preferably, the oral preparation be pill, tablet,
Capsule, pulvis, granule, syrup, oral solution, effervescent agent；The ejection preparation is freeze-dried powder or injection.
The present invention also provides a kind of methods preparing said medicine, weigh chlorogenic acid and rutaecarpin by weight ratio,
Pharmaceutically acceptable auxiliary material is added with after and is prepared into preparation for mixing.
The present invention also provides above-mentioned pharmaceutical compositions to prepare the drug for preventing and/or treating neurodegenerative disease
In purposes；The neurodegenerative disease is memory dysfunction disease, vascular dementia or senile dementia.
The present invention also provides above-mentioned drugs to prepare the use in preventing and/or treating the drug of neurodegenerative disease
On the way.
Further, the neurodegenerative disease is memory dysfunction disease, vascular dementia or senile dementia.
To enable above-mentioned dosage form to realize, pharmaceutically acceptable auxiliary material need to be added when preparing these dosage forms, such as：Filling
Agent, disintegrant, lubricant, suspending agent, adhesive, sweetener, corrigent, preservative, matrix etc..Filler includes：It is starch, pre-
Gelling starch, lactose, mannitol, chitin, microcrystalline cellulose, sucrose etc.；Disintegrant includes：Starch, pregelatinized starch, crystallite
Cellulose, sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, croscarmellose sodium etc.；
Lubricant includes：Magnesium stearate, lauryl sodium sulfate, talcum powder, silica etc.；Suspending agent includes：Polyvinylpyrrolidine
Ketone, microcrystalline cellulose, sucrose, agar, hydroxypropyl methyl cellulose etc.；Adhesive includes, starch slurry, polyvinylpyrrolidone,
Hydroxypropyl methyl cellulose etc.；Sweetener includes：Saccharin sodium, aspartame, sucrose, honey element, enoxolone etc.；Corrigent packet
It includes：Sweetener and various essence；Preservative includes：Parabens, benzoic acid, sodium benzoate, sorbic acid and its esters, benzene prick bromine
Fixed, eucalyptus oil of ammonium, acetic acid chloroethene etc.；Matrix includes：PEG6000, PEG4000, insect wax etc..
The beneficial effects of the invention are as follows：
(1) present invention, which is provided made of a kind of combination of active principles by natural medicinal raw material, has treatment nervus retrogression
The preparation method and purposes of the pharmaceutical composition of disease and the pharmaceutical composition have good effect, have no toxic side effect, be not likely to produce
Tolerance, advantage convenient to take；
(2) pharmaceutical composition of the present invention has the good property taken into account, good except having to neurodegenerative disease patient
Outside therapeutic effect, lowly there is preferable therapeutic effect to immunity function.
(3) chlorogenic acid, rutaecarpin are to have therapeutic effect to neurodegenerative disease being used alone, when two kinds of ingredients
There is preferable therapeutic effect to neurodegenerative disease after combination and compatibility, after showing chlorogenic acid and rutaecarpin combination and compatibility
Has the function of synergy.
Obviously, the above according to the present invention is not being departed from according to the ordinary technical knowledge and customary means of this field
Under the premise of the above-mentioned basic fundamental thought of the present invention, the modification, replacement or change of other diversified forms can also be made.
The specific implementation mode of form by the following examples remakes further specifically the above of the present invention
It is bright.But the range that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to example below.It is all to be based on the above of the present invention
The technology realized all belongs to the scope of the present invention.
Specific implementation mode
Embodiment 1
Chlorogenic acid 10g is weighed to be uniformly mixed with rutaecarpin 50g.
Embodiment 2
Chlorogenic acid 100g, rutaecarpin 10g are weighed, supplementary product starch 140g is added and pelletizes, magnesium stearate 5g, dextrin 150g,
Microcrystalline cellulose 150g, is uniformly made particle, and tabletting obtains tablet.
