CN110433168A - Secoiridoid derivative prevents and treats the application in neurodegenerative disease drug and its pharmaceutical composition of composition in preparation - Google Patents
Secoiridoid derivative prevents and treats the application in neurodegenerative disease drug and its pharmaceutical composition of composition in preparation Download PDFInfo
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Abstract
The application of new application more particularly to secoiridoid derivative in preparation prevention and treatment neurodegenerative disease drug that the present invention relates to secoiridoid derivatives in pharmaceutical field.Such product is in treatment neurodegenerative disease; neural cell activity can be dramatically increased; play apparent neuroprotection; loganin, the morroniside protective effect of the SH-SY5Y cell model of Hydroperoxide injury being better than under equivalent molar concentration; it can significantly improve the learning memory disorder of aging individuals, hence it is evident that improve total antioxidant capacity in brain tissue.
Description
Technical field
The present invention relates to the purposes of secoiridoid derivative, are preparing more particularly, to secoiridoid derivative
Prevent and treat the application in neurodegenerative disease drug.
Background technique
Alzheimer's disease (Alzheimer's disease, AD) is a kind of serious chronic neurodegenerative disease, main
The senescence phase is betided, the main pathological change of patient's intracerebral is that Basal forebrain, hippocampus and cerebral cortex there are amyloid plaques
(senile plaques, SP) deposition, neurofibrillary tangles (neurofibrilla tangles, NFT), neuron and nerve
Cynapse loss and cholinergic function decline.
Treatment neurodegenerative disease drug mainly has antioxidant, anti-inflammatory agent, anti-apoptotic agent.Wherein for A Er
The therapeutic agent of Ci Haimo disease is mostly anticholinesterase, such as Tacrine, donepezil, Rivastigmine.
Traditional Chinese medicine has long-term clinic in terms of the neurodegenerative diseases such as prevention, alleviation or treatment Alzheimer's disease
Applicating history, these Chinese Herbs are definite, and adverse reaction is small, have become the hot spot of people's research.The study found that people
The Chinese medicines such as ginseng, ginkgo leaf, Morinda officinalis, shiny-leaved yellowhorn and its extract have the nerves such as apparent alleviation or treatment Alzheimer's disease
The effect of degenerative disease.Therefore, the nerves such as prevention, alleviation or treatment Alzheimer's disease are found and developed from Chinese medicine to move back
The new drug of row disease has great importance.
The new glycosides of secoiridiod compound such as Fructus Corni (Cornuside) is a monoterpenoid compounds.Studies have shown that
The new glycosides of Fructus Corni has hypoglycemic (J Agr Food Chem.2011,59 (14), 7743-7751), anti-oxidant, anti-inflammatory (Biol
Pharm Bull.2011,34 (7), 959-966), cardiovascular protection (Biol Pharm Bull.2007,30 (9), 1796-
1799) and other effects, it can be used to improve cardiovascular disease, help to inhibit metabolic disease (such as hyperglycemia, hyperlipidemia), oxidation is answered
Swash the formation (Drug Discov Ther.2010,4 (4): 223-234) with inflammation.
Related secoiridiod compound, Chinese patent application CN105017353A, CN105017353A are public at present
Preparation method is opened, Chinese patent application CN101704857A discloses separation purifying technique, Chinese patent application
CN106680399A, CN104991002A, CN105486775A, CN104147079A disclose content assaying method, are showed no
In neurodegenerative diseases sides such as anti-Alzheimer disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis
Any report in face.
Summary of the invention
The purpose of the present invention is to provide a kind of new applications of secoiridoid derivative, i.e., newly answering in pharmacy
With.
In fact, the present invention relates to secoiridoid derivatives in the medicine for preventing or treating neurodegenerative disease
Using.
Above-mentioned neurodegenerative disease include Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and
Multiple sclerosis class disease.
Inventor has studied secoiridoid derivative to peroxidating by taking the new glycosides of Fructus Corni, morroniside, loganin as an example
The comparative experiments that the SH-SY5Y nerve cell of hydrogen damage influences.On this basis, the new glycosides of Fructus Corni and Monot have further been investigated
The comparative experiments of glycosides, loganin and Fructus Corni total glycosides to D- galactolipin Aging mice ability of learning and memory.Control experiment result
It was found that the new glycosides of Fructus Corni substantially exceeds morroniside, loganin or Fructus Corni total glycosides to neurodegenerative disease protective effect, it can be straight
It connects as bulk pharmaceutical chemicals and is further processed into prevention and treatment Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis
The drug of the neurodegenerative diseases such as disease, multiple sclerosis.
