CN1718578A - Lerivisiticum extract, its preparation method and medicine containing said extract - Google Patents
Lerivisiticum extract, its preparation method and medicine containing said extract Download PDFInfo
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Abstract
An extract of pubescent angelica root, its preparing process by supercritical extracting, and the medicine containing said extract for treating rheumatic arthritis are disclosed.
Description
Technical field
The medicine that the present invention relates to Angelica grosseserrata extract, its preparation method and contain this extract, particularly, the present invention relates to be used for the treatment of the Angelica grosseserrata extract of rheumatoid arthritis, prepare the method for this extract by process for super-critical extracting, and the medicine that contains this extract soft capsule particularly.
Background technology
Rheumatoid arthritis (RA) is common disease, frequently-occurring disease, and the crowd is wide, and active drug is few, and the western medical treatment similar rheumatism is used NSAID (non-steroidal anti-inflammatory drug) always, acts on antiphlogiston and glucocorticosteroid etc. slowly.Though it is certain curative effect is arranged aspect the symptom improving, side effect is obvious, how undesirable after more.
Rheumatoid arthritis is a kind of chronic autoimmune disorder based on arthropathy, belongs to the sick category of traditional Chinese medical science numbness.In ministerial standard Chinese traditional patent formulation preparation and the state-promulgated pharmacopoeia, the Chinese medicine preparation that is used for arthralgia due to wind-cold-dampness pathogen BI syndrome is more, and the Chinese patent medicine that is used for rheumatoid arthritis is few, the Tripterygium Hypoglaucum Hutch Tablet that records in the state-promulgated pharmacopoeia is made of simply Tripterygium hypoglaucum, have and dispel rheumatism, stimulate the circulation of the blood and cause the muscles and joints to relax, effects for removing toxic heat is used for the treatment of rheumatism, rheumatoid arthritis.The Chinese patent medicine of at present commercially available treatment rheumatoid arthritis also comprises Radix Tripterygii Wilfordii tablet, rheumatism panacea capsule etc. except that Tripterygium Hypoglaucum Hutch Tablet, wherein trypterygine is big because of toxicity, has caused extensive attention; And rheumatism panacea capsule is a hard capsule, and toxicity medicinal materials such as monkshood, radix aconiti agrestis are arranged in the prescription.
Levisticum is the dry root of the heavy peristome Radix Angelicae Sinensis of samphire Angelica pubecens, has and dispels rheumatism, and the function of numbness relieving and pain relieving is for tcm clinical practice is used for rheumatoid arthritis product commonly used.Prove through pharmacodynamics, levisticum have dispel rheumatism, immunomodulatory, antalgic and effect promoting blood circulation and removing obstruction in channels.Document all has report to levisticum treatment rheumatoid arthritis at all times, retrieve according to " Puji Fang " data base management system (DBMS), Ancient Times in China doctor family is widespread use compatibility levisticum treatment arthralgia due to wind-cold-dampness pathogen BI syndrome, and the prescription that wherein is used for the treatment of and rheumatoid arthritis closely-related ancient times illness sick with numbness reaches 230 head.Existing at present report (Qiu Lianqun, Chinese materia medica Leader, Hunan 2000,6 (10): 22 of much treating the rheumatoid arthritis aspect about the prescription that contains levisticum; Liu Weijun etc., the Tianjin traditional Chinese medical science 2000,17 (5): 19; Wang Luhai etc., ShanXi Chinese Medicine Academy journal 2000,23 (6): 27; Han Zhengui etc., the Hebei traditional Chinese medical science 2000,22 (12): 906).
Traditional Chinese medical science utilization levisticum compatibility treatment rheumatoid arthritis is quite general.End is got up, and use levisticum treatment rheumatoid arthritis to have following several characteristics at present: 1, used prescription is commonly the big compound of kinds of traditional Chinese medicines, and drug regimen is mixed greatly; 2, can clearly find out from set basic side's formation situation dispel rheumatism, dispersing cold for relieving pain, warming meridians and promoting circulation of qi, promoting flow of QI and blood, stimulate the circulation of the blood and cause the muscles and joints to relax, strong muscles and bones is the base therapy method, share for the number methods in the clinical manifestation, and with dispel rheumatism, the medicinal application of dispersing cold for relieving pain, warming meridians and promoting circulation of qi is more extensive.But all there is the ingredients complicated problems in these compound preparations.
Hence one can see that, the Chinese medicine preparation of using levisticum treatment rheumatoid arthritis so far is compound preparation, still do not have to use separately the medicine of levisticum treatment rheumatoid arthritis, and do not have detailed relevant report yet for the pharmacological component that contains in the levisticum.
Summary of the invention
The object of the present invention is to provide a kind of pharmacological component definite Angelica grosseserrata extract, this preparation method of extract and contain the rheumatoid arthritis treatment medicine of this Angelica grosseserrata extract, particularly contain soft capsule and this preparation of soft capsule method of Angelica grosseserrata extract as effective constituent.
The inventor carries out Separation Research by the efficient part to levisticum, found that and in Angelica grosseserrata extract, contain Columbianedin (Columbianedin), methoxyl group parsley element (Osthol), O-Acetylcolumbianetin (Columbianetin acetate), xanthyletin (Xanthotoxin) and Columbianetin (Columbianetin) isoreactivity composition, and determined the structure of each composition.
In addition, the inventor finds by adopting supercritical CO
2Extraction process is controlled extracting pressure, extraction temperature, extraction time within the specific limits, can so that to Angelica grosseserrata extract in the total content of above-mentioned each activeconstituents reach more than 50% of extract dry weight.
In addition, the inventor will be used to prepare soft capsule by the Angelica grosseserrata extract that the said extracted method obtains, and the result has obtained a kind of bioavailability height, the soft capsule that is used for the treatment of rheumatoid arthritis that pungency is low.
