CN1686495A - Soft capsule using Zhushen fungus as raw material and its preparation method - Google Patents

Abstract

A Chinese medicine in the form of softgel for treating cough, hypertension, hyperlipemia, hyperglycemia, obesity, etc is prepared from Dictyophora, phalloidea through extracting, pulverizing, proportionally mixing it with matrix and preparing softcapsule.

Description

With the Caulis Bambusae In Taeniam is the soft capsule and the preparation method of raw material

Technical field: the present invention be a kind of be the soft capsule and the preparation method of raw material with the Caulis Bambusae In Taeniam, belong to technical field of medicaments.

Background technology: Caulis Bambusae In Taeniam has the title of " bamboo ginseng ", it is a kind of wild edible fungus that is of great rarity, on China's history, once appeared on the dining table in imperial palace as imperial food always, and the good reputation of " white prince wife " was arranged, according to one's analysis, Caulis Bambusae In Taeniam contains 21 seed amino acids, wherein have 8 kinds necessary by human body, especially fine vegetable protein, vitamin B2 content are very high, have lung moistening, brain-strengthening, protect the liver, health-care effect such as kidney and spleen invigorating, and function such as blood pressure lowering, blood fat reducing, fat-reducing.Caulis Bambusae In Taeniam also has certain immune performance, and tumor is had stronger inhibitory action, therefore also is the good medicine that gives protection against cancer, controls cancer.But the time up to now, do not have Caulis Bambusae In Taeniam made preparation, eat it with dish basically, not only its health care and therapeutical effect as medicine is difficult to be displayed, and it uses equal inconvenience transporting, store, carry kimonos.

Summary of the invention: the objective of the invention is to: providing a kind of is the soft capsule and the preparation method of raw material with the Caulis Bambusae In Taeniam, Caulis Bambusae In Taeniam is processed into a kind of soft capsule preparation through development, be used for the cough due to deficiency of the lung, hypertension, hyperlipidemia, hyperglycemia and obesity, hypoimmunity patient's control, along with the progress in epoch, the development of society, people's living standard improves constantly, Caulis Bambusae In Taeniam and goods thereof will yield unusually brilliant results, with the Caulis Bambusae In Taeniam is the preparation that raw material is made, transport, store, carry, take all more conveniently, it will be subjected to inclining of people and look at.The present invention constitutes like this: Caulis Bambusae In Taeniam extract is prepared into powder, then according to powder: substrate be 1: 0.8～2.5 weight ratio powder and substrate mix homogeneously, be pressed into soft capsule, wherein content be yellow extremely pale brown color grease, sweet and slightly bitter taste.Specifically: Caulis Bambusae In Taeniam 2000g is made extract, is prepared into powder, then according to powder: substrate be 1: 1 weight ratio powder and substrate mix homogeneously, be pressed into soft capsule.Substrate among the present invention is for can being that vegetable oil or PEG class material, best substrate are PEG-400.

With the Caulis Bambusae In Taeniam is the preparation of soft capsule method of raw material: get Caulis Bambusae In Taeniam, add 2～16 times of medical material water gagings, heating (50～100 ℃) is extracted 1～5 time, each 1～5 hour, merge extractive liquid, filtered, filtrate is concentrated into the thick paste shape, and drying is pulverized, cross the following sieve of 100 orders, the powder of getting it filled adds 0.8～2.5 times of amount substrate, mix homogeneously, colloid mill ground 10-30 minute, was pressed into 1000 soft capsules, promptly.Preparation method accurately: get Caulis Bambusae In Taeniam 2000g, add 5 times of medical material water gagings, 70 ~ 80 ℃ of heating, extract 3 times, each 3 hours, merge 3 times extracting solution, filter, filtrate-0.06～-be evaporated to the thick paste shape under the 0.08MaP, 70 ~ 80 ℃ condition, 70 ~ 80 ℃ of following drying under reduced pressure are pulverized, cross 160 mesh sieves, the powder of getting it filled adds tween 80 4.5g, add propylene glycol 24g, and to add Polyethylene Glycol 400 to total amount be 600g, mix homogeneously, and colloid mill ground 20 minutes; Rubber is pressed gelatin: glycerol: water=preparation in 1: 0.3: 1, add 2 ‰ compound food colorings, 3 ‰ titanium dioxides and 1 ‰ mud moor gold ethyl esters in the gelatin amount simultaneously, and be pressed into 1000 soft capsules then, promptly.