In the present invention, the secoiridoid derivative preferably has the medicine of following chemical general formula or the compound I
Acceptable salt on object:
Wherein, R1And R2It is separately selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted naphthenic base, takes
Generation or unsubstituted alkylene, substituted or unsubstituted cyclic hydrocarbon radical, substituted or unsubstituted aryl radical.
In some embodiments, R1 be selected from H, Wherein, X is halogen (such as F, Cl, Br, I), the integer between n=1~10.
In some embodiments, R2Selected from H, methyl or CH3CH2CH=C (CH3)CH2-。
In the present invention,Refer to the end that substituent group is connect with mother nucleus structure.
In some embodiments, the present invention involved in secoiridoid derivative include following compound (but
It is not limited to following compounds):
Number is that C1 is the new glycosides of Fructus Corni, and number is that C2-C6 is the new glycoside derivates of Fructus Corni.
We have found compound C1-C6 by a series of cell experiments, Animal Behavior Science experiment and enzyme assay etc.
The neural cell injury activity of significant anti-oxidation stress induction is shown, wherein the new glycosides activity of Fructus Corni is best.
The present invention also provides the pharmaceutical compositions comprising the above secoiridoid derivative.
In some embodiments, the secoiridoid derivative is following chemical general formula or the compound I
Pharmaceutically acceptable salt:
Wherein, R1 and R2 is separately selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted naphthenic base, takes
Generation or unsubstituted alkylene, substituted or unsubstituted cyclic hydrocarbon radical, substituted or unsubstituted aryl radical；
Preferably, R1Selected from H, Wherein, X is halogen, the integer between n=1~10；
Preferably, R2Selected from H, methyl or CH3CH3CH=C (CH3)CH2-。
Preferably, n=1,2,3,4,5,6,7,8,9 or 10.
Pharmaceutically acceptable salt of the present invention be mainly compound I inorganic base salts or organic alkali salt, such as nothing
Machine ammonium salt or organic amine salt.
In some embodiments, described pharmaceutical composition further includes at least one pharmaceutically acceptable carrier.
The type and additive amount of pharmaceutically acceptable carrier, can be comprehensive mainly depending on the dosage form of pharmaceutical composition
It closes depending on considering the factors such as cost, administration route, bioavilability.
Preferably, the dosage form of described pharmaceutical composition is tablet, capsule, granule, oral solution, electuary, dripping pill or micro-
Ball.
In some embodiments, the carrier includes in hydroxypropyl methyl cellulose, water-soluble filler and lubricant
At least one；
Preferably, the water-soluble filler includes one of lactose, sucrose and mannitol or a variety of；
The lubricant is one of magnesium stearate, micro mist, silica gel and talcum powder or a variety of.
The content of hydroxypropyl methyl cellulose is 65.5-82.6wt% in the pharmaceutical composition.
Preferably, the weight ratio of the secoiridoid derivative and hydroxypropyl methyl cellulose is 1:2-1:5, packet
Include but be not limited to 1:2,1:3,1:4,1:5 etc..
Preferably, the content of secoiridoid derivative is 16.5-32.8wt% in the pharmaceutical composition；It is excellent
Selection of land, the content of lubricant is 0.6-1.3wt% in the pharmaceutical composition.
Especially when tablet is made in pharmaceutical composition of the invention, it can achieve preferably using above-mentioned carrier and proportion
Drug effect.
With the purposes of secoiridoid derivative, pharmaceutical composition of the invention is mainly used for preventing or treatment nerve moves back
Row disease.
To better understand the essence of the present invention, will illustrate it with the pharmacological testing of the new glycosides of Fructus Corni and result below
The new opplication in neurodegenerative disease drug is prevented and treated in preparation.
