CN1634293A

CN1634293A - 'Xianlinggubao' new preparation, its preparing method and application

Info

Publication number: CN1634293A
Application number: CN 200410051606
Authority: CN
Inventors: 叶耀良; 廖志钟
Original assignee: Individual
Current assignee: Individual
Priority date: 2004-09-24
Filing date: 2004-09-24
Publication date: 2005-07-06

Abstract

The invention discloses a compound traditional Chinese medicinal extract, which comprises (by weight ratio) epimeddium 1167, dipsacus root 167, root of red rooted saliva 83, anemarrhena rhizome 83, psoralea fruit 83, dried rehmannia root 83, and right amount of pharmaceutically acceptable adjuvant or base material. The compound can be prepared into the dosage form of soft capsule, emulsifying tablet and dressed dispersing tablet, which can be used for treating women's climacteric osteoporosis and senile dementia.

Description

Novel Xianlinggubao preparation and its production and use

Technical field

The present invention relates to compound Chinese medicinal preparation-novel Xianlinggubao preparation and its production and use.

Technical background

XIANLING GUBAO is used for the treatment of osteoporosis due to deficiency of the liver and kindey, the obstruction of collaterals by blood stasis, has nourishing the liver and kidney, promoting blood circulation to remove obstruction in the collateral, the effect of bone and muscle strengthening, but only develop capsule at present, because Chinese medical concrete is easy to the moisture absorption, strict to capsulation, the easy moisture absorption of medicine, effect duration is short.Only crude drug fine powder and medicinal material extract extractum mixing granulation in the former preparation process, not having pin is that the purpose that improves bioavailability and drug effect adds any pharmaceutic adjuvant that helps absorption of human body.Every dress of former capsule 0.5g, capsule is bigger, is not easy to take, and the compliance that the patient uses is relatively poor.

Along with the aging of social population, the senile dementia sickness rate is in rising trend, and the active drug of seeking treatment senile dementia disease (AD) has been subjected to the great attention of various countries, becomes the task of top priority.Become after heart disease, cancer and apoplexy human the 4th the cause of the death at flourishing state AD, there are 250-400 ten thousand people in the AD patient U.S. at present, and the whole world estimates at 1700-2500 ten thousand people.Seemingly a kind of many reasons of AD cause with regard to pathogenesis, relate to multiple pathomechanism and the many of multiple pathological manifestations occur because of different substantiality disease.Chinese scholars is hopeful therefrom to develop the new drug of treatment alzheimer disease having done a large amount of basic research and clinical research aspect the application natural drug effective ingredient treatment senile dementia disease in recent years.But the achievement of not making a breakthrough property as yet.For the research that XIANLING GUBAO prepares the purposes of the new drug for the treatment of alzheimer disease, also be blank basically.

Summary of the invention

The object of the invention is to provide novel Xianlinggubao preparation that has improved bioavailability and drug effect and preparation method thereof, the invention still further relates to the purposes of this novel formulation.

For realizing above purpose, the present invention adds appropriate amount of auxiliary materials in the prescription medicinal substances extract based on Chinese medicine, and the component weight proportion of novel Xianlinggubao preparation of the present invention is:

Herba Epimedii 1167g Radix Dipsaci 167g Radix Salviae Miltiorrhizae 83g

Rhizoma Anemarrhenae 83g Fructus Psoraleae 83g Radix Rehmanniae 83g

Above medical material can prepare its extract with following two kinds of processing steps:

Technology one:

Above Six-element, Radix Dipsaci, Radix Salviae Miltiorrhizae, Fructus Psoraleae are ground into fine powder, three flavors such as all the other Herba Epimedii decoct with water three times, and each 1 hour, collecting decoction, being concentrated into relative density is the thick paste of 1.35～1.38 (30 ℃), add above-mentioned medical material fine powder, mixing, drying, be crushed to 80～200 orders, be the medicinal substances extract of preparation dispersible tablet, soft capsule.

Technology two:

Above Six-element, Radix Dipsaci, Radix Salviae Miltiorrhizae, Fructus Psoraleae are ground into 20 orders～40 purpose coarse powder, 45～65% ethanol percolations with 6～12 times of amounts, collect percolate, reclaim ethanol to there not being the alcohol flavor, get thick paste, three flavors such as percolation medicinal residues and Herba Epimedii decoct with water three times, each 1 hour, collecting decoction, being concentrated into relative density is the thick paste of 1.35～1.38 (30 ℃), with the mutual mixing of above-mentioned percolation thick paste, be the medicinal substances extract of preparation dispersible tablet, soft capsule, or crushed after being dried to 80～200 orders, also for preparing the medicinal substances extract of dispersible tablet, soft capsule.

Above-mentioned medicinal substances extract adopts the pharmaceutically alleged adjuvant or the substrate of suitable kind to make soft capsule, dispersible tablet respectively.

As with filler (80～520g), disintegrating agent (8～48g), (1～3g) etc. makes dispersible tablet to lubricant; Or with disperse medium (60～440g), suspending agent (3～40g), (0.1～3g) makes soft capsule to antiseptic.

The filler of described dispersible tablet: the filling adjuvant that can select general marketed tablet: as starch, precoking starch, microcrystalline Cellulose, lactose etc., to select the dispersion effect of the more suitable dispersible tablet of the present invention of precoking starch proportioning lactose, precoking starch: lactose is used in 30: 22 ratios, and the disintegrate effect is best;

Described dispersible tablet disintegrating agent comprises: crospolyvinylpyrrolidone, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, cross-linked carboxymethyl cellulose sodium one or more; The best low-substituted hydroxypropyl cellulose that uses: the mixture of crospolyvinylpyrrolidone (1: 3); Described dispersible tablet lubricant comprises: magnesium stearate, or micropowder silica gel, or Pulvis Talci etc.

