CN101600439B - Oral pharmaceutical composition of glycyrrhizin or its salts and the preparation method thereof - Google Patents
Oral pharmaceutical composition of glycyrrhizin or its salts and the preparation method thereof Download PDFInfo
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- CN101600439B CN101600439B CN200780048410.1A CN200780048410A CN101600439B CN 101600439 B CN101600439 B CN 101600439B CN 200780048410 A CN200780048410 A CN 200780048410A CN 101600439 B CN101600439 B CN 101600439B
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- enteric
- glycyrrhizic acid
- micropill
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4891—Coated capsules; Multilayered drug free capsule shells
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
Abstract
An oral enteric pharmaceutical composition of glycyrrhizin or its salt and the preparation method thereof. The composition is made up of many units. Each unit is composed of outer enteric coating and content. The content comprises glycyrrhizin or salt thereof and at least one uptake increasing agent of intestinal absorption.
Description
Technical field
The present invention relates to combination of oral medication of glycyrrhizic acid or its salt and preparation method thereof, specifically contain the oral enteric pharmaceutical composition of glycyrrhizic acid or its salt.
Background technology
Radix Glycyrrhizae (Glycyrrhiza) is a kind of conventional medicinal plants, and its main active is Radix Glycyrrhizae acid, i.e. the glycyrrhizic acid of 18-beta comfiguration and the glycyrrhizic acid (also referred to as Isoglycyrrhiza acid) of 18-α configuration.The research of pharmacology, biochemistry and Structure-activity analysis proves, glycyrrhizic acid or its salt has very strong antiinflammatory, protect hepatocyte and improve the effect (see open CN1381462A and CN1569005A of Chinese patent) of liver function.
At present, all there is the low problem of oral administration biaavailability in all glycyrrhizic acids or the oral formulations of its salt, reason is that glycyrrhizic acid or its salt belong to high polarity, large hydrophilic molecular material, absorb poor in gastrointestinal tract, and easily form molecule aggregation body under glycyrrhizic acid or its salt sour environment under one's belt.Therefore the Radix Glycyrrhizae acids oral formulations that exploitation has high bioavailability is needed badly.
Above-mentioned publication number is the enteric coated preparation that the Chinese patent application of CN1569005A discloses glycyrrhizic acid and salt thereof, adopts the form of enteric coated preparation to solve Radix Glycyrrhizae acids preparation and forms polymeric problem under one's belt.
Publication number is the phosphatide complexes that the Chinese patent application of CN1594332A discloses glycyrrhizic acid and salt thereof, by glycyrrhizic acid and phospholipid compound to promote the body absorption of glycyrrhizic acid.
Above-mentioned two sections of patent documentations all provide the method for the bioavailability improving Radix Glycyrrhizae acids oral formulations, but the bioavailability of Radix Glycyrrhizae acids oral formulations does not still get a desired effect.Inventor thinks that the Radix Glycyrrhizae acids oral formulations having the above-mentioned improvement of following 2 cause influences at least plays drug effect:
The first, the enteric coated preparation of glycyrrhizic acid that prepared by enteric coating or enteric capsule shell, that be made up of single dose drug delivery unit or its salt is difficult to the enteric solubility ensureing said preparation.Under the crunch of gastric peristalsis, enteric coated capsule or enteric coating are once break, and the enteric performance of whole preparation will completely lose.
The second, after the glycyrrhizic acid prepared by enteric capsule shell or the enteric coated preparation of its salt enter intestinal, medicine concentrates on small intestinal release.The phosphatide complexes of glycyrrhizic acid or its salt very easily forms gelatinous-like masses under intestinal juice environment, affects medicine finally affects medicine absorption with fully contacting of small bowel.Meanwhile, with carrier related, may there is saturated phenomenon in the absorption of Radix Glycyrrhizae acid in small intestinal, the absorbance that medicine concentrates the absorbance obtained during release will to obtain when disperseing far below medicaments uniformity.
