CN101411758B - Chinese medicine solid formulation for treating insomnia and preparation method thereof - Google Patents
Chinese medicine solid formulation for treating insomnia and preparation method thereof Download PDFInfo
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- CN101411758B CN101411758B CN2008102272471A CN200810227247A CN101411758B CN 101411758 B CN101411758 B CN 101411758B CN 2008102272471 A CN2008102272471 A CN 2008102272471A CN 200810227247 A CN200810227247 A CN 200810227247A CN 101411758 B CN101411758 B CN 101411758B
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Abstract
The invention provides a solid traditional Chinese medicine preparation for treating insomnia, which comprises traditional Chinese medicine compositions and auxiliary medicines, wherein the traditional Chinese medicine compositions comprise the following raw materials in portion by weight: 2 to 8 portions of wild jujube, 0.5 to 1.5 portions of radix salviae miltiorrhizae and 0.5 to 1.5 portions of Schisandra chinensis; and the auxiliary medicines comprise any or the mixture of calcium sulphate, microcrystalline cellulose, crosslinking polyvinylpyrrolidone, low-substituted hydroxy propyl cellulose, superfine silica gel powder and starch. The solid preparation overcomes the defect that the prior oral liquid is easy to generate deposits during the placing process and is inconvenient to store and carry, is quick to release medicines, and has good bioavailability.
Description
Technical field
The present invention is solid preparation of Chinese medicine of relevant a kind of Cure for insomnia and preparation method thereof,, the invention relates to a kind of solid preparation of Chinese medicine that contains Semen Ziziphi Spinosae, Radix Salviae Miltiorrhizae and Fructus Schisandrae Chinensis and preparation method thereof that is.
Background technology
Present insomnia is a kind of common clinical disease, effect is better though present western medical treatment is had a sleepless night, and has certain clinical adverse, particularly the calm class medicines of some psychosiss, being everlasting medicine occurs after taking medicine and leaves over reaction, influences the mental status, the live and work of next day.In insomniac group, many patients are just slight, the moderate insomnia, thereby are difficult to accept for the untoward reaction due to the said medicine.And Chinese medicine is accumulating a large amount of experiences aspect the Cure for insomnia disease, controls by examining because of opinion, and Chinese medicine can be treated various clinical common insomnia pattern of syndrome.In addition, because Chinese medicine is few to nerve, the untoward reaction of spiritual aspect, thereby has vast potential for future development aspect the treatment of insomnia.
ZAOREN ANSHEN YE (WS3-B-3429-98) is recorded in the Chinese medicine ministry standard, is Tongrentang's tradition prescription, that is, traditional oral liquid formulation, its main component is: Semen Ziziphi Spinosae, Radix Salviae Miltiorrhizae, Fructus Schisandrae Chinensis.The sweet property of Semen Ziziphi Spinosae sour in the mouth is flat in the side, sour and sweet drugs can transforme into YIN, and the master goes into the conscience warp, the liver benefiting that can nourish heart, nourishing blood to tranquillize the mind for the key medicine of the irritated sleeplessness of treatment blood deficiency, is to be monarch drug.Radix Salviae Miltiorrhizae bitter in the mouth, cold nature master go into the conscience warp, and the merit of the relieving restlessness of clearing away heart-fire, nourishing blood to tranquillize the mind is arranged, and are minister.The Fructus Schisandrae Chinensis sour in the mouth is warm in nature, and the property of the gentle convergence of tool main is gone into lung, kidney, heart channel, the gas of astringing the lung, kidney nourishing water is arranged, the effect of the moon that nourishes heart, to conscience lose support due to sleeplessness, the energy of tranquilizing by nourishing the heart is arranged, be to help.Three medicine concurrence reinforcing the heart nourishing the liver, the merit of nourishing blood to tranquillize the mind.Be used for the treatment of diseases such as forgetful insomnia due to the conscience deficiency of YIN-blood, dizziness, headache.
The present dosage form of ZAOREN ANSHEN YE only is an oral liquid, and there be carrying of medicine in it and take inconvenience, the problem that dose is excessive.For addressing the above problem, the oral liquid that this research will have been gone on the market changes dosage form, makes the sedative jujube kernel solid preparation, to adapt to the demand in patient and market better.Make it can keep it former effective in cure, dissolution rate and bioavailability are better again, steady quality, and production mechanization, automaticity height, output are big, the medicament health is easily up to standard; Take, carry, storage etc. is more convenient, is convenient to modern production, and the novel form of taking convenience.
Summary of the invention
In view of the conventional dosage forms ZAOREN ANSHEN YE of present this area and all drawbacks and the defective of dosage form and preparation technology's existence thereof, the present inventor gropes through experiment in a few years, specific tradition prescription preparation has been carried out big cholic innovation, developed the repertoire that has both comprised traditional prescription, the fixed mixing ratio that has kept the raw material components of former prescription again, and curative effect is constant, is easier to the novel form of the conventional medicament extensively used.
The object of the present invention is to provide a kind of solid preparation of Chinese medicine of Cure for insomnia, said preparation had both comprised the repertoire of traditional prescription, the fixed mixing ratio that has kept the raw material components of former prescription again, curative effect is constant, dissolution rate and bioavailability are better than traditional oral liquid formulation, and take, carry, storage etc. is more convenient, be easier to extensively be used.
The present invention also aims to screen and provide a kind of preparation method of solid preparation of Chinese medicine of Cure for insomnia according to the characteristics of this solid preparation of Chinese medicine, the solid preparation of Chinese medicine of the Cure for insomnia that this preparation method of process obtains, the fixed mixing ratio that has kept the raw material components of former prescription, and curative effect is constant, is easier to extensively be used.
Intended purposes of the present invention and beneficial effect are achieved through the following technical solutions.
The invention provides a kind of solid preparation of Chinese medicine of Cure for insomnia, comprise Chinese medicinal components and excipient substance, this Chinese medicinal components is made up of the raw material of following weight portion: Semen Ziziphi Spinosae 2-8 part, Radix Salviae Miltiorrhizae 0.5-1.5 part and Fructus Schisandrae Chinensis 0.5-1.5 part; Wherein, in this solid preparation of Chinese medicine, Semen Ziziphi Spinosae, Radix Salviae Miltiorrhizae and Fructus Schisandrae Chinensis are that the form with separately alcohol extract exists; Described excipient substance comprises arbitrary or its mixture in calcium sulfate, microcrystalline Cellulose, crospolyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, Aspartane, micropowder silica gel, the starch.
Solid preparation of Chinese medicine of the present invention is mainly used in treatment by heart-liver blood deficiency, diseases such as the insomnia forgetfulness that the neurasthenia causes, dizziness, headache.
Its former dosage form of Chinese medicine composition in the above-mentioned solid preparation product of the present invention is an oral liquid, in put procedure, be prone to precipitation, the inconvenience accumulating is carried, and the characteristics of Chinese medicine composition of the present invention are that the crude drug amount is big, make the crude drug amount that oral liquid wherein contains 10g/1ml, certainly will cause oral liquid muddiness and wall built-up, the inventor has developed solid preparation for this reason, and especially dispersion solid medicine (also claiming solid dispersed formulation) is the preparation of representative.
After original traditional oral liquid formulation was improved, the solid preparation of Chinese medicine of Cure for insomnia of the present invention comprised preparations such as tablet, granule, powder, the watered pill, honeyed pill, condensed water honeyed pill, capsule; Be preferably tablet, more preferably dispersible tablet.The different excipient substances that preparation adopted is different, and it is the general knowledge of this area, also is the routine techniques that those skilled in the art are familiar with, and does not repeat them here.
Excipient substance described in the above-mentioned solid preparation of Chinese medicine of the present invention is a calcium sulfate, microcrystalline Cellulose, crospolyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, micropowder silica gel or its mixture, preferred this excipient substance is for comprising calcium sulfate at least, microcrystalline Cellulose, the mixture of crospolyvinylpyrrolidone and low-substituted hydroxypropyl cellulose, (comprise dispersible tablet for embodying solid dispersed formulation of the present invention, pill) Space, after promptly spatially making preparation absorb moisture, moisture enters the inside of preparation, said preparation moment disintegrate is scattered, whole space distributed in composition (ingredient and the adjunct ingredient) utmost point short time, and embodying chronergy (for example disintegration time of dispersible tablet) simultaneously, the excipient substance that the present invention adopts more preferably comprises calcium sulfate, microcrystalline Cellulose, crospolyvinylpyrrolidone, the mixture of low-substituted hydroxypropyl cellulose and micropowder silica gel.
