CN103830322B - Soft capsule containing salvia miltiorrhiza extract and preparation method thereof - Google Patents

Abstract

The invention discloses a soft capsule containing a salvia miltiorrhiza extract and a preparation method thereof. The content of the soft capsule disclosed by the invention contains the salvia miltiorrhiza extract, medium-chain triglyceride, edible oil and phospholipid, wherein corresponding to 1 part by weight of the salvia miltiorrhiza extract, the content of medium-chain triglyceride is 40-600 parts by weight; the content of edible oil is 50-650 parts by weight; the content of phospholipid is 40-600 parts by weight; the content of unsaturated fatty acid in edible oil is not less than 70% by weight; the content of phosphatidylcholine in phospholipid is 20-80% by weight, and the content of dilinolein diplmitoyl phosphtidyl choline is 20-80% by weight. The preparation method of the soft capsule disclosed by the invention comprises the following steps of: mixing various components to obtain the content of the soft capsule; packaging the content in the shell of soft capsule. The soft capsule disclosed by the invention is capable of effectively improving chemical liver injury and alcoholic liver injury and reducing blood fat; furthermore, the active components, such as the salvia miltiorrhiza extract, phospholipid and the like, can exist stably for a long time.

Description

A kind of soft capsule containing Salvia root P.E and preparation method thereof

Technical field

The present invention relates to a kind of soft capsule containing Salvia root P.E and preparation method thereof.

Background technology

The red sage root is Labiatae herbaceos perennial, and clinic is usually used in cardiovascular and cerebrovascular disease promoting blood circulation and removing blood stasis.Modern study shows, The red sage root can promote hepatocyte differentiation to breed, and improve the regeneration power of liver, can partly reverse the inhibitory action to liver regeneration for the alcohol. Tanshinone iia is one of main effective active composition of the red sage root, is natural.Tanshinone iia passes through scavenging activated oxygen, Performance is anti-oxidant, mitigate lipid peroxidation shields to liver.(Jiang Huidi, Huang Xiaqin and Yang Yi, nine kinds of protect liver Chinese medicines resist The research [j] of lipid peroxidation, Chinese medicine, 1997,20 (12): 624-626).Tanshinone iia is almost insoluble in water, Oral absorption is poor, and bioavilability is low, half-life short, is not suitable for making oral formulations (Xuchang victory etc., tanshinone iia and its class Like the fully synthetic of thing and structural modification progress [j], pharmacy progress 2013, (37) 2:58-65).In order to improve tanshinone iia The effect of active component, prior art becomes tanshinone iia sodium sulfonate using chemical modification, such as cn1624474a.Tanshinone iia sulphur Sour sodium injection Clinical practice is affected by transfusion ph value, easily the phenomenons such as muddiness, crystallization occurs, is also restricted use.

Soybean lecithin is the mixtures such as phosphatid ylcholine, phosphatidyl-ethanolamine, phosphatidylinositols and phosphatidylserine.No With molecular configuration phosphatide, there are different biological functions.Research has shown that: dilinoleoylphosphatidylcholine is also referred to as " polyene phosphatidyl Choline " has and improves nervous function, reduces and damages, promote nerve cell for the phagocytosis of ectogenic amyloid-beta and (Zhang Xiaohui etc., Polyene Phosphatidylcholine causes Alzheimer disease model rat to amyloid-beta (a β 1-40) to metabolic degradation Therapeutic action [j], modern biomedical be in progress, 2011,11(13): 2438-2442).Dilinoleoylphosphatidylcholine contains Abundant oleic acid content is also the extraordinary emulsifying agent of fat-soluble compound and surfactant.Phospholipid acid choline is most biology The phosphatide of activity.Phosphatid ylcholine is different with saturation degree due to 1 length with the chain of 2 conjugated fatty acids of glyceryl, thus Various phosphatid ylcholine biological functions are also different.Germany scientist is further purified to soybean lecithin, obtains two alkyl Unsaturated double strong linoleic phosphatid ylcholine (dilinoleoylphosphatidylcholine) is all contained on side chain, also has title " polyene phosphatidyl Choline (ppc) ".Polyenoid phosphatide can substitute endogenous saturated phospholipid, so that membrane fluidity is strengthened with transmembrane transport system activity, easily Impaired liver plasma membrane is made to be recovered.It is also that fat-soluble medicine is extraordinary that Polyene Phosphatidylcholine contains abundant oleic acid content Emulsifying agent and surfactant.

Median chain triglyceride oil (also referred to as midchain oil) main component is the triglycerides of octanoic acid and capric acid.Medium chain triglyceride three acid Ester has fat-soluble well, is 100 times of LCFA, frequently as various clinical parenteral nutrition using not producing fat Accumulation.

