CN100396308C - Xianlinggubao soft capsule for treating osteoporosis and its preparing method - Google Patents

Abstract

The present invention relates to a Xianlinggubao soft capsule for treating osteoporosis and a preparation method thereof. Epimedium herb, himalayan teasel root, red sage root, common anemarrhena rhizome, psoralea fruit and rehmanniae are counted by weight and are extracted, the extracts are prepared into powder, and then, substrate is added; the mixture is uniformly mixed and is pressed into soft capsules; the product has the functions of invigorating the kidney and strengthening the bones and is mainly suitable for osteoporosis caused by insufficiency of the liver and kidney and static blood obstruction for the network vessels; compared with the prior art, the product has the advantages of good therapeutic efficacy, no side effect, long term administration, stable quality and convenient storage, transportation and administration.

Description

The XIANLING GUBAO RUANJIAONANG and the preparation method of treatment osteoporosis

Technical field:

The present invention relates to a kind of XIANLING GUBAO RUANJIAONANG for the treatment of osteoporosis and preparation method thereof, belong to technical field of Chinese medicine.

Background technology:

Osteoporosis be one worldwide, more and more cause the health problem that people pay attention to, about 200,000,000 people in the whole world suffer from osteoporosis at present, its sickness rate has leapt to commonly encountered diseases, frequently-occurring disease the 7th.Current research shows that in fact the osteoporosis in that China is considered to the peculiar disease of old people always just exists in the Childhood.It is emphasized that does not especially medically also have safe and effective radical cure method at present, helps loose skeleton to restore to the original state, and therefore, correct understanding, early prevention seem particularly important.Along with aged tendency of population becomes clear day by day, as degenerative disease one osteoporosis and the complication thereof of person in middle and old age's pilosity, become a social health problem and enjoyed geriatrist's concern, and caused the great attention of national governments.The main hazard result of osteoporosis easily causes fracture, image height blood pressure diseases control is bad, and easily to cause apoplexy the same, osteoporosis is the incidence rate height in the women of west development country, in the U.S. 2,500 ten thousand patients are arranged approximately, the concurrent fracture of 1,500,000 patients is arranged every year approximately, about 20% fracture patient is in 1 year concurrent pulmonary infarction of endogenous cause of ill, pneumonia and death, the mortality rate that causes at women's osteoporotic fracture surpasses the summation of mastocarcinoma, cervical cancer and carcinoma of uterine body, the survivor of half Hip Fracture loses the ability of living on one's own life, and about 20% patient can only live in the nursing home.The osteoporotic fracture medical expense is costly, and the U.S. estimated 6,100,000,000 dollars in 1984, estimates recently to reach 10,000,000,000 dollars, continuous aging and average expected life-span growth along with population, if do not take effective intervention, following 25 years, this medical guide may also will be doubled and redoubled.March toward 21 century, China's population is nearly 1,300,000,000, and the crowd more than 60 years old reaches 10%, and this indicates that China begins to enter aging society, and osteoporosis patient certainly will rapidly increase.Constituted a serious public health issue in China.

Modern medicine treatment osteoporosis is mainly used medicines such as estrogen, calcium preparation, vitamin D, but effect is not satisfactory at present, and has certain side effect.A kind of Xianlinggubao effervescent tablet for the treatment of orthopaedic disease was once disclosed in the prior art, its patent No. is 200410046192.6, this Xianlinggubao effervescent tablet is a Chinese medicine preparation, comparatively speaking osteoporosis had certain therapeutic effect, and side effect is little, for the treatment osteoporosis has found an economy, effective, safe approach.But the quality of this Xianlinggubao effervescent tablet is not very stable, can occur the phenomenon of flower sheet, medicine Moisture high UCL in storage, and the volatile ingredient in the medicine loses easily, has influenced its curative effect.

Summary of the invention:

The objective of the invention is to: a kind of XIANLING GUBAO RUANJIAONANG for the treatment of osteoporosis and preparation method thereof is provided, and its steady quality, clinical efficacy is good and it is more convenient to preserve, carry, take, to overcome the deficiency that prior art exists.

The present invention constitutes like this: calculate according to components by weight percent, it is prepared into powder after extracting with Herba Epimedii 1100～1200, Radix Dipsaci 150～170, Radix Salviae Miltiorrhizae 70～90, the Rhizoma Anemarrhenae 70～90, Fructus Psoraleae 70～90 and Radix Rehmanniae 70～90, then according to medicated powder: substrate is 1: 0.8～3 weight ratio, mix homogeneously, be pressed into soft capsule, specifically, calculate according to components by weight percent, it uses Herba Epimedii 1167g, Radix Dipsaci Radix Dipsaci 167g, Radix Salviae Miltiorrhizae 83g, Rhizoma Anemarrhenae 83g, Fructus Psoraleae 83

G, Radix Rehmanniae 83g are prepared into powder after extracting, then according to medicated powder: substrate is 1: 1 weight ratio, and mix homogeneously is pressed into soft capsule, described soft capsule is made of medicinal liquid and softgel shell two parts, and wherein the composition of liquid medicine material and part by weight thereof are: medicated powder: substrate is 1: 0.8～3; The composition of capsule casing material and part by weight thereof are: gelatin: glycerol: water: antiseptic is 0.9～1.1: 0.3～0.6: 0.6～1.1: 0.0005～0.005, specifically, soft capsule is made of medicinal liquid and softgel shell two parts, and wherein the composition of liquid medicine material and part by weight thereof are: medicated powder: substrate is 1: 1; The composition of capsule casing material and part by weight thereof are: gelatin: glycerol: water: antiseptic is 1: 0.4: 1: 0.001, substrate is vegetable oil, it consists of soybean oil: Cera Flava is 94: 6, antiseptic is a mud moor gold ethyl ester, its consumption accounts for 0.5 of glue amount～5.0 ‰, used pigment is compound food coloring, its consumption accounts for 0 of glue amount～5.0 ‰, used covering agent is a titanium dioxide, consumption accounts for 0 of glue amount～5.0 ‰, and specifically, the consumption of mud moor gold ethyl ester accounts for 1 ‰ of glue amount, compound food coloring consumption accounts for 2 ‰ of glue amount, and amount of titanium accounts for 3 ‰ of glue amount.

