CN109078002A - Cyclovimbuxine D solid dispersions preparation method and its new medical use - Google Patents
Cyclovimbuxine D solid dispersions preparation method and its new medical use Download PDFInfo
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Abstract
The invention discloses the solid dispersions from the cyclovimbuxine D preparation extracted in little leaf boxwood Buxus micr ophylla Sieb.et Zucc.var.sinica Rehd.et Wils. and congener and the applications in prevention and treatment senile dementia, it is proved through zymetology and zoopery, cyclovimbuxine D solid dispersions have the function of preventing and treating senile dementia well.Further studies have shown that cyclovimbuxine D solid dispersions activity increases significantly compared with the activity tool of cyclovimbuxine D.The present invention relates to chemical pharmacy, pharmaceutical preparation, pharmacokinetics and pharmacodynamics fields.Cyclovimbuxine D solid dispersions of the invention not only have the advantages that preparation method is simple and easy to operate, but also substantially increase the solubility and intestinal mucosa transmitance of cyclovimbuxine D, to improve bioavilability.
Description
Technical field
The present invention relates to chemical pharmacy, pharmaceutical preparation, pharmacokinetics and pharmacodynamics fields, and in particular to Yi Zhonghuan
Virobuxine D solid dispersions and its application in treatment senile dementia.
Background technique
Senile dementia is a kind of nervous centralis degenerative disease.There is progressive memory impairment during being mainly manifested in person in middle and old age
And mental loss, the symptoms such as memory disorders, abstract thinking obstacle, language competence be not normal, behavior and direction obstacle.Its machine of falling ill
Reason is not fully aware of, is a kind of extremely complex nerve and cellular senescence process.Gu the prevention and treatment mesh of this senile dementia
Before be still a world-famous puzzle.Anti- β-can be divided into substantially using pathological characters as point of penetration to senile dementia prevention at present
Amyloid beta deposition drug, quinoline drug promote acetic acid choline and discharge drug, Porcine HGF promotor, and brain function changes
Kind drug etc..Listed or be going into clinical research drug have acetylcarnitine, tacrine, tie up that crin, silymarin,
Eserine, huperzine and timosaponin etc. (Chinese herbal medicine 8 phases attached 4-5 of volume 32 in 2001).The drug toxic side effect listed
It is all larger.So research and development toxic side effect is small, safely and effectively anti senile dementia drug is of great significance.
Little leaf boxwood Buxus micr ophylla Sieb.et Zucc.var.sinica Rehd.et Wils. system is yellow
Yang Ke Chinese littleleaf box platymiscium originates in each provinces and regions on the south the Qinling Mountains.Chinese littleleaf box platymiscium is in 17 kinds of China's production and several subspecies and mutation, richness
Containing alkaloid, referred to as buxus alkaloids (Buxus Alkaloids), belong to derivatives of pregnane.Its main component is that ring dimension is yellow
Yang Xing D, early period research shows that cyclovimbuxine D have the function of treat and prevent senile dementia.
The structural formula of cyclovimbuxine D (cyclovirobuxine D)
Although cyclovimbuxine D has the function for the treatment of and preventing senile dementia, it is not at present yet as a kind of anti-
The medicinal application of senile dementia is controlled in clinic, mainly since cyclovimbuxine D oral absorption is poor, bioavilability is low.It grinds
Study carefully and show cyclovimbuxine D oral administration biaavailability only < 5%, therefore drug effective blood drug concentration is not easy to maintain.Limit ring
The clinical application of virobuxine D.The main reason for causing cyclovimbuxine D intestinal absorption poor be intestinal mucosa transmitance it is low and dissolution
It is poor to spend.
In order to improve cyclovimbuxine D bioavilability, document report uses following methods: cyclovimbuxine D at salt, with
Amino acid is at ester, PEG modification, chitosan derivatives, PHEG modification, PHEA modification etc..