Test example 1:
Protective effect of the new glycosides of Fructus Corni (Cornuside) to oxidative stress induction SH-SY5Y neural cell injury
By human neuroblastoma (SH-SY5Y) cell with complete DMEM/F12 culture medium (contain 10% fetal calf serum,
100U/mL penicillin, 100 μ g/mL streptomysins, 1% glutamine), in 37 DEG C, 5%CO2It is cultivated under the conditions of saturated humidity.Often
2-3d changes a not good liquor.Logarithmic growth phase cell adds 0.25% trypsin digestion, extremely with complete medium diluting cells concentration
It 105/mL, is seeded in 96 porocyte culture plates, every 100 μ L of hole, after culture 24 hours, the new glycosides of Fructus Corni (0.3,1,3 μM)
With 10 μM of pretreatment cell 2h of positive drug vitamin E (VE), (280 μm) processing SH-SY5Y cell 12h of hydrogen peroxide, at cell
Cell viability is detected using CCK8 method after reason, utilizes the metrics evaluations drug effect such as LDH, NO.
Experimental result is not as shown in Figure 1, the new glycosides of Fructus Corni finds to make the toxicity of SH-SY5Y cell at (0.03-30) μM
With.
Experimental result is as shown in Fig. 2, in the measurement cell survival rate experiment of CCK8 method, and compared with normal group, model group is thin
Born of the same parents' survival rate significantly reduces (P < 0.01)；Compared with model group, the new glycosides administration group cell survival rate of Fructus Corni is significantly increased, performance
Apparent neuroprotection out, reaches maximum antibody Monoclonal effect (P < 0.01) at 1 μM, and protective rate is close to 80%.
Experimental result is as shown in figure 3, in LDH measurement experiment, and compared with normal group, model group LDH leakage is obviously risen
High (P < 0.01)；Compared with model group, the new glycosides administration group LDH leakage of Fructus Corni is significantly reduced, reach at 1 μm it is minimum (P <
0.01)。
Experimental result is as shown in figure 4, in the experiment of NO assay, and compared with normal group, model group NO content is obviously risen
High (P < 0.01)；Compared with model group, the new glycosides administration group NO content of Fructus Corni significantly reduces (P < 0.01).
It is above-mentioned the results showed that the new glycosides of Fructus Corni can increase neural cell activity, play apparent neuroprotection and make
With.
Test example 2:
The new glycosides of Fructus Corni and the comparative experiments of morroniside, loganin to Hydroperoxide injury SH-SY5Y cytoprotection
Experimental result is as shown in figure 5, the new glycosides of Fructus Corni and morroniside can produce Hydroperoxide injury SH-SY5Y cell
Raw protective effect, wherein the new glycosides of Fructus Corni is in 0.3 μM, the protective effect of 1 μM of SH-SY5Y cell model to Hydroperoxide injury
The morroniside being better than under equivalent molar concentration.
Experimental result is as shown in fig. 6, the new glycosides of Fructus Corni and loganin can produce Hydroperoxide injury SH-SY5Y cell
Raw protective effect, wherein the new glycosides of Fructus Corni is in 0.3 μM, the protective effect of 1 μM of SH-SY5Y cell model to Hydroperoxide injury
The loganin being better than under equivalent molar concentration.
Test example 3:
The new glycosides of Fructus Corni and morroniside, loganin and Fructus Corni total glycosides are to D- galactolipin Aging mice ability of learning and memory
The comparative experiments of protective effect.
The preparation of D- galactolipin Aging mice model:
D- galactolipin 100mgkg is subcutaneously injected in the nape of the neck-1, establish aging model within 8 weeks.
Grouping and administration:
Healthy 2 monthly age KM mouse are randomly divided into 6 groups, every group 12 (half male and half female), and respectively normal group, model group, that is, D-
Galactolipin causes aging group, the new glycosides group of Fructus Corni (95% or more purity, self-control), morroniside group, loganin group, Fructus Corni total glycosides
Group.