Described soft capsule disperse medium comprises: oiliness disperse medium and aqueous dispersion medium;

1. described oiliness disperse medium comprises: the triglyceride oils of crude vegetal (as: soybean oil, Oleum Arachidis hypogaeae semen) or long-chain and medium-chain saturation in various degree, as: oleic acid sorbitol ester, olein: propylene glycol (90: 10), Oleum Cocois C8/C10 monoglyceride or dibasic acid esters, Oleum Cocois C8/C10 propylene glycol ester, Oleum Cocois triglyceride, the acetylizad monoglyceride of purification, olein, glyceryl linoleate, Polyethylene Glycol glyceryl laurate ester, purification Oleum helianthi monoglyceride, the best Oleum Cocois that uses;

2., described aqueous dispersion medium comprises: one or more of PEG400, Polyethylene Glycol 500, Macrogol 600, isopropyl alcohol, glycerol, propylene glycol and water.

Described soft capsule suspending agent comprises: can increase the solid matter of disperse medium viscosity, as Cera Flava, aluminum monostearate, ethyl cellulose etc.;

Described soft capsule antiseptic comprises: one or more in glycerol, propylene glycol, methyl parahydroxybenzoate, ethylparaben, propyl p-hydroxybenzoate, butyl p-hydroxybenzoate, benzyl p-hydroxybenzoate, the P-hydroxybenzoic acid phenyl ester.

The preparation technology of preparation is as follows:

The preparation dispersible tablet: the material extract of getting it filled, add the disintegrating agent mix homogeneously that adds in filler and the part, granulate with the wetting agent moistening, drying, granulate adds remaining and adds disintegrating agent and lubricant, mix homogeneously tabletting, promptly gets dispersible tablet.The adding of disintegrating agent adds mode respectively before and after adopt granulating, and the disintegrate effect is better, but the amount that adds before granulating, and should not surpass 50% of disintegrating agent total amount with the amount of disintegrating agent in promptly, should be less than 10% of disintegrating agent total amount.

This dispersible tablet can coatedly again be made coated dispersing tablet.

This coating solution makes dispersible tablet behind the bag film-coat owing to use special aqueous coatings material, still can satisfy the requirement of disintegrate in three minutes.

Coating solution is made up of polymer film-forming material, plasticizer and solvent etc., can also add surfactant as defoamer, coloring agent etc., or select commercially available finished product coating solution to be used.

A kind of preferable suitable XIANLING GUBAO film coating prescription is:

6% hypromellose (HPMC) (50%) alcoholic solution 1650g

Pulvis Talci 60g

Titanium dioxide 25g

Polyoxyethylene sorbitan monoleate 20g

Propylene glycol 20g

The wherein effect of each component in the film coating liquid prescription:

1. hypromellose is the film-coat filmogen

2. ethanol is solvent

3. Pulvis Talci is a masking agent

4. titanium dioxide is masking agent

5. polyoxyethylene sorbitan monoleate is a plasticizer

6. propylene glycol is a plasticizer

The preparation soft capsule: the material extract of getting it filled, get 50～340 parts of the disperse medium that suspending agent (3～40 parts) is dissolved in part, be preheated to 60～65 ℃ standby; The antiseptic (0.1～3 part) of getting the prescription share adds in 10～100 parts of disperse medium of above-mentioned share remainder, stirs, and is mixed to 37 ℃ with above-mentioned disperse medium, add medicinal substances extract, mix homogeneously grinds homogenizing, promptly get soft capsule content, the compacting soft capsule.

Novel Xianlinggubao preparation by above technology preparation has the unexistent outstanding advantage of former dosage form, is described in detail as follows:

Soft capsule: the soft capsule introduction also claims the flexible glue pill, and it is not have a kind of preparation that forms in sealings such as the non-water-soluble liquid of dissolution or suspension and the capsule shells with oils or to the gelatin thing.Soft capsule is the tablet that continues, and a kind of novel form that grows up after the injection, its shell are to form with the gelatin compacting, the aqueous medicinal liquid of bag in the softgel shell.Be characterized in slower than injection onset, but than tablet, capsule, granule is rapid-action.More easy to carry than oral liquid.Because the optimization of soft capsule liquid of the present invention prescription, its content can be in human body self emulsifying to a certain degree, increase absorption area, thus the bioavailability height.Reduced patient's dose, made that compliance was higher when the patient used this medicine.But because the soft capsule complicated process of preparation has higher requirements to preparations shaping technology, need screening appropriate supplementary product kind, proportioning, just might make stay-in-grade finished product soft capsule.The present invention has provided XIANLING GUBAO RUANJIAONANG cutting Preparation Method really.Lecithin in the adjuvant, as pharmaceutic adjuvant, it can increase medicine and disperse in gastrointestinal emulsifying, help absorbing, multinomial physiological function is arranged again simultaneously, as 1. nourishing the brain and improving intelligence: after lecithin is absorbed by small intestinal, can hydrolysis go out choline, along with blood enters in the brain, combine with acetic acid and to be converted into acetylcholine, just memory is plain.It is a kind of nerve conduction material, and its content is high more, and the speed of transmitting the dwelling is fast more, and memory is just strong more; 2. lecithin has the effect that emulsifying cuts grease, and can promote blood circulation, improve serum matter, removes peroxide, and cholesterol and neutral fat content in the blood are reduced, and reduces the holdup time of fat at blood vessel.Promote the dissipation of atherosis speckle, the tunica intima operation that prevents to cause by cholesterol, lecithin has obvious effect to hyperlipidemia and hypercholesterolemia, can prevent and treat arteriosclerosis; 3. replenish the content that lecithin can improve acetylcholine in the brain cell, activation and regenerating brain cells, thus recover and improve the function of brain.Especially its brain tonic and intelligence development functions and pharmic function of the present invention have synergism, thereby have outstanding substantial effect.

