CN1274309C - Enteric-coated formulation of glycyrrhizic acid and its salt and its preparing method - Google Patents
Enteric-coated formulation of glycyrrhizic acid and its salt and its preparing method Download PDFInfo
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- CN1274309C CN1274309C CN 03132067 CN03132067A CN1274309C CN 1274309 C CN1274309 C CN 1274309C CN 03132067 CN03132067 CN 03132067 CN 03132067 A CN03132067 A CN 03132067A CN 1274309 C CN1274309 C CN 1274309C
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Abstract
The present invention provides an enteric-coated preparation of glycyrrhizic acid and salt thereof and a preparing method. Glycyrrhizic acid and the salt thereof are mixed with lecithin with a certain proportion, other auxiliary materials are added, and the mixture are filled in enteric capsules. The enteric-coated preparation of the glycyrrhizic acid and the salt thereof obviously improve the bioavailability of oral preparations of the glycyrrhizic acid and the salt thereof. The preparing method has good reproducibility, and is suitable for industrial production.
Description
Technical field
The present invention relates to the enteric coated preparation and the preparation method of glycyrrhizic acid and salt thereof.
Background technology
Mainly contain the glycyrrhizic acid of the α configuration of the glycyrrhizic acid of beta comfiguration and only a few in the root of natural plant Radix Glycyrrhizae (Glycyrrhiza Uralensis), by certain reaction, the glycyrrhizic acid of beta comfiguration can be converted into the glycyrrhizic acid of α configuration, sees patent CNl381462A.At present, the preparation listing of more existing both at home and abroad glycyrrhizic acids and salt thereof.External with the glycyrrhizic acid be principal agent oral tablet by " the flourish sheet of sweet think of " of the development of Japanese Minophagen pharmaceutical factory (Glycyron), be used for the treatment of hepatitis and anaphylactic disease, the clinical steadiness treatment that is usually used in chronic hepatitis, to be intravenously administrable to liver function normal or near after normal, change oral medication into; And be preparation compound glycyrrhizin sheet, the compound glycyrrhizin injection of main component with the monoammonium glycyrrhizinate, be used for the treatment of chronic hepatopathy and eczema, dermatitis, urticaria etc.Domestic is the glycyrrhizin tablet of raw material with glycyrrhizic acid list potassium, is produced by Changsha Chinese medicine one factory, and the curative effect of treatment chronic hepatitis is not as good as the compound glycyrrhizin injection (trade name potenlin) of intravenously administrable, and untoward reaction is also more.The diammonium glycyrrhizinate injection of Jiangsu Zhengda Tianqing Drug Industry Co., Ltd's production and selling and capsule (trade name diammonium glycyrrhizinate) are applied to clinical existing 8 years, have obtained clinical effectiveness preferably.
Diammonium glycyrrhizinate by glycyrrhizic acid two step ammonifications after refining getting.Pharmacological testing proves; the serum glutamic pyruvic transminase that diammonium glycyrrhizinate causes tetrachloro charcoal, D-Gal and thioacetamide, glutamic oxaloacetic transaminase, GOT raise; has tangible reduction effect; can also significantly alleviate D-Gal to the damage of the form of liver with improve the chronic injury of immune factor to the liver form, diammonium glycyrrhizinate has stronger antiinflammatory, protect hepatocyte and improve the effect of liver function.Diammonium glycyrrhizinate capsule has taking convenience, does not need advantages such as long-term hospitalization.But compare with injection,, in gastrointestinal tract, absorb relatively poor because glycyrrhizic acid or its salt belong to high polarity, hydrophilic macromolecular substances.But diammonium glycyrrhizinate is compared with glycyrrhizic acid, owing to do not form molecule aggregation body (micelle), thereby after oral, the blood drug level of glycyrrhizic acid is improved, and has to a certain degree improved the characteristics of glycyrrhizic acid digestive tract absorption difference.