Extract from plant and there is medicinal and health-care effect edible oil contain abundant unrighted acid, such as small-mouthed jar Grain seed oil, Purple Perilla Seed Oil, oenothera seed oil, sunflower oil, corn oil etc..Research has shown that poppy seed oil unrighted acid accounts for More than 88%, the composition that poppy seed oil has identified also containing hydro carbons, aldehydes, ketone, the containing oxygen derivative of aromatic compound and The containing oxygen derivative of furan compound, also (ancestral is new, poppy seed oil aliphatic acid group composition for part organic acid and its ester type compound Analysis [j], oil and foodstuffs science and technology, 2010,18 (6): 20-21).Poppy seed oil has softening blood vessel prevents blood fat heavy on vascular wall Long-pending, suppression liver low-density lipoprotein synthesis improves the health care of sleep quality.Poppy seed oil also has fabulous fat-soluble effect and spy Different fragrant.Fish oil is rich in ω -3 series polyunsaturated fatty acid eicosapentaenoic acid (epa) and DHA (dha).Epa, dha are aliphatic acid necessary to human body.

Liver is that human body carries out metabolic large-scale organ.It is true that all of chemical substance is thin by damaging liver The mode of after birth is damaging liver.According to statistics, the average attack rate of China big or middle city fatty liver has reached the 8- of population The overweight people of 10%, 60-90% is suffering from fatty liver.30 years old about the male sex in there are about 20% people and suffer from different degrees of fat Liver, fatty liver in male is significantly more than women within less than 45 years old.The chronic wine-head of 75-90% has fatty liver, and alcoholic fatty liver is fallen ill Become rejuvenation, and China has become as hepatopathy big country, and all kinds hepatopathy has increasingly becomed one of principal disease.

Pharmaceutically prior art application mostly adopts polyoxyethylene type compounds as tanshinone cosolvent to tanshinone iia. Cn101732409a is related to a kind of salvia miltiorrhiza soft capsule and preparation method thereof, and primary solvent is PEG400, Macrogol 6000 With a small amount of propane diols.Cn102100741a is related to a kind of total tanshinone composite preparation although employing median chain triglyceride oil, but It is still to adopt Crodaret and 1,2-PD as surfactant.

The use of some conventional surfactants is not widely approved, for example, the lot of documents of announcement Prove, polyethylene glycol (peg) is almost free from side effects and toxicity, but EFSA's research is thought, in peg human body Degree of absorption depends on the molecular weight of its polymer, and the peg of low-molecular-weight is easier to be absorbed.Her Majesty the Queen in right of Canada as represented by the minister of Healt is defended with the world The limit that raw tissue who let pass as product approval to the zooscopy data of peg in nineteen sixty-eight.The degree of absorption of peg depends on In its molecular weight, i.e. low-molecular-weight peg(such as 1000 or less) than HMW peg(such as 4000 or 6000) easily internal Absorb.There are different requirements in different countries to everyone intake average of polyethylene glycol, and therefore this kind of compound is people's length Eating in a large number of phase need to be recognized.

Content of the invention

The purpose of the present invention is to overcome the deficiencies in the prior art, provides a kind of health-care effect preferably and avoids using routine Soft capsule for improving hepatic injury and reducing blood lipid of surfactant and preparation method thereof.

To achieve these goals, in a first aspect, the invention provides a kind of soft capsule, the content of this soft capsule contains Salvia root P.E, median chain triglyceride oil, edible oil and phosphatide, wherein, with respect to the Salvia root P.E of 1 weight portion, middle chain is sweet The content of oily three acid esters is 40-600 weight portion, and the content of edible oil is 50-650 weight portion, and the content of phosphatide is 40-600 weight Amount part, the unsaturated fatty acid content in described edible oil is not less than 70 weight %, the content of the phosphatid ylcholine in described phosphatide Content for 20-80 weight % and dilinoleoylphosphatidylcholine is 20-80 weight %.

Second aspect, the invention provides the preparation method of the soft capsule described in first aspect, the method is included the red sage root Extract, median chain triglyceride oil, edible oil and phosphatide mixing obtain the content of soft capsule, and this content are encapsulated in soft In capsule softgel shell.

Prove through animal Efficacy experiments, the soft capsule of the present invention can improve chemical damage, Alcoholic effectively Hepatic injury and reduction blood fat.

And, investigate regulation checking with reference to relevant stability of drug products, the soft capsule of the present invention is not using tables such as polyethylene glycol Face activating agent, but Salvia root P.E, phosphatide isoreactivity composition can exist steadily in the long term.

Other features and advantages of the present invention will be described in detail in subsequent specific embodiment part.

Brief description

Accompanying drawing is used to provide a further understanding of the present invention, and constitutes the part of specification, with following tool Body embodiment is used for explaining the present invention together, but is not construed as limiting the invention.In the accompanying drawings:

Fig. 1 is shown that the microscope of icr male mice liver tissue slices morphological observation (400 ×) in test case 1 Photo；

Fig. 2 is shown that the microscope of icr male mice liver tissue slices morphological observation (400 ×) in test case 2 Photo.