Same amount of normal saline is subcutaneously injected in the daily stomach-filling equivalent distilled water of normal group: KM mouse, the nape of the neck；
Model group: 100 mgkg of D- galactolipin is subcutaneously injected in the daily stomach-filling equivalent distilled water of KM mouse, the nape of the neck-1。
The new glycosides group of Fructus Corni: the daily new glycosides of gastric infusion Fructus Corni of KM mouse, dosage 30mgkg-1, the nape of the neck is subcutaneous
Injection of d-galactose 100mgkg-1。
Morroniside group: the daily gastric infusion morroniside of KM mouse, dosage 22mgkg-1(molecular weight is different, according to molecule
Amount is scaled equivalent molar concentration), 100 mgkg of D- galactolipin is subcutaneously injected in the nape of the neck-1。
Loganin group: the daily gastric infusion loganin of KM mouse, dosage 21mgkg-1(molecular weight is different, according to molecule
Amount is scaled equivalent molar concentration), 100 mgkg of D- galactolipin is subcutaneously injected in the nape of the neck-1。
(its source is: the fruit of Fructus Corni drying and ripening is through water heating and refluxing extraction, after reduced pressure for Fructus Corni total glycosides group
Upper D101 macroporous absorbent resin absorption, then successively 35% ethanol elution object is merged, is subtracted with 15% ethyl alcohol, 35% ethanol elution
Pressure is concentrated and dried to get Fructus Corni total glycosides, and chemical analysis shows that the part is mainly made of loganin and morroniside): KM mouse
Daily gastric infusion Fructus Corni total glycosides, dosage 50mgkg-1, the nape of the neck subcutaneous injection D- galactolipin 100mgkg-1。
As a result it and analyzes:
It is damaged after being administered 6 weeks by behavioral indexes (water maze, new object identification) come the memory for D- galactolipin model of testing and assessing
Hurt degree and drug to the improvement result of damage.Model group incubation period is longer, wears that platform number is fewer, and object identification ability is got over
Difference illustrates that the learning and memory function damage of animal is more serious.Administration group incubation period is shorter, and it is more to wear platform number, object identification energy
Power is stronger, and the improvement result of drug is stronger.
Table 1 is that the new glycosides of Fructus Corni and morroniside, loganin and Fructus Corni total glycosides position boat to D- galactolipin Aging mice
The comparison result of row capacity.
Table 1
Table 2 is that the new glycosides of Fructus Corni and morroniside, loganin and Fructus Corni total glycosides visit the galactolipin Aging mice space D-
The comparison result that Suo Nengli (incubation period) influences.
Table 2
Table 3 is that the new glycosides of Fructus Corni and morroniside, loganin and Fructus Corni total glycosides visit the galactolipin Aging mice space D-
The comparison result that Suo Nengli (wearing platform number) influences.
Table 3
Table 4 is the new glycosides of Fructus Corni and morroniside, loganin and Fructus Corni total glycosides to the new object of D- galactolipin Aging mice
The comparison result that index of discrimination influences in identification experiment.
Table 4
The experimental results showed that in orientation navigation experiment, with the increase of frequency of training and experiment number of days, each experimental mice
Incubation period shows as shortening trend, and the results are shown in Table 1.In space exploration experiment, compared with normally group mouse, model group
The space exploration ability of mouse declines, and the time for showing as first time spanning platform extends (P < 0.05), and the results are shown in Table 2.
The number of spanning platform substantially reduces (P < 0.05), and the results are shown in Table 3.Compared with model group, the new glycosides of Fructus Corni can obviously be mentioned
High ability of learning and memory in mice shows as spanning platform time first time reduction (P < 0.05), the increase of spanning platform number, has
Significant difference (P < 0.01).In new object identification experiment, compared with normally group mouse, under the index of discrimination of model group mouse
Drop, and there is significant difference (P < 0.01), compared with model group, the new glycosides of Fructus Corni can significantly improve the index of discrimination of mouse,
With significant difference (P < 0.01), the results are shown in Table 4.
It is above-mentioned the experiment results show that the mice age caused by D- galactolipin experiment in, stomach-filling gives Fructus Corni new glycosides
30mg·kg-1, the learning memory disorder of mouse, including Learning memory disorder and Episodic Memory impairment can be significantly improved.
Morroniside, loganin and Fructus Corni total glycosides, the new glycosides 30mgkg of Fructus Corni are given in the stomach-filling that compares-1Mouse can more be dramatically increased
Ability of learning and memory shows the pharmacological action of more excellent effect.
Test example 4:
Influence of the new glycosides of Fructus Corni to D- galactolipin Aging mice brain tissue oxidizing stress damage
(the 8th week) puts to death mouse immediately after Behaviors survey, separating mouse hippocampus and brain in pre- cold saline
Cortex albumen, -80 DEG C of refrigerators freeze.Cortex is weighed before measurement, 1:9 is added physiological saline and is made 10% homogenate, and 4 DEG C, 3500r
min-1It is centrifuged 10min, takes supernatant, -80 DEG C of refrigerator packing freeze, and are used for subsequent acetylcholinesterase (AChE), superoxides discrimination
Change the measurement of the oxidative stress index such as enzyme (SOD), glutathione peroxidase (GSH-Px), total antioxidant capacity (T-AOC).