The adding mode and the consumption of said medicine adjuvant are: at first add the Fructus Schisandrae Chinensis filler so that obtain the Fructus Schisandrae Chinensis powder of intensive drying in Fructus Schisandrae Chinensis extrat, this Fructus Schisandrae Chinensis filler is calcium sulfate and microcrystalline Cellulose, and part by weight is about: schisandra chinensis medicinal material: calcium sulfate: microcrystalline Cellulose=22-15:2-1:1; Then, in the system shaping particles, add compound disintegrating agent, this compound disintegrating agent is crospolyvinylpyrrolidone (PVPP) and low-substituted hydroxypropyl cellulose (L-HPC), and the disintegrating agent addition is the 3-5% of medical material total amount, and PVPP:L-HPC wherein is 2-0.5:1.
In the solid dispersed formulation of the present invention, especially at some dosage form, the pill of dispersible tablet, decentralized pressing preparation for example, excipient substance preferably can also comprise micropowder silica gel, the amount of micropowder silica gel generally is no more than 3% of total formulation weight amount, preferably is no more than 1%, and the effect of micropowder silica gel in preparation is except providing water transport channel, also can be considered as satisfying the weight of final product, supply weight with micropowder silica gel for all the components weight sum of said preparation.
Solid preparation of Chinese medicine of the present invention comprises tablet, granule, powder, the watered pill, honeyed pill, condensed water honeyed pill, capsule.
In order to reach better therapeutic effect, solid preparation of Chinese medicine of the present invention is preferably solid dispersed formulation, wherein, the excipient substance in the described solid dispersed formulation comprises calcium sulfate, microcrystalline Cellulose, crospolyvinylpyrrolidone and low-substituted hydroxypropyl cellulose; The weight proportion of the crude drug (schisandra chinensis medicinal material) of Fructus Schisandrae Chinensis is 1:1-2:15-22 in this microcrystalline Cellulose, calcium sulfate and the described Chinese medicinal components, and this crospolyvinylpyrrolidone and low-substituted hydroxypropyl cellulose are the 3-5% of the Chinese crude drug crude drug gross weight that adopted in the described Chinese medicinal components.
Therefore, if described solid preparation of Chinese medicine is dispersible tablet or pill, the excipient substance in the described solid dispersed formulation comprises calcium sulfate, microcrystalline Cellulose, crospolyvinylpyrrolidone, low-substituted hydroxypropyl cellulose and micropowder silica gel; The weight proportion of the crude drug (schisandra chinensis medicinal material) of Fructus Schisandrae Chinensis is 1:1-2:15-22 in this microcrystalline Cellulose, calcium sulfate and the described Chinese medicinal components, this weight ratio is that the crospolyvinylpyrrolidone of 2-0.5:1 and low-substituted hydroxypropyl cellulose are the 3-5% of the Chinese crude drug crude drug gross weight that adopted in the described Chinese medicinal components, the weight of this micropowder silica gel be no more than described solid dispersed formulation weight 3%.
Therefore, the Chinese medicinal components in the solid preparation of the present invention preferably preferably obtains by the following method:
Get Semen Ziziphi Spinosae and Radix Salviae Miltiorrhizae, add 4-10 and doubly measure the 30-70% alcohol reflux, extracting solution concentrates, and filters, filtrate is passed through macroporous adsorptive resins, the water eluting, eluent discards, reuse 50-90% ethanol elution, collect ethanol elution, reclaim ethanol and be concentrated into the magma that relative density is 1.0-1.02 (60～70 ℃), drying, the powder that gets dry extract is the extract of Semen Ziziphi Spinosae and Radix Salviae Miltiorrhizae;
Get Fructus Schisandrae Chinensis, add 5-10 and doubly measure the 50-85% ethanol extraction, extracting solution is concentrated into the thick paste of 60～70 ℃ of following relative density 1.0-1.20, adds 1-5 times of water gaging to thick paste, leaves standstill, and is centrifugal, is precipitated as Fructus Schisandrae Chinensis extrat;
The extract of above-mentioned Semen Ziziphi Spinosae and Radix Salviae Miltiorrhizae and Fructus Schisandrae Chinensis extrat are described Chinese medicinal components.
The inventor has developed solid preparation, and especially dispersible tablet is as the tablet of representative.Dispersible tablet of the present invention has that disintegrate is fast, release rapidly, the bioavailability advantages of higher, can also improve stability of drug simultaneously.
Can add the Aspartane that also can not add as correctives in the preparation of the present invention.
In a preferred embodiment of the invention, described preparation is a dispersible tablet, and it is the dispersible tablet that contains the Chinese medicine composition composition of traditional prescription, and its incomplete similarity is the special rapidly tablet of a kind of release in the conventional tablet that contains Chinese medicine composition.
The solid preparation of Chinese medicine of Cure for insomnia of the present invention is the improvement of tradition prescription dosage form (oral liquid formulation), it can keep it former effective in cure, has better, the stay-in-grade advantage of solid dosage forms dissolution rate and bioavailability again, and said preparation production mechanization, automaticity height, output are big, the medicament health is easily up to standard, take simultaneously, carry, storage etc. is more convenient, being convenient to modern production, is to meet the novel form that the medical sci-tech modernization requires.
Also can understand like this, solid preparation of Chinese medicine of the present invention obtains by the following method:
The invention provides a kind of preparation method of solid preparation of Chinese medicine of Cure for insomnia, this method comprises:
Get Semen Ziziphi Spinosae and Radix Salviae Miltiorrhizae, add 4-10 and doubly measure the 30-70% alcohol reflux, extracting solution concentrates, and filters, filtrate is passed through macroporous adsorptive resins, the water eluting, eluent discards, reuse 50-90% ethanol elution, collect ethanol elution, reclaim ethanol and be concentrated into the magma that relative density is 1.02 (60～70 ℃), drying, the powder that gets dry extract is the extract of Semen Ziziphi Spinosae and Radix Salviae Miltiorrhizae;
Get Fructus Schisandrae Chinensis, add 5-10 and doubly measure the 50-85% ethanol extraction, extracting solution is concentrated into the thick paste of 60～70 ℃ of following relative densities 1.20, and thick paste adds 1-5 times of water gaging, leaves standstill, and is centrifugal, is precipitated as Fructus Schisandrae Chinensis extrat;
The Semen Ziziphi Spinosae that above-mentioned preparation method obtains and the extract of Radix Salviae Miltiorrhizae and Fructus Schisandrae Chinensis extrat mixing are Chinese medicinal components of the present invention, this Chinese medicinal components is mixed with excipient substance, handle by conventional preparation process again, can obtain the solid preparation of Chinese medicine of Cure for insomnia of the present invention.
For example: above-mentioned Fructus Schisandrae Chinensis extrat adds excipient substance, the ratio of Fructus Schisandrae Chinensis and excipient substance is a schisandra chinensis medicinal material: calcium sulfate: microcrystalline Cellulose=22-15:2-1:1 stirs drying, mix with the dried cream powder of the extract of above-mentioned Semen Ziziphi Spinosae and Radix Salviae Miltiorrhizae, add excipient substance, addition is that the 5-3% of medical material total amount, wherein PVPP: L-HPC is 2-0.5:1, granulate, mix, make needed dosage form.
Above-mentioned preparation method is preferably: get Semen Ziziphi Spinosae and Radix Salviae Miltiorrhizae, add 4-10 and doubly measure the 30-70% alcohol reflux, extracting solution concentrates, and filters, filtrate is passed through macroporous adsorptive resins, the water eluting, eluent discards, reuse 50-90% ethanol elution, collect ethanol elution, reclaim ethanol and be concentrated into the magma that relative density is 1.02 (60～70 ℃), drying, the powder that gets dry extract is the extract of Semen Ziziphi Spinosae and Radix Salviae Miltiorrhizae;
Fructus Schisandrae Chinensis adds 5-10 and doubly measures the 50-85% ethanol extraction, and it is 1.20 thick paste that extracting solution is concentrated into 60～70 ℃ of following relative densities, and thick paste adds 1-5 times of water gaging, leaves standstill, and is centrifugal, is precipitated as Fructus Schisandrae Chinensis extrat;
Above-mentioned Fructus Schisandrae Chinensis extrat adds calcium sulfate and microcrystalline Cellulose (1-2:1) mixture, the ratio of Fructus Schisandrae Chinensis and calcium sulfate and microcrystalline cellulose mixt is 6-8:1, stir, dry, mix with the dried cream powder of the extract of above-mentioned Semen Ziziphi Spinosae and Radix Salviae Miltiorrhizae, add crospolyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, ratio is that PVPP: L-HPC is 2-0.5:1, addition is the 5-3% of medical material total amount, granulates, and adds micropowder silica gel and microcrystalline Cellulose 1.5-1% again, the additional proportion of dried cream powder and micropowder silica gel and microcrystalline Cellulose is 1.5-0.1%, mix, make needed dosage form (solid dispersed formulation), preferred dispersible tablet and/or pill.