Phospholipid is the general name of the lipid material of phosphorous acid group, mainly contain lecithin (PC), cephalin (PE), lipositol (PI) and phosphatidic acid (PA) etc., they are the basis of cell membrane in the animal and plant cells, nuclear membrane and class plasma membrane, and the important physical function is arranged in the organism metabolism.Phospholipid extensively is present in the seed of brains, internal organs, blood, milk, egg yolk and plant of animal, has wide material sources, advantage such as nontoxic.Lecithin has emulsifying, disperse, help ooze, characteristic such as moistening, and skin and mucosa had very strong affinity, in medicament, be used as dispersant, wetting agent, emulsifying agent, stabilizing agent, transdermal enhancer, prodrug carrier etc.
Summary of the invention
The enteric coated preparation that the purpose of this invention is to provide a kind of glycyrrhizic acid and salt thereof.
Another object of the present invention provides the preparation method of the enteric coated preparation of a kind of glycyrrhizic acid and salt thereof, this method is by adding a certain amount of lecithin in adjuvant, and in the enteric coated capsule of packing into, promote the absorption of glycyrrhizic acid at intestinal, improve the bioavailability of glycyrrhizic acid and salt thereof, thereby increase the curative effect of oral glycyrrhizic acid preparation, reduce untoward reaction.
Purpose of the present invention can reach by following measure:
The enteric coated preparation of a kind of glycyrrhizic acid and salt thereof is characterized in that: the weight ratio of glycyrrhizic acid or its salt and lecithin is 1: 1-20, preferred 1: 1-5.
Enteric coated preparation according to above-described glycyrrhizic acid and salt thereof is characterized in that: glycyrrhizic acid comprises the glycyrrhizic acid of α configuration and beta comfiguration.Glycyrrhetate comprises the inorganic salt of glycyrrhizic acid such as ammonium salt, magnesium salt, sodium salt, potassium salt, zinc salt etc.Lecithin comprises soybean lecithin, Ovum Gallus domesticus Flavus lecithin or hydrolecithin.
The enteric coated preparation of glycyrrhizic acid of the present invention and salt thereof, its preparation method are for being 1 by weight with glycyrrhizic acid and salt thereof: the 1-20 ratio is mixed with lecithin, adds other adjuvants, in the enteric coated capsule of packing into.Because lecithin has emulsifying, disperse, help ooze, characteristic such as moistening, can promote glycyrrhizic acid and salt thereof from intestinal absorption, obviously improved the oral bioavailability of glycyrrhizic acid and salt thereof.
Glycyrrhetate of the present invention is preferably diammonium glycyrrhizinate.In prescription, added lecithin, promoted the absorption of principal agent diammonium glycyrrhizinate, and made and to avoid medicine partial hydrolysis or form micelle and micelle and influence its absorption, the minimizing untoward reaction behind the enteric coated capsule with direct contact of gastric acid.
Below by the oral bioavailability of diammonium glycyrrhizinate enteric coated capsule and diammonium glycyrrhizinate capsule rat and the comparison of test for intestinal absorption, further specify the practicality of glycyrrhetate enteric coated capsule of the present invention.
One, the bioavailability study of oral diammonium glycyrrhizinate enteric coated capsule of rat and diammonium glycyrrhizinate capsule.
1, material and method:
Medicine: diammonium glycyrrhizinate capsule, diammonium glycyrrhizinate enteric coated capsule respectively contain active component diammonium glycyrrhizinate 50mg, are provided by Jiangsu Zhengda Tianqing Drug Industry Co., Ltd.
Compound method: the two capsules content is made the solution that every ml contains diammonium glycyrrhizinate 22mg with 0.9% sodium chloride solution, pH5.0～7.0.
Animal: SD cleaning level rat is available from Zhejiang Province's medical experiment animal center.Male rat 178g ± 6g, 6 of every group of rats, animal fasting 12h before the test, all animals of duration of test all freely drink water.
The test key step:
(1) medicine and reagent: interior mark indomethacin, Sigma product; Acetic acid is analytical pure; Absolute methanol, acetonitrile are the HPLC level; Diammonium glycyrrhizinate standard substance (content 99.32%)
(2) method: get 12 of SD ♂ rats, divide 2 groups at random, 6 every group.One group of rat is used diammonium glycyrrhizinate capsule content ig, dosage 1.5ml/100g; Another group diammonium glycyrrhizinate enteric coated capsule content ig, dosage 1.5ml/100g.10min, 30min, 1hr, 1.5hr, 2hr, 3hr, 4hr, 6hr, 8hr, 10hr, 24hr tail vein blood after the administration, separated plasma ,-20 ℃ of storages, to be measured.