Embodiment 3
Chlorogenic acid 50g, rutaecarpin 10g are weighed, supplementary product starch 75g granulations, magnesium stearate 3g, dextrin 80g, crystallite is added
Cellulose 80g, is uniformly made particle, and tabletting obtains tablet.
Embodiment 4
Chlorogenic acid 10g, rutaecarpin 50g are weighed, supplementary product starch 75g granulations, magnesium stearate 3g, dextrin 80g, crystallite is added
Cellulose 80g, is uniformly made particle, and tabletting obtains tablet.
Embodiment 5
Chlorogenic acid 10g, rutaecarpin 100g are weighed, supplementary product starch 140g is added and pelletizes, magnesium stearate 5g, dextrin 150g,
Microcrystalline cellulose 150g, is uniformly made particle, and tabletting obtains tablet.
Embodiment 6
Chlorogenic acid 1g, rutaecarpin 20g are weighed, supplementary product starch 20g granulations, magnesium stearate 2g, dextrin 10g, crystallite is added
Cellulose 10g, is uniformly made particle, and tabletting obtains tablet.
Embodiment 7
Chlorogenic acid 20g, rutaecarpin 5g are weighed, supplementary product starch 30g granulations, magnesium stearate 2g, dextrin 15g, crystallite is added
Cellulose 15g, is uniformly made particle, and tabletting obtains tablet.
Embodiment 8
It weighs chlorogenic acid 10g, rutaecarpin 50g, is added supplementary product starch 100g granulations, magnesium stearate 5g is dextrin 100g, micro-
Crystalline cellulose 100g, is uniformly made particle, and tabletting obtains tablet.
Embodiment 9
It weighs chlorogenic acid 30g, rutaecarpin 50g, is added supplementary product starch 120g granulations, magnesium stearate 5g is dextrin 110g, micro-
Crystalline cellulose 110g, is uniformly made particle, and tabletting obtains tablet.
Embodiment 10
It weighs chlorogenic acid 50g, rutaecarpin 70g, is added supplementary product starch 150g granulations, magnesium stearate 5g is dextrin 150g, micro-
Crystalline cellulose 150g, is uniformly made particle, and tabletting obtains tablet.
Embodiment 11
Chlorogenic acid 70g, rutaecarpin 100g are weighed, supplementary product starch 200g is added and pelletizes, magnesium stearate 6g, dextrin 200g,
Microcrystalline cellulose 200g, is uniformly made particle, and tabletting obtains tablet.
Embodiment 12
Chlorogenic acid 100g, rutaecarpin 100g are weighed, supplementary product starch 350g granulations, magnesium stearate 10g, dextrin is added
300g, microcrystalline cellulose 300g, are uniformly made particle, and tabletting obtains tablet.
Embodiment 13
Chlorogenic acid 100g, rutaecarpin 150g are weighed, supplementary product starch 400g granulations, magnesium stearate 10g, dextrin is added
350g, microcrystalline cellulose 300g, are uniformly made particle, and tabletting obtains tablet.
Embodiment 14
Chlorogenic acid 150g, rutaecarpin 200g are weighed, supplementary product starch 450g granulations, magnesium stearate 12g, dextrin is added
380g, microcrystalline cellulose 350g, are uniformly made particle, and tabletting obtains tablet.
Embodiment 15
Chlorogenic acid 180g, rutaecarpin 250g are weighed, supplementary product starch 600g granulations, magnesium stearate 15g, dextrin is added
500g, microcrystalline cellulose 500g, are uniformly made particle, and tabletting obtains tablet.
Embodiment 16
Chlorogenic acid 200g, rutaecarpin 300g are weighed, supplementary product starch 800g granulations, magnesium stearate 20g, dextrin is added
Particle is uniformly made in 600g, microcrystalline cellulose 600g, is packed into capsule, obtains capsule.
Embodiment 17
It weighs chlorogenic acid 10g, rutaecarpin 50g, is added supplementary product starch 100g granulations, magnesium stearate 5g is dextrin 100g, micro-
Particle is uniformly made in crystalline cellulose 100g, is packed into capsule, obtains capsule.