Particularly, the present invention relates to a kind of Angelica grosseserrata extract, wherein contain following (1)-(5) and plant at least a in the chemical active ingredient,
The invention still further relates to a kind of extracting method of Angelica grosseserrata extract, it is characterized in that may further comprise the steps:
The levisticum crushed material of certain particle size is added CO
2In the supercritical extraction reactor, extraction kettle and extraction-container are heated;
When temperature reaches extraction temperature and resolution temperature, extraction kettle and extraction-container are pressurizeed, when pressure reaches extracting pressure respectively and resolves pressure, begin to carry out cycling extraction, and keep constant temperature and pressure;
Behind the extraction certain hour,, get Angelica grosseserrata extract from the discharge hole for discharge of extraction-container.
In the said extracted method, the granularity of Angelica grosseserrata extract is preferably by 60 mesh sieves, and extraction temperature is 35～50 ℃, is preferably 40 ℃, resolution temperature is about 55～75 ℃, be preferably 65 ℃, extracting pressure is 15～25MPa, is preferably 20MPa, parsing pressure is 2～10MPa, be preferably 5Mpa, the extraction time is 2～5 hours, is preferably 3 hours.
The invention still further relates to a kind of levisticum soft capsule, form by content and softgel shell, content is made up of Angelica grosseserrata extract and solvent thereof, wetting agent, suspending agent, and the weight ratio of each component is an Angelica grosseserrata extract: solvent: wetting agent: suspending agent=1: 3～5: 0.4～0.6: 0.06～0.08.
In above-mentioned levisticum soft capsule, solvent is for dissolving the material of extract, the preferred soybean oil of using, wetting agent is generally tensio-active agent, can use Tweens, spans etc., preferably use poly(oxyethylene glycol) 400, Polysorbate 80, suspending agent can use the solid matter that can increase dispersion medium viscosity, as beeswax, aluminum monostearate, ethyl cellulose etc., preferably use beeswax.
The preferred a kind of levisticum soft capsule of the present invention is composed as follows in 1000 soft capsule content:
Angelica grosseserrata extract 100 grams
Soybean oil 350 grams
Polyoxyethylene glycol-400 50 gram
Polysorbate 80 4 grams
Beeswax 6 grams
Embodiment
(preparation of Angelica grosseserrata extract)
Because the activeconstituents that is used for the treatment of rheumatism that contains in the levisticum is a coumarin kind compound, mostly be the little compound of some polarity, so the present invention adopts supercritical CO
2The prepared Angelica grosseserrata extract of fluid extraction.
It is as follows that the present invention prepares the concrete grammar of Angelica grosseserrata extract: get levisticum medicinal material (dry root of the heavy peristome Radix Angelicae Sinensis of samphire Angelica pubecens) and pulverize by 60 mesh sieves, drop in the supercritical extraction reactor, extraction kettle and extraction-container are heated, when extraction temperature and resolution temperature reach 35～50 ℃ and 55～75 ℃ respectively, by compression pump extraction kettle and extraction-container are pressurizeed, when extracting pressure reaches 15～25Mpa and 2～10Mpa respectively with parsing pressure, begin to carry out cycling extraction, and keep the constant temperature and pressure extraction after 2～5 hours, from the discharge hole for discharge of extraction-container, get Angelica grosseserrata extract.Remove upper strata moisture, lower floor's medicinal extract is 1.130 in 50～75 ℃ of drying under reduced pressure to density, gets extract.
(to the affirmation of contained effective active composition in the Angelica grosseserrata extract)
Get the above-mentioned extract that makes, separate with thin layer chromatography, visible 5 above fluorescence spots separate obtaining 5 main active ingredient then with silica gel column chromatography, identify through ultraviolet, infrared, mass spectrum and NMR (Nuclear Magnetic Resonance) spectrum, prove conclusively the structure of each activeconstituents.
(1) Columbianedin (Columbianedin) (C
19H
20O
5)
Colourless needle (sherwood oil-vinyl acetic monomer), mp 115-117 ℃; Be bluish voilet fluorescence under the UV-light; UV λ nm:326,260,250; IR ν (KBr) (cm
-1): 1727,1618,1267,1113,1066,834; EIMS m/z (%) 328 (M
+), 228,213 (100), 83,55:
1H-NMR (CDCl
3) δ ppm:1.59 (3H, s), 1.63 (3H, s), 1.67 (3H, s), 1.89 (3H, d, J=8Hz), 3.38 (2H, d, J=9Hz), 5.12 (1H, t, J=9Hz), 5.97 (1H, q, J=8Hz), 6.21 (1H, d, J=9Hz), 6.73 (1H, d, J=8Hz), 7.26 (1H, d, J=8Hz), 7.62 (1H, d, J=9Hz);
13C-NMR (CDCl
3) δ ppm:167.1,164.1,161.1,151.3,143.9,137.6,128.9,128.6,113.5,112.9,112.2,106.7,89.2,82.0,27.6,22.3,21.2,20.5,15.6.
(2) methoxyl group parsley element (Osthol) (C
15H
16O
3)
Colourless needle (dehydrated alcohol), is blue-fluorescence under the UV-light by mp 82.2-82.8 ℃; UV λ nm:257,322; IR ν (KBr) (cm
-1): 1720,1605,1560,1480; EIMS m/z (%): 244 (M
+, 100), 228,201,189;
1H-NMR (CDCl
3) δ ppm:1.66 (3H, s), 1.83 (3H, s), 3.53 (2H, d, J=7.2Hz), 3.90 (3H, s), 5.20 (1H, t, J=7.2Hz), 6.22 (1H, d, J=9Hz), 6.83 (1H, d, J=8Hz), 7.27 (1H, d, J=8Hz), 7.59 (1H, d, J=9Hz);
13C-NMR (CDCl
3) δ ppm:161.2,160.3,152.9,143.7,132.6,126.2,121.1,118.1,113.0,113.1,107.3,56.0,25.7,21.9,17.9.