Dictyophora fungus polysaccharide soft capsule provided by the invention 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, its proportion: medicated powder: substrate is 1: 0.8～2.5; The composition of capsule casing material and part by weight thereof are: gelatin: glycerol: water: antiseptic is 1: 0.4: 1: 0.001, and the proportion that it is best: gelatin: glycerol: water: antiseptic is 0.9～1.1: 0.3～0.6: 0.6～1.1: 0.0005～0.005.

The substrate that the present invention uses can be vegetable oil or PEG class material, and this product optimum substrate is PEG-400, and its PEG-400 that fills a prescription: propylene glycol: tween 80 is 90.5: 8: 1.5.According to the scope of survival dose, its this product matrix formulations scope PEG-400: propylene glycol: tween 80 is 60～100: 0～20: 0～20.

The used antiseptic of the present invention 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, this product is a mud moor gold ethyl ester with best antiseptic, account for 1 ‰ of glue amount, press the edible safety scope and consider that it is 0.5 ~ 5.0 ‰ that this product is used model.Be subjected to the illumination oxidation for shading prevents medicine, so add food coloring and covering agent in rubber, its pigment can be monochromatic or compound food coloring, covering agent has red, yellow or brown ferrum oxide, white carbon black, titanium dioxide (titanium dioxide).This product pigment is compound food coloring, and consumption accounts for 2 ‰ of glue amount, presses the edible safety scope and considers that it is 0～5.0 ‰ that this product is used model.This product covering agent is titanium dioxide (titanium dioxide), and consumption accounts for 3 ‰ of glue amount, presses the edible safety scope and considers that it is 0～5.0 ‰ that this product is used model.Effect: boosting qi and nourishing yin, nourishing the lung to arrest cough, the skin moistening skin care, the weight reducing fat-reducing, blood lipid regulation strengthens body immunity.Indication: cough due to deficiency of the lung, hypertension, hyperlipidemia, hyperglycemia and obesity, hypoimmunity patient.Usage and dosage: oral, one time 3,3 times on the one.Specification: every dress 600mg contains Caulis Bambusae In Taeniam extract 300mg.

Compared with prior art, the present invention is processed into a kind of soft capsule preparation with Caulis Bambusae In Taeniam through development, be used for the cough due to deficiency of the lung, hypertension, hyperlipidemia, hyperglycemia and obesity, hypoimmunity patient's control makes that not only its medical value is embodied, and is the preparation that raw material is made with the Caulis Bambusae In Taeniam, transporting, storing, carrying, taking all more convenient.

The research of preparation method:

1, Study on extraction:

1.1 water absorption rate: get Caulis Bambusae In Taeniam 100g, add 5 times of water gagings (being 500ml) and soak, observed every 30 minutes and soak into situation 1 time, until all saturating heart of medical material, the time is 90 minutes, leaches whole unabsorbed water liquid, wet medical material is weighed as 220g, tries to achieve the medical material water absorption rate to be:

$=\frac{220-100}{100}\×100\%=120\%$

So when decocting with water first, the water absorption that should supply medical material 120%.

1.2 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 the content of paste-forming rate and dictyophora fungus polysaccharide wherein, 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

Level	Factor
				Extraction time A	Decocting time B	Amount of water C
	??1 ??2 ??3	2 times 3 times 4 times	2 hours 3 hours 4 hours				4 times 5 times 6 times

1.3 sample preparation: get each 100g of Caulis Bambusae In Taeniam, 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.