The intestinal mucosa for increasing cyclovimbuxine D in the present invention using the enteron aisle absorption enhancers sodium caprate of high effect nontoxic is penetrating
Property.Studies have shown that sodium caprate mainly passes through cell bypass and intracellular pathways increase the permeability of intestinal mucosa, to improve
Drug biological utilisation.The absorption enhancers such as cyclovimbuxine D and sodium caprate are used in combination the present inventor, can increase HuanweihuangyangxingD
D improves its blood concentration in the absorption of enteron aisle, improves the bioavilability of cyclovimbuxine D to a certain extent, solves
Cyclovimbuxine D intestinal mucosa transmitance low problem.
The present invention solves the problems, such as cyclovimbuxine D poorly water-soluble using solid dispersion technology, solid dispersion technology be
Disperse poorly water soluble drugs in carrier, increase the solubility and dissolution rate of drug, it is a kind of to improve drug oral bioavilability
Nanotechnology, the solid dispersions for using solid dispersion technology to prepare refer to drug with molecule, colloid or nanoparticle (1-
100nm) and amorphous state is highly dispersed in inert carrier, a kind of dispersion existing in solid form of formation,
1. main pass through makes to be decreased to nanoscale by packaging medicine partial size；2. reducing reassociating and agglomerating for drug, inhibit drug
Crystallization；3. increasing the specific surface area of medicament nano granule to increase the wetability of drug；4. increasing drug to spread in carrier
Solubility in layer, to increase the oral administration biaavailability of drug.
So far, there are no document report cyclovimbuxine Ds with carrier and absorption enhancers, and that solid dispersions are made is significant
The report for improving cyclovimbuxine D bioavilability, is also made without document report cyclovimbuxine D with carrier and absorption enhancers
Solid dispersions are used to treat the effect of senile dementia.
Summary of the invention
It is an object of the invention to the problems low for cyclovimbuxine D poorly water-soluble and intestinal mucosa Penetration ration, provide one
Cyclovimbuxine D solid dispersions of the kind containing main pharmacodynamics ingredient cyclovimbuxine D and absorption enhancers sodium caprate and its preparation
Method, and its application in treatment senile dementia.
The purpose of the present invention is what is realized by following methods: the cyclovimbuxine D solid dispersions are by following weight
The raw material of number proportion is made:
1 part of cyclovimbuxine D, 1~8 part of carrier material, 0.1~1 part of sodium caprate；
Wherein, the carrier material is PEG4000, PEG6000, PVP K30, and hydroxypropyl first class cellulose or pool Lip river are husky
One or more of mixtures of nurse.
Cyclovimbuxine D solid dispersions of the present invention can be prepared as follows: cyclovimbuxine D is dissolved in organic molten
In agent, carrier material is added, is completely dissolved carrier material, absorption enhancers sodium caprate is added, then revolves at reduced pressure conditions
Turn evaporation of solvent, heat drying pulverizes and sieves to obtain the final product；The organic solvent is ethyl alcohol, methanol, chloroform, tetrahydro furan
It mutters, ethyl acetate, methylene chloride, the mixed solvent of acetone or its any two.Preferred alcohol.
Cyclovimbuxine D solid dispersions of the present invention can also be with one in diluent, adhesive, disintegrating agent, lubricant
Kind or several be prepared by mixing into various dosage forms.Preferred dosage form has capsule, tablet and pill.
The cyclovimbuxine D solid dispersions apparent solubility that the present invention is prepared can increase 7-8 compared with cyclovimbuxine D
Times；Dissolution in vitro, which increases by 500, to be controlled, and bioavilability has apparent technological progress by increasing to 31.76% less than 5%
And it is innovative.
It is a further object of the present invention to provide cyclovimbuxine D solid dispersions in treating and preventing senile dementia
Using.Specifically cyclovimbuxine D solid dispersions are used to prepare the new application for preventing and treating medicine for senile dementia.Ring ties up Chinese littleleaf box
Star D solid dispersions show the activity with obvious acetylcholine esterase inhibition through enzymology；It is proved through animal experiment,
With significantly improving dementia mice learning and memory function, and the activity of SOD can be significantly improved, reduce the content of MDA, improve brain system
Several effects.Further studies have shown that cyclovimbuxine D solid dispersions have stronger medicine compared with cyclovimbuxine D
Reason activity, has and apparent technological progress.