Inventor finds unexpectedly, and the oral enteric pharmaceutical composition of glycyrrhizic acid of the present invention or its salt solves above-mentioned defect existing in Glycyrrhizin by suitable dosage form, and solves the low problem of bioavailability.
Summary of the invention
One aspect of the present invention is the oral enteric pharmaceutical composition providing glycyrrhizic acid or its salt.
The oral enteric pharmaceutical composition of glycyrrhizic acid of the present invention or its salt belongs to dosage decentralized preparation, it is composed of multiple units, each unit comprises the enteric coating composition of content and this content of parcel, described content can be micropill or particle form, preferred micropill, and this content contains glycyrrhizic acid or its salt, isolated by enteric coat layer and external environment.
The oral enteric pharmaceutical composition of glycyrrhizic acid of the present invention or its salt, wherein the weight ratio of content and enteric coating is 1: 0.15 ~ 0.45, preferably 1: 0.2 ~ 0.4, more preferably 1: 0.25 ~ 0.35.
The oral enteric pharmaceutical composition of glycyrrhizic acid of the present invention or its salt, wherein the maximum gauge of each unit must not more than 2mm, preferably between 0.5mm ~ 1.5mm, more preferably between 0.7mm ~ 1.2mm.Multiple described unit forms compositions of the present invention, and each compositions contains 1-500mg glycyrrhizic acid or its salt, preferably containing 25-150mg glycyrrhizic acid or its salt, more preferably containing 40-100mg glycyrrhizic acid or its salt.
Enteric-coating material of the present invention selects the conventional enteric coating material being applicable to micropill or granule being carried out coating, as: CAP class, Lac class, crylic acid resin or HP-55 class etc., preferred acrylic resins class enteric-coating material.
Content of the present invention contains glycyrrhizic acid or its salt and at least one intestinal absorption enhancers, and described intestinal absorption enhancers refers to the material that can strengthen medicine intestinal permeability, promote drug absorption, improve drug bioavailability.
The intestinal absorption enhancers used in the present invention can be any intestinal absorption enhancers being pharmaceutically applicable to oral application, includes but not limited to: phospholipid substance; The bioadhesive high molecular polymers such as Chitosan-phospholipid complex, polyvinylpyrrolidone, carbomer; Amino acid derivativges; Cholic acids material and the salt thereof such as natural bile, deoxycholic acid, sodium deoxycholate, NaGC, sodium taurocholate; Fatty acid and its esters such as sodium caprylate, Capric acid sodium salt, sodium laurate, enuatrol; The surfactants such as sodium lauryl sulphate, polyethenoxy ether class, esters, Arlacels.Wherein, preferred intestinal absorption enhancers is phospholipid substance.Preferred embodiment is the phosphatide complexes that content of the present invention contains glycyrrhizic acid or its salt be made up of glycyrrhizic acid or its salt and phospholipid substance.Described glycyrrhizic acid or the phosphatide complexes of its salt are compounded to form by glycyrrhizic acid or its salt and phospholipid substance, and wherein the weight ratio of glycyrrhizic acid or its salt and phospholipid substance is 1: 0.3 ~ 2, and preferred weight ratio is 1: 0.5 ~ 1.5.
Glycyrrhizic acid of the present invention or its salt can be 18-α glycyrrhizic acid or its salt, also can be 18-β glycyrrhizic acid or its salt, preferred 18-α glycyrrhizic acid or its salt.
Glycyrrhetate of the present invention includes, but are not limited to the ammonium salt of glycyrrhizic acid, magnesium salt, sodium salt, potassium salt, zinc salt, calcium salt, bismuth salt or silver salt, the magnesium salt of preferred glycyrrhizic acid and ammonium salt, the most preferably magnesium salt of glycyrrhizic acid.