What deserves to be mentioned is, the preferred solid dispersed formulation of the present invention is the dispersion dosage form that contains the Chinese medicine composition composition of traditional prescription, dispersible tablet for example, it not exclusively is similar to the conventional tablet that contains Chinese medicine composition, it is the special rapidly tablet of a kind of release, for a person skilled in the art, screening is fit to the extraction and purification process of the improvement dosage form (for example dispersible tablet) of the especially specific prescriptions of Chinese medicine that is suitable for liquid dosage form of certain specific prescription, the adjuvant of preparation and proportioning thereof, its difficulty is far longer than the screening at the improvement dosage form of chemicals, even difficulty is also greater than the formulation and technology at the common solid preparation of the specific prescriptions of Chinese medicine that is suitable for liquid dosage form, the screening of adjuvant and proportioning thereof.
As herein described times of amount is the weight multiple, and alcoholic acid percent concentration is mass percent concentration.
The present invention is as follows to the extraction and purification process research of each component of Chinese medicine composition:
To content of danshinolic acid B assay method in jujuboside A content assaying method and the Radix Salviae Miltiorrhizae referring to pharmacopeia.
1 Semen Ziziphi Spinosae, Radix Salviae Miltiorrhizae Study on extraction.
1.1 extract the preferred of solvent.
Taking by weighing Semen Ziziphi Spinosae 50g, Radix Salviae Miltiorrhizae 10g by recipe quantity, is solvent with 8 times of water gagings and different concentration ethanol, is index with jujuboside A and salvianolic acid B extracted amount, carries out reflux, extract,, the results are shown in Table 1.
Table 1 Semen Ziziphi Spinosae, Radix Salviae Miltiorrhizae extract solvent preferred result table
The result shows, Different concentrations of alcohol to the extraction ratio of jujuboside A and salvianolic acid B than water height, the ethanol of 30%-70% is higher to jujuboside A and salvianolic acid B extraction ratio, and determining alcohol is higher than 80% content of danshinolic acid B to be reduced on the contrary, so select for use 30-70% ethanol to extract.
1.2 it is preferred to extract the solvent load experiment.
Take by weighing Semen Ziziphi Spinosae 50g, Radix Salviae Miltiorrhizae 10g by recipe quantity, with different concentration ethanol, different volumes and extraction time be the influence factor, every factor is selected two levels, arranges orthogonal experiment with L8 (27) orthogonal table.With jujuboside A, content of danshinolic acid B is index, analyzes orthogonal experiments and omits herein.
By intuitive analysis as can be known, influence the factor that jujuboside A extracts: the ethanol volume〉extraction time, influence the factor that salvianolic acid B extracts: the ethanol volume〉extraction time, through variance analysis, ethanol volume, extraction time are to jujuboside A and salvianolic acid B extraction ratio there was no significant difference, carry out demonstration test respectively by said extracted technology, the results are shown in Table 2.
Table 2 Semen Ziziphi Spinosae, Radix Salviae Miltiorrhizae extract the demonstration test result
The result shows that extraction conditions stablizes feasible.
2 Semen Ziziphi Spinosaes, Radix Salviae Miltiorrhizae purification with macroreticular resin technical study.
Macroporous adsorbent resin is a class organic polymer adsorbent, has absorption property preferably, begin to be applied to the extraction separation of Chinese herbal medicine chemical constituent in recent years, be extraction separation Chinese herbal medicine water soluble ingredient effective ways, still adopt this method purification Semen Ziziphi Spinosae, Radix Salviae Miltiorrhizae extract, improve curative effect to reduce dose.
2.1 the concentrated solution volume is optimized.
Get and contain recipe quantity Semen Ziziphi Spinosae, Radix Salviae Miltiorrhizae 3 parts of the extracting solution of 20g medical material altogether, reclaim ethanol respectively, be concentrated into volume and be 4,6,8 times of medical material amount, filter, HPLC measures jujuboside A, content of danshinolic acid B in the filtrate, the results are shown in Table 3.
Table 3 concentrated solution volume is optimized the result
The result shows, extracting solution concentrate volume to 6 times and 8 times of medical material amount difference little.
2.2 the macroporous adsorbent resin model is selected
The preparation of sample solution: take by weighing Semen Ziziphi Spinosae 5kg by recipe quantity, Radix Salviae Miltiorrhizae 1kg extracts as stated above, concentrates, and filters, and as sample solution, HPLC measures jujuboside A and content of danshinolic acid B in the filtrate.
2.2.1 static adsorption is investigated
Select the macroporous adsorbent resin (having removed a lot of impurity) of HPD100, HPD300, HPD450, HPD600, HPD700 and AB-8 six kind of different model according to the chemical property of medicine, clean with distilled water after the pretreatment respectively, decompressing and extracting 5min, standby, get 10ml respectively, put in the tool plug conical flask, add sample solution 200mL, fully stir the back standing over night, filter, measure jujuboside A and content of danshinolic acid B in the filtrate respectively, calculate, the results are shown in Table 4 than adsorbance and adsorption rate.
Table 4 jujuboside A resin static adsorption amount, adsorption rate result
Amass/the dried resin quality than adsorbance=(sample liquid concentration before the absorption-absorption back sample liquid concentration) * sample liquid; Sample liquid concentration * 100% before adsorption rate=(sample liquid concentration before the absorption-absorption back sample liquid concentration)/absorption.
2.2.2 steady-state solution absorption is investigated
Get the resin behind the above-mentioned absorption sample liquid, add 95% ethanol 100mL respectively, fully stir the back standing over night, filter, measure jujuboside A and content of danshinolic acid B in the filtrate respectively, calculate the steady-state solution adsorbance, the results are shown in Table 5.
Table 5 jujuboside A resin desorption amount, desorption efficiency result
Than sample liquid concentration after desorption quantity=desorbing * stripping liquid volume/dried resin quality, desorption efficiency=than desorption quantity/than adsorbance * 100%
The result shows that HPD100 type macroporous adsorbent resin is better to absorption of jujuboside A and salvianolic acid B and desorption effect, so selection HPD100 type macroporous adsorbent resin.
2.23 last sample flow velocity and maximal absorptive capacity are investigated
Take by weighing HPD100 macroporous adsorbent resin 70g after the pretreatment, 3 parts, distilled water dress post, last sample (sample liquid concentration is 6 times of medical material volumes), flow velocity are respectively 1,2 and 3BV/h, collected post liquid, (0.167g medical material/ml), measured jujuboside A and content of danshinolic acid B in the post liquid is a vertical coordinate with jujuboside A and content of danshinolic acid B to 50mL/ part, it is long-pending for the abscissa mapping to cross post liquid, draws leakage plot.
By leakage plot as can be known, last sample flow velocity is 1,2 and during 3BV/h, crossing in the post liquid salvianolic acid B obviously leaks 14,14 and 12 parts of beginnings respectively, therefore determine that going up the sample flow velocity is 1-2BV/h, do not detect jujuboside A in the effluent this moment, so with the leakage point of the salvianolic acid B foundation as definite maximum applied sample amount, sample concentrated solution 700ml on this moment, contain medical material 116.7g, i.e. medical material: resin (g)=1.7:1.Maximum applied sample amount is a medical material when therefore, determining big production by 80% of maximum applied sample amount: wet resin (g)=1.3:1.
2.2.4 blade diameter length ratio is investigated
Take by weighing HPD100 macroporous adsorbent resin 70g after the pretreatment, blade diameter length ratio is respectively 1:3,1:5,1:7, sample liquid 700ml, last sample flow velocity 2BV/h, 2BV distilled water eluting, flow velocity 2BV/h, the 4BV70% ethanol elution, flow velocity 2BV/h collects ethanol elution, measure wherein jujuboside A content of danshinolic acid B respectively, the results are shown in Table 6.