The preparation method of this product is: take by weighing the medical material Herba Epimedii, Radix Dipsaci, Radix Salviae Miltiorrhizae, the Rhizoma Anemarrhenae, Fructus Psoraleae and Radix Rehmanniae are pulverized, and cross 60 mesh sieves, add 4～16 times of medical material water gagings, heating extraction 1～5 time, each 1～5 hour, merge extractive liquid,, filter, filtrate is concentrated into the thick paste shape, adds the medical material powder, mixing, dry, pulverize, cross 100 mesh sieves, the powder of getting it filled, add 0.8～3 times of amount substrate, mix homogeneously, colloid mill ground 5-30 minute, and rubber is by gelatin: glycerol: water: antiseptic is 0.9～1.1: 0.3～0.6: prepare at 0.6～1.1: 0.0005～0.005, be pressed into 1000 soft capsules, promptly.

Best preparation method is: take by weighing medical material Herba Epimedii, Radix Dipsaci, Radix Salviae Miltiorrhizae, the Rhizoma Anemarrhenae, Fructus Psoraleae and Radix Rehmanniae, micronizing, cross 200 mesh sieves, add 8 times of water gagings, decoct 3 times, 3 hours for the first time, 2 hours, 1 hour for the third time for the second time, filter, filtrate-0.06～-be evaporated to the thick paste shape under the 0.08MaP, 70～80 ℃, add the medical material powder, mixing, 60 ℃ are descended decompression, drying, pulverize, cross 160 mesh sieves, the powder of getting it filled, adding 1.0 times of amount substrate to total amounts is 600g, mix homogeneously, colloid mill ground 20 minutes; Rubber is by gelatin: glycerol: water is preparation in 1: 0.3: 1, adds 2 ‰ compound food colorings, 3 ‰ titanium dioxides and 1 ‰ mud moor gold ethyl esters again, is pressed into 1000 soft capsules, promptly.

This product has the effect of invigorating the kidney and strengthening the bones, mainly is applicable to the osteoporosis due to deficiency of the liver and kindey, the obstruction of collaterals by blood stasis.The dialectical main points of this product are the osteoporosis due to deficiency of the liver and kindey, the obstruction of collaterals by blood stasis, and suffering from a deficiency of the kidney is that osteoporotic morbidity is crucial, and the kidney being the origin of congenital constitution, store essential substances, and main bone, spermatogenesis is given birth to marrow, and marrow is hidden in the bone and is nourished skeleton, and kidney essense abundance then marrow is filled and bone is tough and tensile; Deficiency of the kidney then is difficult to give birth to marrow and fills bone and cause osteoporosis, controls and works as with invigorating the kidney and strengthening the bones.

Herba Epimedii in the side: acrid in the mouth, sweet, warm in nature, return liver, kidney channel, function reinforcing the kidney and supporting YANG, expelling wind and removing dampness, strengthening the tendons and bones; Radix Dipsaci: bitter in the mouth, suffering, little puckery, slightly warm in nature is returned liver, kidney channel, the function invigorating the liver and kidney, the nourishing muscle and tendon bone, sharp blood vessels are got round by bribery; Radix Salviae Miltiorrhizae: bitter in the mouth, cold nature, GUIXIN, pericardium, Liver Channel, function is invigorated blood circulation, blood stasis dispelling, pain relieving; The Rhizoma Anemarrhenae: bitter in the mouth, sweet, cold in nature, return lung, stomach, kidney channel, function is nourshing Yin and drynsessmoistening prescription, gives birth to marrow nourishing bone; Fructus Psoraleae: acrid in the mouth, warm in nature, return kidney, spleen channel, the function reinforcing the kidney and supporting YANG; Radix Rehmanniae: sweet in the mouth, little hardship, cool in nature, GUIXIN, liver, kidney channel, function enriching yin and nourishing kidney, body-building.

Make a general survey of full side, this product is a principal agent with the excessive foster leaves of pulse plants, and merit is at kidney invigorating and YANG supporting, bone and muscle strengthening, expelling wind and removing dampness; Be equipped with the pain relieving of Radix Dipsaci tonify deficiency, promoting blood circulation, bone and muscle strengthening; 5 use the Fructus Psoraleae warming the kidney to activate YANG, the Radix Salviae Miltiorrhizae stasis-dispelling and pain-killing, and the Rhizoma Anemarrhenae, Radix Rehmanniae enriching yin and nourishing kidney, living marrow nourishing bone, body-building, all medicines are harmonious, and play the merit of invigorating the kidney and strengthening the bones altogether.

Adopt the Therapeutic Method of medicines such as estrogen, calcium preparation, vitamin D to compare with prior art, this product therapeutic effect is good, has no side effect, and can take for a long time; Simultaneously, compare with existing Xianlinggubao effervescent tablet, this constant product quality, clinical efficacy is better, preserves, transports, takes more convenient.Its comparative result is as follows:

Drug quality stability compares: press the check of medicine routine inspection method, Comparative formulation has tablet, hard capsule, and three kinds of preparations were all placed 1.5～2 years, the results are shown in following table.

The quality stability comparing result of subordinate list different dosage form

Kind	Character	Moisture	The molten diffusing time of disintegrate
				XIANLING GUBAO JIAONANG	Caking	Exceed standard	49 minutes
XIANLING GUBAO PIAN	The flower sheet	Exceed standard	54 minutes
				XIANLING GUBAO RUANJIAONANG	Evenly	---------	23 minutes

The result shows that the quality stability of XIANLING GUBAO RUANJIAONANG of the present invention is all good than XIANLING GUBAO JIAONANG and XIANLING GUBAO PIAN.