For experimental result as shown in fig. 7, compared with normal group, model group total antioxidant capacity significantly reduces (P < 0.01).With
Model group is compared, and total antioxidant capacity is significantly raised in the new glycosides administration group Mice brain tissues of Fructus Corni.
Experimental results are shown in figure 8, and compared with normal group, model group glutathione peroxidase level significantly reduces (P
<0.01)；Compared with model group, the horizontal obvious liter of the corresponding brain tissue Glutathione Peroxidase of the new glycosides administration group of Fructus Corni
High (P < 0.01).
Experimental result as shown in figure 9, compared with normal group, model group acetylcholine ester enzyme level significantly increase (P <
0.01)；Compared with model group, in the corresponding brain tissue of the new glycosides administration group of Fructus Corni acetylcholine ester enzyme level significantly reduce (P <
0.05)。
A series of screening active ingredients experiment through anti-neural cell injuries, compound C1-C6 show significantly anti-oxidant answer
Swash the neural cell injury activity of induction, wherein the new glycosides activity of Fructus Corni is best.
The present invention is studies have shown that such secoiridoid derivative can significantly improve ability of learning and memory in mice, table
Now for spanning platform time first time is reduced in space exploration experiment, spanning platform number increases；In new object identification experiment,
Significantly improve the index of discrimination of mouse；Total antioxidant capacity is significantly raised in Mice brain tissues；Acetylcholine ester enzyme level is significant
It reduces；Moreover it is possible to effectively inhibit neuronal cell injury caused by hydrogen peroxide.To sum up, such secoiridoid is derivative
Object can be prepared into the neurologicals such as anti-Alzheimer disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis
The drug or health care product of property disease carry out using.
To sum up, compared with prior art, invention achieves following technical effects:
(1) present invention has excavated new medical application to secoiridoid derivative, has opened up a new application
Field；
(2) secoiridoid derivative of the invention is safe and non-toxic, and pharmacological action is strong, imply well it is medicinal before
Scape；
(3) products material source natural plants of the invention, it is inexpensive, have no toxic side effect, preparation process is simple, and can do
It is easy to use at peroral dosage form, injection type, tablet etc.；
(4) products configuration of the invention at drug can increase neural cell activity, play apparent neuroprotection and make
With；
(5) products configuration of the invention at protective effect of the drug to the SH-SY5Y cell model of Hydroperoxide injury
Loganin, the morroniside being better than under equivalent molar concentration；
(6) products configuration of the invention at drug can significantly improve the learning memory disorder of aging individuals, and be better than
Morroniside, loganin and Fructus Corni total glycosides, hence it is evident that improve total antioxidant capacity in brain tissue.
Detailed description of the invention
The accompanying drawings constituting a part of this application is used to provide further understanding of the present invention, and of the invention shows
Examples and descriptions thereof are used to explain the present invention for meaning property, does not constitute improper limitations of the present invention.Wherein:
Neurotoxic effect of the new glycosides of Fig. 1 Fructus Corni to SH-SY5Y cell；
Influence of the new glycosides of Fig. 2 Fructus Corni to the cell survival rate of Hydroperoxide injury SH-SY5Y cell；
Influence of the new glycosides of Fig. 3 Fructus Corni to the LDH burst size of Hydroperoxide injury SH-SY5Y cell；
Influence of the new glycosides of Fig. 4 Fructus Corni to the NO burst size of Hydroperoxide injury SH-SY5Y cell；
The comparative experiments that the new glycosides of Fig. 5 Fructus Corni and morroniside influence Hydroperoxide injury SH-SY5Y cell survival rate；
The comparative experiments that the new glycosides of Fig. 6 Fructus Corni and loganin influence Hydroperoxide injury SH-SY5Y cell survival rate；
Influence of the new glycosides of Fig. 7 Fructus Corni to D- galactolipin Aging mice intracerebral T-AOC level；
Influence of the new glycosides of Fig. 8 Fructus Corni to D- galactolipin Aging mice intracerebral GSH-Px level；
Influence of the new glycosides of Fig. 9 Fructus Corni to D- galactolipin Aging mice intracerebral AChE level.
Specific embodiment
Several embodiments of the present invention are described below, but the contents of the present invention are completely not limited to this.
Embodiment 1:
Using the new glycosides of Fructus Corni as the tablet of bulk pharmaceutical chemicals.