Phospholipid substance of the present invention is lecithin matter, cephalin class material, lipositol class material or phospholipid acid, preferably lecithin class material, more preferably polyene phosphatidylcholine or phosphatidylcholine.
Except glycyrrhizic acid or its salt and at least one intestinal absorption enhancers, also can containing other intestinal absorption enhancers and other customary adjuvant in described content.Described adjuvant can be Blank Pellets ball core, filler (diluent), wetting agent, binding agent, disintegrating agent, lubricant, fluidizer etc.
Described celphere is the carrier of micropill, but the present invention does not have particular/special requirement to selected Blank Pellets ball core, as long as it does not react with active component and other adjuvant, do not affect active component and detect, profile rounding, easily carries out ball core and add medicine to.
Described filler (diluent) is adjuvant required when preparing pastille micropill or granule, the filler that the present invention selects can be selected from starch, pregelatinized Starch, dextrin, microcrystalline Cellulose, lactose, sucrose, glucose, mannitol, sorbitol, xylitol, dextran, fructose, calcium sulfate, calcium hydrogen phosphate, calcium phosphate, calcium carbonate, micropowder silica gel one or more.
Be applicable to the alcohol-water solution that wetting agent of the present invention can be distilled water, dehydrated alcohol or various concentration.
Be applicable to that binding agent of the present invention is selected from methylcellulose, ethyl cellulose, Polyethylene Glycol, polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, sucrose, maltose, starch slurry, gelatin, arabic gum one or more.
Described disintegrating agent is the mixture of material maybe this kind of material contributing to compositions easy disintegrate and stripping in intestinal in the present invention, disintegrating agent be selected from starch, carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose, cross-linked hydroxypropyl methylcellulose, polyvinylpolypyrrolidone, low-substituted hydroxypropyl cellulose one or more.
Described lubricant and fluidizer be selected from Pulvis Talci, magnesium stearate, calcium stearate, zinc stearate, liquid Paraffin, Polyethylene Glycol, Stepanol MG, sodium lauryl sulphate, long-chain fatty acid, stearic acid, micropowder silica gel, hydrogenated vegetable oil one or more.
In addition, other conventional additives can also be used if desired, as coloring agent, aromatic, correctives, antioxidant.
Can be the dosage form being suitable for oral administration by the oral enteric pharmaceutical composition prescription of glycyrrhizic acid of the present invention or its salt, as capsule, tablet and granule etc.Wherein capsule shells can select any capsule form beyond enteric capsule shell; Tablet can coating or not coating, and coatings can select any coating form beyond enteric coating.Every capsules or tablet contain glycyrrhizic acid or its salt 25-150mg, preferred 40-100mg, preferably the oral enteric pharmaceutical composition of glycyrrhizic acid of the present invention or its salt are loaded administration after conventional capsule.
Another aspect of the present invention is the preparation method of the oral enteric pharmaceutical composition providing glycyrrhizic acid or its salt.
Preparation in accordance with the present invention one specific embodiments, the following step that has of the oral enteric pharmaceutical composition of described glycyrrhizic acid or its salt obtains:
First, by glycyrrhizic acid or its salt and intestinal absorption enhancers and or other adjuvant of getting along well be prepared into micropill or granule according to a conventional method; Then with enteric-coating material, the micropill of gained or granule are carried out enteric coating, obtain compositions unit; Multiple described compositions unit mixing is formed described compositions.
In the preferred embodiment of the present invention, first, glycyrrhizic acid or its salt and phospholipid substance are carried out compound, obtains the phosphatide complexes of glycyrrhizic acid or its salt; Then by the phosphatide complexes of glycyrrhizic acid or its salt and or other adjuvant of getting along well be prepared into micropill or granule; With enteric-coating material, the micropill of gained or granule are carried out enteric coating subsequently, obtain compositions unit; Finally multiple described compositions unit mixing is formed compositions of the present invention.