Table 6 blade diameter length ratio is investigated jujuboside A, salvianolic acid B eluting rate
The result shows, jujuboside A when blade diameter length ratio is 1:5 and 1:7, salvianolic acid B eluting rate are approaching, all greater than 1:3.
2.2.5 the water elution multiple is investigated.
Take by weighing HPD100 macroporous adsorbent resin 70g after the pretreatment, sample liquid 700mL is by sample on the above-mentioned condition, distilled water eluting, flow velocity 2BV/h collects eluent, and 1BV/ part is measured wherein jujuboside A and content of danshinolic acid B, and measure an amount of eluent, evaporate to dryness is measured its solid content, the results are shown in Table 7.
Table 7 water elution multiple is investigated the result
The result shows that behind the distilled water eluting, solid content promptly obviously descends, and is 1BV so select the water elution volume.
2.2.6 ethanol elution concentration and multiple are investigated.
Take by weighing HPD100 macroporous adsorbent resin 70g after the pretreatment, 3 parts, sample liquid 700mL is by sample, water elution on the above-mentioned condition, respectively with 30,50,70,90,95% ethanol elution, flow velocity 2BV/h collects eluent, every part of 1/2BV, measure wherein jujuboside A and content of danshinolic acid B, be vertical coordinate with jujuboside A and salvianolic acid B respectively, eluent stream part is an abscissa, draws elution curve.
By elution curve as can be known, 50-90% ethanol is stronger to jujuboside A, salvianolic acid B eluting power, 70% ethanol elution effect optimum, and elution volume is defined as 4BV.
2.2.7 determining of ethanol elution flow velocity.
Take by weighing HPD100 macroporous adsorbent resin 70g after the pretreatment, 3 parts, sample liquid 700mL is by sample on the above-mentioned condition, distilled water eluting, respectively with 70% ethanol elution, flow velocity is respectively 2,3,4BV/h, collects eluent, every part of 1/2BV, measure wherein jujuboside A and content of danshinolic acid B, the results are shown in Table 8.
The different elution flow rate of table 8 index eluting rates to be measured (%)
The result shows that elution flow rate is little to the influence of salvianolic acid B eluting rate; Elution flow rate is 2, jujuboside A eluting rate is more or less the same during 3BV/h, is better than elution flow rate 4BV/h.
2.28 drying process.
According to the physicochemical property of extract, list of references
[6]Selecting spray drying, just have precipitation to separate out when eluent is concentrated into relative density after greater than 1.02 (60～70 ℃) through test, is 1.02 (60～70 ℃) so definite eluent is concentrated into relative density.This moment, material viscosity was moderate, the sticking wall of blocking pipeline not during spraying, and powder is loose, and color and luster is even, and character is good.
2.2.9 scale-up research.
Take by weighing recipe quantity medical material 3.0kg (Semen Ziziphi Spinosae 2500g, Radix Salviae Miltiorrhizae 500g), measure 50% alcohol reflux 3 times with 8 times, each 2 hours, merge extractive liquid, filters filtrate recycling ethanol to 6 times medical material volume, filter, (the HPD100 resin: 2308g), 1BV distilled water eluting discards HPD100 post on the filtrate, reuse 4BV70% ethanol elution, collect alcohol eluen, decompression recycling ethanol also is concentrated into the magma that relative density is 1.02 (60～70 ℃), spray drying (150 ℃ of intake air temperatures, 75 ℃ of air outlet temperature, feed liquor speed 25ml/min), the results are shown in Table 9, prove that this scheme is feasible.
Table 9 Semen Ziziphi Spinosae, Radix Salviae Miltiorrhizae extract purification scale-up result
3 Fructus Schisandrae Chinensis Study on extraction
The schisandrin content assaying method:
The system suitability test: with octadecylsilane chemically bonded silica is filler; Methanol-water (65:35) is mobile phase; The detection wavelength is 250nm.
The preparation of reference substance solution: it is an amount of that precision takes by weighing the schisandrin reference substance, adds methanol and make the solution that 1ml contains schisandrin 0.06mg, promptly.
The preparation of need testing solution: the accurate extracting solution 5ml that draws, put the 25ml measuring bottle, extract solvent dilution to scale, shake up, promptly.
Algoscopy: accurate respectively reference substance solution 5ul and each 10 μ l of need testing solution of drawing, inject chromatograph of liquid, measure, promptly.
3.1 it is preferred to extract solvent
The tranquillizing and allaying excitement active ingredient is mainly lignin in the Fructus Schisandrae Chinensis, select schisandrin as the index sexual element, getting 50g Fructus Schisandrae Chinensis (schisandrin content 4.175mg/g) respectively extracts with 40,50,60,75,85,95% ethanol, each 1.5h that extracts, extract 2 times, merge extractive liquid, is measured schisandrin content in the extracting solution, the results are shown in Table 10.
Table 10 Fructus Schisandrae Chinensis extracts the solvent preferred result
The result shows that 50-85% ethanol is higher for schisandrin extraction ratio in the Fructus Schisandrae Chinensis, therefore selects for use 50-85% ethanol that Fructus Schisandrae Chinensis is extracted.
3.2 orthogonal experiment is preferred
With extraction time, extraction time and ethanol volume is the influence factor, and every factor is selected three levels, with L9 (3
4) orthogonal table is arranged orthogonal experiment, is index with schisandrin content, analyzes orthogonal experiments, the results are shown in Table 11,12,13.
Table 11 Fructus Schisandrae Chinensis extracts orthogonal test factor level table
Table 12 Fructus Schisandrae Chinensis extraction process orthogonal experiments
13 Fructus Schisandrae Chinensis The results of analysis of variance
Through intuitive analysis as can be known, influence the factor of schisandrin extracted amount: extraction time (A)〉ethanol multiple (C)〉extraction time (B).Through variance analysis, extraction time (A) has the significance influence to the schisandrin extracted amount, and extraction time (B) ethanol multiple (C) does not have the significance influence to the schisandrin extracted amount.Determine that thus the Fructus Schisandrae Chinensis extraction process is A
3B
1C
2, promptly measure 75% ethanol extraction 3 times, each 1 hour for 8 times.Carry out demonstration test 3 times by above-mentioned optimised process, the results are shown in Table 14.
Table 14 Fructus Schisandrae Chinensis extracts the demonstration test result
The result shows that the preferred process stabilizing of orthogonal test is feasible.
3.3 Fructus Schisandrae Chinensis purifying process research.
3.3.1 Fructus Schisandrae Chinensis water precipitating density is preferred.
Get Fructus Schisandrae Chinensis (schisandrin content 5.89mg/g) 600g, extract as stated above, extracting solution is divided into 3 parts, being concentrated into relative density respectively is the thick paste of 1.1,1.2,1.3 (60～70 ℃), adds 3 times of water gagings of thick paste respectively, leaves standstill 24h after fully stirring, centrifugal, precipitation part drying under reduced pressure (70 ℃) is measured wherein schisandrin content, the results are shown in Table 15.
Table 15 Fructus Schisandrae Chinensis water precipitating density preferred result
The result shows, it is that schisandrin content is higher in 1.2 o'clock precipitation parts that extracting solution is concentrated into relative density, is 1.2 (60～70 ℃) so select concentrated relative density.
3.3.2 Fructus Schisandrae Chinensis water precipitating volume is preferred.
Take by weighing Fructus Schisandrae Chinensis 800g, extract as stated above, extracting solution is divided into 4 parts, being concentrated into relative density is the thick paste of 1.2 (60～70 ℃), adds 1,3,5,7 times of water gagings of thick paste respectively, leaves standstill 24h (0～4 ℃) after fully stirring, centrifugal, precipitation part drying under reduced pressure (70 ℃) is measured wherein schisandrin content, the results are shown in Table 16.
Table 16 Fructus Schisandrae Chinensis water precipitating volume preferred result
When the result added 3 times of thick paste water gagings, precipitation part schisandrin content was higher, and selecting to add the water multiple is 3 times of thick paste volumes.
3.3.3 the Fructus Schisandrae Chinensis water precipitating time is investigated.
Take by weighing Fructus Schisandrae Chinensis 600g, extract as stated above, extracting solution is divided into 3 parts, being concentrated into relative density is the thick paste of 1.2 (60～70 ℃), adds 3 times of water gagings of thick paste respectively, leaves standstill 12,24 after fully stirring respectively, 36h, centrifugal, precipitation part drying under reduced pressure (70 ℃) is measured schisandrin content, sees Table 17.