1.4 index examination method: get above-mentioned 9 kinds of Caulis Bambusae In Taeniam extractum and measure paste-forming rate and dictyophora fungus polysaccharide extracted amount respectively, in conjunction with this product effect and related data result for retrieval, with paste-forming rate and dictyophora fungus polysaccharide 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: accurately draw above-mentioned sample solution 50ml, put in the evaporating dish, 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. dictyophora fungus polysaccharide content: accurately draw above-mentioned sample solution 2ml, put in the round-bottomed flask, water bath method by the preparation of Caulis Bambusae In Taeniam need testing solution preparation method, is measured, 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 dictyophora fungus polysaccharide of comprehensive dictyophora fungus polysaccharide %=dictyophora fungus polysaccharide * 60% ÷

Table 2 extraction process quadrature is table as a result

Sequence number	Factor				Paste-forming rate (%)	Dictyophora fungus polysaccharide (%)	Comprehensive grading (X I)	Relative value X=X I-93.86
									????A	????B	???C	Empty
	??1 ??2 ??3 ??4 ??5 ??6 ??7 ??8 ??9	????1 ????1 ????1 ????2 ????2 ????2 ????3 ????3 ????3	????1 ????2 ????3 ????1 ????2 ????3 ????1 ????2 ????3	???1 ???2 ???3 ???2 ???3 ???1 ???3 ???1 ???2									???1 ???2 ???3 ???3 ???1 ???2 ???2 ???3 ???1	????13.0 ????13.2 ????13.6 ????14.8 ????15.2 ????14.6 ????15.1 ????14.7 ????14.9	????15 ????20 ????18 ????19 ????20 ????16 ????18 ????18 ????16	????88.75 ????90.65 ????91.65 ????95.20 ????98.02 ????95.36 ????96.12 ????94.62 ????94.38	????-5.12 ????-3.22 ????-2.22 ????1.34 ????4.16 ????1.50 ????2.26 ????0.76 ????0.52
??K1 ??K2 ??K3 ??R					???-10.55 ????7.00 ????3.55 ????17.55	???-1.51 ????1.71 ???-0.19 ????1.90	??-2.85 ??-1.35 ???4.21 ???7.06	??-0.43 ???0.55 ??-0.11 ???0.98

Table 3 extraction process analysis of variance table

Soruces of variation	Quadratic sum	Degree of freedom	Mean square	??F	Factor affecting
						Extraction time A amount of water B extraction time C error	??57.6249 ??1.7436 ??9.2185 ??0.1658	??2 ??2 ??2 ??2	??28.8124 ??0.8718 ??4.6092 ??0.0829	??347.5095 ??10.5148 ??55.5923	The not remarkable highly significant of highly significant

*F0.05(2，2)＝19.00；F0.01(2，2)＝99

The result shows: with paste-forming rate and dictyophora fungus polysaccharide 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 5.6 times of water gagings (supplying the water absorption of medical material 120%) for the first time, second and third time adds 5 times of water gagings, decocts 3 hours at every turn.

1.5 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 dictyophora fungus polysaccharide content as stated above, the results are shown in Table 4.

Table 4 decocts optimised process checking result

Sequence number	Extractum yield (%)	Dictyophora fungus polysaccharide extracted amount (g)
			123 meansigma methodss	??15.1 ??14.9 ??15.2 ??15.1	??1.8 ??1.7 ??1.8 ??1.8

Checking is the result show, this technology extractum yield and dictyophora fungus polysaccharide extracted amount are all stablized (the dictyophora fungus polysaccharide extraction ratio is 72%), can be used as the optimised process of extraction.

1.6 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 an index with the content of dictyophora fungus polysaccharide, 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

Method for concentration	Tested number	Extractum proportion	Dictyophora fungus polysaccharide content (%)
				Atmospheric depressurized	??1 ??2 ??3 ??1 ??2 ??3	??1.15 ??1.25 ??1.35 ??1.15 ??1.25 ??1.35	??20.6 ??20.6 ??20.1 ??20.2 ??20.6 ??20.3

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 dictyophora fungus polysaccharide content.