In preparation method of the present invention, the weight ratio of the micropill of gained or granule and enteric-coating material is 1: 0.15-1: 0.45, is preferably 1: 0.2-1: 0.4, is more preferably 1: 0.25-1: 0.35.
In preferred embodiment of the present invention, glycyrrhizic acid or its salt and phospholipid substance are carried out compound with weight ratio 1: 0.3 ~ 2, and preferred weight ratio is 1: 0.5 ~ 1.5
The technique preparing pastille micropill can select extrusion spheronization technique, general ball technique and ball core drug layering.Preferred employing ball core drug layering prepares pastille micropill.
Another aspect of the present invention is the method providing treatment hepatitis, comprises and the individuality of oral enteric pharmaceutical composition to the described treatment of needs of glycyrrhizic acid of the present invention or its salt is carried out administration.
Another aspect of the present invention is to provide the method improving individual abnormal liver function, comprises and the oral enteric pharmaceutical composition of glycyrrhizic acid of the present invention or its salt is carried out administration to described individuality.
Another aspect of the invention is to provide the purposes of the oral enteric pharmaceutical composition of glycyrrhizic acid of the present invention or its salt in the medicine for the preparation for the treatment of hepatitis.
Another aspect of the invention is to provide the oral enteric pharmaceutical composition of glycyrrhizic acid of the present invention or its salt for the preparation of the purposes improved in the medicine of abnormal liver function.
In oral enteric pharmaceutical composition of the present invention, by glycyrrhizic acid or its salt and intestinal absorption enhancers administration simultaneously, improve the bioavailability of medicine, especially glycyrrhizic acid or its salt and phospholipid substance are carried out the phosphatide complexes that compound is prepared into glycyrrhizic acid or its salt, improve hydrophilic and the lipotropy of glycyrrhizic acid or its salt simultaneously, thus facilitate the absorption of active component in intestinal.
In addition, medicine is made dosage decentralized enteric coated preparation, each preparation is composed of multiple units, and the quality to this unit, such as the weight ratio of particle diameter, content and enteric coating controls, and improves the bioavailability of medicine further.By controlling the particle diameter of enteric coated micropill, making medicaments uniformity enter intestinal dispersedly, expanding the contact area of medicine and intestinal, medicaments uniformity is fully contacted with small bowel dispersedly, not easily form the gelatinous-like masses of adhesion, thus promote the absorption of medicine.By effectively controlling the weight ratio of content and enteric coating, both the enteric coating because of enteric coated micropill can have been avoided to break under the crunch of gastric peristalsis causes glycyrrhizic acid or its salt to form polymer under gastric acid environment, can ensure that again the medicine of enteric coated micropill form can discharge rapidly completely in intestinal.In addition, the rate of release of medicine in intestinal can be controlled by the weight ratio controlling content and enteric coating.
Glycyrrhizic acid or its salt reliably, steadily, effectively absorb in intestinal, not only increase the bioavailability of glycyrrhizic acid or its salt, reach the object improving glycyrrhizic acid or its salt oral formulations curative effect, and decrease its untoward reaction, ensure that drug safety and facility.
Accompanying drawing explanation
Fig. 1: the 18-α glycyrrhizic acid magnesium enteric coated micropill vitro release curve chart that embodiment 1 is obtained.
Detailed description of the invention
The following example is intended to citing further and describes the present invention, instead of limits the present invention by any way.