Specific embodiment

Hereinafter the specific embodiment of the present invention is described in detail.It should be appreciated that it is described herein concrete Embodiment is merely to illustrate and explains the present invention, is not limited to the present invention.

The content of the soft capsule that the present invention provides contains Salvia root P.E, median chain triglyceride oil, edible oil and phosphatide, Wherein, with respect to the Salvia root P.E of 1 weight portion, the content of median chain triglyceride oil is 40-600 weight portion (preferably 60- 400 weight portions), the content of edible oil is 50-650 weight portion (preferably 60-600 weight portion), and the content of phosphatide is 40-600 Weight portion (preferably 60-400 weight portion), the unsaturated fatty acid content in described edible oil is not less than 70 weight %(such as 70- 95 weight %), the content of the phosphatid ylcholine in described phosphatide for the content of 20-80 weight % and dilinoleoylphosphatidylcholine is 20-80 weight %.

According to the present invention, described Salvia root P.E is had no particular limits, the red sage root that can obtain for conventional method carries Take thing, e.g., the ethanol extract of the red sage root.Under preferable case, the content of the tanshinone iia in the Salvia root P.E of employing is in 20 weights Amount more than % (such as 20-99.9 weight %, more preferably 30-60 weight %).Obtain the tanshinone iia content red sage root within the above range The method of extract is well known to those skilled in the art (can also pass through commercially available), will not be described here.

According to the present invention, described median chain triglyceride oil is the mixture of the common saturated triglycerides in this area, preferably Ground, described median chain triglyceride oil is the mixture containing Trivent OCG and Triglyceride DDD, Trivent OCG Content is 50-80 weight %, and the content of Triglyceride DDD is 20-50 weight % and Trivent OCG and Triglyceride DDD is total Amount is not less than 95 weight %.

According to the present invention, the edible oil that unsaturated fatty acid content is not less than 70 weight % may be incorporated for the present invention, but excellent In the case of choosing, described edible oil is poppy seed oil, grape-kernel oil, evening primrose oil, 'Heijialun ' seed oil, Purple Perilla Seed Oil, flax oilseeds At least one in oil, olive oil, fish oil, soybean oil, corn oil and sunflower oil, more preferably poppy seed oil.Can pass through The milling process of routine, lixiviation process, supercritical extraction or water substitution obtain above-mentioned edible oil from plant, and these methods are As it is known to those skilled in the art that will not be described here.

In the present invention, " phosphatide " refers to contain one or more phosphates in molecule, and the complex lipid of polarized One of, its molecule is made up of glycerine, aliphatic acid and band hydroxy compound (having polarity) three part, and it represents thing phosphatidic acid, phosphorus Phosphatidyl glycerol, cuorin, phosphatid ylcholine, phosphatidyl-ethanolamine, phosphatidylserine, phosphatidylinositols, and pass through ester bond The Plasmalogens that are combined with aliphatic acid, ether lipid etc., used in the present invention, phosphatide refers to that the content of phosphatid ylcholine is The content of 20-80 weight % and dilinoleoylphosphatidylcholine is the phosphatide of 20-80 weight %, can be from animal brain and/or soybean Deng in extract obtain.Preferably, described phosphatide is soybean lecithin.It should be noted that commercially available soybean lecithin also contains phosphatide The compositions such as acyl monoethanolamine, phosphatidylinositols, phosphatidic acid, phosphatidyl glycerol.But these compositions can't be to soft capsule of the present invention Improvement hepatic injury and lipid-lowering effect produce impact, therefore, it can be directly used in the preparation present invention can be used as health products or medicine The soft capsule of product.

According to the present invention, in order to strengthen the antioxygenic property of soft capsule, thus extending the shelf life, the content of described soft capsule Thing also contains antioxidant.Described antioxidant can for commonly used in the art various can oxidation resistant material, it is highly preferred that Described antioxidant is vitamin e.

According to the present invention, the softgel shell of described soft capsule can be various conventional soft capsule shells, for example, it is possible to by inciting somebody to action Gelatin, pure water, glycerine, sorbierite, glycine and titanium dioxide add appropriate pigment (lemon yellow or light blue) carrying out glue to obtain ?.

The method preparing above-mentioned soft capsule that the present invention provides includes Salvia root P.E, median chain triglyceride oil, eats Oil and the content of phosphatide mixing acquisition soft capsule, and this content is encapsulated in soft capsule shell.

Wherein, soft capsule shell can by using preparing in the way of conventional, for example, by gelatin, pure water, glycerine, sorbierite, Glycine and titanium dioxide add appropriate pigment (lemon yellow or light blue) carrying out glue to obtain.Then can be using conventional molding side Method pill, sizing are dried, wash ball, the ball that dries in the air, pick up ball, make semi-finished product, packaging.