Result of the test shows, at concentrated extract proportion is 1.15～1.25 o'clock, normal pressure concentrate with concentrating under reduced pressure the other side in the effective ingredient dictyophora fungus polysaccharide all do not have obvious influence, but when concentrated extract proportion reaches 1.35, the spissated extractum dictyophora fungus polysaccharide 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 1.35, the speed of concentrating under reduced pressure obviously slowed down, and the extractum wall cling phenomenon is serious, so concentrated extract proportion is decided to be 1.35 (70 ℃).

1.7 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 dictyophora fungus polysaccharide 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

Temperature (℃)	Drying time (hour)	Moisture (%)	Dictyophora fungus polysaccharide (%)
				??60 ??70 ??80 ??90 ??100	??48 ??48 ??24 ??24 ??12	??2.8 ??2.6 ??2.4 ??2.3 ??2.7	??18.2 ??18.0 ??17.8 ??16.5 ??15.3

Result of the test shows that between 60～100 ℃, baking temperature decreases along with the rising of temperature to the dictyophora fungus polysaccharide content in the preparation, and actual in conjunction with producing, it is 80 ℃ that the baking temperature of this product is drafted.

2, preparations shaping technical study:

2.1 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 existing many reports of domestic and foreign literature.And this product extractum to be Caulis Bambusae In Taeniam obtain through refining through water, its water solublity is stronger, it does not dissolve in vegetable oil, layering is separated out easily, disperses inhomogeneously, is prone to solids in the plunger rod sample introduction process, the obstruction injection port can't load soft capsule; And water miscible PEG-400 is applicable to that as the new diluent of soft capsule water soluble drug prepares soft capsule.Simultaneously, PEG-400 can improve the bioavailability of preparation because of having good water-solubility, is diluent so determine to select for use PEG-400.

2.2 the adjuvant addition is investigated: (1) 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 Caulis Bambusae In Taeniam dry extract is basicly stable about 10%, and therefore, having screened different proportion PEG-400 according to the Caulis Bambusae In Taeniam paste-forming rate is diluent and tween 80 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

Level	Factor
				Extract powder granularity A	Extract powder: substrate B	PEG-400: tween 80: propylene glycol C
	??1 ??2 ??3	100 orders, 120 orders, 160 orders	?1∶1 ?2∶3 ?1∶2				??90∶2∶8 ??90∶0∶10 ??90.5∶1.5∶8

(2) mensuration of sample preparation and settling ratio: get 1 recipe quantity Caulis Bambusae In Taeniam, add 5 times of water gagings, decoct 3 times, the each decoction 3 hours merges decoction liquor, is concentrated into proportion and is 1.35 extractum, dry below 80 ℃, pulverize, 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

Sequence number	Factor					Settling ratio F
							??A	??B	??C	Empty
	??1 ??2 ??3 ??4 ??5 ??6 ??7 ??8 ??9	??1 ??1 ??1 ??2 ??2 ??2 ??3 ??3 ??3	??1 ??2 ??3 ??1 ??2 ??3 ??1 ??2 ??3	??1 ??2 ??3 ??2 ??3 ??1 ??3 ??1 ??2	??1 ??2 ??3 ??3 ??1 ??2 ??2 ??3 ??1							??96.9 ??97.8 ??97.9 ??98.7 ??99.1 ??98.4 ??98.9 ??98.3 ??99.2
??K1 ??K2 ??K3 ??R							??292.6 ??296.2 ??296.4 ??3.8	??294.5 ??295.2 ??295.5 ??1	??293.6 ??295.7 ??295.9 ??2.3	??295.2 ??295.1 ??294.9 ??0.3

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 PEG-400: tween 80: propylene glycol was by 90.5: 1.5: 8.