Dispersible tablet: be a kind of solidified liquid form of administration, disintegrate fully in 3 minutes at normal temperatures, the effective ingredient stripping is rapid.But solid state is taken, but also liquid condition is taken, and makes things convenient for the patient.The development of dispersible tablets of Chinese medicine need overcome and extract the difficult point that the extractum moisture absorption influences disintegrate, and the present invention is by the screening adjuvant, thereby it is stable to reach end product quality, and disintegrate is characteristics rapidly.Dispersible tablet of the present invention can be taken by solid, but also liquid is taken, and absorbs rapidly.By new extract drugs technology two provided by the invention, the further enrichment of effective ingredient makes not contain the former powder of crude drug in the finished product preparation that finished product hygiology quality is more guaranteed.

Simultaneously, through control experiment explanation novel Xianlinggubao preparation to the treatment osteoporosis aspect outstanding effect of comparing with former dosage form.

In addition, to preventing and treating alzheimer disease (AD) definite effect is arranged through Chronic Aluminum poisoning alzheimer disease animal model experiment result of study explanation novel Xianlinggubao preparation.

The situation of relevant experimentation is described in detail as follows:

One of effect of the present invention: novel Xianlinggubao preparation is to the comparative test of treatment osteoporosis aspect and former dosage form

Be objective evaluation XIANLING GUBAO treatment osteoporosis clinical efficacy and safety, novel Xianlinggubao preparation soft capsule, dispersible tablet and former dosage form are contrasted clinical comparison, pathology all comes internal medicine clinic case since two thousand three, take random packet, the test method of contrast, XIANLING GUBAO FENSANPIAN group 93 examples (male 33 examples, women 60 examples), XIANLING GUBAO RUANJIAONANG group 92 examples (male 30 examples, woman's 62 examples), XIANLING GUBAO JIAONANG group 72 examples (male 23 examples, women 49 examples).This medicine treatment osteoporosis clinical efficacy is observed.

1, case selection

Age is more than 50 years old, idiopathic osteoporosis.Have sore waist and aching in the waist and the back or arthralgia symptom person and possess dual intensity x one bone densitometry report, and the bone density at one of them position of waist or hip must be lower than 1 of peak bone mass or 2 marks and pushes away the above person of difference.

2, physical data

2.1 sex distributes

Table 1 case sex distributes

Masculinity femininity

The total routine number of group

Example number % example number %

Dispersible tablet group 93 33 35.48 60 64.51

Soft capsule group 92 30 32.60 62 67.39

Capsules group 72 23 31.94 49 68.05

Compare with Capsules group, check through t: P＞0.05, relatively there was no significant difference has comparability.

2.2 age distribution: see Table 2.

The age distribution of table 2 case

50 ~ 59 years old 60 ~ 69 years old more than 70 years old

The total routine number of group

Example number % example number % example number %

Dispersible tablet group 93 21 22.58 41 44.08 31 33.33

Soft capsule group 92 24 26.08 38 41.30 30 32.60

Capsules group 72 18 25 32 44.44 22 30.55

3, observed content

Pain: divide 3 of rest pains, movable pain, percussion pain, its degree is divided into, serious (3 minutes), medium (2 minutes), slight (1 minute), painless (0 minute).

Bone density: measure lumbar vertebra with dual intensity x line, hip is made the treatment cross-reference, and measuring before and after the treatment must be same instrument.Measurement result sees Table 3 before and after the treatment.

The distribution (example) of bone density degree before table 3 treatment

Lumbar vertebra L2-4 hip

Group

＞1SD ＞2SD ＞2.5SD ＞1SD ＞2SD ＞2.5SD

Dispersible tablet group 19 21 34 25 19 32

Soft capsule group 17 22 33 22 18 32

Capsules group 15 19 30 21 13 29

Toxicity: the back of taking medicine is observed not gastrointestinal reaction, anaphylaxis and other side reactions.

4 instructions of taking and the course of treatment

XIANLING GUBAO FENSANPIAN is oral, and every day 2 times, each 3,3 months is a course of treatment.

XIANLING GUBAO RUANJIAONANG is oral, and every day 2 times, each 3,3 months is a course of treatment.

XIANLING GUBAO JIAONANG is oral, and every day 2 times, each 3,3 months is a course of treatment.

5 efficacy evaluations

5.1 individual event curative effect

Symptom: it is produce effects that the pain integration reduces greater than 2/3; It is effective that the pain integration reduces greater than 1/3; Less than 1/3 is invalid.

5.2 bone density increase＞2%BMD is a produce effects; It is effective increasing 2%-0%; Be invalid below＜0%.

5.3 the total effects produce effects: symptom is obviously improved, integration reduces greater than 2/3, or bone density increases＞2%; Effectively: symptom makes moderate progress, and integration reduces greater than 1/3, or bone density increases 2-0%; Invalid: symptom unit improves, and integration reduces deficiency, or bone density reduction person.

6 results

6.1 total effects

Table 4 case curative effect of disease relatively

Produce effects enabledisable total effective rate

The total routine number of group

Example number % example number % example number % %

Dispersible tablet group 93 67 72.04 20 21.50 6 6.45 93.55

Soft capsule group 92 66 71.73 20 21.73 6 6.52 93.48

Capsules group 72 45 62.50 16 22.22 11 15.27 84.73

Compare with Capsules group, learn check by statistics, Ridit analyzes: P＜0.05, significant difference is arranged, and treatment group curative effect is better than matched group.

6.2 the pain effect all has tangible analgesic effect for three groups, generally at 1-2 obvious analgesic effect is arranged in week,

Can control about 1 month or the alleviating pain symptom, the observed result effective percentage is near 100% in the time of 3 months.