(3) O-Acetylcolumbianetin (Columbianetin acetate) (C
16H
16O
5)
Colourless prism (dehydrated alcohol), is bluish voilet fluorescence by mp.133-134 ℃ under the UV-light; UV λ nm:250,260,325; IR ν (KBr) (cm
-1): 1741,1617,1453,1251,841; EIMS m/z (%): 288 (M
+), 228,213 (100), 187,159,131;
1H-NMR (CDCl
3) δ ppm:1.52 (3H, s), 1.57 (3H, s), 1.99 (3H, s), 3.28 (2H, m), 5.15 (1H, t), 6.20 (1H, d, J=9.5Hz), 6.74 (1H, d, J=8Hz), 7.27 (1H, d, J=8Hz), 7.64 (1H, d, J=9.5Hz);
13C-NMR (CDCl
3) δ ppm:170.1,163.9,161.0,151.3,143.9,128.8,114.5,113.1,112.2,106.6,88.7,82.0,27.5,22.2,21.9,20.9.
(4) xanthyletin (Xanthotoxin) (C
12H
8O
4)
Colourless needle (dehydrated alcohol), is yellow fluorescence under the UV-light by mp.142.8-143.6 ℃; UV λ nm:299,248; IR ν (KBr) (cm
-1): 1705,1675,1580; EIMSm/z (%): 216 (M
+, 100), 201,188,173,145,89,63;
1H-NMR (CDCl
3) δ ppm:4.30 (3H, s), 6.37 (1H, d, J=9Hz), 6.82 (1H, d, J=2.5Hz), 7.35 (1H, s), 7.68 (1H, d, J=2.5Hz), 7.75 (1H, d, J=9Hz);
13C-NMR (CDCl
3) δ ppm:160.4,147.7,146.6,144.3,143.0,132.8,126.1,116.5,114.8,112.9,106.7,61.3.
(5) Columbianetin (Columbianetin) (C
14H
14O
4)
Colourless cylindrulite (dehydrated alcohol), is bluish voilet fluorescence by mp.157.8-158.6 ℃ under the UV-light; UV λ nm:328,261; IR ν (KBr) (cm
-1): 3500,1700,1610; EIMS m/z (%): 246 (M
+), 228,213,187 (100), 131,59;
1H-NMR (CDCl
3) δ ppm:1.24 (3H, s), 1.36 (3H, s), 1.73 (1H, s, adding D
2Disappear behind the O ,-OH), 3.31 (2H, m), 4.79 (1H, t), 6.19 (1H, d, J=9.5Hz), 6.74 (1H, d, J=8Hz), 7.25 (1H, d, J=8Hz), 7.61 (1H, d, J=9.5Hz);
13C-NMR (CDCl
3) δ ppm:163.7,160.9,151.3,143.9,128.7,114.0,113.1,112.3,106.6,91.4,71.8,27.6,26.0,24.0.
(preparation of soft capsule that contains Angelica grosseserrata extract)
Angelica grosseserrata extract of the present invention can be made common oral preparations by common method, as formulations such as tablet, capsule, granule, oral liquids.But because the supercritical extract of levisticum is the hydrophobicity composition, it is being made in the preparation process as middle extract, the bioavailability that improves its activeconstituents is the technical problem that needs to consider solution, the present invention considers that common solid orally ingestible exists little, the oral post-absorption of solubleness relatively poor, thereby Plasma Concentration is exerted an influence, be difficult to reach the defective of the clinical efficacy of expection.And soft capsule is to be wrapped in liquid hydrophobic drug by hydrophilic gelatin rubber, and these medicines are formed with forms such as oil solution, suspension, mashed prod or polyglycol solutions.Can disintegration in digestive tube soon after oral, the soup after the disintegration adheres to tissue surface rapidly widely, promotes the absorption of activeconstituents, thereby obtains high bioavailability.Experiment confirm, the bioavailability of soft capsule is better than closing the particulate hard capsule and more is better than tablet and coating tablet.Soft capsule also can reduce its pungency after making because of its unique embedding with cover effect in addition.Based on above-mentioned consideration, the present invention makes Angelica grosseserrata extract the soft capsule that contains suspension.
Levisticum soft capsule content of the present invention is the suspension that Angelica grosseserrata extract (activeconstituents) and matrix are made, and its mesostroma forms for adding auxiliary material in as the soybean oil of solvent.Because unusual thickness under the Angelica grosseserrata extract normal temperature, the matrix add-on is unsuitable very few, and for guarantee to add matrix less under the prerequisite of good mobility as far as possible, the amount ratio that the present invention proposes Angelica grosseserrata extract and matrix is (by weight) about 1: 3～5.In addition because the supercritical CO of levisticum
2Be unusual heavy-gravity jelly under the extract room temperature, can only be partly dissolved in the soybean oil, so need to add suitable auxiliary material---wetting agent and suspending agent, make suspension, the weight ratio of each component is preferably Angelica grosseserrata extract under the situation that adds auxiliary material: solvent: wetting agent: suspending agent=1: 3～5: 0.4～0.6: 0.06～0.08.Wetting agent is generally tensio-active agent, as Tweens, and spans etc.Suspending agent can be selected the solid matter that can increase dispersion medium viscosity for use, as beeswax, single-stearic acid aluminium, ethyl cellulose etc.General wetting agent suitably cooperates the effective of more single suspending agent with suspending agent.It is wetting agent that the present invention preferably adopts polyoxyethylene glycol-400 and Polysorbate 80, uses beeswax as suspending agent.The screening formulation of levisticum soft capsule content of the present invention following (in 1000):
Angelica grosseserrata extract 100 grams
Soybean oil 350 grams
Poly(oxyethylene glycol) 400 50 grams
Polysorbate 80 4 grams
Beeswax 6 grams
Levisticum soft capsule shell of the present invention can use softgel shell commonly used, is sizing material with the gelatin, and glycerine is softening agent, and ethyl p-hydroxybenzoate is made sanitas, makes opalizer with red iron oxide.