Embodiment 18
Chlorogenic acid 30g, rutaecarpin 50g are weighed, supplementary product starch is added according to common process, is prepared into pill.
Embodiment 19
Chlorogenic acid 50g, rutaecarpin 70g are weighed, supplementary product starch is added according to common process, is prepared into pill.
Embodiment 20
Chlorogenic acid 70g, rutaecarpin 100g are weighed, supplementary product starch is added according to common process, is prepared into injection.
Embodiment 21
Chlorogenic acid 100g, rutaecarpin 100g are weighed, supplementary product starch is added according to common process, is prepared into injection.
Embodiment 22
Chlorogenic acid 100g, rutaecarpin 150g are weighed, supplementary product starch is added according to common process, is prepared into granule.
Embodiment 23
Chlorogenic acid 150g, rutaecarpin 200g are weighed, supplementary product starch is added according to common process, is prepared into granule.
Embodiment 24
Chlorogenic acid 180g, rutaecarpin 250g are weighed, supplementary product starch is added according to common process, is prepared into effervescent agent.
Embodiment 25
Chlorogenic acid 200g, rutaecarpin 300g are weighed, supplementary product starch is added according to common process, is prepared into effervescent agent.
Beneficial effects of the present invention are verified below by specific pharmacy test：Pharmaceutical formulation of the present invention by chlorogenic acid and
Rutaecarpin compatibility forms, and represents chlorogenic acid with P-15 during the experiment, rutaecarpin is represented with EI.
The nootropic effect research that test example 1, P-15 are combined with EI
1. material
1.1 drug
Aricept：Donepezil hydrochloride tablet (Aircept, 10mg/ piece), Pharmaceutical Co., Ltd. of health material；
P15 (chlorogenic acid) compounds are provided by Chinese medicine encephalopathy drug integration transformation research institute of Chengdu University of Traditional Chinese Medicine, are derived from
Dredging collateral restoring consciouness effervescent tablet simple and other Chinese medical extracts, compound are configured to the deposit of a concentration of 10mM with anhydrous DMSO
Liquid.
EI (rutaecarpin) is provided by Chengdu Rett grace Science and Technology Ltd., lot number：RL20140828.
1.2 animal
SPF grades of male Kunming strain mices, weight (20 ± 2) g are provided up to large bio tech ltd by Chengdu, are moved
Object production licence number：SCXK (river) 2015-030.
1.3 main agents and instrument
Scopolamine hydrobromide injection (0.3mg/ml)；Xuzhou Lai En pharmaceutcal corporation, Ltds；Acetylcholinesterase
(AchE) testing cassete, acetylcholine transferase (ChAT) testing cassete, Coomassie brilliant blue albumen test box are purchased from Nanjing and build up life
Object Graduate School of Engineering.Water maze video analytic system (Chengdu TME Technology Co., Ltd.)；All-wave length readout instrument (U.S. Thermo
Company)；Refrigerated centrifuge (Thermo Fisher companies of the U.S.)；Precision electronic balance (German Sartorius companies)；Whirlpool
Vortex mixer (medical apparatus and instruments factory of Jintan City).
2. method
2.1 groupings, modeling and administration
100 Kunming mouses are randomly divided into 10 groups by weight, every group 10, respectively blank group, model group, peace
Manage Shen group, P15 (chlorogenic acid) group, EI (rutaecarpin) group, experiment A (P15：EI=1:1) group, experiment B (P15：EI=5:1)
Group, experiment C (P10：EI=10:1) group, experiment D (P15：EI=1:5) group, experiment E (P15：EI=1:10) group.Aricept group
Dosage presses 1.4mg/kg/d, and P15 (chlorogenic acid) organizes dosage and presses 2mg/kg/d, and EI (rutaecarpin) organizes dosage and presses 2mg/
Kg/d, experiment A, B, C, D, E group administration total amount are pressed 2mg/kg/d and are administered.After successive administration 10 days, except naive mice is given
It injects outside isodose physiological saline, remaining each group mouse gives intraperitoneal injection hyoscine (3mg/kg) and prepares Memory acquisition
Sexual dysfunction model.Start Behavior test after modeling 30min, continues gastric infusion during Behavior test.