6.3 changes of bone mineral density sees Table 5 from the increase example number at each position of bone density

Table 5 bone density therapeutic outcome (example)

＞2％ 2-0％＜0％

Dispersible tablet group 56 25 12

Soft capsule group 57 26 13

Capsules group 46 14 12

6.4 the toxicity initial stage of taking medicine has the minority sufferer constipation to occur, not drug withdrawal can keep clear after with aperitive; Other has individual patients that the xerocheilia reaction is arranged, but can both adhere to taking medicine, and all recovers normal after one month, need not use aperitive.

7 brief summaries

The reported literature of treatment by Chinese herbs osteoporosis is more, but in the clinical observation all improving symptom, and observing time is shorter, and is general all at 3 months.This report selects the objective indicator of dual intensity x line bone density as the osteoporosis treatment effect for use.The result confirms that XIANLING GUBAO FENSANPIAN, XIANLING GUBAO RUANJIAONANG treatment osteoporosis is effective, clinical symptoms can be improved and alleviate on the one hand, bone density can be improved on the other hand, comparing curative effect with XIANLING GUBAO JIAONANG has significant difference, is better than XIANLING GUBAO JIAONANG but does not have significant difference improving aspect the bone density curative effect.Motherland's medical science is recognized: " the kidney being the origin of congenital constitution, and renal failure and all kinds of diseases and ailments are given birth to ".Osteoporosis and sclerotin are dredged orthopaedic diseases such as disease, are person in middle and old age's common frdquently encountered disease disease that the renal failure damage of essence causes.Theoretical dialectical by the traditional Chinese medical science " kidney governing bones ", when with kidney invigorating and YANG supporting, maintain congenital and control it.Because of XIANLING GUBAO FENSANPIAN is by the excessive red bean jelly in mountain range, Guizhou Province, Radix Dipsaci, the Fructus Psoraleae medicine is formed, and has the kidney warming bone strengthening, and reunion of bone is kept fit the function of strong bone, so the treatment osteoporosis can obtain certain effect.

By above test, the more former dosage form treatment of XIANLING GUBAO novel form osteoporosis effect has outstanding substantive advantage.

Two, two of effect of the present invention: novel Xianlinggubao preparation is to the protective effect research of modeling dementia mice

The present invention is applied to senile dementia with XIANLING GUBAO RUANJIAONANG, dispersible tablet, claims Alzheimer again, obtained definite pharmacodynamics test support, and this does not see any relevant public information under former dosage form condition.

Another remarkable result of the present invention is, on the therapeutic effect of the senile dementia rat of modeling, show: novel Xianlinggubao preparation has therapeutical effect to senile dementia.Be described in detail as follows:

Chronic Aluminum poisoning alzheimer disease animal model has been duplicated in this research, further studies the effect that novel Xianlinggubao preparation is prevented and treated alzheimer disease by experiment, and the presentation of results novel Xianlinggubao preparation has definite effect to control AD.

1, materials and methods

Medicament preparation: the extract for preparing novel Xianlinggubao preparation by embodiment 4 respectively.Every extract g is equivalent to crude drug 30g.

2, animal

60 of the healthy male white mouses of Kunming kind, body weight 20 ± 2g.Be divided into 6 groups at random: normal control group (10), Model of Dementia group (10), dementia+XIANLING GUBAO tablet (10), dull-witted+hold up first BUNAO CHONGJI little, in, heavy dose of treatment group (each 10).

3, reagent standard calcium testing cassete builds up bio-engineering research institute available from Nanjing.

4, Model of Dementia duplicate and Drug therapy except that the normal control group, all the other every Mus are irritated stomach ALCl ₃0.2g/kg raised altogether 90 days every day, duplicating Chronic Aluminum poisoning senile dementia model, and irritates stomach simultaneously and make and take relative medicine (for details see attached table 1), the normal control group is irritated stomach equal-volume normal saline, after 90 days, get specimen detect organize between contrast.

5, sample preparations and index detect brain coefficient mice sacrificed by decapitation, and speed is got the above full brain of basilar part of pons upper limb level, gets brain immediately and washes with cold saline, weighs.Press cutaneous horn weight/body weight * 100% and calculate the brain coefficient.

Getting the full brain of mice (removing decerebellation) when 6, the mensuration of cerebral tissue calcium content is tested weighs, made 10% homogenate 3000r/ minute with 0.9% ice-cold normal saline, centrifugal, 10 minutes, get the content of supernatant with chemical colorimetry mensuration Na-K-ATP enzyme, Mg-ATP enzymatic activity and MDA, assay method is undertaken by the test kit read-me.

7, the sPSS10.0 computed in software is used in the data statistics data statistics, and each organizes data, and (x ± s) expression, mean relatively adopts the one factor analysis of variance check between group with mean i standard deviation.

Result of the test:

1, XIANLING GUBAO is to the influence of mouse brain coefficient

Table 1 is respectively organized the comparison of mouse brain coefficient, mean ± standard deviation

Group number of animals (only) dosage (g/kg days) brain coefficient

Normal control group 10 equivalent normal saline 0.618 ± 0.058

Model of Dementia group 10 equivalent normal saline 0.496 ± 0.046

XIANLING GUBAO JIAONANG group 10 12 0.507 ± 0.052

XIANLING GUBAO RUANJIAONANG group 10 12 0.545 ± 0.055

XIANLING GUBAO FENSANPIAN group 10 12 0.547 ± 0.061

Model group and normal group relatively, significant difference (P＜0.05), the more former capsule of novel formulation is influencing aspect the dementia mice brain coefficient, advantage is comparatively remarkable.