Preparation embodiment
Preparation embodiment 1:18-α glycyrrhizic acid magnesium (magnesium isoglycyrrhetate) enteric-coated pellet capsule
Micropill prescription:
Ingredient names 1000 capsules consumption (g)
18-α glycyrrhizic acid magnesium 50 is (with C
42h
60mgO
16meter)
Medicinal Blank Pellets ball core (cane sugar type) 100
Soybean lecithin 50
Polyethylene glycol 6000 0.16
Pulvis Talci 5
Appropriate amount of ethanol
The prescription of enteric coating liquid:
Every 1000 grams of micropills consumption (g) of ingredient names
Opadry (ACRYC-EZE MP) 300
Water 2000
Production technology:
1, (a small amount of water can be dripped if desired and make dissolving) evaporate to dryness ethanol after recipe quantity 18-α glycyrrhizic acid magnesium and soybean lecithin being dissolved in ethanol, obtain the complex of 18-α glycyrrhizic acid magnesium and soybean lecithin;
2, the complex obtained in item 1 to be scattered in distilled water and to add polyethylene glycol 6000 and the Pulvis Talci of recipe quantity, stirring;
3, by recipe quantity, medicinal Blank Pellets ball core (cane sugar type) is put into fluid bed, the suspension obtained slowly is sprayed into, make pastille micropill in item 2;
4, by recipe quantity, Opadry is added in suitable quantity of water, be mixed with coating solution;
5, in fluid bed, the coating solution that item 4 is prepared slowly is sprayed into, make diameter 0.5mm ~ 1.2mm enteric coated micropill;
6, fill capsule after enteric coated micropill mensuration content.
Preparation embodiment 2:18-α diammonium glycyrrhizinate enteric-coated pellet capsule
Micropill prescription:
Ingredient names 1000 capsules consumption (g)
Diammonium Glycyrrihizinate 50 is (with C
42h
68n
2o
16meter)
Polyene phosphatidylcholine 25
Microcrystalline Cellulose 100
Low-substituted hydroxypropyl cellulose 100
Pulvis Talci 37.5
Appropriate amount of ethanol
15% alcohol-water solution is appropriate
The prescription of enteric coating liquid:
Every 1000 grams of micropills consumption (g) of ingredient names
Opadry (ACRYC-EZE MP) 300
Water 2000
Production technology:
1, (a small amount of water can be dripped if desired and make dissolving) evaporate to dryness ethanol after recipe quantity Diammonium Glycyrrihizinate and polyene phosphatidylcholine being dissolved in ethanol, obtain the complex of Diammonium Glycyrrihizinate and polyene phosphatidylcholine;
2, the microcrystalline Cellulose of the complex obtained in item 1, recipe quantity, low-substituted hydroxypropyl cellulose, Pulvis Talci are all pulverized rear mistake 80 mesh sieve for subsequent use;
3, the described complex after pulverizing and sieving, microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, the Pulvis Talci mix homogeneously that will obtain in item 2, with 15% alcohol-water solution soft material, extrude with the screen cloth of 0.6mm and round as a ball one-tenth pastille micropill;
4, pastille micropill is dry in 40 DEG C of fluid beds;
5, by recipe quantity, Opadry is added in suitable quantity of water, be mixed with coating solution;
6, in fluid bed, the coating solution that item 5 is prepared slowly is sprayed into, make diameter 0.5mm ~ 1.2mm enteric coated micropill;
7, fill capsule after enteric coated micropill mensuration content;
Preparation embodiment 3:18-β glycyrrhizic acid dipotassium enteric-coated pellet capsule
Micropill prescription:
Ingredient names 1000 capsules consumption (g)
18-β glycyrrhizic acid dipotassium 100 is (with C
42h
60k
2o
16meter)
Cephalin 30
Lactose 30
Microcrystalline Cellulose 100
Low-substituted hydroxypropyl cellulose 5
Pulvis Talci 10
Appropriate amount of ethanol
30% alcohol-water solution is appropriate
The prescription of enteric coating liquid:
Every 1000 grams of micropills consumption (g) of ingredient names
Especially strange (EUDRAGIT) (L100-55) 300
Water 2000
Adopt the production technology of preparation described in embodiment 2, use the various components of the recipe quantity described in above-mentioned prescription to prepare the enteric coated micropill that diameter is 0.5mm ~ 1.5mm, then measure fill capsule after the medicament contg of enteric coated micropill.