(3) determining of capsule liquid prescription: finding in the process of preparation sample, is diluent when preparing soft capsule with PEG-400, and capsule liquid is conglomerate very easily, or is ground into pie when colloid mill grinds, and extract can not well be uniformly dispersed; Test helps capsule liquid suspendible to the tween 80 that wherein adds different proportion, through experiment sieving, effect is best after adding 1.5% tween 80 of measuring, and can be good at being uniformly dispersed, but finished product is after placing a period of time (about 10 days), the softgel shell hardening, prolong disintegration, and reason is in put procedure, and the PEG-400 in the capsule liquid absorbs the moisture in the softgel shell, cause the softgel shell hardening, prolong the disintegration of soft capsule.The back adds the propylene glycol of different proportion in capsule liquid is write out a prescription, substitute the PEG-400 of part, comes the moisture between balance softgel shell and the capsule liquid, suppresses the moisture in the capsule liquid absorption softgel shell.Propylene glycol in varing proportions substitutes part PEG-400, prepares sample again, after placing a period of time (20 days, T=14～20 ℃, RH=40%～60%), measures its disintegration, and experimental result sees Table 9.

The different prescription of table 9 capsule liquid is to EFFECT OF CORK STOPPER

Diluent	Disintegration (0 day)	Disintegration (20 days)
			PEG-400+ tween PEG-400+ tween+propylene glycol 2% PEG-400+ tween+propylene glycol 5% PEG-400+ tween+propylene glycol 8% PEG-400+ tween+propylene glycol 11%	19 minutes 15 minutes 16 minutes 15 minutes 17 minutes	37 minutes 26 minutes 25 minutes 17 minutes 18 minutes

Measurement result shows, the propylene glycol of adding 8% or 11%, the disintegration of softgel shell basic no change, the hardening phenomenon does not appear in softgel shell, compare also suitable substantially its disintegration with the sample that has just made, in conjunction with producing reality, determine the propylene glycol of adding 8% in the prescription of soft capsule, prevent soft capsule hardening and prolongation disintegration in depositing process.

According to above result of the test, dictyophora fungus polysaccharide soft capsule liquid prescription is defined as: extract powder, PEG-400, propylene glycol, tween 80, by extract powder: PEG-400: propylene glycol: tween 80 is counted 100: 90.5: 8: 1.5.

2.3 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 10.

Table 10 incorporation time the selection result of the test

Milling time	The material situation
		10 minutes 20 minutes 30 minutes	Granular sensation is arranged, mix inhomogeneous feel exquisiteness, the even feel exquisiteness of mixing of materials, mixing of materials is even

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.

2.4 the rubber prescription is preferred:

(1) 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 11 rubber foreign side ratio

The prescription number	Gelatin (g)	Water (g)	Glycerol (g)	Lemon yellow (g)
					??1 ??2 ??3	?1 ?1 ?1	?1 ?1 ?1	?0.3 ?0.4 ?0.5	?0.04 ?0.04 ?0.04

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 12:

Table 12 rubber rate of dissolution measurement result

The prescription number	Rubber heavy (g)	Dissolve required time (min) fully	Rate of dissolution (min/g)
				??1 ??2 ??3	??1.6211 ??1.7042 ??1.8280	??27 ??26 ??24	??16.7 ??15.3 ??13.1

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 13:

The different prescription of table 13 rubber solubility property examine stability

The prescription number	Rubber heavy (g)	Dissolve required time (min) fully	Rate of dissolution (min/g)
				??1 ??2 ??3	??1.5210 ??1.6801 ??1.7133	??27 ??27 ??31	??17.8 ??16.1 ??18.1

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.

(2) 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 14 in 25 ℃ of following balances of room temperature:

Table 14 rubber solidification temperature is investigated

Temperature (℃)	Rubber heavy (g)	Dissolve required time (min) fully	Rate of dissolution (min/g) rubber character
				??10 ??4 ??0	??1.2213 ??1.1810 ??1.1921	?21 ?18 ?11	17.2 plasticity is poor, it is moderate to cross soft 15.2 softnesses, plasticity 9.2 matter are crisp, and porosity is arranged

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.

2.5 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 15.

The selection result of the test of table 11 sprinkler body temperature

The sprinkler body temperature	Soft capsule finished product situation
		??40～42℃ ????42～44℃ ????44～46℃	Pressing is bad, easy leakage yield rate height, the little soft capsule appearance poor of content uniformity, the out-of-flatness of pressing position

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

2.6 setting and drying process condition are selected:

(1) selection of 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 16.