Levisticum soft capsule of the present invention specifically can adopt following preparation method:
1, the preparation of levisticum soft capsule content: take by weighing each batching by prescription, add suspending agent in soybean oil, heating makes the suspending agent fusion, puts cold back gel; Get Angelica grosseserrata extract with wetting agent dilution, stir evenly, add in the lump in the gelatinous solution, put in the colloidal mill and grind well, capsule 's content, standby.
2, the preparation of levisticum soft capsule shell: taking ethylparaben is with alcohol dilution (preferably to concentration be 16%), soak (preferred 2 hours) in the lump with gelatin, glycerine, red iron oxide, gelatin is expanded, then, put heating (preferably being heated to 65 ℃) in the glue pot, mix, be evacuated to and do not have bubble, filter with stainless steel mesh (preferably using 100 mesh sieves), filtrate is put in the glue-storing barrel and is left standstill (preferably keeping 3-4 hour down at 50 ℃), makes the foam come-up, scrapes off the bubble socks of come-up, the glue that takes off face is as softgel shell, heat preservation for standby use.
3, above-mentioned soft capsule content and softgel shell glue are rolled into soft capsule through encapsulating machine.
(pharmacological testing)
Medicine and reagent used in the following test of pesticide effectiveness example comprise levisticum soft capsule of the present invention (0.42g/ grain, every contains extract 84mg, is equivalent to crude drug amount 3.36g); The rheumatism panacea capsule (positive control drug) that Jilin Huinan Tiantai Pharmaceutical Co., Ltd. produces; The carrageenin that Pharmaceutical Factory, Shenyang Medicine Science Univ. produces; The acetic acid that Shenyang chemical reagent work produces; 2 of Shanghai chemical reagent work production, 4-dinitrochlorobenzene (DNCB); The crystal bovine serum albumin (BSA) that the Shanghai City biological factory is produced; Except that specifying, test is a physiological saline with the solvent of soup.
The Kunming mouse of experimental animal for providing by the Shenyang Medical College Experimental Animal Center, body weight 18-22g; The Wistar rat is male, body weight 140g-160g; Rabbit (the big ear in Beijing is white) body weight 2.0-2.5kg.
(levisticum soft capsule of the present invention is to the restraining effect test of adjuvant-induced arthritis)
Get 60 of rats, male, body weight 140-160g, every group 10, be divided into 6 groups at random, be control group (0.5g/kg physiological saline (every kg rat is used 0.5g physiological saline), below roughly the same), rheumatism panacea prevention group (0.5g/kg), the wet panacea treatment group (0.5g/kg) of phoenix, levisticum prevention group (0.15g/kg contains extract 30mg, is equivalent to crude drug 1.2g), levisticum treatment I group (0.15g/kg, contain extract 30mg, be equivalent to crude drug 1.2g), levisticum treatment II group (0.30g/kg contains extract 60mg, is equivalent to crude drug 2.4g).Every rat is right side foot intradermal injection Frenumd ' s Freund's complete adjuvant (self-control) 0.05ml (including fast knot nuclear bacillus 0.5mg), what injection adjuvant promptly began administration the same day is the prevention group, beginning administration in the 8th day be the treatment group, adopt gastric infusion, observed 21 days continuously, continue after the drug withdrawal to observe 3 days.Injection adjuvant before and after 3 hours and every 3 days with the glass-tube volumetric method sufficient volume 1 time about each is surveyed, giving the difference of adjuvant front and back volume with parapodum is the swelling degree, calculate and respectively organize swelling degree average, each administration group and control group relatively and carry out t check, experimental result sees Table 1.
Table 1 levisticum soft capsule of the present invention is to the influence of rat adjuvant inflammation
n＝10
| Foot is not | Group | Dosage (g/kg) | Cause scorching back different time (my god) swelling degree value (X ± SD) | ||||||||
| 3h | 3 | 6 | 9 | 12 | 15 | 18 | 21 | 24 | |||
| Cause scorching foot (right side) offside group (left side) | The treatment of control group levisticum prevention group levisticum treatment group I levisticum treatment group II rheumatism panacea prevention rheumatism panacea treatment control group levisticum prevention group levisticum treatment group I levisticum treatment group II rheumatism panacea prevention rheumatism panacea | With capacity NS 0.15 0.15 0.30 0.50 0.50 with capacity NS 0.15 0.15 0.30 0.50 0.50 | 1.23±0.26 1.18±0.23 0.21±0.27 1.17±0.32 1.13±0.28 1.25±0.32 | 1.25±0.24 0.91±0.32 1.23±0.30 1.26±0.24 0.92±0.21 1.10±0.30 | 1.30±0.15 0.72±0.24 ** 1.25±0.28 1.28±0.26 0.79±0.30 ** 1.08±0.27 | 1.46±0.21 0.65±0.27 ** 1.08±0.31 1.12±0.30 0.80±0.25 ** 1.05±0.31 | 1.68±0.33 0.52±0.27 ** 0.71±0.23 ** 0.69±0.28 ** 0.85±0.27 ** 0.82±0.24 ** 0.32±0.13 0.10±0.12 ** 0.23±0.21 0.25±0.30 0.12±0.13 0.25±0.30 | 1.89±0.28 0.98±0.31 ** 1.11±0.27 ** 1.03±0.32 ** 0.91±0.31 ** 1.15±0.30 ** 0.30±0.11 0.06±0.11 ** 0.21±0.20 0.19±0.30 0.10±0.17 ** 0.13±0.20 ** | 2.10±0.44 1.12±0.30 ** 1.07±0.32 ** 1.10±0.29 ** 1.14±0.28 ** 0.23±0.23 ** 0.36±0.13 0.10±0.12 ** 0.13±0.15 ** 0.12±0.14 ** 0.12±0.13 ** 0.13±0.21 ** | 2.56±0.35 1.65±0.26 ** 1.26±0.25 ** 1.24±0.28 ** 1.60±0.27 * 1.35±0.29 0.56±0.20 0.13±0.13 ** 0.16±0.14 * 0.15±0.15 ** 0.15±0.14 ** 0.18±0.20 ** | 2.21±0.42 1.63±0.23 1.32±0.41 1.30±0.39 1.58±0.32 1.43±0.32 0.65±0.12 0.15±0.14 ** 0.33±0.15 ** 0.34±0.13 ** 0.25±0.16 ** 0.30±0.20 ** |
Compare with control group
*P＜0.05;
*P＜0.01
As can be seen from Table 1, levisticum prevention group of the present invention can obviously suppress the early stage inflammatory reaction (after the 6th day) that adjuvant causes, and can obviously suppress later swelling once again in 12 days, and can suppress other parapodum again and cause swelling because of delayed hypersensitivity, action intensity is suitable with the rheumatism panacea.Obviously suppressed the swelling of injection adjuvant parapodum after levisticum treatment group (I, the II) administration, and the degree of swelling is once again obviously descended, other side delayed hypersensitivity foot swelling is also had the obvious suppression effect, its action intensity is suitable with the rheumatism panacea.