2, respectively organize mouse brain Ca ²⁺The influence of content

Table 2 is respectively organized mouse brain Ca ²⁺The influence of content

Group number of animals (only) dosage (g/kg days) Ca ²⁺(mol/g)

Normal control group 10 equivalent normal saline 0.084 ± 0.018

Model of Dementia group 10 equivalent normal saline 0.132 ± 0.026

XIANLING GUBAO JIAONANG group 10 12 0.128 ± 0.052

XIANLING GUBAO RUANJIAONANG group 10 12 0.091 ± 0.055

XIANLING GUBAO FENSANPIAN group 10 12 0.103 ± 0.061

Conclusion:

The cause of disease of AD and pathogenesis are not clear and definite fully as yet so far, and poisoning by aluminum, disorder of calcium metabolism and immunologic injury etc. are the theories of relatively generally acknowledging in recent years.Have and studies show that in a large number aluminum has tangible neurotoxic effect, generation development to AD has direct relation, can make that the animal learning memory ability descends, the cholinergic nerve system function reduction for the oral or injection aluminum chloride of animal, the series of features sex expression of can produce AD such as neurofibrillary tangles and motionless learning disorder for rabbit intracerebral injection aluminum, thereby the present invention has selected for use aluminum chloride to duplicate the mechanism of action that the alzheimer disease model is observed new XIANLING GUBAO ZHIJI control AD.

It is generally acknowledged that cerebral tissue is owing to be rich in lipid, oxygen consumption is big, and activities of antioxidant enzymes is relatively low, subjects to radical damage, makes neuronal structure and function impaired, activates the Ca of excitatory amino acid receptor gate ²⁺Passage makes a large amount of Ca ²⁺In stream and unbalance, Ca in the born of the same parents ²⁺Overload can make Ca ²⁺The dependence protein enzymatic activity increases unusually, impels protein to decompose, and structure of mitochondria is impaired, respiratory chain complex enzymatic activity descends, energy metabolism impairment, and low-level ATP can cause the APP Developmental and Metabolic Disorder, promote that APP is cracked into A β, A β deposition is increased, senile plaque occurs.And oxygen-derived free radicals increases and Ca ²⁺Overload easily causes the unusual phosphorylation of Protein tau again, neurofibrillary tangles occurs, causes neurocyte functional deterioration even death at last.

Of the present invention studies show that, the model group mouse brain is organized Ca ²⁺The normal matched group of content raise, and after novel Xianlinggubao preparation agent treatment, the Ca of mouse brain tissue ²⁺Content obviously reduces than model group, points out this preparation can obviously regulate the cell traffic function, thereby suppresses " calcium overload ", prevents neuronal death, and this may be one of mechanism of action of this medicine control AD.

Studies confirm that (90～100g), neurocyte reduces more remarkable the normal minimizing 7～10% of the heavy average specific of senile dementia brain, cerebral atrophy, brain weight alleviates, and document announcement is pointed out, senile dementia causes that brain volume dwindles (comprise that the cerebral tissue capacity reduces, the ventricles of the brain enlarge, gyrus broadening).This result of study shows, the normal matched group of poisoning by aluminum model mice brain weight obviously reduces, supported above-mentioned viewpoint, also caused neurocyte degeneration death, cell quantity to reduce, and caused that the result that brain weight alleviates, learns to go down is similar with the neurotoxic effect of bibliographical information aluminum.

After the novel Xianlinggubao preparation treatment, intending the dementia mice brain weight increases, and calcium ion concentration significantly descends, and shows that novel Xianlinggubao preparation has the neurotoxic effect of obvious antagonism aluminum, and the inhibition brain weight alleviates, the generation of cerebral atrophy.And the pharmacological action of original capsule type is from brain coefficient, calcium ion concentration evaluation, and therapeutic effect is not remarkable.Therefore, the more former dosage form of novel Xianlinggubao preparation has outstanding substantive distinguishing features.

The specific embodiment:

Further specify content of the present invention below by embodiment:

By following medical material component weight proportion, adopt the mode of embodiment 1-6 to prepare medicinal substances extract:

Herba Epimedii 1167g Radix Dipsaci 167g Radix Salviae Miltiorrhizae 83g

Rhizoma Anemarrhenae 83g Fructus Psoraleae 83g Radix Rehmanniae 83g

Embodiment 1: the preparation of medicinal substances extract

Radix Dipsaci, Radix Salviae Miltiorrhizae, Fructus Psoraleae are ground into 80 order fine powders, and three flavors such as all the other Herba Epimedii decoct with water three times, and each 1 hour, collecting decoction, being concentrated into relative density is the thick paste of 1.35 (30 ℃), adds above-mentioned medical material fine powder, mixing; Drying is crushed to 80 purpose fine powders, promptly gets the medicinal substances extract for preparing dispersible tablet or soft capsule.

Embodiment 2: the preparation of medicinal substances extract

Radix Dipsaci, Radix Salviae Miltiorrhizae, Fructus Psoraleae are ground into 160 order fine powders, and three flavors such as all the other Herba Epimedii decoct with water three times, and each 1 hour, collecting decoction, being concentrated into relative density is the thick paste of 1.38 (30 ℃), adds above-mentioned medical material fine powder, mixing; Drying is crushed to 160 purpose fine powders, promptly gets the medicinal substances extract for preparing dispersible tablet or soft capsule.

Embodiment 3: the preparation of medicinal substances extract

Radix Dipsaci, Radix Salviae Miltiorrhizae, Fructus Psoraleae are ground into 120 order fine powders, and three flavors such as all the other Herba Epimedii decoct with water three times, and each 1 hour, collecting decoction, being concentrated into relative density is the thick paste of 1.36 (30 ℃), adds above-mentioned medical material fine powder, mixing; Drying is crushed to 120 purpose fine powders, promptly gets the medicinal substances extract for preparing dispersible tablet or soft capsule.