Cyclovimbuxine D solid dispersions raw material sources of the invention are abundant, and auxiliary material is nontoxic, pollution-free, easy to operate, make
With convenient, and the solubility and intestinal mucosa transmitance of cyclovimbuxine D are substantially increased, to improve bioavilability.
The present invention is aided with absorption enhancers sodium caprate and water-soluble carrier material using cyclovimbuxine D as main component,
Cyclovimbuxine D solid dispersions are prepared into, and a series of researchs have been carried out to it.
1, the apparent solubility of cyclovimbuxine D is studied in cyclovimbuxine D solid dispersions
By the excess sample of 20mg, (cyclovimbuxine D is that example 1 is prepared, cyclovimbuxine D solid dispersions are real
Example 2 is prepared) it is placed in 10mL tool plug centrifuge tube, add deionized water to scale, ultrasonic disperse 1min, constant-temperature table shaking
(temperature is 25 DEG C；Shaking frequency is 50 min-1) after 48h, 15000 × g of suspension is centrifuged 10min, after supernatant dilution,
Trap is measured at 242nm, calculates the apparent solubility of cyclovimbuxine D in sample.Experimental result is shown in Fig. 1.
The results show that cyclovimbuxine D, after being prepared by mixing into solid dispersions with sodium caprate, apparent solubility is significant
Increase, highest can increase 7-8 times.Show that cyclovimbuxine D is fully dispersed in the carrier, crystal form changes, and reaches nanoscale
Other amorphous state, so that the specific surface area of cyclovimbuxine D increases, hydrophilic coefficient increases, and finally makes cyclovimbuxine D
Solubility dramatically increase.In addition, absorption enhancers sodium caprate is also simultaneously a kind of surfactant, can also increase to a certain extent
Solubility in cyclovimbuxine D water.
2, in cyclovimbuxine D solid dispersions cyclovimbuxine D study in vitro dissolution
Accurately weighed cyclovimbuxine D (example 1 is prepared) and the solid point for being equivalent to cyclovimbuxine D 100mg
Granular media (example 2 is prepared) sample is set in stripping rotor, and dissolution medium is simulated intestinal fluid (pH7.4) 900mL；Temperature be (37 ±
0.5)℃；Revolving speed is 50rmin-1.In 3,5,10,20,30,60,120min sampling 5mL (while filling into equality of temperature dissolution medium
5mL), after 0.45 μm of filtering with microporous membrane, high effective liquid chromatography for measuring dissolution fluid drug content, and calculate accumulation dissolution hundred
Divide rate.Dissolution curve is shown in Fig. 2.As seen from the figure, compared with cyclovimbuxine D, prepared cyclovimbuxine D solid dispersions are equal
Improve the dissolution rate of cyclovimbuxine D.Dissolution rate measurement result shows: prepared cyclovimbuxine D solid dispersions
The dissolution rate of cyclovimbuxine D is improved, cumulative defaultlogic of the cyclovimbuxine D solid dispersions in 60min reaches
To 82.03%, and the cumulative defaultlogic of cyclovimbuxine D is only 17.22%, shows cyclovimbuxine D solid dispersions
The crystal form as existing for cyclovimbuxine D is changed and the effect of carrier can significantly improve result of extraction.