According to the present invention, to the concrete mode of described mixing, there is no particular limitation, and for example, the mode of mixing can be: At 55-60 DEG C, Salvia root P.E, edible oil and phosphatide are dissolved in median chain triglyceride oil, be then cooled to 35-40 DEG C standby With.Wherein, the dissolving order of Salvia root P.E, edible oil and phosphatide is not particularly required, can dissolve in certain sequence, Can also dissolve simultaneously.It is highly preferred that can first Salvia root P.E be dissolved in median chain triglyceride oil, add edible oil And phosphatide.

The soft capsule of the present invention can be used in improving hepatic injury and/or reducing blood lipid.Wherein, the dose of soft capsule can root Depending on the concrete health of user, for example, the dose of described soft capsule can be 0.1-5g/kg/ days, preferably 0.4-2g/kg/ days.

Hereinafter will be described the present invention by embodiment.In following examples, median chain triglyceride oil is purchased from Tieling Beiya Medical Oil Co., Ltd., the content of Trivent OCG is 70 weight %, and the content of Triglyceride DDD is 30 weights Amount % and Trivent OCG and Triglyceride DDD total amount are 95 weight %；Poppy seed oil is purchased from the Shanghai all ages limited public affairs of pharmacy Department, grape-kernel oil, evening primrose oil, 'Heijialun ' seed oil, Purple Perilla Seed Oil, flax oilseeds oil are biomedical purchased from Changchun modern Application Co., Ltd, olive oil, soybean oil, corn oil, sunflower oil are purchased from Changchun Heng Kelong supermarket, and it is still real that fish oil is purchased from Shanghai east Industry Co., Ltd；Salvia root P.E is purchased from Xi'an Honson Biotechnology Co., Ltd.'s (lot number: 121220), tanshinone iia contains Measure as 42 weight %；Soybean lecithin is purchased from German lipoid company, lot number: 576500: content 45 weight % of phosphatid ylcholine and The content of dilinoleoylphosphatidylcholine is 49 weight %, lot number 1032675: content 30 weight % of phosphatid ylcholine and two sub- oil The content of phosphatidyl choline is 65 weight %.

Embodiment 1

Based on 1000, under nitrogen protection, by 95g median chain triglyceride oil heating water bath to 55 DEG C, and in this temperature Under, add 0.5g Salvia root P.E, stir to dissolving, (unsaturated fatty acid content is 90 weights to add 95g poppy seed oil Amount %), 110g soybean lecithin (lot number: 576500) and 0.06g vitamin e, stir to dissolving, be cooled to 35 DEG C as soft capsule Content stand-by；

According to following weight than preparation soft capsule shell: gelatin: pure water: glycerine: sorbierite: glycine: titanium dioxide= 1:1:0.47:0.02:0.08:0.005 carrying out glue, conventional method of moulding pill, sizing are dried, wash ball, the ball that dries in the air, pick up ball, obtain To soft capsule s-1.

Comparative example 1

Method according to embodiment 1 prepares soft capsule s-d1, and except for the difference that, the consumption of median chain triglyceride oil is 15g, small-mouthed jar The consumption of grain seed oil is 175g.

Comparative example 2

Method according to embodiment 1 prepares soft capsule s-d2, except for the difference that, median chain triglyceride oil is replaced with oleic acid second Ester.

Comparative example 3

Method according to embodiment 1 prepares soft capsule s-d3, except for the difference that, median chain triglyceride oil is replaced with nutmeg Isopropyl propionate.

Embodiment 2

Based on 1000, under nitrogen protection, by 80g median chain triglyceride oil heating water bath to 60 DEG C, and in this temperature Under, add 0.2g Salvia root P.E, stir to dissolving, add 120g soybean oil (unsaturated fatty acid content be 70 weight %), 80g soybean lecithin (lot number 1032675) and 0.06g vitamin e, stir to dissolving, are cooled to 40 DEG C of contents as soft capsule Thing is stand-by；

According to following weight than preparation soft capsule shell: gelatin: pure water: glycerine: sorbierite: glycine: titanium dioxide= 1:1:0.47:0.02:0.08:0.005 carrying out glue, conventional method of moulding pill, sizing are dried, wash ball, the ball that dries in the air, pick up ball, obtain To soft capsule s-2.

Embodiment 3

Based on 1000, under nitrogen protection, by 120g median chain triglyceride oil heating water bath to 58 DEG C, and in this temperature Under, add 2g Salvia root P.E, stir to dissolving, add 120g grape-kernel oil (unsaturated fatty acid content be 75 weight %), 120g soybean lecithin (lot number: 576500), 0.06g vitamin e, stir to dissolving, be cooled to 38 DEG C of contents as soft capsule Thing is stand-by；

According to following weight than preparation soft capsule shell: gelatin: pure water: glycerine: sorbierite: glycine: titanium dioxide= 1:1:0.47:0.02:0.08:0.005 carrying out glue, conventional method of moulding pill, sizing are dried, wash ball, the ball that dries in the air, pick up ball, obtain To soft capsule s-3.