(the restraining effect test of the foot swelling that levisticum soft capsule on Carrageenan of the present invention causes)
Get 50 of male rats, body weight 140g-160g, every group 10, be divided into 5 groups at random, be control group (with capacity physiological saline), the basic, normal, high dosage group of levisticum soft capsule (being respectively 0.15g/kg, 0.30g/kg, 0.60g/kg), rheumatism panacea group (0.5g/kg), measure right back sufficient normal foot volume with the Glass Containers method.Adopt gastric infusion, every day 1 time, for three days on end, time administration did not only cause inflammation at the right back sufficient subcutaneous injection 1% carrageenin 0.1ml/ of rat respectively after 30 minutes, and 1h, 2h, 4h, 6h survey every mouse foot volume by last method subsequently.And calculate swelling rate (%) and inhibiting rate (%) respectively by following formula:
Calculate and respectively organize swelling rate average, each administration group and control group relatively and carry out t check, experimental result sees Table 2.
The influence of the rat paw edema that table 2 levisticum soft capsule of the present invention on Carrageenan causes
| Group | Dosage (g/kg) | Number of animals (only) | Cause scorching back different time swelling rate (%) | |||
| 1h | 2h | 3h | 4h | |||
| Control group | With capacity NS | 10 | 29.6±8.8 | 70.1±9.5 | 68.6±8.5 | 64.2±7.6 |
| Levisticum soft capsule low dose group | 0.15 | 10 | 18.6±5.6 ** (37.2) | 37.6±13.5 ** (46.4) | 48.5±10.5 ** (29.8) | 53.9±8.8 ** (16.0) |
| Dosage group in the levisticum soft capsule | 0.30 | 10 | 17.3±6.5 ** (41.6) | 30.8±11.2 ** (56.1) | 44.3±9.8 ** (35.5) | 52.1±7.5 ** (18.8) |
| Levisticum soft capsule high dose group | 0.60 | 10 | 15.4±7.2 ** (48.6) | 28.3±10.5 ** (59.6) | 41.5±7.6 ** (39.6) | 50.3±6.8 ** (21.6) |
| Rheumatism panacea group | 0.50 | 10 | 19.3±7.5 ** (34.8) | 38.5±11.3 ** (45.1) | 46.3±7.9 ** (32.6) | 52.8±7.6 ** (17.8) |
Compare with control group
*P＜0.01; () is inhibiting rate.
As can be seen from Table 2, the basic, normal, high dosage group of levisticum soft capsule of the present invention can obviously suppress the rat paw edema that carrageenin causes, compare with control group, and the difference highly significant, and certain dose-effect dependence is arranged, its effect is quite omited by force with the rheumatism panacea.
(levisticum soft capsule of the present invention is tested the restraining effect of the rat paw edema that egg white causes)
Get 50 of male rats, body weight 140g-160g, every group 10, be divided into 5 groups at random, the test dose and the method administration of the restraining effect test method of the foot swelling that the above-mentioned levisticum soft capsule on Carrageenan of reference causes, time administration is not after 30 minutes, only cause inflammation at the right back sufficient subcutaneous injection egg white 0.1ml/ of rat respectively, 1h subsequently, 2h, 4h, 6h, survey the right back sufficient volume of rat respectively by embodiment 4 methods, and calculate swelling rate (%) and inhibiting rate (%) respectively, obtain and respectively organize swelling rate average, each administration group and control group relatively and carry out t check, experimental result sees Table 3.
The influence of the rat paw edema that table 3 levisticum soft capsule of the present invention causes egg white
| Group | Dosage (g/kg) | Number of animals (only) | Cause scorching back different time swelling rate (%) | |||
| 1h | 2h | 4h | 6h | |||
| Control group | With capacity NS | 10 | 27.3±6.8 | 68.7±7.6 | 63.5±8.7 | 60.4±7.5 |
| Levisticum soft capsule low dose group | 0.15 | 10 | 17.3±8.5 ** (36.6) | 35.6±6.4 ** (48.1) | 47.5±8.3 ** (25.2) | 50.3±6.8 ** (16.7) |
| Dosage group in the levisticum soft capsule | 0.30 | 10 | 15.8±7.8 ** (42.1) | 33.5±7.7 ** (51.2) | 43.6±9.4 ** (31.3) | 49.5±7.4 ** (18.1) |
| Levisticum soft capsule high dose group | 0.60 | 10 | 13.5 soil 6.2 ** (50.5) | 32.4±6.6 ** (52.8) | 42.4±8.5 ** (33.2) | 48.3±5.6 ** (20.0) |
| Rheumatism panacea group | 0.50 | 10 | 17.8±5.8 ** (34.8) | 36.3±7.4 ** (47.2) | 48.5±6.4 ** (23.6) | 50.4±6.4 ** (16.6) |
Compare with control group
*P＜0.01; () is inhibiting rate.
As can be seen from Table 3, the rat paw edema that the basic, normal, high dosage group of levisticum soft capsule of the present invention causes egg white has very obvious suppression effect, and presents certain dose-effect relationship, and its action intensity and rheumatism panacea are quite slightly strong.