Table 17 Fructus Schisandrae Chinensis water precipitating volume preferred result
Paste-forming rate and schisandrin content are higher during 24 hours sedimentation times as a result, so the selective precipitation time is 24 hours.
3.3.4 scale-up research.
Take by weighing Fructus Schisandrae Chinensis 1.0kg, extract as stated above, concentrate, add water and leave standstill 24h, centrifugal, precipitation part drying under reduced pressure (70 ℃) is measured wherein schisandrin content, repeats 3 times, the results are shown in Table 18, proves that this scheme is feasible.
Table 18 Fructus Schisandrae Chinensis scale-up result
Technology pharmacology evaluation study of the present invention.
Said extracted technology and purifying process and original oral liquid have carried out pharmacologically active comparative study, the results are shown in Table 17.Wherein, the setting of dosage: sedative jujube kernel dispersible tablet extract and original oral liquid are all established high and low two dosage groups, are respectively 6.06,3.03g crude drug/kg, are equivalent to 2 and 1 times of the clinical consumption per day of people.The stable dosage of positive control drug is 0.75mg/kg, is equivalent to people's clinical equivalent dosage.
The influence of the common mouse sleep time that table 18 sedative jujube kernel dispersible tablet different process extract causes pentobarbital sodium
The result shows, two dosage groups of high dose group, craft screening sample 2 and the original oral liquid of sedative jujube kernel dispersible tablet craft screening sample 1 can both obviously prolong the length of one's sleep of the common mice that is caused by pentobarbital sodium, and sample 2 high dose group can obviously shorten common mice dropping asleep latency, interpret sample 1, sample 2 and original oral liquid all have the effect of tranquilizing soporific, technology 2 had both reduced dose, the curative effect that has kept original oral liquid again proves this feasible process.
Study on Forming
1, Chu Fang research.
1.1 the selection of adjuvant.
Report according to domestic and international data of literatures, physicochemical properties in conjunction with this product, this product adopts the wet granule compression tablet method, initial option ethanol is as binding agent, crospolyvinylpyrrolidone (PVPP), microcrystalline Cellulose (MCC), carboxymethylstach sodium, low substituted hydroxy-propyl methylcellulose (L-HPC) screens as disintegrating agent.
1.2 the screening of prescription.
1.2.1 the selection of Fructus Schisandrae Chinensis filler.
Fructus Schisandrae Chinensis extrat is the alcohol extracting-water precipitating thing, and the cream thickness is difficult for directly obtaining exsiccant Fructus Schisandrae Chinensis powder, and according to related data, we select calcium sulfate and microcrystalline Cellulose as the filler of Fructus Schisandrae Chinensis extrat, can obtain dry Fructus Schisandrae Chinensis powder behind mix homogeneously.
The selection of table 19 Fructus Schisandrae Chinensis filler
| Mark | Schisandra chinensis medicinal material amount (g) | Calcium sulfate (g) | Microcrystalline Cellulose (g) | Experimental result |
| 1 | 30 | - | 1.6 | Sticking, can not become powder |
| 2 | 30 | 1.6 | - | Sticking, can not become powder |
| 3 | 30 | - | 3.2 | Sticking, can not become powder |
| 4 | 30 | 3.2 | - | Sticking, can not become powder |
| 5 | 30 | 1.6 | 1.6 | Sticking, can not become powder |
| 6 | 30 | - | 4.8 | Of course, can become powder |
| 7 | 30 | 4.8 | - | Of course, can become powder |
| 8 | 30 | 1.6 | 3.2 | Of course, can become powder |
| 9 | 30 | 3.2 | 1.6 | Of course, can become powder |
| 10 | 30 | 2.4 | 1.6 | Effective, consumption is few, and the stipulated time can disintegrate |
By above test, we determine that the ratio of Fructus Schisandrae Chinensis filler is: schisandra chinensis medicinal material-calcium sulfate-microcrystalline Cellulose=18.75:1.5:1.
1.2.2 the screening of disintegrating agent
According to domestic and international pertinent literature report,, tentatively select crospolyvinylpyrrolidone (PVPP), microcrystalline Cellulose (MCC), carboxymethylstach sodium for use, low substituted hydroxy-propyl methylcellulose (L-HPC) in conjunction with this product character.Experimental result sees the following form.
With 1 part of the extract (50 tablet recipe amounts: Semen Ziziphi Spinosae 178.6g, Radix Salviae Miltiorrhizae 35.7g, Fructus Schisandrae Chinensis 35.7g) of recipe quantity, the design prescription.
Table 20 disintegrating agent kind is to the influence of disintegrate
Conclusion: integrated cost, select PVPP:L-HPC=1:1 for use.
Add influence in table 21 disintegrating agent to disintegrate
| In add | Add | Disintegration time | |
| 1 | 100％ | ＜1.5min can be by No. 2 sieves | |
| 2 | 50％ | 50％ | ＜40 seconds can be by No. 2 sieves |
| 3 | 66.7％ | 33.3％ | ＜1min can be by No. 2 sieves |
Conclusion: by experiment as can be known, inside and outside addition slightly is better than interior addition, but interior addition more is applicable to big production, therefore adopts the interior addition of PVPP: L-HPC (1:1).Disintegration is in 1.5 minutes.
1.2.3 the selection of binding agent
Table 22 different concentration ethanol
| Different determining alcohols | Particle state | Disintegration time (second) | |
| 1 | 60% ethanol | Mouldability is fine, does not almost have loose powder | 155 |
| 2 | 75% ethanol | Mouldability is better, and loose powder is less | 78 |
| 3 | 85% ethanol | Mouldability is relatively poor, and loose powder is less | 56 |
| 4 | 95% ethanol | Almost can not become granule, loose powder is a lot | 48 |
Conclusion: the adhesive of selecting 75% ethanol preparation.
1.2.4 the selection of lubricant quantity
Selecting the conventional lubricants micropowder silica gel for use is lubricant, and the disintegrating agent, the correctives that add in the principal agent powder is reached are granulated, and add the micropowder silica gel of different proportion, observe its flowability.The results are shown in following table 23:
The screening of table 23 lubricant micropowder silica gel consumption
According to above-mentioned experimental result as seen, when the lubricant micropowder silica gel is 0.5%, particle mobile better, in line with reaching the preparation purpose, the few more good more principle of adjuvant, the content that we select lubricant is 0.5%.
In sum, the most preferred production technology prescription determined of the present invention is as follows:
Semen Ziziphi Spinosae (stir-fry) 3572g
Radix Salviae Miltiorrhizae 714g
Fructus Schisandrae Chinensis (vinegar system) 714g
Calcium sulfate: microcrystalline Cellulose=1.5: 1 95g
Crospolyvinylpyrrolidone 95g
Low-substituted hydroxypropyl cellulose 95g
Aspartane 2.3g
Micropowder silica gel 2.3g
Microcrystalline Cellulose adds an amount of tab heavily to 0.45
Make 1000
Carry out three batches of pilot scale researches according to above-mentioned definite process conditions, the results are shown in Table 24.
Three batches of finished product pilot processes of table 24 data
Conclusion: through checking three batch samples qualified.This process stabilizing is rationally feasible, is suitable for big production.
Pilot scale three quality of lot testing results show that this process stabilizing is rationally feasible, are suitable for the big production of industry.
In addition, can also add Aspartane in the preparation of the present invention, it is a correctives.
The drug effect comparative test
1. the sedative jujube kernel dispersible tablet is to the influence of normal mouse autonomic activities.
Select the ICR mice for use, be divided into 6 groups at random according to body weight, every group 10, be respectively the stable group of blank group, positive control drug, the stable dosage of positive control drug is 0.75mg/kg, sedative jujube kernel oral liquid group (3.03g crude drug/kg) be equivalent to people's clinical equivalent dosage, sedative jujube kernel dispersible tablet height (6.06g crude drug/kg), in (3.03g crude drug/kg), low (the dosage group of 1.515g crude drug/kg) is equivalent to 2,1 and 0.5 times of the clinical consumption per day of people respectively.Each medicine all adopts the per os gastric infusion mode consistent with the clinical administration approach, behind oral drugs 60min, 10 mices of each group are put into autonomic activities instrument active box respectively, adapt to the number of times that writes down mice autonomic activities in 10 minutes after 5 minutes automatically, repeat 5 times.This test quiet, room temperature and do not have direct light according under carry out, observe and respectively organize the influence of medicine common mice autonomic activities.The result shows: compare the stable group of autonomic activities (P＜0.01) that can significantly reduce normal mouse with the blank group; Sedative jujube kernel oral liquid group is not seen tangible influence to the autonomic activities of normal mouse; Sedative jujube kernel dispersible tablet high dose group can significantly reduce the autonomic activities (P＜0.05) of normal mouse, in the sedative jujube kernel dispersible tablet, low dose group do not see tangible influence to the autonomic activities of normal mouse.