Embodiment 4: the preparation of medicinal substances extract

Get Radix Dipsaci, Radix Salviae Miltiorrhizae, Fructus Psoraleae with 45% alcohol reflux of 6 times of amounts 1.0 hours, reclaim ethanol, concentrating under reduced pressure gets the alcohol extraction dry extract, and Herba Epimedii, Radix Rehmanniae, the Rhizoma Anemarrhenae of Radix Dipsaci, Radix Salviae Miltiorrhizae, Fructus Psoraleae medicinal residues and recipe quantity added 8 times of amount decoctions of water 2 times, each 1 hour, collecting decoction filters, and relative density was 1.05 thick paste when filtrate was concentrated into 25 ℃, add alcohol-extracted extract, drying is crushed to 80 purpose fine powders, promptly gets the medicinal substances extract for preparing soft capsule, dispersible tablet.

Embodiment 5: the preparation of medicinal substances extract

Get Radix Dipsaci, Radix Salviae Miltiorrhizae, Fructus Psoraleae with 95% alcohol reflux of 12 times of amounts 2.5 hours, reclaim ethanol, concentrating under reduced pressure gets the alcohol extraction dry extract, and Herba Epimedii, Radix Rehmanniae, the Rhizoma Anemarrhenae of Radix Dipsaci, Radix Salviae Miltiorrhizae, Fructus Psoraleae medicinal residues and recipe quantity added 16 times of amount decoctions of water 3 times, each 1 hour, collecting decoction filters, and relative density was 1.35 thick paste when filtrate was concentrated into 25 ℃, add alcohol-extracted extract, drying is crushed to 160 purpose fine powders, promptly gets the medicinal substances extract for preparing soft capsule, dispersible tablet.

Embodiment 6: the preparation of medicinal substances extract

Get Radix Dipsaci, Radix Salviae Miltiorrhizae, Fructus Psoraleae with 75% alcohol reflux of 10 times of amounts 2.0 hours, reclaim ethanol, concentrating under reduced pressure gets the alcohol extraction dry extract, and Herba Epimedii, Radix Rehmanniae, the Rhizoma Anemarrhenae of Radix Dipsaci, Radix Salviae Miltiorrhizae, Fructus Psoraleae medicinal residues and recipe quantity added 12 times of amount decoctions of water 2 times, each 1 hour, collecting decoction filters, and relative density was 1.30 thick paste when filtrate was concentrated into 25 ℃, add alcohol-extracted extract, drying is crushed to 160 purpose fine powders, promptly gets the medicinal substances extract for preparing soft capsule, dispersible tablet.

Embodiment 7: the preparation of XIANLING GUBAO RUANJIAONANG

Adjuvant component weight proportion:

Cera Flava 3g;

Olive oil 60g;

Propylene glycol 0.1g;

Soybean lecithin 0.05g.

Step 1: prepare medicinal substances extract by any means among the embodiment 1 to 6

Step 2: get a prepared medicinal substances extract of recipe quantity 1666g medical material, get the suspending agent Cera Flava be dissolved in the part disperse medium olive oil 30g, be preheated to 60～65 ℃ standby; The preservative propylene glycol of getting the prescription share adds in the disperse medium of above-mentioned share remainder, stirs, and is mixed to 37 ℃ with above-mentioned disperse medium, adds medicinal substances extract, and mix homogeneously grinds homogenizing, promptly gets soft capsule content, makes soft capsule.

The preparation explanation:

Cera Flava is a suspending agent, and the emulsifying agent soybean lecithin is an emulsifying agent in its soft capsule.

Olive oil is that the oil phase disperse medium also can be: the triglyceride oils of crude vegetal (as: soybean oil, Oleum Arachidis hypogaeae semen) or long-chain and medium-chain saturation in various degree, as: oleic acid sorbitol ester, olein: propylene glycol (90: 10), Oleum Cocois C8/C10 monoglyceride or dibasic acid esters, Oleum Cocois C8/C10 propylene glycol ester, Oleum Cocois triglyceride, the acetylizad monoglyceride of purification (Myvacet oil), olein, glyceryl linoleate, Polyethylene Glycol glyceryl laurate ester, purification Oleum helianthi monoglyceride.

Antiseptic is: propylene glycol,

The capsule material of compacting preparation soft capsule is to make the uniform film of thickness with dissolvings such as gelatin and glycerol, distilled water.The capsule material prescription that is fit to this preparation can be: gelatin: arabic gum: glycerol: syrup: distilled water=1: 0.23: 0.74: 0.12: 1.41.

Embodiment 8: the preparation of XIANLING GUBAO RUANJIAONANG

Adjuvant component weight proportion:

PEG400 200g

Glycerol 7g

Water 25ml

Methyl parahydroxybenzoate 2g

Tween 80 0.5g

Cera Flava 20g

Step 2: get a prepared medicinal substances extract of recipe quantity 1666g medical material, get suspending agent Cera Flava 20g be dissolved in the part disperse medium Polyethylene Glycol 120g, be preheated to 60～65 ℃ standby; The antiseptic methyl parahydroxybenzoate 2g that gets the prescription share adds in the 80g disperse medium Polyethylene Glycol of above-mentioned share remainder, glycerol, the water, stir, and be mixed to 37 ℃ with above-mentioned disperse medium, add medicinal substances extract, mix homogeneously, grind homogenizing, promptly get soft capsule content, make soft capsule.

Disperse medium is: PEG400, water, glycerol; Antiseptic is: methyl parahydroxybenzoate; Surfactant is: Tween 80.Antiseptic also can be selected for use: one or more in glycerol, propylene glycol, methyl parahydroxybenzoate, ethylparaben, propyl p-hydroxybenzoate, butyl p-hydroxybenzoate, benzyl p-hydroxybenzoate, the P-hydroxybenzoic acid phenyl ester.