(3) sample treatment plasma sample 100 μ l, the accurate 300 μ l absolute methanols that add, vortex is even, 20,000g * 5min is centrifugal, and precision pipettes supernatant 300 μ l, and nitrogen dries up in 50 ℃ of water-baths, residue dissolves with mark methanol solution (containing indomethacin 20mg/L) in the 50 μ l, and sample introduction 20 μ l make HPLC and analyze.
(4) assay method adopts high effective liquid chromatography for measuring.
A, chromatographic condition
Chromatograph: Tianjin, island LC-9A chromatograph of liquid
Chromatographic column: 0DS, 4.6 * 150mm, 5 μ m
Mobile phase: methanol: water: acetic acid=76: 20: 4
Flow velocity: 1.0ml/min
Detect wavelength: 245nm
Diammonium glycyrrhizinate and interior target retention time are about 2.9min and 4.0min respectively, both separating degrees＞1.5, and the endogenous material in the blood plasma is interference measurement not.
B, standard curve preparation
Get rat blank plasma 100 μ l, add the diammonium glycyrrhizinate standard solution respectively and make that its concentration is respectively 0.375,1.875,3.75,5.625,7.5mg/L, by " sample treatment " operation down, ratio with diammonium glycyrrhizinate and interior mark peak area is dependent variable (Y), diammonium glycyrrhizinate concentration is variable (X), make linear regression, regression equation is:
Y＝0.0432X-0.0153(r＝0.9996)
This law setting-out line scope is 0.375～7.5mg/L.
2, result of the test
Behind two groups of rat oral diammonium glycyrrhizinate capsules of difference and its enteric coated capsule content, average blood drug level sees Table 1.Data are through 3P87 software preference pattern, and the result meets two Room models.Main pharmacokinetic parameter result of calculation sees Table 2.
The average blood drug level of the oral diammonium glycyrrhizinate capsule of table 1 rat and its enteric coated capsule content (n=6, x ± s, mg/L)
| Time (h) | Capsule | Enteric coated capsule |
| 0.1667 | 1.845±0.263 | 10.571±1.683 |
| 0.5 | 3.328±0.415 | 13.166±2.089 |
| 1 | 5.335±0.444 | 14.528±1.837 |
| 1.5 | 6.726±0.313 | 13.345±1.594 |
| 2 | 7.862±0.408 | 12.037±1.366 |
| 3 | 7.152±0.331 | 9.685±1.032 |
| 4 | 5.935±0.268 | 7.893±0.901 |
| 6 | 4.132±0.190 | 5.295±0.558 |
| 8 | 2.802±1.171 | 3.550±0.396 |
| 10 | 2.141±0.105 | 2.550±0.258 |
| 24 | 0.192±0.026 | 0.234±0.026 |
Pharmacokinetic parameter behind the oral diammonium glycyrrhizinate capsule of table 2 rat and its enteric coated capsule content (n=6, x ± s)
| Parameter | Capsule | Enteric coated capsule |
| Cmax(mg/L) | 7.904±0.398 | 14.196±1.867 |
| Tmax(h) | 1.655±0.064 | 0.962±0.073 |
| K 21 | 0.534±0.056 | 0.422±0.021 |
| K 10 | 0.185±0.006 | 0.211±0.003 |
| K 12 | 0.034±0.023 | 0.060±0.008 |
| t 1/2(Ka) | 0.515±0.022 | 0.256±0.028 |
| t 1/2(α) | 1.032±0.348 | 1.329±0.067 |
| t 1/2(β) | 4.087±0.139 | 4.068±0.072 |
| AUC 0-T(mg/L·h) | 63.307±3.269 | 93.826±10.616 |
Both AUC
0-TShow utmost point significant difference (P＜0.001) with Cmax through two one-side t checks.