3, cyclovimbuxine D solid dispersion drug absorption dynamics is studied
24 Wistar rats are randomly divided into 4 groups.Respectively cyclovimbuxine D bulk pharmaceutical chemicals stomach-filling group, intravenous injection group；
Cyclovimbuxine D solid dispersions stomach-filling group, intravenous injection group.Fasting 12h, can't help before adaptable fed 7d is administered before testing
Water prohibits water, whole fasting in 2h after administration.Gastric infusion dosage is 30mgkg-1, tail vein injection dosage is
15mg·kg-1, 5 after administration, 10,20,30,40,60,90,150,210,270,390,570min from tail vein take blood (administration
Afterwards in 2h, every 0.5h intraperitoneal injection supplements the physiological saline being equal with amount for taking blood, allows free water after 2h), separated plasma is close
It is honored as a queen and is placed in -80 DEG C of refrigerators preservations, it is spare.Blood sample centrifugation, takes blood plasma 0.2mL to add 2.0 μ gmL-1Tanshinone IIA (internal standard) first
This mixed liquor is centrifuged 10min, removes egg in 3500rmin-1 after alcoholic solution 0.2mL, vortex oscillation 30s, standing 10min
It is white, supernatant is taken, is added in the 4mL centrifuge tube containing 25mg sodium chloride, whirlpool mixing 10min, 3500r min-1, centrifugation
10min, takes supernatant, and supernatant, which is crossed after 0.45 μm of filter membrane, to be taken 20 μ L sample introduction is analyzed.
Experimental data is handled using 3p97 pharmacokinetics software, obtains the pharmacokinetic parameter of two kinds of samples.According to F/%
=(D intravenous injection is administered orally in AUC)/(AUC is injected intravenously D oral administration) × 100% formula, calculates two kinds of samples
The oral administration biaavailability of Wistar rat.Two kinds of sample different way of administration pharmacokinetic parameters are shown in Table 1-2.
1 different way of administration cyclovimbuxine D pharmacokinetic parameter of table (N=6)
2 different way of administration cyclovimbuxine D solid dispersions pharmacokinetic parameter of table (N=6)
Experimental result it is found that cyclovimbuxine D relative bioavailability be 4.90%, cyclovimbuxine D solid dispersions
Relative bioavailability be 31.76%.Cyclovimbuxine D solid dispersions relative bioavailability increases compared with cyclovimbuxine D
6 times are added.Prompt cyclovimbuxine D and sodium caprate, which are prepared into solid dispersions, can obviously improve the biology benefit of cyclovimbuxine D
Expenditure.
4, pharmacodynamic experiment
Cyclovimbuxine D is prepared according to example 1, and cyclovimbuxine D solid dispersions are prepared by example 2,
It is provided by Jilin Academy of Chinese Medicine Sciences；Positive control drug Doneppezil Hydrochloride is manufactured by Pharmaceutical Co., Ltd. of health material
(170312A).Acetylcholinesterase produces (>=200U/g) by Shanghai Yuan Ye Biotechnology Co., Ltd.
4.1, cyclovimbuxine D solid dispersions and cyclovimbuxine D are to inhibiting activity of acetylcholinesterase
The preparation of the Tris-HCl buffer of 0.05M (pH=7.8): precision claims 6.0501gTris alkali in 1L beaker,
The dissolution of about 800mL distilled water is added, connects pH meter, is continuously added a little concentrated hydrochloric acid, pH value is measured after being sufficiently stirred, is finally adjusted to
PH=7.80 is then transferred in 1L volumetric flask, and beaker and glass bar a little distillation water washing 3 times are transferred to volumetric flask together
In, finally it is settled to 1L.
The Na of 0.2M2HPO4Solution: claim Na2HPO4·12H2The total 7.164g of O is dissolved in water to 100mL.
The NaH of 0.2M2PO4Solution: claim NaH2PO4·2H2The total 3.121g of O is dissolved in water to 100mL.
The PBS of the pH=7.0 of 0.1M: 39mL0.2M NaH is taken2PO4The Na of solution and 61mL 0.2M2HPO4, sufficiently mixed
This liquid is diluted 1 times, the as PBS of 0.1M pH7.0 by the PBS for closing as 0.2M PH=7.0.
The PBS of the pH=8.0 of 0.1M: 5.3mL 0.2M NaH is taken2PO4Solution and 94.7mL 0.2M Na2HPO4Solution,
It is sufficiently mixed the PBS as 0.2M PH=8.0, this liquid is diluted 1 times, the as PBS of 0.1M pH=8.0.