Include following component in every 1000:
Fructus Corni new glycosides 15g, hydroxypropyl methyl cellulose 30g, talcum powder 0.4g, lactose 0.2g, magnesium stearate 0.2g, nothing
Appropriate water-ethanol is made 1000.
When preparing above-mentioned tablet, the new glycosides of Fructus Corni and hydroxypropyl methyl cellulose, talcum powder, lactose, magnesium stearate are taken
It is uniformly mixed, adds dehydrated alcohol that softwood is made, cross 24 meshes, particle is made, it is dry, magnesium stearate is added, mixes, tabletting.
Embodiment 2 is in addition to hydroxypropyl methyl cellulose is 45 g, remaining is the same as embodiment 1.
Embodiment 3 is in addition to hydroxypropyl methyl cellulose is 75 g, remaining is the same as embodiment 1.
Embodiment 4
Using the new glycosides of Fructus Corni as the capsule of bulk pharmaceutical chemicals.
Fructus Corni new glycosides 15g, starch 10g, dextrin 4g, hydroxypropyl cellulose 3g, magnesium stearate 4g, appropriate dehydrated alcohol,
It is made 1500.
It takes the new glycosides of Fructus Corni to be uniformly mixed with starch, dextrin, hydroxypropyl cellulose, adds dehydrated alcohol that softwood is made, cross 24
Particle is made in mesh, dry, and magnesium stearate is added, and mixes, and is packed into capsule.
Embodiment 5
Using the new glycosides of Fructus Corni as the granule of bulk pharmaceutical chemicals.
Fructus Corni new glycosides 15g, sucrose 15g, starch 15g, talcum powder 3g, croscarmellose sodium 7g, magnesium stearate
7g, appropriate dehydrated alcohol are made 1500 bags.
It takes the new glycosides of Fructus Corni to be uniformly mixed with sucrose, starch, talcum powder, croscarmellose sodium, adds dehydrated alcohol
Softwood is made, crosses 24 meshes, particle is made, it is dry, magnesium stearate is added, mixes, pack.
Embodiment 6
Using the new glycosides of Fructus Corni as the oral solutions of bulk pharmaceutical chemicals.
Fructus Corni new glycosides 15g, warfarin 3g, sucrose 12g, sodium hydrogensulfite 3g, methyl p-hydroxybenzoate 3g, bicarbonate
Appropriate sodium, water for injection 15000ml are made 1500.
After said components mix, using oral solution customary preparation methods, packing.
Embodiment 7
Using the new glycosides of Fructus Corni as the pill of bulk pharmaceutical chemicals.
The new glycosides 15g of Fructus Corni, 100g Macrogol 6000, appropriate dehydrated alcohol are made 1500.
The new glycosides of Fructus Corni for weighing recipe quantity is added appropriate dehydrated alcohol and the poly- second two of recipe quantity is added after low-grade fever dissolution
Alcohol 6000 (60 DEG C water-baths heat preservation), is uniformly mixed, until ethyl alcohol is waved until using up, continues to be statically placed in 60 DEG C of water-baths and keeps the temperature
30min is transferred in surge drum after bubble eliminates, and under conditions of 70-80 DEG C, control drop speed instills dropwise condensate liquid
In, to be condensed incline condensate liquid completely, collects dripping pill.
Embodiment 8
Using compound C2 as the tablet of bulk pharmaceutical chemicals.
Include following component in every 1000:
Compound C2 15g, hydroxypropyl methyl cellulose 30g, talcum powder 0.4g, lactose 0.2g, magnesium stearate 0.2g, nothing
Appropriate water-ethanol is made 1000.
When preparing above-mentioned tablet, take compound C2 and hydroxypropyl methyl cellulose, talcum powder, lactose, magnesium stearate mixed
It closes uniformly, adds dehydrated alcohol that softwood is made, cross 24 meshes, particle is made, it is dry, magnesium stearate is added, mixes, tabletting.
Comparative example 1: in addition to replacing hydroxypropyl methyl cellulose using microcrystalline cellulose, remaining is the same as embodiment 1.
Comparative example 2: in addition to replacing hydroxypropyl methyl cellulose using crosslinked polyvinylpyrrolidone, remaining is the same as implementation
Example 1.
Comparative example 3: in addition to replacing hydroxypropyl methyl cellulose using croscarmellose sodium, remaining is the same as implementation
Example 1.