Preparation embodiment 4:18-β zinc glycyrrhetate enteric-coated pellet capsule
Micropill prescription:
Ingredient names 1000 capsules consumption (g)
18-β zinc glycyrrhetate 50 is (with C
42h
60znO
16meter)
Medicinal Blank Pellets ball core (cane sugar type) 110
Phosphatidylcholine 100
Polyethylene glycol 6000 0.22
Pulvis Talci 8
Appropriate amount of ethanol
The prescription of enteric coating liquid:
Every 1000 grams of micropills consumption (g) of ingredient names
Opadry (ACRYC-EZE MP) 300
Water 2000
Adopt the production technology of preparation described in embodiment 1, use the various components of the recipe quantity described in above-mentioned prescription to prepare diameter 0.5mm ~ 1.2mm enteric coated micropill, then measure fill capsule after the medicament contg of enteric coated micropill.
Preparation embodiment 5:18-α glycyrrhizic acid enteric-coated pellet capsule
Micropill prescription:
Ingredient names 1000 capsules consumption (g)
18-α glycyrrhizic acid 50 is (with C
42h
62o
16meter)
Polyene phosphatidylcholine 75
Microcrystalline Cellulose 100
Low-substituted hydroxypropyl cellulose 100
Pulvis Talci 37.5
Appropriate amount of ethanol
15% alcohol-water solution is appropriate
The prescription of enteric coating liquid:
Every 1000 grams of micropills consumption (g) of ingredient names
Opadry (ACRYC-EZE MP) 300
Water 2000
Production technology:
1, microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, Pulvis Talci are all pulverized rear mistake 80 mesh sieve for subsequent use;
2, (a small amount of water can be dripped if desired and make dissolving) semisolid of steaming to rarer after recipe quantity 18-α glycyrrhizic acid and polyene phosphatidylcholine being dissolved in ethanol;
3, the microcrystalline Cellulose after pulverizing and sieving, low-substituted hydroxypropyl cellulose, the Pulvis Talci that obtain in the item 1 of recipe quantity is taken, and mix homogeneously;
4, the powder obtained in item 3 is joined in the semisolid obtained in item 2, be uniformly mixed, make soft material (15% alcohol-water solution moistening can be added if desired), extrude with the screen cloth of 0.6mm and round as a ball one-tenth pastille micropill;
5, pastille micropill is dry in 40 DEG C of fluid beds;
6, by recipe quantity, Opadry is added in suitable quantity of water, be mixed with coating solution;
7, in fluid bed, the coating solution that item 6 is prepared slowly is sprayed into, make 0.5mm ~ 1.2mm enteric coated micropill;
8, fill capsule after enteric coated micropill mensuration content.
Preparation embodiment 6:18-β diammonium glycyrrhizinate enteric coated micropill sheet
Core formulation:
Ingredient names 1000 consumptions (g)
18-β diammonium glycyrrhizinate 50 is (with C
42h
68n
2o
16meter)
Phosphatidic acid 25
Lactose 15
Microcrystalline Cellulose (inside adding) 60
Low-substituted hydroxypropyl cellulose 15
N-butyl alcohol is appropriate
25% alcohol-water solution is appropriate
Microcrystalline Cellulose (additional) 120
Magnesium stearate 3
The prescription of enteric coating liquid:
The every 1000 grams of amount of particles (g) of ingredient names
Opadry (ACRYC-EZE MP) 300
Water 2000
Production technology:
1, (a small amount of water can be dripped if desired and make dissolving) thoroughly evaporate to dryness n-butyl alcohol after recipe quantity 18-β diammonium glycyrrhizinate and phosphatidic acid being dissolved in n-butyl alcohol, obtain the complex of 18-β diammonium glycyrrhizinate and phosphatidic acid;
2, by the lactose of the complex obtained in item 1, recipe quantity, microcrystalline Cellulose (inside adding), that low-substituted hydroxypropyl cellulose all pulverizes rear mistake 80 mesh sieve is for subsequent use;
3, by the described complex after pulverizing and sieving obtained in item 2, lactose, microcrystalline Cellulose (in add), low-substituted hydroxypropyl cellulose mix homogeneously, with 25% alcohol-water solution soft material, extrude with 0.6mm screen cloth and round as a ball one-tenth pastille micropill;
4, micropill is dry in 40 DEG C of fluid beds;
5, by recipe quantity, Opadry is added in suitable quantity of water, be mixed with coating solution;
6, in fluid bed, the coating solution that item 5 is prepared slowly is sprayed into, make diameter 0.5mm ~ 1.5mm enteric coated micropill;
7, enteric coated micropill measures content with after the microcrystalline Cellulose (additional) of recipe quantity and magnesium stearate mix homogeneously, tabletting and get final product.