Clinical efficacy compares: 1, adopt XIANLING GUBAO RUANJIAONANG and XIANLING GUBAO JIAONANG and XIANLING GUBAO PIAN contrast therapy postmenopausal osteoporosis, observe according to clinical research 1, the results are shown in following table.

The clinical efficacy contrast of subordinate list different dosage form

Annotate: with preceding relatively * P＜0.05 of treatment; With matched group comparison ▲ P＜0.05

2, adopt XIANLING GUBAO RUANJIAONANG and XIANLING GUBAO JIAONANG and XIANLING GUBAO PIAN contrast therapy senile osteoporosis (II type primary osteoporosis) patient's 30 examples, the result is as follows.

The variation of BMD value contrast before and after subordinate list is taken medicine

Classification	Age	The example number	BMD value (g/cm before taking medicine 2)	Back BMD value (g/cm takes medicine 2)	Change %
						XIANLING GUBAO RUANJIAONANG	60～79	10	0.486±0.041	0.570±0.061	+7.28
XIANLING GUBAO JIAONANG	60～79	10	0.631±0.068	0.671±0.031	+5.96
						XIANLING GUBAO PIAN	60～79	10	0.407±0.053	0.429±0.030	+5.13

Patient's doing well,improving situation contrast after subordinate list is taken medicine

Classification	Symptom	The example number	Significantly improve (%)	Slightly improve (%)	No change (%)
						XIANLING GUBAO RUANJIAONANG	Whole body osteodynia lumbago and backache limbs fatigue	10	7(70.0)	3(30.0)	---------
XIANLING GUBAO JIAONANG	Whole body osteodynia lumbago and backache limbs fatigue	10	6(60.0)	2(20.0)	2(20.0)
						XIANLING GUBAO PIAN	Whole body osteodynia lumbago and backache limbs fatigue	10	6(60.0)	1(10.0)	3(30.0)

Sum up: by above each side relatively, the XIANLING GUBAO RUANJIAONANG of this product all is better than other dosage forms.

The characteristics of this product soft capsule: this product soft capsule is except that with hard capsule has identical characteristics, also show following several respects: 1, the plasticity of this product soft capsule is strong, elasticity is big: this capsule material that depends on this product soft capsule is formed, be the ratio between gelatin, plasticizer and the water three, adjust the soft capsule that three's ratio can be made into different shape.Can filling liquid or the aqueous medicine of suspendible in the soft capsule preparation, also can fill the solid, shaped medicine, exquisite appearance, the patient is easy to accept.2, this product soft capsule can remedy the deficiency of other solid dosage formss: when general oil content height or liquid drug are difficult for making pill, tablet and hard capsule, can be made into soft capsule.And for example little to taking dose, be insoluble in water, be difficult for the medicine of absorption in the digestive tract, it is dissolved in the suitable oil, make soft capsule again, not only increased gastral absorption, improved curative effect, and stability has preferably been arranged.3, the bioavailability of this product soft capsule is good: this product soft capsule that medicine is made after dissolving with Polyethylene Glycol can obtain good blood drug level.4, the preservation drug quality is good, is specially adapted to contain the more Chinese medicine of volatile ingredient.In the storage process, because the soft capsule sealing of this product is strong, the volatile ingredient loss is little and can cover some bad smells of Chinese medicine.For preventing the photolysis that is subjected to of medicine, simultaneously in the capsule material, also added titanium dioxide (titanium dioxide), pigment etc. and helped the light blocking additives, made and be subjected to light easily to decompose the stability of drug soft capsule dosage form, and the uncomfortable color of filling content in the softgel shell has also been played the covering effect.5, the soft capsule of this product has selection to drug type: (1) water soluble ingredient: this class medicine adopts technical finesses such as absorption, curing usually, as add adjuvants such as absorbent, the dosage form volume will increase, carrying out heat drying in the preparation handles, medicine easily appears from adjuvants such as absorbent, cause the composition loss, affect the treatment.Soft capsule of the present invention be with oiliness medicine and low melting point substance with the fat-soluble solvent dissolving or make emulsion and fill, without this adjuvant of absorbent, volumes of formulation is reduced, avoided problems such as medicine oozes out simultaneously, and can improve bioavailability.(2) Chinese medicine volatile ingredient: be applicable to the Chinese medicine preparation that contains volatile oil, in preparation and storage, the easy volatilization loss of volatile ingredient, and have special odor, be made into soft capsule, volatile ingredient is sealed in the capsule shells, because sealing is tight, be difficult for volatilization loss, the soft capsule of this product can be covered the bad smell in the medicine, improves drug quality.(3) meet the composition of light, wet, thermally labile and easy oxidation: the capsule material of this product soft capsule is made up of gelatin, glycerol etc., and wall thickness does not have breathability again, is the good preparation that prevents oxidation of drug.Especially vitamins is subject to influences such as temperature, oxygen, heavy metal, through mixing with oil, coats its surface with oil, can increase stability.For preventing the photolysis of photosensitizer chance, in the capsule material, add light screening materials such as titanium dioxide or ferrum oxide, contact with air for preventing medicine, in preparation process, feed noble gas.(4) the strong Chinese medical concrete of stickiness: Chinese medicine preparation mostly is the extractum preparation, when Chinese medical concrete contacts with air, moisture absorption easily, it is easily softening to be heated, this type of medicine needs to add more filler if make its solid preparation such as hard capsule, content often occurs and cohere phenomenon in storage, make soft capsule, can be improved.(5) hydrophobic drug of bioavailability difference: as the ciclosporin poorly water-soluble, itself and oiliness carrier are made the soft capsule of packing into behind the microemulsion, can improve its bioavailability greatly.If adopt other solid preparations, then this class medicine is difficult to reach effective blood drug concentration.(6) medicine of tool bad smell and trace active medicine: soft capsule can be covered the bad smell of medicine, is easy to take, and the patient more takes like a shot.Some trace active drug doses are little, should make soft capsule.