Result of study shows that the oral bioavailability of diammonium glycyrrhizinate enteric coated capsule rat obviously is better than diammonium glycyrrhizinate capsule, AUC
0-TBe about 1.5 times of the latter.
Two, compare diammonium glycyrrhizinate enteric coated capsule content and diammonium glycyrrhizinate capsule content absorbing state at small intestinal.
1, material and method:
Medicine: diammonium glycyrrhizinate capsule, diammonium glycyrrhizinate enteric coated capsule respectively contain active component diammonium glycyrrhizinate 50mg, are provided by Jiangsu Zhengda Tianqing Drug Industry Co., Ltd.
Compound method: precision takes by weighing to get except that the diammonium glycyrrhizinate capsule behind the starch and enteric coated capsule content thereof dissolves respectively and makes the solution that every 100ml contains diammonium glycyrrhizinate 80mg with containing phenol red phosphate buffer (pH6.5).
Animal: SD cleaning level rat is available from Zhejiang Province's medical experiment animal center.Male rat 181g ± 10g, 6 of every group of rats, animal fasting 20h before the test.
The test key step:
(1) rat absorption test: 20 hours rat of fasting is used sodium pentobarbital 45mg/kg intraperitoneal anesthesia, back fixation, along the ventrimeson hara kiri, respectively stretch into thin glass tube in duodenum upper end and ileum lower end and tighten with line, after slowly 37 ℃ of normal saline of injection are fully cleaned intestinal tube from duodenum, connect micro-transfusion device and medicinal liquid (37 ℃) and make closed circuit, the medicinal liquid that discards behind the 10ml circulation fluid is 0 o'clock, then under the 2.3ml/min flow velocity, press circulation time 30,60,90, the dose of 120min sampling and measuring circulation medicinal liquid changes, and is calculated as follows the content of diammonium glycyrrhizinate and calculates absorbance for the volume indicator with phenol red.
G＝Gt×A
0/At
G: diammonium glycyrrhizinate content; Gt: diammonium glycyrrhizinate is content when t; A
0: phenol red trap at 0 o'clock; At: phenol red trap (phenol red mensuration: get circulation medicinal liquid 1ml, add caustic lye of soda (1mol/L) 3ml, after shaking up, measure trap in the 560nm place when t.)
(2) assay of diammonium glycyrrhizinate
Assay method: adopt determined by ultraviolet spectrophotometry
Sample treatment: the diammonium glycyrrhizinate reference substance is dried to constant weight 80 ℃ of reduced vacuum, content is 99.32%, the glycyrrhizic acid capsule 's content is used n-butanol extraction after adding dilute hydrochloric acid, be evaporated to dried, diammonium glycyrrhizinate enteric coated capsule content is removed evaporated under reduced pressure behind the insoluble matter with chloroform dissolving, and two evaporate to dryness things are at P
2O
5Dry 24 hours of vacuum desiccator.
Maximum absorption wavelength is selected: accurately takes by weighing the diammonium glycyrrhizinate standard solution, makes the solution that contains 0.04mg among every 1ml approximately with phosphate buffer, and scanning between 190～300nm (day island proper Tianjin UV-2201), the result has absorption maximum at 252 ± 2nm place.
Table 4 diammonium glycyrrhizinate capsule and the accumulation of diammonium glycyrrhizinate enteric coated capsule content rat small intestine absorb the result
| Time (min) | n | Accumulation absorption value (%) | P | |
| Capsule | Enteric coated capsule | |||
| 30 60 90 120 | 6 6 6 6 | 3.22±0.4 7.39±0.7 11.65±0.5 14.21±0.7 | 8.53±0.5 17.02±0.6 19.51±0.9 27.18±0.9 | ＜0.01 ＜0.01 ＜0.01 ＜0.01 |
Result of study shows: the enteric coated capsule prescription can improve the absorption of diammonium glycyrrhizinate at rat small intestine, is about 2.6,2.3,1.7,1.9 times of conventional capsule when 30min, 60min, 90min, 120min respectively, and significant difference is all arranged.