2. the sedative jujube kernel dispersible tablet is to the influence of deficiency of YIN mice autonomic activities.
This test quiet, room temperature and do not have direct light according under carry out, observe and respectively organize the influence of medicine common mice autonomic activities.The result represents: compare with the blank group, model control group autonomic activities number of times obviously increases (P＜0.05); The autonomic activities number of times of sedative jujube kernel oral liquid group, sedative jujube kernel dispersible tablet height, middle dosage group mice obviously reduces (being P＜0.05); The autonomic activities number of times of sedative jujube kernel dispersible tablet low dose group mice is not seen obvious change.Stable, sedative jujube kernel oral liquid group and sedative jujube kernel dispersible tablet height, middle dosage all have tangible sedation to deficiency of YIN mice.
3 sedative jujube kernel dispersible tablets are to the influence of the length of one's sleep due to the normal mouse pentobarbital sodium.
The result of the test prompting: compare with the blank group, stable group (P＜0.01), sedative jujube kernel oral liquid group and high, medium and low each the dosage group of sedative jujube kernel dispersible tablet all can assist pentobarbital sodium obviously to prolong the length of one's sleep (being P＜0.05) of normal mouse.Stable group (P＜0.01) and sedative jujube kernel dispersible tablet high dose group (P＜0.05) all can obviously shorten the normal mouse dropping asleep latency.Sedative jujube kernel dispersible tablet and sedative jujube kernel oral liquid all have tangible syngignoscism.
4 sedative jujube kernel dispersible tablets are to the influence of the length of one's sleep due to the deficiency of YIN mice pentobarbital sodium.
Result of the test is represented: compare with the blank group, the sleep of model control group mice obviously prolongs (P＜0.05) incubation period, then obviously shortens the length of one's sleep (P＜0.05); Compare with model control group, stable group can significantly be shortened deficiency of YIN mice sleep incubation period (P＜0.01), and prolongs its length of one's sleep (P＜0.01); High, medium and low each the dosage group of sedative jujube kernel oral liquid and sedative jujube kernel dispersible tablet all can assist pentobarbital sodium obviously to prolong the length of one's sleep (being P＜0.05) of deficiency of YIN mice; And sedative jujube kernel oral liquid group, sedative jujube kernel dispersible tablet height, middle dosage all can obviously shorten the dropping asleep latency (P＜0.05) of deficiency of YIN model mice; Sedative jujube kernel dispersible tablet low dosage is not seen obvious influence to the dropping asleep latency of deficiency of YIN model mice.
5 sedative jujube kernel dispersible tablets are to the influence of normal mouse pentobarbital sodium sub-threshold lull dosage.
Result of the test: compare with the blank group, stable group (P＜0.01) and sedative jujube kernel dispersible tablet height, middle dosage group can obviously be worked in coordination with the syngignoscism (be P＜0.05) of pentobarbital sodium to normal mouse.Sedative jujube kernel low dose group and sedative jujube kernel oral liquid group are not then seen obvious effect.
6 sedative jujube kernel dispersible tablets are to the influence of deficiency of YIN mice pentobarbital sodium sub-threshold lull dosage.
Result of the test shows: compare with model control group, stable group can significantly increase the sleep number of animals (being P＜0.05) that sleep number of elements (P＜0.01), sedative jujube kernel oral liquid group and the sedative jujube kernel dispersible tablet height of mice, middle dosage group all can obviously increase deficiency of YIN mice, and the syngignoscism of obvious synergistic pentobarbital sodium is all arranged; Sedative jujube kernel dispersible tablet low dose group is not seen significant change.
The above results shows: under this experiment condition, sedative jujube kernel dispersible tablet high dose group can obviously reduce the autonomic activities number of times; Each dosage group of sedative jujube kernel oral liquid and sedative jujube kernel dispersible tablet all can assist pentobarbital sodium obviously to prolong the length of one's sleep of normal mouse, and sedative jujube kernel dispersible tablet high dose group can obviously shorten the normal mouse dropping asleep latency; Sedative jujube kernel dispersible tablet height, middle dosage group have obvious synergistic pentobarbital sodium sub-threshold dose syngignoscism.
To deficiency of YIN model mice, sedative jujube kernel dispersible tablet height, middle dosage group can obviously reduce the autonomic activities number of times, have tangible sedation; Each dosage group of sedative jujube kernel dispersible tablet and sedative jujube kernel oral liquid can prolong the length of one's sleep due to the pentobarbital sodium, and sedative jujube kernel dispersible tablet height, middle dosage all can obviously shorten the dropping asleep latency of deficiency of YIN model mice; Sedative jujube kernel dispersible tablet height, middle dosage group and sedative jujube kernel oral liquid group all can obviously increase the sleep number of animals of deficiency of YIN mice, have obvious synergistic pentobarbital sodium sub-threshold dose syngignoscism.
In sum, show by the pharmacodynamics test that normal and deficiency of YIN mice are carried out: under this experiment condition, the therapeutic effect of sedative jujube kernel dispersible tablet is equivalent to former dosage form on most indexs, is better than former dosage form on some index.
Toxicologic study.
1. acute toxicity test.
The result shows: because of being subjected to the restriction of administration concentration and administration volume, in the sedative jujube kernel dispersible tablet extract 24 hours with maximum administration concentration, maximum administration volume, mouse stomach administration 2 times, accumulative total administration 12.8g extract/kg (the 400g crude drug/kg), be equivalent to clinical 1212 times of drafting consumption, mice does not see tangible toxic reaction.The mice maximum tolerated dose is 12.8 extracts/kg (400g crude drug/kg), be equivalent to 1212 times of clinical plan consumption.
2. long term toxicity test.
The result shows: administration 90,180 days and drug withdrawal 30 days, each treated animal of experimental session all occur dead, just wait ordinary circumstance not have obvious influence to average weight, food-intake, the mental status, the behavioral activity, two of animal.Every hematological indices and serum biochemistry index fluctuateed in normal range, and uroscopy shows no obvious abnormalities.Gross anatomy is not seen the pathologic relevant with medicine with the pathological tissue morphological observation and is changed.
The high, medium and low dosage 0.84,0.42 of sedative jujube kernel dispersible tablet extract, 0.21g (extract)/Kg (26.25,13.125,6.56g (crude drug)/Kg) is equivalent to 79.2,39.6 and 19.8 times of three dosage successive administrations 180 days of clinical consumption, rat does not see the overt toxicity influence.
The specific embodiment
Describe the present invention in detail below in conjunction with embodiment, but do not limit practical range of the present invention.
Embodiment 1: dispersible tablet
Prescription: Semen Ziziphi Spinosae 3750g Radix Salviae Miltiorrhizae 750g Fructus Schisandrae Chinensis 750g
Preparation technology:
Get Semen Ziziphi Spinosae (fragmentation), Radix Salviae Miltiorrhizae, add 8 times of amount 50% alcohol reflux 3 times, each 1 hour, filter, merge extractive liquid, reclaims ethanol, concentrate and filter, filtrate is by HPD100 type macroporous adsorptive resins (medical material: resin (g)=1.3:1, blade diameter length ratio 1:5), last sample flow velocity 1-2BV/h, the 1BV water elution, flow velocity 2BV/h discards, reuse 4BV 70% ethanol elution, flow velocity 2～3BV/h, collect eluent, decompression recycling ethanol also is concentrated into the magma that relative density is 1.02 (60～70 ℃), the spray drying powder that gets dry extract; Get Fructus Schisandrae Chinensis (fragmentation), add 8 times of amount 70% ethanol extractions 3 times, each 1 hour, merge extractive liquid,, reclaim ethanol and be concentrated into the thick paste that relative density is 1.20 (60～70 ℃), add 3 times of water gagings of thick paste, left standstill 24 hours, centrifugal, get precipitation and add calcium sulfate and microcrystalline cellulose mixt (1.5:1) 95g, stir drying under reduced pressure (70 ℃), mix pulverizing with above-mentioned dried cream powder, cross 60 mesh sieves behind the mixing, add crospolyvinylpyrrolidone 95g, low-substituted hydroxypropyl cellulose 95g, Aspartane 2.3g, granulate, add micropowder silica gel 2.3g and an amount of microcrystalline Cellulose again, mix homogeneously, be pressed into 1000, promptly.