Preparation embodiment 7:18-α glycyrrhizic acid calcium enteric-coated pellet capsule
Micropill prescription:
Ingredient names 1000 capsules consumption (g)
18-α glycyrrhizic acid calcium 50 is (with C
42h
60caO
16meter)
Medicinal Blank Pellets ball core 100
Lipositol 50
Polyethylene glycol 6000 0.16
Pulvis Talci 5
N-butyl alcohol is appropriate
The prescription of enteric coating liquid:
Every 1000 grams of micropills consumption (g) of ingredient names
Especially strange (EUDRAGIT) (L30D-55) 1000
Water 1000
Adopt the production technology of preparation described in embodiment 1, use the various components of the recipe quantity described in above-mentioned prescription to prepare diameter 0.5mm ~ 1.2mm enteric coated micropill, then measure fill capsule after the medicament contg of enteric coated micropill.
Preparation embodiment 8:18-α glycyrrhizic acid magnesium enteric coated micropill
Micropill prescription:
Ingredient names 1000 capsules consumption (g)
18-α glycyrrhizic acid magnesium 50 is (with C
42h
60mgO
16meter)
Medicinal Blank Pellets ball core (cane sugar type) 100
Polyvinylpyrrolidone 50
Polyethylene glycol 6000 0.50
Pulvis Talci 9
Dehydrated alcohol is appropriate
The prescription of enteric coating liquid:
Every 1000 grams of micropills consumption (g) of ingredient names
Especially strange (EUDRAGIT) (L30D-55) 1000
Water 1000
Replace soybean lecithin as except intestinal absorption enhancers except using polyvinylpyrrolidone, adopt the production technology of preparation described in embodiment 1, use the various components of the recipe quantity described in above-mentioned prescription to prepare the enteric coated micropill of diameter 0.5mm ~ 1.2mm, then measure fill capsule after the medicament contg of enteric coated micropill
Preparation embodiment 9:18-α diammonium glycyrrhizinate enteric coated particles
Granule prescription:
Ingredient names 1000 capsules consumption (g)
Diammonium Glycyrrihizinate 50 is (with C
42h
68n
2o
16meter)
Sodium lauryl sulphate 3
Lactose 65
Microcrystalline Cellulose 80
Low-substituted hydroxypropyl cellulose 5
3%HPMC aqueous solution is appropriate
The prescription of enteric coating liquid:
The every 1000 grams of amount of particles (g) of ingredient names
Opadry (ACRYC-EZE MP) 300
Water 2000
Production technology:
1, by after recipe quantity Diammonium Glycyrrihizinate and sodium lauryl sulphate mix homogeneously again with other component mix homogeneously described in the granule prescription of recipe quantity.With 3%HPMC aqueous solution soft material, 18 mesh sieves are granulated.
2, granule is dry in 50 DEG C of fluid beds, after crossing 40 mesh sieve removing fine graineds after 20 mesh sieve granulate, put into fluid bed;
3, by recipe quantity, Opadry is added in suitable quantity of water, be mixed with coating solution;
4, in fluid bed, the coating solution that item 3 is prepared slowly is sprayed into, make the enteric coated particles of diameter 0.5mm ~ 2.0mm;
7, enteric coated particles loads conventional capsule, to obtain final product.