2.2Morris water maze test
Experiment is carried out continuously 5 days, and first 3 days are training period, are tested for orientation navigation within the 4th day, are tried for space exploration within the 5th day
It tests.Program and placement platform are set, swimming track is tracked by camera, the time required to record mouse finds and climbs up platform,
That is escape latency.As do not found platform, incubation period is recorded as 90s, and mouse is guided to appear on the stage rest 15s.Remove station within 5th day
Platform sets space search mode, records number, the effective district for entering effective district (2 times of ranges of platform diameter) in animal 90s respectively
It swims in interior residence time, effective district distance.
2.3AchE and ChAT determinations of activity
Animal is put to death after Behavior test, plucks full brain and bloodstain is cleaned with ice-cold normal saline, divide at low ambient temperatures
It from cerebral cortex, hippocampal tissue, is fully ground in homogenate tube, 10% brain tissue homogenate is made, centrifuging and taking supernatant preserves
It is spare in -20 DEG C of refrigerators.10% brain tissue homogenate to be measured is taken, matches reagent by kit requirement, colorimetric determination AchE activity,
ChAT activity.
3. result
3.1 cause the ethological influence of Memory acquisition sexual dysfunction model mice water maze to hyoscine
1. orientation navigation
Table 1 to hyoscine cause Memory acquisition sexual dysfunction mouse escape latency influence (N=10)
Note：The * * P ＜ 0.01 compared with blank group；Compared with model group#P ＜ 0.05,##P ＜ 0.01.
As it can be seen from table 1 in preceding 3 day training period, the average escape latency of each group mouse is in be gradually reduced trend,
Show that the ability of each group mouse study searching platform is improved in all previous learning training.4th day, model group mouse was flat
Equal escape latency is obviously prolonged (P ＜ 0.01) compared with blank group；Each treatment group's average escape latency shortens (P ＜ compared with model group
0.01, P ＜ 0.05), the average escape latency for testing A-E groups is low compared with chlorogenic acid group, rutaecarpin group, illustrates the group of the present invention
Closing object has the function of synergy, wherein the average escape latency of experiment D groups and E groups is most short, with Doneppezil Hydrochloride group
Quite.
2. space search
Table 2 to hyoscine cause Memory acquisition sexual dysfunction mouse space search influence (N=10)
Note：The * * P ＜ 0.01 compared with blank group；Compared with model group##P ＜ 0.01.
From table 2 it can be seen that after removing platform, model group mouse surrounds pool wall more and swims, in the labyrinth outer shroud residence time
Longer, less to swim near original platform, movement locus is randomly distributed in each quadrant, the effective district residence time, effectively
Area's swimming distance, with the obvious reduction (P ＜ 0.01) of blank group.Each treatment group's effective district residence time, effective district swimming road
Journey extends (P ＜ 0.05) compared with model group, tests the effective district residence time of A-E groups, effective district swims distance compared with chlorogenic acid
Group, rutaecarpin group leader illustrate that the composition of the present invention has the function of synergy, wherein the extension of experiment D groups and E groups
Effect is best.
3.2AchE and ChAT Activity Results
Table 3 on hyoscine cause Memory acquisition sexual dysfunction Mice brain tissues AchE, ChAT it is active influence (N=6)
Note：The * * P ＜ 0.01 compared with blank group；Compared with model group#P ＜ 0.05,##P ＜ 0.01.
From table 3 it can be seen that compared with blank group, AchE activity significantly increases (P ＜ in model group Mice brain tissues
0.01), ChAT activity is decreased significantly (P ＜ 0.01).Each treatment group Ach E activity is substantially reduced, and ChAT activity is significantly raised
(P ＜ 0.01, P ＜ 0.05).The AchE activity for testing A-E groups is low compared with chlorogenic acid group, rutaecarpin group, and ChAT activity is compared with chlorogenic acid
Group, rutaecarpin group are high, illustrate that the composition of the present invention has the function of synergy, wherein the effect of experiment D groups and E groups
It is best.