Embodiment 4-11

Method according to embodiment 1 prepares soft capsule s-4 to s-11, except for the difference that, poppy seed oil is replaced with respectively the moon See careless oil, 'Heijialun ' seed oil, Purple Perilla Seed Oil, flax oilseeds oil, olive oil, fish oil, corn oil and sunflower oil.

Test case 1

This test case is used for the defencive function to chemically hepar damnification for the soft capsule of the present invention is described.

By icr male mice, (18-22g, purchased from Jilin University's animal center, cleaning grade, animal licensing numbering syxk (lucky) 2007-0011) it is divided into model administration group, model control group, blank control group and positive administration group (n=8).With gavage side Formula gives, to model administration group mouse, soft capsule (the i.e. s-1 to s-11 and s-d1 to s- that embodiment 1-11 and comparative example 1-3 are obtained D3)；Heliotropism administration group mouse gives Bifendate (lot number is a02121005, Zhejiang Wanbang Pharmaceutical Co., Ltd.)； Give distilled water to blank control group and model control group mouse, be administered once a day, weigh weekly twice, to adjust administration Amount.After administration 30 days, each group mouse fasting overnight 16 hours, then by model administration group, model control group and positive administration group The ccl4(0.1ml/10g of 1 weight % that gives of gavage of mouse, using peanut oil dilution), the flower that blank control group gives Oil generation (0.1ml/10g), model administration group and positive administration group continue to be administered to experiment terminate (little with ccl4 gavage interval 4 When).Put to death mouse after giving 20 hours of ccl4, take blood system from serum, using kit measurement glutamic-oxalacetic transaminease (ast) and paddy (x ± s, concrete grammar is referring to kit specification, and glutamic-oxalacetic transaminease ast kit (lot number for pyruvic transaminase (alt) level 20130426) it is purchased from Nanjing and builds up Bioengineering Research Institute with glutamic-pyruvic transaminase alt kit (lot number 20130427)), knot Fruit is shown in Table 1.

The feeding conditions of mouse: all mouse are raised in level of masking Animal House, 25 DEG C of temperature, humidity 50- during testing 60%, each 12 hours of daily light and shade room, well-ventilated, standard feed, free water.

Table 1

#p < 0.05, ##p < 0.01, model administration group is compared with model control group

* p < 0.05, * * p < 0.01, blank control group is compared with model control group

Model control group serum alt and ast level are higher than blank control group, and modeling success is described.And, model administration group Serum alt level decreases compared with model control group；And model administration group serum ast level decreases compared with model control group, And it is more notable to be administered alt and ast level decline in the model administration group of s-1, s-2 and s-3.

The liver organization of the mouse that clip is put to death, uses 10% formalin fix, and (FFPE, he contaminates for routine pathology film-making Color), carry out Histopathology detection: from the pathological change of one end visual field start recording cell of liver, continuous with 40 times of object lens Observe whole histotomy, result is as shown in Figure 1.It can be seen that the hepatocellular retrogression pathological changes of centrilobular and a few cell are bad Extremely.Major lesions type has ballooning degeneration of liver cells, steatosis, endochylema cohesion, liver cell hydropic degeneration and meronecrosis etc..

Record the area in the visual field shared by various pathologies in each visual field respectively, and the pathology in the accumulative observed visual field is total Point, as shown in table 2, standards of grading are as follows for result:

Ballooning degeneration of liver cells: (cell enlargement, endochylema residual is a little)

Hepatic cell fattydegeneration: (the fat drips cavity of distinct occurs in liver cell endochylema)

Endochylema condenses: (enhancing of endochylema thermophilic Yihong)

Hydropic degeneration:

Necrosis of liver cells: (the thermophilic Yihong of endochylema becomes, coagulation necrosis)

Table 2

Blank control group he chromoscopy liver color and luster is normal, clear-cut margin, smooth surface.Visible lobuli hepatis structure under mirror Clearly, limiting plate smooths, hepatic cell cords, sinus hepaticus marshalling rule.The red dye of liver cell endochylema, core is placed in the middle, have no steatosis and The degeneration pathological change such as meronecrosis.Portal area three-tube structure is clearly visible, and Non Apparent Abnormality is in normal liver tissue structure.

Model control group, near the liver cell retrogression pathological changes annular in shape of central vein, is mainly shown as liver cell balloon sample Change, the cohesion of liver cell endochylema, liver cell hydropic degeneration and necrosis of liver cells etc. change, and the liver cell of leaflet periphery is close to normal.

The model administration group of administration s-1, near the liver cell retrogression pathological changes annular in shape of central vein, is mainly shown as liver Cell cytosol cohesion, liver cell hydropic degeneration and necrosis of liver cells etc. change, and the liver cell of leaflet periphery is close to normal.