Table 16 soft capsule setting temperature selection result table

Setting temperature (℃)	Soft gelatin capsule sum (grain)	Fixing time (h)	Abnormity ball number (grain)	Abnormity ball rate (%)
					??15 ??20 ??25	??475 ??472 ??442	??7.5 ??5.0 ??3.5	??18 ??19 ??27	??3.8 ??4.0 ??6.1

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 17.

Table 17 soft capsule baking temperature selection result table

Baking temperature (℃)	Soft gelatin capsule sum (grain)	Drying time (h)	Disintegration time (min)
				??15 ??20 ??25	??452 ??468 ??441	??36 ??28 ??20	??14 ??15 ??15

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.

2.7 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 18.

Table 18 pilot plant test is table as a result

Lot number	??2005001	??2005002	??2005003
				The medical material total amount (kg) that feeds intake	??20	??20	??20
Amount of water (kg)	For the first time 168 for the second time 150 for the third time 150	For the first time 168 for the second time 150 for the third time 150	For the first time 168 for the second time 150 for the third time 150
				The extraction process parameter	??70～80℃	??70～80℃	??70～80℃
The concentration technology parameter	??-0.06～ ??-0.08MaP ??70～80℃	??-0.06～ ??-0.08MaP ??70～80℃	??-0.06～ ??-0.08MaP ??70～80℃
				Baking temperature (℃)	??70～75	??70～75	??70～75
Dried cream weight (kg)	??3.06	??3.05	??3.05
				160 order dried cream powder weight (kg)	??2.98	??2.97	??2.98
Add substrate amount (kg)	??2.98	??2.97	??2.98

Theoretical yield (0.6g/ grain)	10000	10000	10000
				Actual production (0.4g/ grain)	8680	8640	8660
Yield rate (%)	86.8	86.4	86.6
				Average particle heavy (g)	0.5994	0.5995	0.5998
Character	Content is yellow to pale brown color grease; Sweet and slightly bitter taste.	Content is yellow to pale brown color grease; Sweet and slightly bitter taste.	Content is yellow to pale brown color grease; Sweet and slightly bitter taste.
				Disintegration time	17	18	17
Microbial check	Up to specification	Up to specification	Up to specification
				Dictyophora fungus polysaccharide content (mg/ grain)	54	55	53

Pharmacological effect research:

1, dictyophora fungus polysaccharide is removed O ₂ ^-Reach pharmacological research: the effect that (1) dictyophora fungus polysaccharide is removed: at external generation ultra-oxygen anion free radical _ O to the human erythrocyte membrane free-radical oxidation ₂Reaction system in, add dictyophora fungus polysaccharide component PS respectively, make that polysaccharide concentration in the system is respectively 0,50,100,200,300,400mg/L, the result is under this experimental condition, PS is to O for the dictyophora fungus polysaccharide component ₂Scavenging action (less than 300mg/L) under low concentration comparatively obvious, to O ₂Average suppression ratio reach 40 ~ 70%; And (greater than 300mg/L) effect is not remarkable under higher concentration, and average suppression ratio is less than 15%.May be because under the condition that radical initiator exists, and as monosaccharide, polysaccharide molecule also can autoxidation, produces new organic free radical, makes the organic free radical of polysaccharide generation itself and the free radical of its removing reach balance.And under low concentration, reduced the response probability of polysaccharide and radical initiator, show the effect that polysaccharide is removed superoxide radical.(2) dictyophora fungus polysaccharide is to the protective effect of human erythrocyte membrane lipid peroxidation: test shows that dictyophora fungus polysaccharide has the effect that suppresses human red blood cell shadow vacuolar membrane lipid peroxidation, and oxygenation efficiency is 38 ~ 82% relatively, and this may be that polysaccharide molecule is to H ₂O ₂Affinity bigger, hindered H ₂O ₂To the peroxidating of human red blood cell shadow vacuolar membrane, snperoxiaized protective effect is not directly proportional with concentration but polysaccharide is to human erythrocyte membrane.The main fatty acid of human red blood cell membrane lipid comprises palmitic acid, oleic acid, linoleic acid, stearic acid, arachidonic acid, docosenoic acid, lipid peroxidation is the chain reaction that free radical causes, and very easily destroy unsaturated fatty acid, the aerobic metabolism process of organism constantly produces free radical, when its existence exceeds the removing ability that the body guard system is had, the oxidation that will cause biomacromolecule directly or indirectly destroys, bring out the membrane lipid peroxidating, reduce film fat flowability, cause the aging of organism and the generation of numerous disease.Experimental study shows that dictyophora fungus polysaccharide has the effect of certain removing ultra-oxygen anion free radical, and can suppress the lipid peroxidation of human erythrocyte membrane, may be one of main effect of its antitumor, raising immunity.