Embodiment 2: dispersible tablet
Prescription: Semen Ziziphi Spinosae 3750g Radix Salviae Miltiorrhizae 750g Fructus Schisandrae Chinensis 750g
Preparation technology:
Get Semen Ziziphi Spinosae (fragmentation), Radix Salviae Miltiorrhizae, add 8 times of amount 50% alcohol reflux 3 times, each 1 hour, filter merge extractive liquid,, reclaim ethanol, concentrate, filter, filtrate is by HPD100 type macroporous adsorptive resins (medical material: resin (g)=1.3:1, blade diameter length ratio 1:5), last sample flow velocity 1-2BV/h, 1BV water elution, flow velocity 2BV/h, discard, reuse 4BV 70% ethanol elution, flow velocity 2～3BV/h collects eluent, decompression recycling ethanol also is concentrated into the magma that relative density is 1.02 (60～70 ℃), the spray drying powder that gets dry extract; Get Fructus Schisandrae Chinensis (fragmentation), add 8 times of amount 70% ethanol extractions 3 times, each 1 hour, merge extractive liquid,, reclaim ethanol and be concentrated into the thick paste that relative density is 1.20 (60～70 ℃), add 3 times of water gagings of thick paste, leave standstill 24 hours, centrifugal, get precipitation and add calcium sulfate and microcrystalline cellulose mixt (1.5:1) 100g, stir, drying under reduced pressure (70 ℃) mixes pulverizing with above-mentioned dried cream powder, cross 80 mesh sieves behind the mixing, add crospolyvinylpyrrolidone 50g, low-substituted hydroxypropyl cellulose 50g, Aspartane 5g, granulate, add again and add the 50g crospolyvinylpyrrolidone again, 50g low-substituted hydroxypropyl cellulose, 5g magnesium stearate, micropowder silica gel 5g and an amount of microcrystalline Cellulose, mix homogeneously is pressed into 1000, promptly.
Embodiment 3: tablet
Prescription:
Semen Ziziphi Spinosae (stir-fry) 4167g Radix Salviae Miltiorrhizae 625g Fructus Schisandrae Chinensis (vinegar system) 208g
Preparation technology:
More than three the flavor, get Semen Ziziphi Spinosae (fragmentation), Radix Salviae Miltiorrhizae, add 10 times of amount 70% alcohol reflux 2 times, each 2 hours, filter, merge extractive liquid, reclaims ethanol, concentrates, filter, filtrate is crossed HPD100 type macroporous adsorptive resins (medical material: resin (g)=1:1, blade diameter length ratio 1:5), last sample flow velocity 0.5BV/h, the 2BV water elution, flow velocity 1-3BV/h discards, reuse 2-4BV 50% ethanol elution, flow velocity 2～5BV/h, collect ethanol elution, decompression recycling ethanol also is concentrated into the magma that relative density is 1.02 (60～70 ℃), the spray drying powder that gets dry extract; Get Fructus Schisandrae Chinensis (fragmentation), add 10 times of amount 50% ethanol extractions 2 times, each 1.5 hours, merge extractive liquid,, reclaim ethanol and be concentrated into the thick paste that relative density is 1.20 (60～70 ℃), add 5 times of water gagings of thick paste, leave standstill 24 hours, centrifugal, get precipitation and add calcium sulfate and microcrystalline cellulose mixt (1.5:1) 28g, stir, drying under reduced pressure (70 ℃) mixes pulverizing with above-mentioned dried cream powder, mixing is crossed 60 mesh sieves, add crospolyvinylpyrrolidone 95g, low-substituted hydroxypropyl cellulose 95g, Aspartane 2.3g, granulate, add micropowder silica gel 2.3g and an amount of microcrystalline Cellulose again, mix homogeneously is pressed into 1000.
Embodiment 4: granule
Prescription:
Semen Ziziphi Spinosae (stir-fry) 4762g Radix Salviae Miltiorrhizae 59g Fructus Schisandrae Chinensis (vinegar system) 178g
Preparation technology:
Get Semen Ziziphi Spinosae (fragmentation), Radix Salviae Miltiorrhizae, add 5 times of amount 45% alcohol reflux 3 times, each 2.5 hours, filter, merge extractive liquid,, reclaim ethanol, concentrate, filter, filtrate is by HPD100 type macroporous adsorptive resins (medical material: resin (g)=2.5:1, blade diameter length ratio 1:5), last sample flow velocity is 3BV/h, the 1.5-2BV water elution, flow velocity 1-2BV/h, discard reuse 2-4BV 90% ethanol elution, flow velocity 1～4BV/h, collect ethanol elution, decompression recycling ethanol also is concentrated into the magma that relative density is 1.02 (60～70 ℃), spray drying, and powder gets dry extract; Get Fructus Schisandrae Chinensis (fragmentation), add 10 times of amount 85% ethanol extractions 3 times, 1 hour/time, merge extractive liquid, reclaims ethanol and is concentrated into the thick paste that relative density is 1.20 (60～70 ℃), adds 4 times of water gagings of thick paste, left standstill 24 hours, centrifugal, get precipitation and add calcium sulfate and microcrystalline cellulose mixt (1.5:1) 24g, stir, drying under reduced pressure (70 ℃), mix pulverizing with above-mentioned dried cream powder, mixing is crossed 60 mesh sieves, adds crospolyvinylpyrrolidone 95g, low-substituted hydroxypropyl cellulose 95g, Aspartane 2.3g granulates, promptly.
Embodiment 5: capsule
Prescription:
Semen Ziziphi Spinosae (stir-fry) 4167g Radix Salviae Miltiorrhizae 625g Fructus Schisandrae Chinensis (vinegar system) 625g
Preparation technology:
Get Semen Ziziphi Spinosae (fragmentation), Radix Salviae Miltiorrhizae, add 5 times of amount 45% alcohol reflux 3 times, each 2.5 hours, filter, merge extractive liquid,, reclaim ethanol, concentrate, filter, filtrate is by HPD100 type macroporous adsorptive resins (medical material: resin (g)=2.5:1, blade diameter length ratio 1:5), last sample flow velocity 3BV/h, 1.5-2BV water elution, flow velocity 1-2BV/h, discard reuse 2-4BV 90% ethanol elution, flow velocity 1～4BV/h, collect ethanol elution, decompression recycling ethanol also is concentrated into the magma that relative density is 1.02 (60～70 ℃), spray drying, and powder gets dry extract; Get Fructus Schisandrae Chinensis (fragmentation), add 10 times of amount 85% ethanol extractions 3 times, each 1 hour, merge extractive liquid, reclaimed ethanol and is concentrated into the thick paste that relative density is 1.20 (60～70 ℃), add 4 times of water gagings of thick paste, leave standstill 24 hours, centrifugal, get precipitation and add calcium sulfate and microcrystalline cellulose mixt (1.5:1) 83g, stir, drying under reduced pressure (70 ℃) mixes pulverizing with above-mentioned dried cream powder, crosses 60 mesh sieves behind the mixing, add crospolyvinylpyrrolidone 103g, low-substituted hydroxypropyl cellulose 103g, Aspartane 5g granulates, encapsulated, promptly.
Embodiment 6: pill
Prescription:
Semen Ziziphi Spinosae (stir-fry) 4762g Radix Salviae Miltiorrhizae 59g Fructus Schisandrae Chinensis (vinegar system) 59g
Preparation technology:
Get Semen Ziziphi Spinosae (fragmentation), Radix Salviae Miltiorrhizae, add 8 times of amount 60% alcohol reflux 3 times, each 1.5 hours, filter, merge extractive liquid,, reclaim ethanol, concentrate, filter, filtrate is by HPD100 type macroporous adsorptive resins (medical material: resin (g)=2:1, blade diameter length ratio 1:5), last sample flow velocity is 0.5BV/h, the 1BV water elution, flow velocity 2-3BV/h, discard reuse 2-3BV 60% ethanol elution, flow velocity 2～4BV/h, collect ethanol elution, decompression recycling ethanol also is concentrated into the magma that relative density is 1.02 (60～70 ℃), and spray is done, and powder gets dry extract; Get Fructus Schisandrae Chinensis (fragmentation), add 7 times of amount 60% ethanol extractions 2 times, each 2 hours, merge extractive liquid,, reclaim ethanol and be concentrated into the thick paste that relative density is 1.20 (60～70 ℃), add 4 times of water gagings of thick paste weight, leave standstill 24 hours, centrifugal, get mixture (1.5:1) 8g that precipitation adds calcium sulfate and microcrystalline Cellulose (part), stir, drying under reduced pressure (70 ℃) mixes pulverizing with above-mentioned dried cream powder, cross 60 mesh sieves behind the mixing, add crospolyvinylpyrrolidone 93g, low-substituted hydroxypropyl cellulose 93g, Aspartane 3g, the system granule, drying adds a small amount of micropowder silica gel and surplus microcrystalline Cellulose, makes 1000 balls.