The model administration group of administration s-2, near the liver cell retrogression pathological changes annular in shape of central vein, is mainly shown as liver Cellular fat denaturation, the cohesion of liver cell endochylema, liver cell hydropic degeneration and necrosis of liver cells etc. change, the liver cell of leaflet periphery Close to normal.

The model administration group of administration s-3, near the liver cell retrogression pathological changes annular in shape of central vein, is mainly shown as liver Cell cytosol cohesion, liver cell hydropic degeneration and necrosis of liver cells etc. change, and the liver cell of leaflet periphery is close to normal.

Positive controls, near the liver cell retrogression pathological changes annular in shape of central vein, are mainly shown as liver cell balloon sample Change, the cohesion of liver cell endochylema, liver cell hydropic degeneration and necrosis of liver cells etc. change, and the liver cell of leaflet periphery is close to normal.

Give ast and alt level and the liver pathomorphology testing result of the mouse of the soft capsule of embodiment 4-11 Close with embodiment 1-3.

As can be seen from the above results, the hepatic injury that the soft capsule of the present invention induces for ccl4 has certain protection to make With.

Test case 2

This test case is used for the defencive function that the soft capsule of the present invention damages to alcoholic liver is described.

By icr male mice, (18-22g, purchased from Jilin University's animal center, cleaning grade, animal licensing numbering syxk (lucky) 2007-0011) it is divided into model administration group, model control group, blank control group and positive administration group (n=8).With gavage side Formula gives the soft capsule (i.e. s-1 to s-11 and s-d1 to s-d3) of embodiment 1-11 and comparative example 1-3 to model administration group mouse； Heliotropism administration group mouse gives Bifendate (lot number is a02121005, Zhejiang Wanbang Pharmaceutical Co., Ltd.)；To sky White control group and model control group mouse give distilled water (0.1ml/10g), are administered once a day, weigh weekly twice, to adjust Whole dosage.Gavage of mouse of model administration group, model control group and positive administration group was given 50 weights after 30 days by administration The ethanol 12ml/kg of amount %, blank control group gives distilled water (0.1ml/10g), and fasting puts to death mouse, clip liver in 16 hours Tissue, a part carries out the content of MDA (mda), reductive glutathione (gsh) and triglycerides (tg) in hepatic tissueS) detection (is measured using kit, and reduced glutathione kit (lot number 20130424) and MDA tries Agent box (lot number 20130425) is purchased from Nanjing and builds up Bioengineering Research Institute, and triglyceride reagent box (lot number 006304) is purchased from Beijing Northization safe clinical reagent Co., Ltd, concrete operations are referring to kit specification), the results are shown in Table 3.

The feeding conditions of mouse: all mouse are raised in level of masking Animal House, 25 DEG C of temperature, humidity 50- during testing 60%, each 12 hours of daily light and shade room, well-ventilated, standard feed, free water.

Table 3

#p < 0.05, ##p < 0.01, model administration group is compared with model control group

* p < 0.05, * * p < 0.01, blank control group is compared with model control group

In model control group hepatic tissue, higher than blank control group and gsh content is less than blank control group to mda and tg content, says Bright modeling success.And, model administration group gsh content has raised compared with model control group, and mda content and tg content are compared with model pair All decrease according to group, and be administered in the model administration group of s-1, s-2 and s-3, gsh content raises more notable and mda contains Amount and tg content decline more notable.

Another part of liver organization 10% formalin fix, routine pathology film-making (FFPE, he dyes), enter Row Histopathology detects: from the pathological change of one end visual field start recording cell of liver, whole with 40 times of object lens Continuous Observations Individual histotomy., in the distribution of liver, scope and area, result is as shown in Figure 2 for main detection fat drips.

Hepatocellular fat drips in each visual field are evaluated, as shown in table 4, standards of grading are as follows for result:

Table 4

Blank control group checks that liver color and luster is normal, clear-cut margin, smooth surface.Under mirror, visible lobuli hepatis structure is clear, Limiting plate smooths, hepatic cell cords, sinus hepaticus marshalling rule.The red dye of liver cell endochylema, core is placed in the middle, has no that steatosis and cell are bad Degeneration of waiting indefinitely pathological change.Portal area three-tube structure is clearly visible, and Non Apparent Abnormality is in normal liver tissue structure.

Model control group, near the liver cell retrogression pathological changes annular in shape of central vein, is mainly shown as that liver cell endochylema coagulates Poly-, liver cell hydropic degeneration and necrosis of liver cells etc. change, and the liver cell of leaflet periphery is close to normal；Visible in part of hepatocytes Substantially circular cavity.

The all no obvious pathological change of model administration group.

Visible a small amount of circle cavity in positive administration group liver cell.

Give mouse mda, gsh and tg content and the liver pathomorphology testing result of the soft capsule of embodiment 4-11 Close with embodiment 1-3.

As can be seen from the above results, the hepatic injury that the soft capsule of the present invention induces for alcohol has certain protection to make With.