The advantage of this product soft capsule preparation: 1, in this product soft capsule preparation, the extract powder body is without granulation, and it is dispersed in the oily substrate, through rubber compacting sealing fully, has overcome moisture absorption, has increased the stability of product.2, the medicine in this product soft capsule is impalpable powder (100 order), directly is distributed in the body fluid after the disintegrate to absorb, and is rapid-action, and to be easy to absorb bioavailability more greatly higher because of surface area.

The correlational study of this product:

Clinical research: 1, adopt XIANLING GUBAO RUANJIAONANG treatment postmenopausal osteoporosis (Postmenopausal Oeteoporosis, PMO) variation of bone density (BMD) and interleukin (IL-6), tumor necrosis factor (TNF-α), insulin like growth factor (IGF-1) and bone metabolism index.Method: the PMO at 35～65 years old age of selection is totally 120 examples, and be divided at random: 80 examples are organized in treatment, matched group 40 examples.Each group all adopted the DEXA borne densitometers to measure BMD before and after medication in 7,28 weeks; Put the method for exempting from and measure E2, alkali phosphatase (ALP) level; Quantitative sandwich enzyme-linked immunization (ELISA) is measured Bone Gla protein (BGP), type i collagen N-terminal peptide (NTX), IL-6, TNF-α, IGF-I level.Administrated method: oral XIANLING GUBAO RUANJIAONANG is organized in treatment; Matched group is taken SHENGU JIAONANG.The result is as follows.

Respectively organize bone density (g/cm before and after the subordinate list treatment ²) testing result (X+S)

Annotate: with preceding relatively * P＜0.05 of treatment; With matched group comparison ▲ P＜0.05

Subordinate list is treated the change of respectively organizing gonadal hormone, bone metabolism index, cytokine levels 28 weeks (X ± S)

Annotate: with preceding relatively * P＜0.05 of treatment; With matched group comparison ▲ P＜0.05

2, adopt XIANLING GUBAO RUANJIAONANG treatment postmenopausal osteoporosis (I type primary osteoporosis) patient's 20 examples; Senile osteoporosis (II type primary osteoporosis) patient's 40 examples (male's 15 examples, women's 25 examples), the result is as follows.

The variation of BMD value before and after subordinate list is taken medicine

Patient's doing well,improving situation after subordinate list is taken medicine

The research of preparation method:

Disintegrating process research: get the 500g Radix Salviae Miltiorrhizae, adopt conventional method to pulverize, cross 200 mesh sieves, it gets the powder rate is about 85%, and efficient is low.And adopting micronizing (Bei Li pulverizing), it gets the powder rate is more than 96%.Therefore the optimised process of this product pulverizing is a micronizing.

Study on extraction:

Water absorption rate: take by weighing medical material except that Radix Salviae Miltiorrhizae by prescription, Herba Epimedii, Radix Dipsaci, the Rhizoma Anemarrhenae, Fructus Psoraleae four Chinese medicine material are ground into coarse powder, Radix Rehmanniae is thinly sliced, and mixing is got 100g, adding 5 times of water gagings (being 500ml) soaks, soak into situation 1 time every observation in 1 hour,, leach whole unabsorbed water liquid until all saturating hearts of medical material, wet medical material is weighed as 250g, tries to achieve the medical material water absorption rate to be:

$=\frac{250-100}{100}\×100\%=150\%$

So when decocting with water first, the water absorption that should supply medical material 150%.

The factor level table is established: the factor that influence decocts mainly contains the following aspects: soak time, amount of water, decocting time, decoction number of times etc.According to related data retrieval, in conjunction with the production technology of this kind, orthogonal experiment is adopted in this test, is index with wherein paste-forming rate and content Determination of Icariin, investigates decocting number of times, amount of water, decocting time three factors, to determine extraction process.The factor level table of orthogonal test sees Table 1:

Table 1 Study on extraction factor level table

Sample preparation: each 100g of material that gets it filled, totally 9 parts, decoct by table 3 technological requirement, merge decoction liquor, filter with 120 mesh sieves, filtrate concentrates, and quantitatively is transferred in the 100ml measuring bottle, adds water to scale, shakes up, promptly.

Index examination method: get above-mentioned 9 kinds of extractum and measure paste-forming rate and icariin extracted amount respectively, in conjunction with this product effect and related data result for retrieval, with paste-forming rate and icariin content is that index is carried out comprehensive grading to orthogonal experiments, as index orthogonal test is carried out statistical analysis with each test comprehensive grading relative value, the results are shown in Table 2, method is as follows:

1. paste-forming rate is accurate draws above-mentioned sample solution 50ml, puts in the evaporating dish, and water bath method, residue 105 ℃ of dryings 3 hours in baking oven are taken out, and place exsiccator to place 30 minutes, weigh, and calculate.

2. the above-mentioned sample solution 2ml of the accurate absorption of icariin content puts in the round-bottomed flask, and water bath method is pressed the preparation of Herba Epimedii need testing solution preparation method, measures, and calculates.

The comprehensive grading total points is 100%, and index is allocated as follows:

The comprehensive dried cream rate of paste-forming rate %=* 40% ÷ maximum dry cream rate

The maximum icariin of comprehensive icariin %=icariin * 60% ÷

Table 2 extraction process quadrature is table as a result

Table 3 extraction process analysis of variance table

*F0.05(2，2)＝19.00；F0.0 ₁(2，2)＝99

The result shows: with paste-forming rate and icariin content is that index is made significance test, the influence factor is followed successively by A＞C＞B from big to small, factor A, C have utmost point appreciable impact, size is followed successively by between the level of each factor: A3＞A2＞A1, B3＞B2＞B1, C3＞C2＞C1, therefore, best decocting process can be drafted and be A3B3C3.Actual in conjunction with producing, determine that decocting process is that medical material decocts with water 3 times, add 8 times of water gagings (supplying the water absorption of medical material 150%) for the first time, second and third time adds 8 times of water gagings, and decocting time was respectively 3 hours for the first time, 2 hours, 1 hour for the third time for the second time.