(levisticum soft capsule of the present invention is tested the influence of the III type allergy that bovine serum albumin (BSA) causes)
Get Beijing white family of big ear and exempt from 30, male and female half and half, body weight 2.0g-2.5kg, every group 6, be divided into 5 groups at random, be control group (with capacity physiological saline), levisticum soft capsule low dose group (78.9mg/kg, contains extract 6.6mg, be equivalent to crude drug 0.3g), dosage group in the levisticum soft capsule (157.8mg/kg, contains extract 13.2mg, be equivalent to crude drug 0.6g), levisticum soft capsule high dose group (315.6mg/kg, contain extract 26.4mg, be equivalent to crude drug 1.2g) rheumatism panacea group (240mg/kg).Each treated animal is an auricular vein injection of bovine serum albumin (BSA) 250mg/kg respectively, and duplicate injection once causes rabbit acute serum sickness (allergy of III type) after 3 days, and its symptom is that rabbit is discharged a large amount of proteinuria.Adopt the filling stomach to test medicine, every day 1 time.Continuous use 10 days after 10 days, adopts biuret method to measure the content (mg/10ml) of urine protein, collects rabbit twenty-four-hour urine amount (ml/ day).Calculate and respectively organize rabbit urine protein average, urine amount average, each administration group and control group compare, and carry out the t check, the results are shown in Table 4.
The influence of the rabbit III type allergy that table 4 levisticum soft capsule of the present invention causes BSA
(X±SD)
| Group | Dosage (mg/kg) | Number of animals (only) | Urine protein (mg/10ml) | Urine amount (ml/ day) |
| Control group | With capacity NS | 6 | 120.8±7.8 | 40.0±8.2 |
| Levisticum soft capsule low dose group | 78.9 | 6 | 47.8±7.3 ** | 39.9±6.7 |
| Dosage group in the levisticum soft capsule | 157.8 | 6 | 40.8±5.3 ** | 36.6±15.3 |
| Levisticum soft capsule high dose group | 315.6 | 6 | 18.3±6.8 ** | 43.3±10.3 |
| Rheumatism panacea group | 240 | 6 | 34.9±6.9 ** | 44.7±5.5 |
Compare with control group
*P＜0.01
As can be seen from Table 4, the basic, normal, high dosage group of levisticum soft capsule of the present invention has the obvious suppression effect to the rabbit III type allergy urine protein output that BSA causes, with control group comparing difference highly significant, its action intensity is suitable with the rheumatism panacea, and the urine amount is not had obvious influence.
(levisticum soft capsule of the present invention is tested the influence of the mouse delayed hypersensitivity that DNCB causes)
Get 50 of Kunming mouses, male and female half and half, body weight 18-22g, every group 10, be divided into 5 groups at random, i.e. control group (with capacity physiological saline), the soft capsule low dosage of levisticum glue (0.22g/kg contains extract 18.3mg, quite crude drug 0.86g), dosage in the levisticum soft capsule (0.44g/kg contains extract 36.6mg, quite crude drug 1.72g), levisticum soft capsule high dosage (0.88g/kg, contain extract 73.2mg, quite crude drug 3.44g), rheumatism panacea group (0.7g/kg).Use respectively 5% 2,4-dinitrochlorobenzene (DNCB) ethanol liquid is applied to mouse part skin sensitization, sensitization each treated animal the day before yesterday adopts gastric infusion, every day 1 time, continuous 9 days, sensitization after preceding 7 days the DNCB (being dissolved in the sweet oil) with 1% be applied to mouse right ear respectively, put to death mouse after one day respectively, weighing two ear weight, the difference heavy with mouse two ears is the delayed hypersensitivity value, calculate and respectively organize mouse two ear method of double differences value averages, each administration group and control group relatively and carry out t check, experimental result sees Table 5:
The influence of the mouse delayed hypersensitivity that table 5 levisticum rheumatism capsule of the present invention causes DNCB
| Group | Dosage (g/kg) | Number of animals (only) | The two ear method of double differences values (mg of X ± SD) | Inhibiting rate (%) |
| Control group | With capacity NS | 10 | 7.39±2.26 | - |
| Levisticum soft capsule low dose group | 0.22 | 10 | 3.42±1.23 ** | 53.7 |
| Dosage group in the levisticum soft capsule | 0.44 | 10 | 2.94±1.24 ** | 60.2 |
| Levisticum soft capsule high dose group | 0.88 | 10 | 2.73±1.31 ** | 69.0 |
| Rheumatism panacea group | 0.70 | 10 | 3.40±1.24 ** | 54.0 |
Compare with control group
*P＜0.01
As can be seen from Table 5, the basic, normal, high dosage group of levisticum soft capsule of the present invention has the obvious suppression effect to the mouse delayed hypersensitivity that DNCB causes, and certain dose-effect dependence is arranged, and its effect is quite slightly strong with the rheumatism panacea.
(the analgesic activity test of levisticum soft capsule of the present invention)
Get 50 of body weight 18-22g mouse, male and female half and half, 10 every group, be divided into 5 groups at random, each is organized dosage and tests with the mouse allergy.Adopt gastric infusion, every day 1 time, for three days on end, last administration 30 minutes, every mouse is only injected 0.6% acetic acid 0.2ml/ respectively, observes mouse writhing number of times in 15 minutes then, calculate and respectively to organize mouse writhing number of times average, each administration group and control group relatively and carry out t and check, experimental result sees Table 6.
Table 6 levisticum rheumatism capsule Dichlorodiphenyl Acetate induced mice is turned round the influence of body number of times
| Group | Dosage (g/kg) | Number of animals (only) | Turn round body number of times (X ± SD) |
| Control group | With capacity NS | 10 | 34.9±3.1 |
| Levisticum soft capsule low dose group | 0.22 | 10 | 26.0±2.9 ** |
| Dosage group in the levisticum soft capsule | 0.44 | 10 | 21.6±2.7 ** |
| Levisticum soft capsule high dose group | 0.88 | 10 | 18.0±2.2 ** |
| Rheumatism panacea group | 0.70 | 10 | 25.7±3.6 ** |
Compare with control group
*P＜0.01
As can be seen from Table 6, the writhing response of the mouse that the basic, normal, high dosage group of levisticum soft capsule of the present invention Dichlorodiphenyl Acetate causes has the obvious suppression effect, and its action intensity and rheumatism panacea are quite slightly strong.