Test case 3

This test case is used for illustrating that the soft capsule of the present invention assists the health care of reducing blood lipid.

(1) foundation of Arteriosclerosis rat model

By wistar male rat, (180-220g, purchased from Jilin University's animal center, cleaning grade, animal licensing is numbered Scxk2007-0003) it is divided into high lipid food nursing group (to feed high lipid food, and feed formula is with reference to blood-fat-decreasing function Evaluation method (State Food and Drug Administration)) and basal feed nursing group (nursing basal feed, and feed is big by Jilin Learning Bethune medical college animal experimental center provides), after feeding 14 days, cut tail and take blood, check that the total courage of serum is solid using kit Alcohol (tc or cho), triglycerides (tg), HDL-C (hdl-c) and LDL-C (ldl-c) Level, to determine the formation of high blood lipid model rat (abbreviation rat model).Serum tc, tg, hdl-c and ldl-c level is all adopted Recorded with kit, concrete assay method is referring to kit specification, T-CHOL kit (lot number 006301), triglycerides Kit (lot number 006304), HDL kit (lot number 006328) and low-density lipoprotein kit (lot number 006340) it is purchased from Beijing Northization safe clinical reagent Co., Ltd.

Rat feeding conditions: all rats are raised in level of masking Animal House, 25 DEG C of temperature, humidity 50- during testing 60%, each 12 hours of daily light and shade room, well-ventilated, free water.

(2) lipid-lowering effect of soft capsule measures

, as packet foundation, the triglycerides of each rat is put down to change the most significantly triglyceride levels according to serology Average is substantially suitable, and the rat of high lipid food nursing group is divided into model administration group and model control group (n=8), model administration group Give the soft capsule (i.e. s-1 to s-11 and s-d1 to s-d3) that embodiment 1-11 and comparative example 1-3 are obtained in gavage mode respectively, The rat of model control group is that the high lipid food not giving medicament feeds rat, and arranges blank control group and (that is, do not give medicament Basal feed feed rat, n=8), be administered once a day, be administered 30 days, terminate fasted for one day prior 16 hours, abdomen master in experiment Arterial blood drawing, refrigerated centrifuge 3000 leaves the heart 15 minutes, draws serum, measures serum tc, tg, hdl-c and ldl-c levelAssay method is as shown in step (1)), the results are shown in Table 5.

Table 5

#p < 0.05, ##p < 0.01, model administration group is compared with model control group

* p < 0.05, * * p < 0.01, blank control group is compared with model control group

As can be seen from Table 5, model control group serum tc, tg and ldl-c level is above blank control group, and hdl-c Level is less than blank control group, and modeling success is described.And, serum tc, tg, ldl-c level of model administration group is compared with model pair All decrease according to group, hdl-c level has raised compared with model control group, and is administered the model administration group of s-1, s-2 and s-3 In, tc, tg, ldl-c level reduces more notable and hdl-c level raises more notable.

Give mda, gsh and tg content and the liver pathomorphology detection knot of the rat of the soft capsule of embodiment 4-11 Fruit is close with embodiment 1-3.

As can be seen from the above results, the soft capsule of the present invention has certain protective effect for hyperlipidemia.

Test case 4

This test case is used for the stability of the soft capsule of the present invention is described.

Carry out the accelerated test of 6 months under conditions of 30 DEG C ± 2 DEG C and rh65% ± 5%, the 0th, 1,2,3 during testing Detect the content of tanshinone iia and phosphatid ylcholine two kinds of active components with 6 the end of month samplings, and disintegration time limited and peroxidating The inspection target such as value, result is as shown in table 6.

Table 6

Additionally, the Stability Determination result of the soft capsule of embodiment 4-11 and embodiment 1-3 is close.Can from result above To find out, the stability of the soft capsule of the present invention is preferable.

Tanshinone iia is measured using chromatography with the content of phosphatid ylcholine, and concrete operations are as follows:

1st, tanshinone iia chromatogram analysis method:

(1) chromatographic condition and system suitability: with octadecylsilane chemically bonded silica as filler；With methanol-water (73 27) it is mobile phase；Detection wavelength is 270nm.Number of theoretical plate is calculated by tanshinone iia peak and should be not less than 2000.

(2) preparation of reference substance solution: take tanshinone iia reference substance 10mg, put in 100ml brown bottle, plus methanol dilution To scale, shake up, precision measures 2ml, put in 10ml brown bottle, plus methanol dilution, to scale, makes every 1ml containing about tanshinone The solution of iia20ug, shakes up, and obtains final product.

(3) preparation of need testing solution: take this product 10, remove capsule skin, take content to mix, precision weighs 0.3g, puts In 25ml brown measuring bottle, plus methyl alcohol makes dissolving, ultrasonic 15 minutes, lets cool and puts room temperature, and be diluted to scale, shake up, filtration, takes continuous Filtrate, obtains final product.