The checking of decocting process: get orthogonal test with each 100g of a collection of medical material, press A ₂B ₂C ₂Experimentize, verify 3 batches altogether, measure its paste-forming rate and icariin content as stated above, the results are shown in Table 4.

Table 4 decocts optimised process checking result

Checking is the result show, this technology extractum yield and chlorogenic acid extracted amount are all stablized (the icariin extraction ratio is 40%), can be used as the optimised process of extraction.

The concentration technology screening: concentration technology is bigger to the influence of effective ingredient.In conjunction with the pharmaceutical factory production equipment, this test is index with the content Determination of Icariin, has carried out normal pressure and has concentrated and concentrating under reduced pressure (vacuum 0.06～0.08Mpa, 80 ℃ of temperature) contrast test result such as table 5:

Table 5 concentration technology screening test

Annotate: test method---get 1/5 recipe quantity medical material respectively, after press optimised process and extracting, press correlation method and concentrate, press preceding method mensuration icariin content.

Result of the test shows, at concentrated extract proportion is 1.10～1.15 o'clock, normal pressure concentrate with concentrating under reduced pressure the other side in the effective ingredient icariin all do not have obvious influence, but when concentrated extract proportion reaches 1.25, the spissated extractum icariin of normal pressure content decreases, concentrating under reduced pressure does not then have influence, so concentration technology is selected concentrating under reduced pressure.In addition, when concentrated extract proportion reached 1.25, the speed of concentrating under reduced pressure obviously slowed down, and the extractum wall cling phenomenon is serious, was difficult for mixing when the cream powder mixes simultaneously, so concentrated extract proportion is decided to be 1.20～1.25 (60～70 ℃).

Drying process is investigated: in the Chinese patent medicine preparation, baking temperature can have a significant impact the effective ingredient of some drugs, in this test moulding process, with the icariin is that content is index, get each 100g of sample of homogeneous preparation respectively, dry by the fire to moisture at 60～100 ℃ and to be lower than 3%, investigate the baking temperature of preparation, investigate and the results are shown in Table 6.

Table 6 drying process is investigated the result

Result of the test shows that between 60～100 ℃, baking temperature reduces along with the rising of temperature the icariin content in the preparation, and actual in conjunction with producing, it is below 70 ℃ that the baking temperature of this product is drafted.

The preparations shaping technical study:

The selection of diluent: the selection of pharmaceutical diluents is the important step of soft capsule preparation, should be able to guarantee the accuracy and the stability of formulation of content.As disperse medium, be more suitable for the development in hydrophobic drug with vegetable oil, stability is stronger.

The adjuvant addition is investigated: capsule liquid prescription is determined with the method for investigationing: the 1. selection of capsule liquid prescription: the adjuvant addition how much directly have influence on stability of formulation.The consumption of diluent directly influences the loading amount and the content uniformity of finished product.Ratio is low excessively, and then medicinal liquid is mobile bad, and content uniformity is bigger; Ratio is excessive, and then the drug administration amount increases, the inconvenience of taking medicine.From the test of front as can be known, after extracting, the yield of dry extract is basicly stable about 17%, and therefore, having screened the different proportion soybean oil according to paste-forming rate is diluent and Cera Flava suspending agent, thereby determines the optimal proportion of capsule liquid prescription.2. investigate determining of method: according to Stock ' s formula V=2r ²(d ₁-d ₂) (V is the microgranule sedimentation velocity to g/9 η, and r is a particle radius, d ₁Be density of particle, d ₂Be disperse medium density, η is a disperse medium viscosity), with settling ratio F (F=H _u/ H ₀* 100%, H ₀For disperseing the original height of item, H _uThe height that sedimentation is shown after leaving standstill) is index, investigates, in conjunction with producing the actual best capsule liquid prescription of determining with consumption three factors of extract powder granularity, diluent PEG-400, tween 80.The factor level table of orthogonal test sees Table 7.

Table 7 capsule liquid prescription factor level table

The mensuration of sample preparation and settling ratio: get 1 recipe quantity medical material, the Radix Salviae Miltiorrhizae superfine powder is broken into micropowder, crosses 200 mesh sieves, and is standby; All the other Herba Epimedii, Radix Dipsaci, the Rhizoma Anemarrhenae, Fructus Psoraleae four Chinese medicine material are ground into coarse powder, and Radix Rehmanniae is thinly sliced, with above-mentioned coarse powder mixing, add 8 times of water gagings (water absorption of supplying medical material 150% for the first time), decoct 3 times,, 3 hours for the first time, 2 hours, 1 hour for the third time for the second time.Merge decoction liquor, being concentrated into proportion is the extractum of 1.20～1.25 (60～70 ℃), adds Radix Salviae Miltiorrhizae powder, mixing in dry below 70 ℃, is pulverized, be divided into 3 parts, cross 100 mesh sieves, 120 mesh sieves, 160 mesh sieves respectively, add substrate on request, ground 20 minutes, get respectively and respectively organize suspension 10ml, put in the centrifuge rotating speed that changes with per minute 500 centrifugal 3 hours, and measured settling ratio F, result of the test sees Table 8.