Aspartane is a correctives, can add also in the preparation of the present invention and can not add.
Claims (9)
1. the solid preparation of Chinese medicine of a Cure for insomnia comprises Chinese medicinal components and excipient substance, and this Chinese medicinal components is made up of the raw material of following weight portion: Semen Ziziphi Spinosae 2-8 part, Radix Salviae Miltiorrhizae 0.5-1.5 part and Fructus Schisandrae Chinensis 0.5-1.5 part; Wherein, in this solid preparation of Chinese medicine, Semen Ziziphi Spinosae, Radix Salviae Miltiorrhizae and Fructus Schisandrae Chinensis are that the form with separately alcohol extract exists; Described excipient substance comprises arbitrary or its mixture in calcium sulfate, microcrystalline Cellulose, crospolyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, micropowder silica gel, the starch;
Wherein, described Chinese medicinal components obtains by the following method:
Get Semen Ziziphi Spinosae and Radix Salviae Miltiorrhizae, add 4-10 and doubly measure the 30-70% alcohol reflux, extracting solution concentrates, and filters, filtrate is passed through macroporous adsorptive resins, the water eluting, eluent discards, reuse 50-90% ethanol elution, collect ethanol elution, reclaim ethanol and be concentrated into the magma of 60-70 ℃ of following relative density 1.0-1.02, drying, the powder that gets dry extract is the extract of Semen Ziziphi Spinosae and Radix Salviae Miltiorrhizae;
Get Fructus Schisandrae Chinensis, add 5-10 and doubly measure the 50-85% ethanol extraction, extracting solution is concentrated into the thick paste of 60-70 ℃ of following relative density 1.0-1.20, adds 1-5 times of water gaging to thick paste, leaves standstill, and is centrifugal, is precipitated as Fructus Schisandrae Chinensis extrat;
The extract of above-mentioned Semen Ziziphi Spinosae and Radix Salviae Miltiorrhizae and Fructus Schisandrae Chinensis extrat are described Chinese medicinal components.
2. solid preparation of Chinese medicine as claimed in claim 1, wherein, described solid preparation comprises tablet, granule, powder, the watered pill, honeyed pill, condensed water honeyed pill, capsule.
3. solid preparation of Chinese medicine as claimed in claim 1, wherein, described solid preparation is a solid dispersed formulation.
4. solid preparation of Chinese medicine as claimed in claim 3, wherein, the excipient substance in the described solid dispersed formulation comprises calcium sulfate, microcrystalline Cellulose, crospolyvinylpyrrolidone and low-substituted hydroxypropyl cellulose; The weight proportion of the crude drug of Fructus Schisandrae Chinensis is 1 in this microcrystalline Cellulose, calcium sulfate and the described Chinese medicinal components: 1-2: 15-22, this crospolyvinylpyrrolidone and low-substituted hydroxypropyl cellulose are the 3-5% of the Chinese crude drug crude drug gross weight that adopted in the described Chinese medicinal components.
5. solid preparation of Chinese medicine as claimed in claim 3, wherein, described solid dispersed formulation is dispersible tablet or pill.
6. solid preparation of Chinese medicine as claimed in claim 5, wherein, the excipient substance in the described solid dispersed formulation comprises calcium sulfate, microcrystalline Cellulose, crospolyvinylpyrrolidone, low-substituted hydroxypropyl cellulose and micropowder silica gel; The weight proportion of the crude drug of Fructus Schisandrae Chinensis is 1 in this microcrystalline Cellulose, calcium sulfate and the described Chinese medicinal components: 1-2: 15-22, this weight ratio is 2-0.5: 1 crospolyvinylpyrrolidone and low-substituted hydroxypropyl cellulose are the 3-5% of the Chinese crude drug crude drug gross weight that adopted in the described Chinese medicinal components, the weight of this micropowder silica gel be no more than described solid dispersed formulation weight 3%.
7. the preparation method of the described solid preparation of Chinese medicine of claim 1, this method comprises:
Get Semen Ziziphi Spinosae and Radix Salviae Miltiorrhizae, add 4-10 and doubly measure the 30-70% alcohol reflux, extracting solution concentrates, and filters, filtrate is passed through macroporous adsorptive resins, the water eluting, eluent discards, reuse 50-90% ethanol elution, collect ethanol elution, reclaim ethanol and be concentrated into the magma of 60～70 ℃ of following relative density 1.0-1.02, drying, the powder that gets dry extract is the extract of Semen Ziziphi Spinosae and Radix Salviae Miltiorrhizae;
Get Fructus Schisandrae Chinensis, add 5-10 and doubly measure the 50-85% ethanol extraction, extracting solution is concentrated into the thick paste of 60～70 ℃ of following relative density 1.0-1.20, adds 1-5 times of water gaging of thick paste, leaves standstill, and is centrifugal, is precipitated as Fructus Schisandrae Chinensis extrat;
Above-mentioned Fructus Schisandrae Chinensis extrat adds microcrystalline Cellulose and calcium sulfate, wherein the weight ratio of microcrystalline Cellulose, calcium sulfate and schisandra chinensis medicinal material is 1: 1-2: 15-22, stir, dry, its dried cream powder with the extract of above-mentioned Semen Ziziphi Spinosae and Radix Salviae Miltiorrhizae is mixed, by the Chinese crude drug crude drug gross weight that is adopted in the described Chinese medicinal components is 100%, the weight ratio 2-0.5 that adds 3-5%: 1 crospolyvinylpyrrolidone and low-substituted hydroxypropyl cellulose, granulate, make needed solid dosage forms.
8. the preparation method of solid preparation of Chinese medicine as claimed in claim 7, this method comprises:
Get Semen Ziziphi Spinosae and Radix Salviae Miltiorrhizae, add 4-10 and doubly measure the 30-70% alcohol reflux, extracting solution concentrates, and filters, filtrate is passed through macroporous adsorptive resins, the water eluting, eluent discards, reuse 50-90% ethanol elution, collect ethanol elution, reclaim ethanol and be concentrated into the magma of 60～70 ℃ of following relative density 1.0-1.02, drying, the powder that gets dry extract is the extract of Semen Ziziphi Spinosae and Radix Salviae Miltiorrhizae;
Get Fructus Schisandrae Chinensis, add 5-10 and doubly measure the 50-85% ethanol extraction, extracting solution is concentrated into the thick paste of 60～70 ℃ of following relative density 1.0-1.20, adds 1-5 times of water gaging of thick paste, leaves standstill, and is centrifugal, is precipitated as Fructus Schisandrae Chinensis extrat;
It is 1-2 that above-mentioned Fructus Schisandrae Chinensis extrat adds weight ratio: 1 calcium sulfate and microcrystalline cellulose mixt, wherein the part by weight of this calcium sulfate and microcrystalline cellulose mixt and described schisandra chinensis medicinal material is 1: 6-8, and this microcrystalline Cellulose is the part of the microcrystalline Cellulose total amount in the said preparation, stir, dry, mix with the dried cream powder of the extract of above-mentioned Semen Ziziphi Spinosae and Radix Salviae Miltiorrhizae again, the adding weight ratio is 2-0.5: 1 crospolyvinylpyrrolidone and low-substituted hydroxypropyl cellulose, the weight of this crospolyvinylpyrrolidone and low-substituted hydroxypropyl cellulose is the 5-3% of the Chinese crude drug crude drug gross weight that this solid preparation adopted, granulate, the microcrystalline Cellulose that adds micropowder silica gel and surplus again, mix, make needed solid dosage forms.
9. the preparation method of solid preparation of Chinese medicine as claimed in claim 8, wherein, making the solid dosage forms described in the needed solid dosage forms is dispersible tablet or pill.
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