(the influence test that levisticum soft capsule of the present invention forms granuloma induced by implantation of cotton pellets)
Get 40 of Wistar rats, body weight 140-160g, 8 every group, be divided into 5 groups at random, each organizes the restraining effect test of the foot swelling that dosage causes with levisticum soft capsule on Carrageenan.With vetanarcol 30mg/kg intraperitoneal injection of anesthesia rat, knee with the tincture of iodine and 75% alcohol disinfecting after, cut the osculum of about 1cm, with the ophthalmology tweezers of the sterilization autoclaving cotton balls that 20mg is heavy (soaking oven dry) with penicillin and Streptomycin sulphate mixed solution 0.2ml, put into by incision subcutaneous, skin suture immediately.Each group all adopts gastric infusion, and every day 1 time, continuous use 7 days was opened former otch on the 8th day, and cotton balls is taken out together with reticular tissue, put into 70 ℃ of oven dry of baking oven, weighed.With claim weight deduct cotton balls weight and be granuloma weight.Calculate and respectively organize granuloma weight average, each administration group and control group relatively and carry out t check, experimental result sees Table 7.
Table 7 levisticum rheumatism capsule of the present invention is to the swollen influence of rat granuloma
| Group | Dosage (g/kg) | Number of animals (only) | Granuloma dry weight (the mg of X ± SD) |
| Control group | With capacity NS | 8 | 98.7±5.8 |
| Levisticum soft capsule low dose group | 0.15 | 8 | 80.1±2.4 ** |
| Dosage group in the levisticum soft capsule | 0.30 | 8 | 78.5±1.9 ** |
| Levisticum soft capsule high dose group | 0.60 | 8 | 76.6±1.6 ** |
| Rheumatism panacea group | 0.50 | 8 | 81.3±2.2 ** |
Compare with control group
*P＜0.01
As can be seen from Table 7, the be formed with obvious suppression effect of the basic, normal, high dosage group of levisticum soft capsule to rat granuloma is swollen, its action intensity and rheumatism panacea are quite slightly strong.
By above pharmacological testing as can be known, levisticum soft capsule of the present invention has very significantly prevention and therapeutic action to the adjuvanticity inflammation, and the inflammatory reaction that on Carrageenan, fresh albumen cause also has the obvious suppression effect, and good anti-inflammatory action is arranged.The III type allergy that delayed hypersensitivity due to the DNCB and BSA are caused has the obvious suppression effect, and the immunoreactive effect of good restraining is arranged.Stimulate the pain reaction that causes that the obvious suppression effect is arranged to thermal stimulus and acetic acid, good analgesic activity is arranged.The obvious suppression effect that is formed with to granuloma induced by implantation of cotton pellets has the good restraining proliferative effect.In sum, can think that the function of the dispelling rheumatism of above pharmacological tests and levisticum soft capsule of the present invention, numbness relieving and pain relieving conforms to, illustrate that levisticum soft capsule of the present invention is a kind of to the effective medicine of rheumatoid arthritis.
(embodiment)
The present invention is further elaborated below in conjunction with specific embodiment, but the present invention and be limited to these embodiment.
The preparation of embodiment 1 Angelica grosseserrata extract
Take by weighing the 3360g levisticum and (press the 215th page of Chinese Pharmacopoeia version in 2000, available from Sichuan Province's medicinal material company), pulverize by 60 mesh sieves, drop in the supercritical extraction reactor (used extraction instrument is the HP7680A supercritical fluid extraction instrument that hewlette-packard is produced), extraction kettle and extraction-container are heated, when extraction temperature and resolution temperature reach 40 ℃ and 65 ℃ respectively, by compression pump extraction kettle and extraction-container are pressurizeed, when extracting pressure reaches 20MPa and 5Mpa respectively with parsing pressure, begin to carry out cycling extraction, and keep constant temperature and pressure.Extract after 3 hours,, get Angelica grosseserrata extract from the discharge hole for discharge of extraction-container.Remove upper strata moisture, it is 1.130 that lower floor's medicinal extract is dried to density for 70 ℃, makes 100 gram extracts.After testing, the content of total coumarins is not less than 500mg in every this extract of gram, and the content of methoxyl group parsley element is not less than 60mg, and the content of Columbianedin is not less than 120mg.
Embodiment 2 levisticum preparation of soft capsule (agents useful for same is delicatessen food level or pharmaceutical grade)
Add the 6g beeswax in the 350ml soybean oil, heating makes the beeswax fusion, puts cold back gel; The 100g Angelica grosseserrata extract of getting by embodiment 1 preparation dilutes with 50ml polyoxyethylene glycol-400, adds the 4ml Polysorbate 80 and stirs evenly, and adds in the lump in the gelatinous solution, puts in the colloidal mill to grind well, and it is standby to get capsule 's content.Get Tegosept E lactone 0.2g, with alcohol dilution to concentration is 16% to add water 300ml in the lump with gelatin 250g, glycerine 85g, red iron oxide 3.8g and soaked 2 hours, be heated to 65 ℃ then, stir, being evacuated to does not have bubble, and with 100 order stainless steel sift net filtrations, filtrate is placed 3-4 hour (maintaining the temperature at 50 ℃) to glue-storing barrel, all float on the surface to bubble, the glue that takes off face is standby as softgel shell.Above-mentioned capsule 's content and softgel shell glue through the rolling soft capsule of soft capsule machine, are made 1000 of the soft capsules of every 420mg.After testing, the content of total coumarins is not less than 40mg in every soft capsule, and the content of methoxyl group parsley element is not less than 6mg.