Table 8 adjuvant addition is investigated table as a result

The result shows: the factor that influences the suspension settling ratio is followed successively by A＞C＞B, factor A, C is a major influence factors, size is followed successively by between the level of each factor: A3＞A2＞A1, B3＞B2＞B1, C3＞C2＞C1, therefore, best adjuvant adds technology and should be A3B3C3, but because B is not a major influence factors, select B1 or B3 in the extraction process, little to the product quality influence, thus consider from the angle of saving cost and minimizing dose, in the actual production, adjuvant is added technology be defined as A3B1C3, be that extract powder is crossed 160 mesh sieves, extract powder: substrate added by 1: 1, and the proportioning of substrate is a soybean oil: Cera Flava was by 94: 6.

Determining of capsule liquid prescription: according to three batches of checkings, determine that capsule liquid prescription is extract powder: substrate added by 1: 1, and the proportioning of substrate is a soybean oil: Cera Flava was by 94: 6.

Incorporation time selection: the content of soft capsule is wanted sufficient mix homogeneously, otherwise layering easily in compacting or put procedure, influences the accuracy of medicine loading amount.General mixing apparatus adopts colloid mill or dispersing emulsification machine.In conjunction with our factory's reality, adopt the colloid mill polishing, compared the situation of different milling time materials.Colloid mill mill spacing 5um has compared the situation of material after different milling times, the results are shown in Table 9.

Table 9 incorporation time the selection result of the test

By above result as can be known, with the colloid mill polishing, ground 20 minutes and 30 minutes material situation zero differences, but all be better than grinding 10 minutes.So determine to grind 20 minutes with colloid mill.

It is preferred that rubber is write out a prescription: the soft capsule shell prescription is investigated: according to the literature, the ratio of gelatin, G ﹠ W was generally 1: 0.3～0.5: 1 in the soft capsule shell.The fixing ratio of gelatin and water changes the ratio of glycerol, makes rubber rate of dissolution indicator with lemon yellow, is that index is investigated the glycerol addition with the dissolution time of rubber.1. rubber preparation: measure lemon yellow in prescription ratio in the table 11, be dissolved in water, add glycerol and stir evenly, the gelatin granule put in the lemon yellow aqueous solution soak 36h, 70 ℃ of heating down make it dissolving (in order to make the shading and anticorrosion of rubber energy, adding 3 ‰ titanium dioxides and 1 ‰ mud moor gold ethyl esters respectively), behind the vacuum degassing bubble, fully stir, evenly be laid on (the about 2mm of thickness) on the glass plate, put 25 ℃ of dryings 2 hours, blade cuts into the rubber piece of 2cm * 2cm, and is standby.

Table 10 rubber prescription ratio

2. the rubber rate of dissolution is measured: it is an amount of that precision is got above-mentioned each rubber, by " two appendix dissolution methods of Chinese pharmacopoeia version in 2000 transfer basket method is measured, and is dissolution medium with the 500ml distilled water, and temperature is 37 ± 0.5 ℃, rotating speed is 30rpm, after waiting not have obvious rubber granule, per minute sampling 1 time, the 5ml that at every turn takes a sample (and add the equivalent distilled water replenish), until dissolving fully, measure absorbance in wavelength 427nm place, determine the content of lemon yellow, dissolve required time fully to record rubber.The results are shown in Table 11:

Table 11 rubber rate of dissolution measurement result

3. rubber study on the stability: above-mentioned 1～No. 3 prescription sample was preserved 30 days down at 40 ℃, and the same method is surveyed every required time of gram rubber dissolving of various kinds, the results are shown in Table 12:

The different prescription of table 12 rubber solubility property examine stability

2., 3. result of the test shows, different prescription rubber can both dissolve in 30 minutes fully, explanation is all better with the soft capsule shell dissolubility that these prescriptions make, under the gelatin condition identical with the water yield, 1, the solubility property of No. 2 prescription rubber is more stable, be optional No. 1 prescription, the i.e. gelatin of saving production cost: glycerol: water=1: 0.3: 1.

The rubber solidification temperature is selected: press the rubber prescription and prepare glue, make rubber after, be divided into 3 parts, respectively at 10 ℃, 4 ℃, cool off 10min under 0 ℃ of three kinds of temperature.All, observe rubber character and press the dissolubility that preceding method method is measured various kinds rubber, the results are shown in Table 13 in 25 ℃ of following balances of room temperature:

Table 13 rubber solidification temperature is investigated

Result of the test shows that the dissolubility of rubber increases along with the reduction of rubber cooling curing temperature.Water freezing in rubber below 0 ℃ and to cause rubber loose porous, though be beneficial to dissolving, unfavorable for capsular sealing, easy oil impregnate; 10 ℃ of cooling curing rubber are too soft, and poor plasticity selects 4 ℃ of cooling curings to be advisable by contrast.

The selection of sprinkler body temperature: in the pressing process of soft capsule, the sprinkler body temperature is the key factor that influences soft capsule content uniformity and yield rate.The sprinkler body temperature is low excessively, and the capsule pressing is bad, leakage easily; The sprinkler body temperature is too high, can influence the outward appearance of soft capsule.Investigate the pressing situation and the yield rate of soft capsule under the different temperatures for this reason, the results are shown in Table 14.

The selection result of the test of table 14 sprinkler body temperature

As seen from the experiment, the sprinkler body temperature should be controlled at 42～44 ℃ and is advisable.

Setting and drying process condition are selected: the selection of (1) soft capsule setting temperature: get no-set soft capsule and formalize (rule of thumb down at 15 ℃, 20 ℃, 25 ℃ respectively, envionmental humidity is controlled at about 30% during setting), be that index is carried out preferably setting temperature with fixing time, special-shaped ball rate.The results are shown in Table 15.