The preparation of acetylcholinesterase (AChE) solution: the acetylcholinesterase of 100U is dissolved in the Tris-HCl of 50mL
In (0.05M, pH=7.8) buffer, the Bovine serum albumin for adding 50mg stablizes enzyme solution to get the enzyme solutions of 2U/mL.
The enzyme solution of 2U/mL is used with the enzyme solution that the PBS of pH=8.0 is diluted to 0.5U/mL for Ellman method.
The preparation of 2mM DTNB: 3.96mg DTNB first uses the dehydrated alcohol of 500 μ L to dissolve, then plus 1.5mg NaHCO3, so
Afterwards with the PBS constant volume of pH=7.0 to 5mL.
The preparation of 15mM ATCI: 21.67mg ATCI adds distilled water to dissolve and is settled to 5mL.4 DEG C of refrigerators save.
The configuration of Doneppezil Hydrochloride solution: the Doneppezil Hydrochloride of 10mg is dissolved in the PBS of the pH=8.0 of 5mL,
The solution for being made into 2mg/mL fullys shake, then successively with the PBS of pH=8.0 be diluted to 0.025mg/mL, 0.05mg/mL,
The stand-by solution of 0.1mg/mL, 0.25mg/mL, 0.5mg/mL, 1.0mg/mL.
The configuration of the sample solution to be tested: taking correct amount sample appropriate, is made into the PBS solution dissolution of pH=8.0 and (is equivalent to ring
Virobuxine D) concentration be 2mgmL-1Solution, be then diluted to 0.001mg/mL, 0.025mg/ with the PBS of pH=8.0
The stand-by solution of mL, 0.05mg/mL 0.1mg/mL, 0.25mg/mL, 0.5mg/mL, 1.0mg/mL.
Sample well: 140 μ L PBS buffer solution (0.1M, pH=8.0), 20 μ L samples to be tested are added in ELISA Plate aperture
Solution and 15 μ L enzyme solutions, after mixing in 4 DEG C of preservation 20min.It takes out and 10 μ L DTNB (2mM) and 10 μ L ATChI is added
(15mM) can read absorbance value in 405nm after 37 DEG C of reaction 20min.
Sample Background control wells: 15 μ L enzyme solutions are replaced with 15 μ L PBS buffer solution, other conditions are constant.
Blank control wells: 20 μ testing sample solutions are replaced with 20 μ L PBS buffer solution, other conditions are constant.
Experimental result is shown in Fig. 3-5.According to suppression curve it is found that cyclovimbuxine D and cyclovimbuxine D solid dispersions compared with
Positive control drug Doneppezil Hydrochloride has stronger inhibitory activity, and cyclovimbuxine D solid dispersions tie up Chinese littleleaf box compared with ring
Star D activity is stronger, the IC of positive control drug Doneppezil Hydrochloride50For 187.2 μ g/mL, HuanweihuangyangxingD IC50For 10.6 μ g/
ML, the IC of HuanweihuangyangxingD solid dispersions50For 1.5 μ g/mL.
4.2, cyclovimbuxine D solid dispersions and cyclovimbuxine D are to AlCl3Cause the influence of memory deficits in mice
Mouse 90 are taken, is randomly divided into 9 groups, is grouped by table 1.1st day to the 7th day, physiology was subcutaneously injected in control group daily
Salt water, remaining each group mouse subcutaneous injection AlCl350mg/kg.Medication group distinguishes stomach-filling successive administration, and (dosage is suitable within 2 weeks
In the amount of cyclovimbuxine D).Keep away dark test, record the errors number that mouse in 3min enters darkroom, for 24 hours after with mistake
Number and wrong percentage test Memory result.Experimental result is shown in Table 3.