To sum up, under conditions of identical dosage, when P15 (chlorogenic acid) groups and EI (rutaecarpin) is used alone, tool
There is nootropic effect, can will clearly enhance nootropic effect after P15 (chlorogenic acid) groups and EI (rutaecarpin) compatible use, experiment shows
P15 (chlorogenic acid) is organized and EI (rutaecarpin) compatibility has the function of synergy.
Claims (10)
1. a kind of pharmaceutical composition for preventing and/or treating neurodegenerative disease, it is characterised in that：It is by following heavy
The group of amount proportioning is grouped as：1~10 part of chlorogenic acid, 1~10 part of rutaecarpin.
2. pharmaceutical composition according to claim 1, it is characterised in that：It is that the group matched by following weight is grouped as：
1 part of chlorogenic acid, 1~10 part of rutaecarpin.
3. pharmaceutical composition according to claim 2, it is characterised in that：It is that the group matched by following weight is grouped as：
1 part of chlorogenic acid, 5~10 parts by weight of rutaecarpin.
4. pharmaceutical composition according to claim 3, it is characterised in that：It is that the group matched by following weight is grouped as：
1 part of chlorogenic acid, 5 parts of rutaecarpin.
5. a kind of drug for preventing and/or treating neurodegenerative disease, it is characterised in that：It is with Claims 1 to 4
Any one of them pharmaceutical composition is active constituent, the preparation being prepared along with pharmaceutically acceptable auxiliary material.
6. drug according to claim 5, it is characterised in that：The preparation is oral preparation or ejection preparation；Preferably,
The oral preparation is pill, tablet, capsule, pulvis, granule, syrup, oral solution, effervescent agent；The ejection preparation is
Freeze-dried powder or injection.
7. a kind of method preparing the drug of claim 5 or 6, it is characterised in that：Chlorogenic acid and Wu are weighed by weight ratio
Pharmaceutically acceptable auxiliary material is added with after and is prepared into preparation for fruit of medicinal cornel alkali, mixing.
8. Claims 1 to 4 any one of them pharmaceutical composition is preparing the medicine for preventing and/or treating neurodegenerative disease
Purposes in object；The neurodegenerative disease is memory dysfunction disease, vascular dementia or senile dementia.
9. drug described in claim 5 or 6 is preparing the purposes in preventing and/or treating the drug of neurodegenerative disease.
10. purposes according to claim 9, it is characterised in that：The neurodegenerative disease be memory dysfunction disease,
Vascular dementia or senile dementia.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101829117A (en) * | 2010-05-05 | 2010-09-15 | 中国医学科学院实验动物研究所 | Application of evodiamine in preparation of medicaments for treating alzheimer disease |
-
2018
- 2018-07-27 CN CN201810846203.0A patent/CN108578411A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101829117A (en) * | 2010-05-05 | 2010-09-15 | 中国医学科学院实验动物研究所 | Application of evodiamine in preparation of medicaments for treating alzheimer disease |
Non-Patent Citations (2)
| Title |
|---|
| GANIYU OBOH等: "Comparative Study on the Inhibitory Effect of Caffeic and Chlorogenic Acids on Key Enzymes Linked to Alzheimer’s Disease and Some Pro-oxidant Induced Oxidative Stress in Rats’ Brain-In Vitro", 《NEUROCHEM RES.》 * |
| PARUL AGARWAL等: "HERBAL REMEDIES FOR NEURODEGENERATIVE DISORDER (ALZHEIMER"S DISEASE): A REVIEW", 《INTERNATIONAL JOURNAL OF PHARMACEUTICAL SCIENCES AND RESEARCH》 * |
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Application publication date: 20180928 |