Embodiment 9: the preparation of XIANLING GUBAO RUANJIAONANG

Adjuvant component weight proportion:

PEG400 400g

Glycerol 15g

Water 25ml

Tween 80 0.5g

Cera Flava 40g

Methyl parahydroxybenzoate 3g

Step 2: get a prepared medicinal substances extract of recipe quantity 1666g medical material, get suspending agent Cera Flava 40g be dissolved in the part disperse medium 300g, be preheated to 60～65 ℃ standby; The antiseptic methyl parahydroxybenzoate 3g that gets the prescription share adds in the 100g disperse medium Polyethylene Glycol of above-mentioned share remainder, water, the glycerol, stir, and be mixed to 37 ℃ with above-mentioned disperse medium, add medicinal substances extract, mix homogeneously, grind homogenizing, promptly get soft capsule content, make soft capsule.

Embodiment 10: the preparation of XIANLING GUBAO FENSANPIAN

Adjuvant component weight proportion:

Filler: pregelatinized Starch 60g and lactose 20g form;

Disintegrating agent crospolyvinylpyrrolidone 8g;

Lubricant is magnesium stearate 1g;

Correctives is xylitol 0.5g;

Polyvinylpyrrolidone alcoholic solution 50ml,

Step 2: get a prepared medicinal substances extract of recipe quantity 1666g medical material, add the disintegrating agent 3～5g mix homogeneously that adds in filler and the part, granulate with the wetting agent moistening, dry, granulate adds remaining and adds disintegrating agent and lubricant 1g, mix homogeneously tabletting, promptly gets dispersible tablet.

The preparation explanation:

Crospolyvinylpyrrolidone is a The disintegrating agents of dispersible tablets, removes crospolyvinylpyrrolidone can also be: carboxymethyl starch sodium or low-substituted hydroxypropyl cellulose or cross-linked carboxymethyl cellulose sodium.

The adding of disintegrating agent adds mode respectively before and after adopt granulating, and the disintegrate effect is better, but the amount that adds before granulating, and should not surpass 50% of disintegrating agent total amount with the amount of disintegrating agent in promptly, should be less than 10% of disintegrating agent total amount.

The dilute alcohol solution of polyvinylpyrrolidone is the wetting agent in the dispersible tablet.Wetting agent in its dispersible tablet can also be the alcoholic solution of 40% ethanol～95% alcoholic solution or starch slurry or polyvinylpyrrolidone, best 52% alcoholic solution that contains 2～4% polyvinylpyrrolidones that uses, promptly 2～4g polyvinylpyrrolidone is dissolved in the ethanol water that 100ml contains ethanol 52%.

The alcoholic solution of alcoholic solution or starch slurry or polyvinylpyrrolidone.

Magnesium stearate lubricant in the above-mentioned dispersible tablet can also be: micropowder silica gel or Pulvis Talci.

Correctives xylitol in the above-mentioned dispersible tablet can also be sweet or mannitol or other medicinal correctives of A Basi.

Embodiment 11: the preparation of XIANLING GUBAO FENSANPIAN

Adjuvant component weight proportion:

Filler: pregelatinized Starch 200 and lactose 140;

Disintegrating agent crospolyvinylpyrrolidone 24g;

Lubricant: magnesium stearate 2g;

Correctives is xylitol 3g;

Polyvinylpyrrolidone alcoholic solution 70ml,

Step 2: get a prepared above-mentioned medicinal substances extract of recipe quantity 1666g medical material, add the disintegrating agent 3～12g part mix homogeneously that adds in filler and the part, granulate with the wetting agent moistening, dry, granulate, add remaining and add disintegrating agent part and lubricant 2g, mix homogeneously tabletting, promptly get dispersible tablet.

The preparation explanation:

Crospolyvinylpyrrolidone is a The disintegrating agents of dispersible tablets, removing crospolyvinylpyrrolidone can also be: carboxymethyl starch sodium or low-substituted hydroxypropyl cellulose or cross-linked carboxymethyl cellulose sodium, the best is a carboxymethyl starch sodium: the mixture of low-substituted hydroxypropyl cellulose (1: 3).

The dilute alcohol solution of polyvinylpyrrolidone is the wetting agent in the dispersible tablet.Wetting agent in its dispersible tablet can also be the alcoholic solution of 40% ethanol～95% alcoholic solution or starch slurry or polyvinylpyrrolidone,, best 52% alcoholic solution that contains 2～4% polyvinylpyrrolidones that uses.

Embodiment 12: the preparation of XIANLING GUBAO FENSANPIAN

Adjuvant component weight proportion:

Filler: pregelatinized Starch 300 and lactose 220;

Disintegrating agent crospolyvinylpyrrolidone 48g;

Lubricant: magnesium stearate 3g;

Correctives is xylitol 3g;

Polyvinylpyrrolidone alcoholic solution 90ml,

Step 2: get a prepared above-mentioned medicinal substances extract of recipe quantity 1666g medical material, add the disintegrating agent 5～24g mix homogeneously that adds in filler and the part, granulate with the wetting agent moistening, dry, granulate, add remaining and add disintegrating agent 24～43g and lubricant 3g, mix homogeneously tabletting, promptly get dispersible tablet.

The preparation explanation:

Filler: the filling adjuvant that can select general marketed tablet: as starch, precoking starch, microcrystalline Cellulose, lactose etc., to select the dispersion effect of the more suitable dispersible tablet of the present invention of precoking starch proportioning lactose, precoking starch: lactose is used in 30: 22 ratios, and the disintegrate effect is best.

This dispersible tablet art for coating is again made film-coated dispersion tablet; Coating solution is made up of polymer film-forming material, plasticizer and solvent etc., can also add surfactant as defoamer, coloring agent etc., or select commercially available finished product coating solution.