Table 3, solid dispersions and cyclovimbuxine D are to AlCl3Cause the influence (n=10, X ± S) of memory deficits in mice
* compared with normal group, P < 0.01 * P < 0.05, * *；△Compared with model group,△P < 0.05,△△P<0.0l
Illustrate cyclovimbuxine D and ring dimension yellow star D solid dispersions difference metering to AlCl3Cause memory disorders different
The confrontation effect of degree.Reduce the wrong frequency and error generation rate of mouse.Under the conditions of same dose, it is solid that ring ties up yellow star D
Body dispersion has preferable activity compared with ring dimension yellow star D, and conspicuousness becomes apparent from.
4.3, cyclovimbuxine D solid dispersions and cyclovimbuxine D cause the influence of memory deficits in mice to hyoscine
Mouse 90 are taken, is randomly divided into 9 groups, is grouped by table 2.1st day to the 7th day, control group and model group to distilled water,
(dosage is the amount for being equivalent to cyclovimbuxine D) is administered by table 2 in remaining each group.Once a day, continuous 7 days, last dose 1h
Afterwards, physiological saline 0.1ml/10g is given for normal group, remaining each group gives scopolamine hydrobromide 3mg/kg, and it is real to carry out diving tower after 10min
It tests, training 3min carries out test result afterwards for 24 hours.It the results are shown in Table 4.
Table 4, solid dispersions and cyclovimbuxine D cause the influence (n=10, X ± S) of memory deficits in mice to hyoscine
* compared with normal group, P < 0.01 * P < 0.05, * *；△Compared with model group,△P < 0.05,△△P<0.0l
More normal group of scopolamine hydrobromide group mouse wrong times dramatically increase, and medication group considerably reduces the mistake of mouse
Accidentally number, has apparent antagonism to memory deficits in mice caused by scopolamine hydrobromide group.Significantly reduce the mistake of mouse
Accidentally frequency and error generation rate.Under the conditions of same dose, ring ties up yellow star D solid dispersions to be had preferably compared with ring dimension yellow star D
Activity.
4.4, cyclovimbuxine D solid dispersions and cyclovimbuxine D cause the influence of memory deficits in mice to 30% ethyl alcohol
Mouse 90 are taken, is randomly divided into 9 groups, is grouped by table 3.1st day to the 7th day, control group and model group to distilled water,
(dosage is the amount for being equivalent to cyclovimbuxine D) is administered by table 3 in remaining each group.Once a day, continuous 7 days, last dose 1h
Afterwards, physiological saline 0.1ml/10g is given for normal group, remaining each group gives 30% ethyl alcohol, carries out Jumping test, test record after 15min
The errors number of every mouse in 5min.It the results are shown in Table 5.
Table 5, solid dispersions and cyclovimbuxine D cause the influence (n=10, X ± S) of memory deficits in mice to 30% ethyl alcohol
* compared with normal group, P < 0.01 * P < 0.05, * *；△Compared with model group,△P < 0.05,△△P<0.0l
30% more normal group of ethanol group mouse wrong times dramatically increase, and medication group division ring is tieed up in yellow star D, low dose is outer,
Remaining each group has apparent antagonism to memory deficits in mice caused by 30% ethyl alcohol.Under the conditions of same dose, ring ties up yellow star D
Solid dispersions are stronger to memory deficits in mice antagonism caused by 30% ethyl alcohol compared with ring dimension yellow star D.
4.5, cyclovimbuxine D solid dispersions and cyclovimbuxine D are to Senlie dementia model mouse brain mitochondria super oxygen
The influence of compound mutase SOD activity, malonaldehyde (MDA) content and brain coefficient.
Mouse 90 are taken, Normal group and model group are randomly divided into.Model group is to A1C13Solution, starts to press for 70 days
2g/L A1C1 is used always in 400mg/kg/d stomach-filling later3Solution is drunk；The distilled water of Normal group stomach-filling equivalent.By model
Group is randomly divided into 8 groups, by shown in table 4, gastric infusion 60 days (dosage is the amount for being equivalent to cyclovimbuxine D), and normal control
Group Model of Dementia group fills the distilled water to measure.Whole experiment process avoids contacting with aluminum products.Mouse is put to death, in ice bath rapidly
Brain tissue is taken out, and is accurately weighed, measure SOD, MDA respectively and calculates brain coefficient.Experimental result is shown in Table 6.