2, the pharmacological research of Caulis Bambusae In Taeniam blood fat reducing: the cardiovascular diseases is the human at present one of the main reasons of extremely forgetting, great mass of data shows, cardiovascular diseases's sickness rate and hyperlipidemia are closely related, so blood fat reducing is the effective measures of anti-angiocardiopathy, and emphasize to want early prevention, though existing many lipid lowerers have side effect more, should not make the usefulness of long-term prevention.Hyperlipidemia and atherosclerotic generation are closely related, there is the expert further to study serum high-density LP (HDL) and Coronary Heart Disease from the angle of morphology, biochemistry and ergology, the result shows that coronary artery pathological changes degree and serum high-density LP cholesterol (HDL-C) concentration are negative correlation, the effect of HDL is that restricted cholesterol stores up at intra-arterial, and promotes cholesterol transport to go out arterial wall to rush down to place accelerated degradation such as liver and row.Therefore, it is a kind of antiatherogenic lipoprotein, in addition, the Epidemiological study data also shows, the increase of low-density lipoprotein cholesterol in the blood (LDL-C) also is atherosclerosis and the pathogenetic key factor of coronary disease, increasing of low density lipoprotein, LDL in the blood (LDL) can be passed through cell surface ldl receptor intravasation endotheliocyte, and cause the accumulation of cell inner cholesterol (CE) and change the vacuolar membrane like cell into, the final atherosclerosis purplish or white patches on the skin piece that forms, dimension, come in the past few decades, people's door is indicated the serum total cholesterol TC that reduces serum always as the effect of anti-atherogenic medicine be inappropriate, atherosclerosis may not easily take place in the TC superelevation, and the normal person of serum TC also may not be difficult for taking place atherosclerosis, and key is to want comprehensive HDL-C, both situations of LDL-C are analyzed.This experimental study is found, when giving the experimental rat high lipid food, the Caulis Bambusae In Taeniam that adds various dose respectively, after 60 days, except that the no significant change of serum trig lyceride (TG) of low dose group, the value added of the TG of TC, LDL-C value added, HDL-C, HDL-C/TC drop-out value and high dose group all significantly is lower than simple food high lipid food, after the Caulis Bambusae In Taeniam nursing experimental rat of doses is described, the effect that not only has prevention TC, TG to raise, prevent the effect that LDL-C raises and HDL-C descends simultaneously in addition, this is significant to further preventing and treating atherosclerosis.

The specific embodiment:

Embodiments of the invention 1: get Caulis Bambusae In Taeniam 2000g, add 5 times of medical material water gagings, 70 ~ 80 ℃ of heating, extraction 3 times, each 3 hours, merge 3 times extracting solution, filter, filtrate-0.06～-be evaporated to the thick paste shape under the 0.08MaP, 70 ~ 80 ℃ condition, 70 ~ 80 ℃ of following drying under reduced pressure are pulverized, cross 160 mesh sieves, the powder of getting it filled adds tween 80 4.5g, add propylene glycol 24g, and to add Polyethylene Glycol 400 to total amount be 600g, mix homogeneously, and colloid mill ground 20 minutes; Rubber is pressed gelatin: glycerol: water=preparation in 1: 0.3: 1, also can add 2 ‰ compound food colorings, 3 ‰ titanium dioxides and 1 ‰ mud moor gold ethyl esters, and be pressed into 1000 soft capsules then, promptly.