Claims

1, a kind of XIANLING GUBAO RUANJIAONANG comprises Herba Epimedii, Radix Dipsaci, Radix Salviae Miltiorrhizae, the Rhizoma Anemarrhenae, Fructus Psoraleae, Radix Rehmanniae in its composition, it is characterized in that:

(1) used medical material proportioning is: Herba Epimedii 1167, Radix Dipsaci 167, Radix Salviae Miltiorrhizae 83, the Rhizoma Anemarrhenae 83, Fructus Psoraleae 83, Radix Rehmanniae 83;

(2) make medicinal substances extract through following technology:

Above Six-element, Radix Dipsaci, Radix Salviae Miltiorrhizae, Fructus Psoraleae are ground into fine powder, and three flavors such as all the other Herba Epimedii decoct with water three times, and each 1 hour, collecting decoction, being concentrated into relative density is the thick paste of 1.35～1.38 (30 ℃), adds above-mentioned medical material fine powder, mixing, drying is pulverized; Promptly get the extract for preparing dispersible tablet or soft capsule;

(3) medicinal substances extract of above-mentioned component and disperse medium, suspending agent, antiseptic are made soft capsule.

2, XIANLING GUBAO RUANJIAONANG as claimed in claim 1, it is characterized in that: the medicinal substances extract in the step (2) is through following prepared: get Radix Dipsaci, Radix Salviae Miltiorrhizae, Fructus Psoraleae was with 45%～95% alcohol reflux of 6～12 times of amounts 1.0～2.5 hours, reclaim ethanol, concentrating under reduced pressure gets alcohol-extracted extract, with Radix Dipsaci, Radix Salviae Miltiorrhizae, the Herba Epimedii of Fructus Psoraleae medicinal residues and recipe quantity, Radix Rehmanniae, the Rhizoma Anemarrhenae adds 8～16 times of amounts of water and decocts 2～3 times, each 1 hour, collecting decoction, filter, relative density was 1.05～1.35 thick paste when filtrate was concentrated into 25 ℃, added alcohol-extracted extract, drying, pulverize, promptly get medicinal substances extract.

3, a kind of XIANLING GUBAO FENSANPIAN comprises Herba Epimedii, Radix Dipsaci, Radix Salviae Miltiorrhizae, the Rhizoma Anemarrhenae, Fructus Psoraleae, Radix Rehmanniae in its composition, it is characterized in that:

(2) make medicinal substances extract through following technology:

(3) medicinal substances extract of above-mentioned component and filler, disintegrating agent, wetting agent, lubricant are made dispersible tablet, or the coated again coated dispersing tablet of making.

4, XIANLING GUBAO FENSANPIAN as claimed in claim 3, it is characterized in that: the medicinal substances extract in the step (2) is through following prepared: get Radix Dipsaci, Radix Salviae Miltiorrhizae, Fructus Psoraleae was with 45%～95% alcohol reflux of 6～12 times of amounts 1.0～2.5 hours, reclaim ethanol, concentrating under reduced pressure gets alcohol-extracted extract, with Radix Dipsaci, Radix Salviae Miltiorrhizae, the Herba Epimedii of Fructus Psoraleae medicinal residues and recipe quantity, Radix Rehmanniae, the Rhizoma Anemarrhenae adds 8～16 times of amounts of water and decocts 2～3 times, each 1 hour, collecting decoction, filter, relative density was 1.05～1.35 thick paste when filtrate was concentrated into 25 ℃, added alcohol-extracted extract, drying, pulverize, promptly get medicinal substances extract.

5, XIANLING GUBAO RUANJIAONANG according to claim 1 and 2 is characterized in that described medicinal substances extract is crushed to 80 orders～160 purpose fine powders.

6,, it is characterized in that described medicinal substances extract is crushed to 80 orders～160 purpose fine powders according to claim 3 or 4 described XIANLING GUBAO FENSANPIAN.

7, XIANLING GUBAO RUANJIAONANG according to claim 1 and 2 is characterized in that described disperse medium comprises: one or more of oiliness disperse medium and aqueous dispersion medium; Described suspending agent comprises: can increase the solid matter of disperse medium viscosity, as one or more of Cera Flava, aluminum monostearate, ethyl cellulose etc.; Described antiseptic comprises: one or more of glycerol, propylene glycol, methyl parahydroxybenzoate, ethylparaben, propyl p-hydroxybenzoate, butyl p-hydroxybenzoate, benzyl p-hydroxybenzoate, P-hydroxybenzoic acid phenyl ester etc.

8, according to the described XIANLING GUBAO RUANJIAONANG of claim 6, it is characterized in that:

1. described oiliness disperse medium comprises: the triglyceride oils of crude vegetal (as: soybean oil, Oleum Arachidis hypogaeae semen) or long-chain and medium-chain different saturation, as: oleic acid sorbitol ester, olein: one or more of propylene glycol (90: 10), Oleum Cocois C8/C10 monoglyceride or dibasic acid esters, Oleum Cocois C8/C10 propylene glycol ester, Oleum Cocois triglyceride, the acetylizad monoglyceride of purification, olein, glyceryl linoleate, Polyethylene Glycol glyceryl laurate ester, purification Oleum helianthi monoglyceride etc., the best Oleum Cocois that uses;

2., described aqueous dispersion medium comprises: one or more of PEG400, Polyethylene Glycol 500, Macrogol 600, isopropyl alcohol, glycerol, propylene glycol and water etc.

9, according to claim 3 or 4 described XIANLING GUBAO FENSANPIAN, it is characterized in that described disintegrating agent comprises: one or more of crospolyvinylpyrrolidone, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, cross-linked carboxymethyl cellulose sodium etc., the best low-substituted hydroxypropyl cellulose that uses: the mixture of crospolyvinylpyrrolidone (1: 3); Its described binding agent comprises: one or more of the alcoholic solution of 40% ethanol～95% alcoholic solution or starch slurry or polyvinylpyrrolidone etc.; Its described lubricant comprises magnesium stearate, or micropowder silica gel, or one or more of Pulvis Talci etc.

10, be used to prepare the purposes of the XIANLING GUBAO ZHIJI for the treatment of senile dementia as claims 1 or 2 or 3 or 4 described medicinal substances extracts.