Table 6, solid dispersions and cyclovimbuxine D are to Senlie dementia model mouse brain SOD activity, MDA content and brain system
Several influences (n=10, X ± S)
* compared with normal group, P < 0.01 * P < 0.05, * *；△Compared with model group,△P < 0.05,△△P<0.0l
Model control group brain SOD activity reduces, and MDA content increases, and brain coefficient reduces (P < 0.05).Compared with model group,
The high, medium and low dosage group SOD activity of cyclovimbuxine D solid dispersions increases, and MDA content reduces, cyclovimbuxine D high dose
Group SOD activity increases, and MDA content reduces (P < 0.05 or P < 0.01), illustrates cyclovimbuxine D solid dispersions and ring dimension Chinese littleleaf box
Star D has apparent antioxidation, improves the excess metabolism of free radical in vivo, increases SOD content, enhance anti-oxidant energy
Power accelerates the removing of free radical, inhibits peroxidization, and Peroxidation Product MDA is inhibited to generate and remove the work of excessive MDA
With cyclovimbuxine D solid dispersions increase significantly brain coefficient compared with cyclovimbuxine D, so that explanation has stronger anti-encephalatrophy disease
The effect of contracting.
4.6, the shadow of cyclovimbuxine D solid dispersions and cyclovimbuxine D to Senlie dementia model acetyl choline content
It rings.
Mouse 90 are taken, Normal group and model group are randomly divided into.Model group is to A1C13Solution, starts to press for 70 days
2g/L A1C1 is used always in 400mg/kg/d stomach-filling later3Solution is drunk；The distilled water of the appearances such as Normal group stomach-filling.By model
Group is randomly divided into 8 groups, by shown in table 5, gastric infusion 60 days (dosage is the amount for being equivalent to cyclovimbuxine D), and normal control
Group Model of Dementia group is filled with isometric distilled water.Whole experiment process avoids contacting with aluminum products.Rat sacrificed by decapitation, rapidly
Cranium removing brain tissue (removal cerebellar tissue) is opened, takes in the brain tissue physiological saline of part and rinses, removes blood, filter paper is wiped dry, adds
Enter cold saline and be put into homogenate tube and sufficiently ground in ice bath, 10% brain homogenate is made, is centrifuged, supernatant is taken to be surveyed with colorimetric method
Determine brain tissue enzyme acetylcholine content.Experimental result is shown in Table 7.
Influence (n=10, the X of table 7, solid dispersions and cyclovimbuxine D to Senlie dementia model acetyl choline content
±S)
* compared with normal group, P < 0.01 * P < 0.05, * *；△Compared with model group,△P < 0.05,△△P<0.0l
Each treatment group and model group compare, and acetyl choline content reduces, and has significant difference.Under same dose, ring dimension
Chinese littleleaf box star D solid dispersions influence the content of acetylcholine compared with cyclovimbuxine D more significant.
The pharmacodynamic study of cyclovimbuxine D solid dispersions is shown, compared with cyclovimbuxine D, cyclovimbuxine D
Solid dispersion product has the function for the treatment of senile dementia significantly, and cyclovimbuxine D is prompted only to be combined with sodium caprate
Be made its significant effect for placing senile dementia of cyclovimbuxine D solid dispersions competence exertion, and with hydrochloric acid mostly how piperazine
Compared to result as can be seen that cyclovimbuxine D solid dispersions have the function of prompting ring to tie up Chinese littleleaf box better than Doneppezil Hydrochloride
Star D solid dispersions have good development prospect.
Detailed description of the invention
The present invention is further described with embodiment with reference to the accompanying drawing.