Comparative example 4: in addition to replacing hydroxypropyl methyl cellulose using sodium cellulose glycolate, remaining is the same as embodiment 1.
Comparative example 5: in addition to replacing hydroxypropyl methyl cellulose using PVP K30, remaining is the same as embodiment 1.
Comparative example 6: in addition to hydroxypropyl methyl cellulose is 25g, remaining is the same as embodiment 1.
Comparative example 7: in addition to hydroxypropyl methyl cellulose is 80g, remaining is the same as embodiment 1.
Comparative example 8: in addition to replacing hydroxypropyl methyl cellulose using microcrystalline cellulose, remaining is the same as embodiment 8.
Secoiridoid derivative Dissolution of Tablet measurement experiment research
It is situated between according to dissolution method (two the second methods of annex XC of China's coastal port) with 1000 ml of water for dissolution
Matter, revolving speed are 75 turns per minute, are operated according to methods, and when through 15,45 minutes, take out solution filtration, precision measures subsequent filtrate 2ml, sets
It is fixed molten with 0.1mol/L hydrochloric acid solution in 50ml volumetric flask, as test solution.Precision measures 32mg, sets 50ml volumetric flask
In, precision measures 2ml and sets in 50ml volumetric flask, and it is fixed molten with 0.1mol/L hydrochloric acid solution, as reference substance solution.Confession is taken respectively
Test product and reference substance solution measure absorbance according to UV-VIS spectrophotometry respectively at the wavelength of 345nm, calculate every
The amount of dissolution of a dosage, limit are the 70% of labelled amount, should meet regulation.
The dissolution determination result of 5 secoiridoid derivative tablet of table
Experimental result is as shown in table 5, and the present invention is existed using the secoiridoid derivative tablet of specific disintegrating agent preparation
45min drug dissolves out completely substantially, and the dissolution rate of 15min is also 95% or more, wherein when hydroxypropyl methyl cellulose is 30g
When, i.e., the embodiment 1 and 8 effect of embodiment when it with the ratio of the new glycosides of Fructus Corni or compound C2 is 2:1 are best；Work as hydroxypropyl
The amount ranges of methylcellulose outside the scope of the present invention when, as shown in comparative example 6-7, effect far below the present invention
Embodiment；When disintegrating agent uses this field others disintegrating agent, when the disintegrating agent as shown in comparative example 1-5, with driffractive ring
The poor compatibility of iridoid derivative, dissolution rate are poor.
Secoiridoid derivative difference preparation, which tests the new object identification of mouse, influences research
According to 3 method of test example.KM mouse is randomly divided into 18 groups, respectively blank group, model group, real in preparation embodiment
Apply a 1-8, comparative example 1-8, every group 10.Test medicine is dissolved in distilled water before experiment by 10ml/kg weight, is filled
(30mg/kg) is administered in stomach.Mouse is administered 30min and carries out new object identification experiment.It tests in peace and quiet, 25 DEG C of rooms of room temperature, in
9:00 is carried out between 17:00.
The influence that 6 secoiridoid derivative difference preparation of table tests the new object identification of mouse
Experimental result is as shown in table 6, in new object recognition test, stomach-filling give secoiridoid derivative tablet,
When capsule, granule, oral solution and dripping pill, it can increase the new object index of discrimination (P < 0.05) of mouse.In particular, using special
When determining the secoiridoid derivative tablet of disintegrating agent preparation, when the ratio of hydroxypropyl methyl cellulose and the new glycosides of Fructus Corni is
Effect is best when 2:1, i.e. embodiment 1 (P < 0.01), better than hydroxypropyl methyl cellulose amount ranges the scope of the invention it
(such as comparative example 6-7) outside, the capsule better than prepared using secoiridoid derivative as bulk pharmaceutical chemicals, take orally granule
Liquid and dripping pill (embodiment 4-7).
The above is only a preferred embodiment of the present invention, is not intended to restrict the invention, and comes for those skilled in the art
It says, the invention may be variously modified and varied.All within the spirits and principles of the present invention, made any modification, equivalent
Replacement, improvement etc., should all be included in the protection scope of the present invention.
Claims (10)
1. application of the secoiridoid derivative in the drug of preparation prevention or treatment neurodegenerative disease.
2. application according to claim 1, the neurodegenerative disease includes Alzheimer's disease, Parkinson's disease, flesh
Meat atrophic lateral schlerosis and multiple sclerosis class disease.