Claims (9)
1, Angelica grosseserrata extract wherein contains at least a in the chemical active ingredient of following formula (1)-(5) expressions,
2, the extracting method of the described Angelica grosseserrata extract of claim 1 is characterized in that may further comprise the steps:
The levisticum crushed material of certain particle size is added CO
2In the supercritical extraction reactor, extraction kettle and extraction-container are heated;
When temperature reaches extraction temperature and resolution temperature, extraction kettle and extraction-container are pressurizeed, when pressure reaches extracting pressure respectively and resolves pressure, begin to carry out cycling extraction, and keep constant temperature and pressure;
Behind the extraction certain hour,, get Angelica grosseserrata extract from the discharge hole for discharge of extraction-container.
3, extracting method as claimed in claim 2, wherein the granularity of Angelica grosseserrata extract is for passing through 60 mesh sieves, and extraction temperature is 35～50 ℃, resolution temperature is about 55～75 ℃, extracting pressure is 15～25MPa, and parsing pressure is 2～10MPa, and the extraction time is 2～5 hours.
4, extracting method as claimed in claim 3, wherein extraction temperature is 40 ℃, and resolution temperature is 65 ℃, and extracting pressure is 20Mpa, and parsing pressure is 5MPa, the extraction time is 3 hours.
5, levisticum soft capsule, form by content and softgel shell, content is made up of Angelica grosseserrata extract, solvent, wetting agent, suspending agent, the weight ratio of each component is an Angelica grosseserrata extract: solvent: wetting agent: suspending agent=1: 3～5: 0.4～0.6: 0.06～0.08, described Angelica grosseserrata extract are the described Angelica grosseserrata extract of claim 1.
6, levisticum soft capsule, form by content and softgel shell, content is made up of Angelica grosseserrata extract, solvent, wetting agent, suspending agent, the weight ratio of each component is an Angelica grosseserrata extract: solvent: wetting agent: suspending agent=1: 3～5: 0.4～0.6: 0.06～0.08, described Angelica grosseserrata extract are the extract that each described extracting method makes among the claim 2-4.
7, as claim 5 or 6 described levisticum soft capsules, wherein solvent uses soybean oil, and wetting agent uses Tweens, spans, and suspending agent uses beeswax, aluminum monostearate, ethyl cellulose.
8, levisticum soft capsule according to claim 7 is characterized in that soft capsule content composed as follows of 1000 meters:
Angelica grosseserrata extract 100 grams
Soybean oil 0.35 gram
Polyoxyethylene glycol-400 0.05 gram
Polysorbate 80 0.004 gram
Beeswax 6 grams
9, claim 5 or 6 described levisticum preparation of soft capsule methods may further comprise the steps:
(1) preparation of levisticum soft capsule content: take by weighing each batching by prescription, in soybean oil, add suspending agent, heating makes the suspending agent fusion, put cold back gel, get Angelica grosseserrata extract with wetting agent dilution, stir evenly, add in the lump in the gelatinous solution, put in the colloidal mill and grind well, get capsule 's content, standby;
(2) preparation of levisticum soft capsule shell: the taking ethylparaben alcohol dilution, soak in the lump with gelatin, glycerine, red iron oxide, gelatin is expanded, then, put in the glue pot and heat, mix, being evacuated to does not have bubble, use the stainless steel sift net filtration, filtrate is put in the glue-storing barrel and is left standstill, and makes the foam come-up, scrapes off the bubble socks of come-up, the glue that takes off face is as softgel shell, heat preservation for standby use;
(3) above-mentioned capsule 's content and softgel shell glue are rolled into soft capsule through encapsulating machine.
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| CNA2004100688037A CN1718578A (en) | 2004-07-05 | 2004-07-05 | Lerivisiticum extract, its preparation method and medicine containing said extract |
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| CNA2004100688037A CN1718578A (en) | 2004-07-05 | 2004-07-05 | Lerivisiticum extract, its preparation method and medicine containing said extract |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102329323A (en) * | 2011-05-31 | 2012-01-25 | 苏州派腾生物医药科技有限公司 | Method for extracting columbianadin from ligusticum daucoides franch |
| CN102399208A (en) * | 2011-10-26 | 2012-04-04 | 辽宁大学 | Method for extracting osthole and imperatorin from fructus cnidii through inclusion crystallizing method |
| CN106719856A (en) * | 2017-02-06 | 2017-05-31 | 青岛大学 | A kind of extractive of pubescent angelica root coumarin preparation method and applications with killing activity of pine wood nematode |
| CN111808154A (en) * | 2020-08-06 | 2020-10-23 | 天津中医药大学 | Purification method and application of dihydrooroselol-beta-D-glucoside |
| CN112791082A (en) * | 2021-02-04 | 2021-05-14 | 天津中医药大学 | Application of columbianadin in preparing medicine for treating and/or preventing rheumatoid arthritis |
-
2004
- 2004-07-05 CN CNA2004100688037A patent/CN1718578A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102329323A (en) * | 2011-05-31 | 2012-01-25 | 苏州派腾生物医药科技有限公司 | Method for extracting columbianadin from ligusticum daucoides franch |
| CN102399208A (en) * | 2011-10-26 | 2012-04-04 | 辽宁大学 | Method for extracting osthole and imperatorin from fructus cnidii through inclusion crystallizing method |
| CN106719856A (en) * | 2017-02-06 | 2017-05-31 | 青岛大学 | A kind of extractive of pubescent angelica root coumarin preparation method and applications with killing activity of pine wood nematode |
| CN106719856B (en) * | 2017-02-06 | 2019-11-12 | 青岛大学 | A kind of extractive of pubescent angelica root coumarin preparation method and applications with killing activity of pine wood nematode |
| CN111808154A (en) * | 2020-08-06 | 2020-10-23 | 天津中医药大学 | Purification method and application of dihydrooroselol-beta-D-glucoside |
| CN112791082A (en) * | 2021-02-04 | 2021-05-14 | 天津中医药大学 | Application of columbianadin in preparing medicine for treating and/or preventing rheumatoid arthritis |
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