Fig. 1 is cyclovimbuxine D solid dispersions and cyclovimbuxine D solubility experiment result figure；
Fig. 2 is cyclovimbuxine D solid dispersions and cyclovimbuxine D Dissolution experiments result figure；
Fig. 3 is positive control drug acetylcholine esterase inhibition suppression curve figure；
Fig. 4 is cyclovimbuxine D acetylcholine esterase inhibition suppression curve figure；
Fig. 5 is cyclovimbuxine D solid dispersions acetylcholine esterase inhibition suppression curve figure.
Specific embodiment
The present invention is to be achieved (confirmation) by following embodiment, but technical solution of the present invention is without being limited thereto.
Embodiment 1, cyclovimbuxine D preparation
Little leaf boxwood 5kg is ground into coarse powder, with containing 2% glacial acetic acid 80% alcohol reflux extract 3 times, 2 hours every time,
0.2% active carbon of medicine liquid volume is added in combined extract, stirs, and filtering, decompression filtrate recycling ethanol obtains medicinal extract, is dissolved in water,
Make every 1ml medicinal material containing 1g, is centrifuged, supernatant is taken, by D001-CC macroporous type storng-acid cation exchange resin, first with 15%
5 times of resin volumes of ethanol elution, then 70% ethanol elution, the 5 times of resin volumes for being 11 with ammonium hydroxide tune pH are collected ammonia ethyl alcohol and are washed
De- liquid, recycling design are dried under reduced pressure to get with cyclovimbuxine D composition as main component.HuanweihuangyangxingD in composition
D content is 83.5%；It takes with cyclovimbuxine D composition 1.0g as main component, is dissolved with 5000ml water, adjust pH most 7,
It is first extracted 4 times, each 100ml with chloroform shaking, water layer is again 10 with ammonium hydroxide tune pH, extracts 5 with chloroform shaking, often
Secondary 100ml collects chloroform liquid, and after anhydrous sodium sulfate dehydration, directly by neutral alumina column, recycling design is dry, and third
Ketone recrystallization, obtains cyclovimbuxine D.
Embodiment 2, cyclovimbuxine D solid dispersions preparation
Take cyclovimbuxine D 10g, PEG6000 60g, sodium caprate 5g；Cyclovimbuxine D is dissolved in 500ml ethyl alcohol,
PEG6000 is added, makes to be completely dissolved, absorption enhancers sodium caprate is added, then rotary evaporation removes solvent at reduced pressure conditions,
Heat drying pulverizes and sieves to obtain the final product.
Claims (5)
1. a kind of cyclovimbuxine D solid dispersions, it is characterised in that: the cyclovimbuxine D solid dispersions are by following heavy
The raw material of amount number proportion is made: 1 part of cyclovimbuxine D, 1~8 part of carrier material, 0.1~1 part of sodium caprate；Wherein, described
Carrier material be PEG4000, PEG6000, PVP K30, hydroxypropyl first class cellulose or poloxamer.
2. a kind of cyclovimbuxine D solid dispersions according to claim 1, preparation method are as follows: by cyclovimbuxine D
It is dissolved in organic solvent, adds carrier material, be completely dissolved carrier material, absorption enhancers sodium caprate is added, is then subtracting
Evaporation of solvent is rotated under press strip part, heat drying pulverizes and sieves to obtain the final product；The organic solvent is ethyl alcohol, methanol, three chloromethanes
The mixed solvent of alkane, tetrahydrofuran, ethyl acetate, methylene chloride, acetone or its any two.
3. a kind of cyclovimbuxine D solid dispersions according to claim 2, it is characterised in that: the organic solvent is
Ethyl alcohol.
4. a kind of drug of cyclovimbuxine D solid dispersions preparation as described in claims 1 or 2 or 3, it is characterised in that:
The cyclovimbuxine D solid dispersions mix system with one or more of diluent, adhesive, disintegrating agent, lubricant
The standby drug at various dosage forms, the dosage form of the drug includes capsule, tablet and pill.
5. cyclovimbuxine D solid dispersions described in claims 1 or 2 or 3 or 4 treat or prevent senile dementia in preparation
Drug in application.
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