Table 15 soft capsule setting temperature selection result table

From result of the test as can be known, fixing time shortens along with increasing of setting temperature, but temperature is high more, the water evaporates on soft capsule shell surface is just fast more, and special-shaped ball rate also increases thereupon, is unfavorable for the soft capsule shell setting, by contrast, it is short that setting has the time under 20 ℃, and the low advantage of special-shaped ball rate is a setting temperature so select this temperature.(2) selection of soft capsule baking temperature: investigate the process conditions compacting soft capsule that optimizes by above-mentioned technology, after the setting, oil stain with 95% ethanol flush away softgel shell surface, be divided into 3 parts, extremely neither too hard, nor too soft 15 ℃, 20 ℃, 25 ℃ down dry (relative humidity is 30%) respectively, drying time also measured disintegration time in record.The results are shown in Table 16.

Table 16 soft capsule baking temperature selection result table

Result of the test shows that shorten along with increasing of temperature drying time, and by contrast, 25 ℃ of following drying effects are good, is the soft capsule baking temperature so select this temperature.

Three batches of pilot scale creation datas: according to above preferred technology, test agent is produced in the our factory in three batches: carry out in the big production equipments such as multi-function extractor, triple effect concentration tank, drying under reduced pressure case, vertical colloid mill, automatic encapsulating machine, this technology advanced person is described, feasible, be suitable for big production.

The 10 times of recipe quantities that feed intake, to each batch paste-forming rate, yield rate, and the outward appearance of soft capsule is investigated.The result shows that the technology of said preparation is basicly stable.Every data see Table 17.

Table 17 pilot plant test is table as a result

Lot number	200501	200502	200503
				The medical material total amount (kg) that feeds intake	35	35	35
Medical material icariin content (%)	0.56	0.56	0.53
				Pulverize parameter	Below 200 orders	Below 200 orders	Below 200 orders

Amount of water (kg)	For the first time 335 for the second time 280 for the third time 280	For the first time 335 for the second time 280 for the third time 280	For the first time 335 for the second time 280 for the third time 280
				Extraction time (h)	For the first time 3 for the second time 2 for the third time 1	For the first time 2 for the second time 1.5 for the third time 1	For the first time 2 for the second time 1.5 for the third time 1
The extraction process parameter	90～100 ℃	90～100 ℃	90～100 ℃
				The concentration technology parameter	-0.06～-70～80 ℃ of 0.08MaP	-0.06～-70～80 ℃ of 0.08MaP	-0.06～-70～80 ℃ of 0.08MaP
Baking temperature (℃)	＜70	＜70	＜70
				Dried cream weight (kg)	6.28	6.30	6.27
160 order dried cream powder weight (kg)	6.03	6.05	6.01
				Add substrate amount (kg)	6.03	6.05	6.01
Theoretical yield (0.6g/ grain)	20000	20000	20000
				Actual production (0.6g/ grain)	17960	17980	17910
Yield rate (%)	89.8	89.9	89.6
				Average particle heavy (g)	0.596	0.593	0.597
Character	Content is yellow to sepia grease; Mildly bitter flavor.	Content is yellow to sepia grease; Mildly bitter flavor.	Content is yellow to sepia grease; Sweet-bitter flavor.
				Disintegration time	14	12	16
Microbial check	Up to specification	Up to specification	Up to specification
				Icariin content (mg/ grain)	2.66	2.71	2.62
The chlorogenic acid rate of transform (%)	40.7	41.5	40.1

When studying, the present invention select for use vegetable oil and PEG class as substrate respectively, but make the soft capsule of substrate processing by testing this medicinal PEG class material, bigger to the molten diffusing time effects of disintegrate, and make the soft capsule hardening easily, controlled trial the results are shown in Table 18, but is to use vegetable oil not produce such situation; So this product substrate is selected vegetable oil for use, according to the scope of survival dose, what this product matrix formulations was more satisfactory is soybean oil: Cera Flava=94: 6.

Table 18 different substrates is to the influence of molten diffusing time of soft capsule disintegrate

Common used antiseptic can be that mud pool tortoise beetle ester, mud moor gold ethyl ester, mud are moored one or more the mixing in the golden propyl ester, and the antiseptic that this product adopts is a mud moor gold ethyl ester, and consumption is 0.5 of glue amount～5.0 ‰, and optimum amount is 1 ‰ of a glue amount.Be subjected to the illumination oxidation for shading prevents medicine, added food coloring and covering agent in rubber, used pigment is compound food coloring, and consumption is 0 of glue amount～5.0 ‰, and optimum amount is 2 ‰ of a glue amount; Used covering agent is titanium dioxide (titanium dioxide), and consumption is 0 of glue amount～5.0 ‰, and optimum amount is 3 ‰ of a glue amount.

The specific embodiment:

Embodiments of the invention 1: take by weighing medical material Herba Epimedii 1167g, Radix Dipsaci Radix Dipsaci 167g, Radix Salviae Miltiorrhizae 83g, Rhizoma Anemarrhenae 83g, Fructus Psoraleae 83g, Radix Rehmanniae 83g, the Radix Salviae Miltiorrhizae superfine powder is broken into micropowder, cross 200 mesh sieves, standby; All the other Herba Epimedii, Radix Dipsaci, the Rhizoma Anemarrhenae, Fructus Psoraleae four Chinese medicine material is ground into coarse powder, Radix Rehmanniae is thinly sliced, with above-mentioned coarse powder mixing, add 8 times of water gagings (water absorption of supplying medical material 150% for the first time), decoct 3 times, 3 hours for the first time, 2 hours for the second time, 1 hour for the third time, collecting decoction, filter, filtrate-0.06～-0.08MaP, being evaporated to relative density under 70～80 ℃ is the thick paste of 1.15～1.25 (50 ℃), adds the Radix Salviae Miltiorrhizae micropowder, mixing, low-temperature vacuum drying gets dry extract below 60 ℃, gets extract powder and pulverizes, and crosses 160 mesh sieves, the powder of getting it filled, the substrate (soybean oil: Cera Flava is 94: 6) that adds 1.0 times is 600g to total amount, mix homogeneously, and colloid mill ground 20 minutes; Rubber is by gelatin: glycerol: water is preparation in 1: 0.3: 1, adds 2 ‰ compound food colorings, 3 ‰ titanium dioxides and 1 ‰ mud moor gold ethyl esters again, is pressed into 1000 soft capsules, be that 20 ℃, relative humidity are to formalize under 30% condition in temperature at last, removing soft capsule appearance oil reservoir, is that 25 ℃, relative humidity are dry under 30% condition in temperature, gets product, this product oral, one time 4, every the dress 0.6g, 2 times on the one, 4～6 weeks were a course of treatment, or followed the doctor's advice.