The specific embodiment
About supplementary material is originated and quality standard:
| The supplementary material title | Manufacturer | Quality standard |
| Diammonium glycyrrhizinate | Jiangsu Zhengda Tianqing Drug Industry Co., Ltd | WS-019(X-015)-94 |
| Soybean lecithin, Ovum Gallus domesticus Flavus lecithin, hydrolecithin | Shanghai Oil Factory No.1 | The accurate word (1995) of medicine is defended No. 2178-088005 in Shanghai |
| Starch | Distributions in Liaocheng of Shandong Province An Hua pharmaceutical Co. Ltd | Version Chinese Pharmacopoeia in 2000 |
| Sodium lauryl sulphate | Shanghai spark chemical industry in morning Industrial Co., Ltd. | Version Chinese Pharmacopoeia in 2000 |
| Ethanol | Nanjing chemical reagent one factory | GB679-94 |
The following example is intended to further describe for example the present invention, rather than limits the present invention by any way.
Embodiment one:
Group component (gram/grain)
Diammonium glycyrrhizinate 0.05
Soybean lecithin 0.05
Starch 0.15
Sodium lauryl sulphate 0.0025
Ethanol is an amount of
Embodiment two:
Group component (gram/grain)
Diammonium glycyrrhizinate 0.05
Soybean lecithin 0.25
Calcium hydrogen phosphate 0.10
Magnesium stearate 0.0025
Ethanol is an amount of
Embodiment three:
Group component (gram/grain)
Diammonium glycyrrhizinate 0.05
Soybean lecithin 0.5
Cycloheptaamylose 0.15
Pulvis Talci 0.05
Magnesium stearate 0.001
Ethanol is an amount of
Embodiment four:
Group component (gram/grain)
Diammonium glycyrrhizinate 0.05
Soybean lecithin 0.75
Lactose 0.05
Sodium lauryl sulphate 0.0035
Ethanol is an amount of
Embodiment five:
Group component (gram/grain)
Diammonium glycyrrhizinate 0.05
Soybean lecithin 1.00
Starch 0.15
Micropowder silica gel 0.0035
Magnesium stearate 0.0035
Ethanol is an amount of
Embodiment six:
Group component (gram/grain)
Diammonium glycyrrhizinate 0.025
Ovum Gallus domesticus Flavus lecithin 0.125
Carboxymethyl starch 0.1
Polyethylene glycol 6000 0.005
Ethanol is an amount of
Embodiment seven:
Group component (gram/grain)
Diammonium glycyrrhizinate 0.10
Hydrolecithin 0.10
Carboxymethyl starch 0.1
Polyethylene glycol 6000 0.005
Ethanol is an amount of
Embodiment eight:
Group component (gram/grain)
Ammonium glycyrrhizinate 0.05
Soybean lecithin 0.05
Starch 0.15
Sodium lauryl sulphate 0.0025
Ethanol is an amount of
Embodiment nine:
Group component (gram/grain)
Glycyrrhizic acid 0.05
Soybean lecithin 0.05
Starch 0.15
Sodium lauryl sulphate 0.0025
Ethanol is an amount of
Embodiment ten:
Group component (gram/grain)
Dipotaccium glycyrrhizate 0.05
Ovum Gallus domesticus Flavus lecithin 0.05
Starch 0.15
Sodium lauryl sulphate 0.0025
Ethanol is an amount of
Embodiment 11:
Group component (gram/grain)
Glycyrrhizic acid magnesium 0.05
Ovum Gallus domesticus Flavus lecithin 0.05
Starch 0.15
Sodium lauryl sulphate 0.0025
Ethanol is an amount of
Embodiment 12:
Group component (gram/grain)
Sodium glycyrrhetate 0.05
Hydrolecithin 0.05
Starch 0.15
Sodium lauryl sulphate 0.0025
Ethanol is an amount of
Embodiment 13:
Group component (gram/grain)
Zinc glycyrrhetate 0.05
Hydrolecithin 0.05
Starch 0.15
Sodium lauryl sulphate 0.0025
Ethanol is an amount of
The preparation technology of above embodiment product is:
1. raw material glycyrrhizic acid or its salt are crossed 60 mesh sieves, standby.
2. lecithin is added in an amount of ethanol, heating adds starch or other adjuvants after making its dissolving that refluxes, and behind the stirring and evenly mixing, reclaims ethanol, and drying is pulverized, and crosses 60 mesh sieves, and is standby.