Embodiments of the invention 2: get Caulis Bambusae In Taeniam 1000g, add 2 times of medical material water gagings, heating (50 ℃) is extracted 5 times, each 5 hours, merge extractive liquid, filtered, filtrate is concentrated into the thick paste shape, and drying is pulverized, cross the following sieve of 100 orders, the powder of getting it filled adds 2.5 times of amount substrate: soybean oil, mix homogeneously, colloid mill ground 30 minutes, was pressed into 1000 soft capsules, promptly; Can add 2 ‰ compound food colorings, 3 ‰ titanium dioxides and 1 ‰ mud moor gold ethyl esters, be pressed into 500 soft capsules then, promptly.

Embodiments of the invention 3: get Caulis Bambusae In Taeniam 5000g, add 16 times of medical material water gagings, heating (100 ℃) is extracted 1 time, each 1 hour, merge extractive liquid, filtered, filtrate is concentrated into the thick paste shape, and drying is pulverized, cross the following sieve of 100 orders, the powder of getting it filled adds 0.8 times of amount substrate: Macrogol 600, mix homogeneously, colloid mill ground 10 minutes, was pressed into 1000 soft capsules, promptly.

Claims (6)

1, a kind of is the soft capsule of raw material with the Caulis Bambusae In Taeniam, it is characterized in that: Caulis Bambusae In Taeniam is extracted processing and preparing become extract powder, then according to extract powder: substrate be 1: 0.8～2.5 weight ratio powder and substrate mix homogeneously, be pressed into soft capsule, wherein content is yellow to pale brown color grease, sweet and slightly bitter taste.

2, described according to claim 1 is the soft capsule of raw material with the Caulis Bambusae In Taeniam, it is characterized in that: Caulis Bambusae In Taeniam 2000g is extracted processing and preparing becomes extract powder, then according to extract powder: substrate be 1: 1 weight ratio powder and substrate mix homogeneously, be pressed into soft capsule.

3, according to claim 1 or 2 described be the soft capsule of raw material with the Caulis Bambusae In Taeniam, it is characterized in that: substrate is for can being vegetable oil or PEG class material.

4, described according to claim 3 is the soft capsule of raw material with the Caulis Bambusae In Taeniam, and it is characterized in that: substrate is PEG-400.

5, as claimed in claim 1 or 2 is the preparation of soft capsule method of raw material with the Caulis Bambusae In Taeniam, it is characterized in that: get Caulis Bambusae In Taeniam, add 2～16 times of medical material water gagings, 50～100 ℃ of heating extraction 1～5 time, each 1～5 hour, merge extractive liquid,, filter, filtrate is concentrated into thick paste shape, drying, pulverize, cross the following sieve of 100 orders, the powder of getting it filled, add 0.8～2.5 times of amount substrate, mix homogeneously, colloid mill ground 10-30 minute, be pressed into 1000 soft capsules, promptly.

6, described according to claim 5 is the preparation of soft capsule method of raw material with the Caulis Bambusae In Taeniam, it is characterized in that: get Caulis Bambusae In Taeniam 2000g, add 5 times of medical material water gagings, 70～80 ℃ of heating, extraction 3 times, each 3 hours, merge 3 times extracting solution, filter, filtrate-0.06～-be evaporated to the thick paste shape under the 0.08MaP, 70～80 ℃ condition, 70～80 ℃ of following drying under reduced pressure are pulverized, and cross 160 mesh sieves, the powder of getting it filled, add tween 80 4.5g, add propylene glycol 24g, and to add Polyethylene Glycol 400 to total amount be 600g, mix homogeneously, colloid mill ground 20 minutes; Rubber is pressed gelatin: glycerol: water=preparation in 1: 0.3: 1, add 2 ‰ compound food colorings, 3 ‰ titanium dioxides and 1 ‰ mud moor gold ethyl esters in the gelatin amount simultaneously, and be pressed into 1000 soft capsules then, promptly.