Embodiments of the invention 2:

Take by weighing Herba Epimedii 1100g, Radix Dipsaci 150g, Radix Salviae Miltiorrhizae 70g, Rhizoma Anemarrhenae 70g, Fructus Psoraleae 70g, Radix Rehmanniae 70g, the Radix Salviae Miltiorrhizae superfine powder is broken into micropowder, cross 200 mesh sieves, standby; All the other Herba Epimedii, Radix Dipsaci, the Rhizoma Anemarrhenae, Fructus Psoraleae four Chinese medicine material are ground into coarse powder, and Radix Rehmanniae is thinly sliced, with above-mentioned coarse powder mixing; Add 4 times of medical material water gagings, heating extraction 1 time, one time 5 hours, merge extractive liquid, filters, filtrate-0.06～-be evaporated to the thick paste that relative density is 1.15～1.25 (50 ℃) under the 0.08MaP, 70～80 ℃, add the Radix Salviae Miltiorrhizae micropowder, mixing, low-temperature vacuum drying gets dry extract below 60 ℃, getting extract powder pulverizes, cross 100 mesh sieves, the powder of getting it filled, vegetable oil substrate (soybean oil: Cera Flava is 94: 6) to the total amount that adds 0.8 times is 500g, mix homogeneously, colloid mill ground 5 minutes; Rubber is by gelatin: glycerol: water is preparation in 0.9: 0.4: 0.6, add 0.5 ‰ mud moor gold ethyl esters again, do not add pigment and titanium dioxide covering agent, be pressed into 1000 soft capsules, be that 20 ℃, relative humidity are to formalize under 30% condition in temperature at last, removing soft capsule appearance oil reservoir, is that 25 ℃, relative humidity are dry under 30% condition in temperature, gets product.

Embodiments of the invention 3: take by weighing Herba Epimedii 1200g, Radix Dipsaci 170g, Radix Salviae Miltiorrhizae 90g, Rhizoma Anemarrhenae 90g, Fructus Psoraleae 90g, Radix Rehmanniae 90g, the Radix Salviae Miltiorrhizae superfine powder is broken into micropowder, cross 200 mesh sieves, standby; All the other Herba Epimedii, Radix Dipsaci, the Rhizoma Anemarrhenae, Fructus Psoraleae four Chinese medicine material are ground into coarse powder, and Radix Rehmanniae is thinly sliced, with above-mentioned coarse powder mixing; Add 16 times of medical material water gagings, heating extraction 5 times, one time 1 hour, merge extractive liquid, filters, filtrate-0.06～-be evaporated to the thick paste that relative density is 1.15～1.25 (50 ℃) under the 0.08MaP, 70～80 ℃, add the Radix Salviae Miltiorrhizae micropowder, mixing, low-temperature vacuum drying gets dry extract below 60 ℃, getting extract powder pulverizes, cross 100 mesh sieves, the powder of getting it filled, vegetable oil substrate (soybean oil: Cera Flava is 94: 6) to the total amount that adds 3 times is 700g, mix homogeneously, colloid mill ground 30 minutes; Rubber is by gelatin: glycerol: water is preparation in 1.1: 0.6: 1.1, add 5.0 ‰ mud moor gold ethyl esters again, 5.0 ‰ compound food coloring, 5.0 ‰ titanium dioxide, being pressed into 1000 soft capsules, is that 20 ℃, relative humidity are to formalize under 30% condition in temperature at last, removes soft capsule appearance oil reservoir, in temperature is that 25 ℃, relative humidity are dry under 30% condition, gets product.

Claims (1)

1. the XIANLING GUBAO RUANJIAONANG of treatment osteoporosis is prepared from Herba Epimedii 1167g, Radix Dipsaci 167g, Radix Salviae Miltiorrhizae 83g, Rhizoma Anemarrhenae 83g, Fructus Psoraleae 83g, Radix Rehmanniae 83g, it is characterized in that: the Radix Salviae Miltiorrhizae superfine powder is broken into micropowder, crosses 200 mesh sieves, and standby; All the other Herba Epimedii, Radix Dipsaci, the Rhizoma Anemarrhenae, Fructus Psoraleae four Chinese medicine material is ground into coarse powder, Radix Rehmanniae is thinly sliced, with above-mentioned coarse powder mixing, add 8 times of water gagings, the water absorption of supplying medical material 150% for the first time, decoct 3 times, 3 hours for the first time, 2 hours for the second time, 1 hour for the third time, collecting decoction filtered, filtrate-0.06～-0.08MaP, be evaporated to relative density under 70～80 ℃ and be 1.15～1.25 thick paste 50 ℃ of surveys, add the Radix Salviae Miltiorrhizae micropowder, mixing, low-temperature vacuum drying gets dry extract below 60 ℃, getting extract powder pulverizes, cross 160 mesh sieves, the powder of getting it filled adds 1.0 times substrate: soybean oil: Cera Flava be 94: 6 to total amount be 600g, mix homogeneously, colloid mill ground 20 minutes; Rubber is by gelatin: glycerol: water is preparation in 1: 0.3: 1, adds 2 ‰ compound food colorings, 3 ‰ titanium dioxides and 1 ‰ mud moor gold ethyl esters again, is pressed into 1000 soft capsules.