3. with above-mentioned former, adjuvant mixing, add lubricant, put and mix in the mixing machine after 30 minutes, measure intermediate content, fill is in enteric capsule shell, and the plastic-aluminum pressing mold is packed, promptly.
Claims (7)
1, the enteric coated capsule of a kind of glycyrrhizic acid or its salt is characterized in that: the weight ratio of glycyrrhizic acid or its salt and lecithin is 1: 1.
2, the enteric coated capsule of glycyrrhizic acid according to claim 1 or its salt is characterized in that: glycyrrhizic acid or its salt comprise glycyrrhizic acid or its salt of α configuration and beta comfiguration.
3, the enteric coated capsule of glycyrrhizic acid according to claim 1 and 2 or its salt is characterized in that: glycyrrhetate is ammonium salt, magnesium salt, sodium salt, potassium salt or the zinc salt of glycyrrhizic acid.
4, the enteric coated capsule of glycyrrhizic acid according to claim 1 and 2 or its salt is characterized in that: glycyrrhetate is a diammonium glycyrrhizinate.
5, the enteric coated capsule of glycyrrhizic acid according to claim 1 and 2 or its salt is characterized in that: lecithin is soybean lecithin, Ovum Gallus domesticus Flavus lecithin or hydrolecithin.
6, the preparation method of the enteric coated capsule of glycyrrhizic acid according to claim 1 or its salt is characterized in that: with glycyrrhizic acid or its salt and lecithin is 1: 1 mixed by weight, adds other adjuvant, in the enteric coated capsule of packing into.
7, the preparation method of the enteric coated capsule of glycyrrhizic acid according to claim 6 or its salt is characterized in that: lecithin is soybean lecithin, Ovum Gallus domesticus Flavus lecithin or hydrolecithin.
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|---|---|---|---|
| CN 03132067 CN1274309C (en) | 2003-07-18 | 2003-07-18 | Enteric-coated formulation of glycyrrhizic acid and its salt and its preparing method |
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| CN1274309C true CN1274309C (en) | 2006-09-13 |
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Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
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| RU2304430C2 (en) | 2005-08-12 | 2007-08-20 | Александр Иванович Арчаков | Method for preparing injection medicinal formulation of phospholipid preparation "fosfogliv" for treatment and prophylaxis of acute and chronic hepatic diseases |
| CN101081227B (en) * | 2006-05-31 | 2011-12-21 | 江苏正大天晴药业股份有限公司 | Composition of diammonium glycyrrhizinate |
| CN101600439B (en) * | 2006-12-29 | 2015-07-22 | 正大天晴药业集团股份有限公司 | Oral pharmaceutical composition of glycyrrhizin or its salts and the preparation method thereof |
| CN102188404A (en) * | 2010-03-11 | 2011-09-21 | 江苏润邦药业有限公司 | Diammonium glycyrrhizinate capsules and preparation method thereof |
| CN102018659A (en) * | 2010-11-04 | 2011-04-20 | 武汉华纳联合药业有限公司 | Intestine positioning preparation of glycyrrhetic acid, glycyrrhetinic acid and salts of glycyrrhetic acid and glycyrrhetinic acid, and preparation method and application thereof |
| CN102499925B (en) * | 2011-10-21 | 2015-11-11 | 上海中医药大学 | A kind of neutrophil elastase inhibitor |
| CN115154417B (en) * | 2022-08-15 | 2023-03-07 | 黑龙江中桂制药有限公司 | Ambroxol hydrochloride oral solution and preparation method and application thereof |
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Address after: 222006 Sinpo City, Lianyungang Province, North Road, No. 8, No. Patentee after: CHIA TAI TIANQING PHARMACEUTICAL GROUP Co.,Ltd. Address before: 222006 Sinpo City, Lianyungang Province, North Road, No. 8, No. Patentee before: JIANGSU CHIATAI TIANQING PHARMACEUTICAL Co.,Ltd. |
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| CX01 | Expiry of patent term |
Granted publication date: 20060913 |
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| CX01 | Expiry of patent term |