(4) assay method: accurate absorption reference substance solution, each 20ul of need testing solution respectively, injects liquid chromatograph, note Record chromatogram, by external standard method with calculated by peak area.

2nd, phosphatid ylcholine chromatogram analysis method:

(1) chromatographic condition and system suitability silica gel are filler (chromatographic column 255mm × 4.6mm, 5 μm), with Methanol-water-glacial acetic acid-triethylamine (85 15 0.45 0.05) is mobile phase a, with n-hexane-isopropanol-mobile phase a(20 48 32) it is mobile phase b, column temperature is 40 DEG C, and according to the form below 7 carries out gradient elution, detector is EISD.

Table 7

Time (minute)	Mobile phase a(%)	Mobile phase b(%)
			0	10	90
20	30	70
			35	95	5
36	10	90
			41	10	90

(2) take phosphatid ylcholine, lysophosphatidyl choline reference substance each appropriate, dissolved simultaneously with chloroform-methyl alcohol (2 1) Every 1ml μ g containing phosphatid ylcholine 200, the mixed solution containing lysophosphatidyl choline 200 μ g are made in quantitative dilution, take above-mentioned solution 20 μ l injection liquid chromatographs, elute, separating degree should meet regulation, number of theoretical plate should be not less than by phosphatid ylcholine peak successively 1550.

(3) regression equation

Precision weighs phosphatid ylcholine reference substance in right amount, and with chloroform-methyl alcohol (2 1) dissolving, simultaneously quantitative dilution is made often 1ml contains phosphatid ylcholine and is respectively 55 μ g, 100 μ g, 155 μ g, 200 μ g, 300 μ g, the solution of 400 μ g as reference substance solution. Precision measures reference substance solution 20 μ l, injects liquid chromatograph, records chromatogram, with the logarithm value of reference substance solution concentration and phase The peak area logarithm value answered calculates regression equation.

(4) measure

Precision weighs this product about 15mg, puts in 55ml measuring bottle, plus chloroform-methyl alcohol (2:1) dissolves and is diluted to scale, Shake up, precision measures 20 μ l, inject liquid chromatograph, record chromatogram.Content by regression equation calculation phosphatid ylcholine.

The preferred embodiment of the present invention described in detail above, but, the present invention is not limited in above-mentioned embodiment Detail, in the range of the technology design of the present invention, multiple simple variant can be carried out to technical scheme, this A little simple variant belong to protection scope of the present invention.

It is further to note that each particular technique feature described in above-mentioned specific embodiment, in not lance In the case of shield, can be combined by any suitable means, in order to avoid unnecessary repetition, the present invention to various can The combination of energy no longer separately illustrates.

Additionally, can also be combined between the various different embodiment of the present invention, as long as it is without prejudice to this The thought of invention, it equally should be considered as content disclosed in this invention.

Claims (8)

1. a kind of soft capsule containing Salvia root P.E is it is characterised in that the content of this soft capsule is sweet by Salvia root P.E, middle chain Oily three acid esters, edible oil and phosphatide composition or by Salvia root P.E, median chain triglyceride oil, edible oil, phosphatide and anti-oxidant Agent forms, and wherein, with respect to the Salvia root P.E of 1 weight portion, the content of median chain triglyceride oil is 40-600 weight portion, eats The content of oil is 50-650 weight portion, and the content of phosphatide is 40-600 weight portion, the tanshinone iia's in described Salvia root P.E More than 20 weight %, the unsaturated fatty acid content in described edible oil is not less than 70 weight % to content, in described phosphatide The content of phosphatid ylcholine is 20-80 weight % for the content of 20-80 weight % and dilinoleoylphosphatidylcholine.

2. soft capsule according to claim 1, wherein, with respect to the Salvia root P.E of 1 weight portion, median chain triglyceride oil Content be 60-400 weight portion, the content of edible oil is 60-600 weight portion, and the content of phosphatide is 60-400 weight portion.

3. soft capsule according to claim 1 and 2, wherein, the content of the tanshinone iia in described Salvia root P.E is 30-60 weight %.

4. soft capsule according to claim 1 and 2, wherein, described median chain triglyceride oil is containing Trivent OCG With the mixture of Triglyceride DDD, the content of Trivent OCG is 50-80 weight %, and the content of Triglyceride DDD is 20-50 weight % and Trivent OCG and Triglyceride DDD total amount are not less than 95 weight %.

5. soft capsule according to claim 1 and 2, wherein, described edible oil is poppy seed oil, grape-kernel oil, evening primrose In oil, 'Heijialun ' seed oil, Purple Perilla Seed Oil, flax oilseeds oil, olive oil, fish oil, soybean oil, corn oil and sunflower oil at least A kind of.

6. soft capsule according to claim 1 and 2, wherein, described edible oil is poppy seed oil.

7. soft capsule according to claim 1 and 2, wherein, described phosphatide is soybean lecithin.

8. soft capsule according to claim 1, wherein, described antioxidant is vitamin e.