3. application according to claim 1, the secoiridoid derivative has following chemical general formula or describedization
Close the pharmaceutically acceptable salt of object I:
Wherein, R1And R2Separately selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted naphthenic base, substitution or
Unsubstituted alkylene, substituted or unsubstituted cyclic hydrocarbon radical, substituted or unsubstituted aryl radical.
4. application according to claim 3, the secoiridoid derivative is the new glycosides of Fructus Corni or the new glycosides of Fructus Corni
Derivative；
Preferably, R1Selected from H, Wherein, X is halogen, the integer between n=1~10；
Preferably, R2Selected from H, methyl or CH3CH3CH=C (CH3)CH2-。
5. a kind of pharmaceutical composition, which is characterized in that including secoiridoid derivative；
Preferably, the secoiridoid derivative is the pharmaceutically acceptable of following chemical general formula or the compound I
Salt:
Wherein, R1 and R2 be separately selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted naphthenic base, substitution or
Unsubstituted alkylene, substituted or unsubstituted cyclic hydrocarbon radical, substituted or unsubstituted aryl radical；
Preferably, R1Selected from H, Wherein, X is halogen, the integer between n=1~10；
Preferably, R2Selected from H, methyl or CH3CH3CH=C (CH3)CH2-。
6. pharmaceutical composition according to claim 5, which is characterized in that the pharmaceutically acceptable salt is compound I
Inorganic base salts or organic alkali salt.
7. pharmaceutical composition according to claim 5, which is characterized in that described pharmaceutical composition further includes at least one medicine
Acceptable carrier on.
8. pharmaceutical composition according to claim 5, which is characterized in that the dosage form of described pharmaceutical composition is tablet, glue
Wafer, granule, oral solution, electuary, dripping pill or pellet.
9. pharmaceutical composition according to claim 7, the carrier includes hydroxypropyl methyl cellulose, water-soluble filler
At least one of with lubricant；
Preferably, the water-soluble filler includes one of lactose, sucrose and mannitol or a variety of；
The lubricant is one of magnesium stearate, micro mist, silica gel and talcum powder or a variety of.
10. pharmaceutical composition according to claim 8, which is characterized in that hydroxypropyl methyl in the pharmaceutical composition
The content of cellulose is 65.5-82.6wt%；
Preferably, the weight ratio of the secoiridoid derivative and hydroxypropyl methyl cellulose is 1:2-1:5；
Preferably, the content of secoiridoid derivative is 16.5-32.8wt% in the pharmaceutical composition；
Preferably, the content of lubricant is 0.6-1.3wt% in the pharmaceutical composition.
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| CN201910834734.2A CN110433168B (en) | 2019-09-05 | 2019-09-05 | Application of cornuside in preparation of medicine for treating Alzheimer's disease |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117942347A (en) * | 2024-03-26 | 2024-04-30 | 北京大学第一医院(北京大学第一临床医学院) | Application of cornus officinalis neoside in skin ultraviolet protection, ultraviolet injury resistance and aging resistance |
Citations (2)
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|---|---|---|---|---|
| CN1565469A (en) * | 2003-07-03 | 2005-01-19 | 和记黄埔医药企业有限公司 | Cornel extract oral medicine compositions low irritative to gastrointestinal tract and its preparation |
| CN104784195A (en) * | 2015-03-24 | 2015-07-22 | 陕西师范大学 | Antidiabetic application of dogwood iridoid glycoside |
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2019
- 2019-09-05 CN CN201910834734.2A patent/CN110433168B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1565469A (en) * | 2003-07-03 | 2005-01-19 | 和记黄埔医药企业有限公司 | Cornel extract oral medicine compositions low irritative to gastrointestinal tract and its preparation |
| CN104784195A (en) * | 2015-03-24 | 2015-07-22 | 陕西师范大学 | Antidiabetic application of dogwood iridoid glycoside |
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| HIMANSHU KUMAR BHAKTA等: "Potential anti-cholinesterase and b-site amyloid precursor protein cleaving enzyme 1 inhibitory activities of cornuside and gallotannins from Cornus officinalis fruits", 《ARCH. PHARM.RES》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117942347A (en) * | 2024-03-26 | 2024-04-30 | 北京大学第一医院(北京大学第一临床医学院) | Application of cornus officinalis neoside in skin ultraviolet protection, ultraviolet injury resistance and aging resistance |
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