Preparation embodiment 10:18-α glycyrrhizic acid enteric coated particles
Granule prescription:
Ingredient names 1000 capsules consumption (g)
18-α glycyrrhizic acid 50 is (with C
42h
62o
16meter)
Carbomer 4
Lactose 95
Microcrystalline Cellulose 65
Appropriate amount of ethanol
The prescription of enteric coating liquid:
The every 1000 grams of amount of particles (g) of ingredient names
Opadry (ACRYC-EZE MP) 300
Water 2000
Replace sodium lauryl sulphate as except intestinal absorption enhancers except using carbomer, adopt the production technology of preparation described in embodiment 12, use the various components of the recipe quantity described in above-mentioned prescription to prepare diameter 0.5mm ~ 2.0mm enteric coated particles, then enteric coated particles is loaded conventional capsule.
Preparation embodiment 11:18-α disodium glycyrrhizinate enteric coated micropill
Micropill prescription:
Ingredient names 1000 capsules consumption (g)
18-α disodium glycyrrhizinate 50 is (with C
42h
60na
2o
16meter)
Medicinal Blank Pellets ball core (cane sugar type) 100
Deoxycholic acid 10
Polyethylene glycol 6000 0.2
Pulvis Talci 3
3%HPMC aqueous solution is appropriate
The prescription of enteric coating liquid:
Every 1000 grams of micropills consumption (g) of ingredient names
Especially strange (EUDRAGIT) (L30D-55) 1000
Water 1000
Replace soybean lecithin as except intestinal absorption enhancers except using deoxycholic acid, adopt the production technology of preparation described in embodiment 1, use the various components of the recipe quantity described in above-mentioned prescription to prepare diameter 0.5mm ~ 1.2mm enteric coated micropill, then enteric coated micropill incapsulated and get final product.
Zoopery example: the oral relative bioavailability of 18-α glycyrrhizic acid magnesium enteric-coated pellet capsule in Beagle dog
Illustrate that the enteric-coated medicament combination of glycyrrhizic acid involved in the present invention or its salt is that a kind of toxic and side effects is low below by zoopery, treatment chronic viral hepatitis evident in efficacy, and improve the pharmaceutical preparation of abnormal liver function.
Glycyrrhizic acid in explanation the present invention simultaneously or the enteric-coated medicament combination of its salt are compared with the common enteric coated capsule of glycyrrhizic acid or its salt, and bioavailability is significantly improved.
This research is based upon HPLC-UV method and detects on the basis of 18-α glycyrrhizic acid magnesium in Beagle dog plasma, the blood drug level observing the 18-α glycyrrhizic acid magnesium enteric-coated pellet capsule of Beagle dog oral Jiangsu Zhengda Tianqing Drug Industry Co., Ltd development through time process, calculate corresponding pharmacokinetic parameter, and with common enteric coated capsule for reference preparation, calculate its relative bioavailability.
1, test material:
Trial drug: 18-α glycyrrhizic acid magnesium (abbreviation magnesium isoglycyrrhetate) enteric-coated pellet capsule, every capsules containing magnesium isoglycyrrhetate 50mg, and is prepared according to the method in the embodiment of the present application 1; The common enteric coated capsule of 18-α glycyrrhizic acid magnesium, (after wherein 18-α glycyrrhizic acid magnesium and phosphatidylcholine are prepared into complex by weight 1: 1, add microcrystalline Cellulose and Pulvis Talci as adjuvant, use enteric capsule shell, be prepared into common enteric coated capsule according to a conventional method) every containing magnesium isoglycyrrhetate 50mg.
Experimental animal: Beagle dog, 11.7 ± 1.2kg, ♀
half and half, totally 6.Thered is provided by Animal Experimental Study center, Yadong, Nanjing.
2, detection method:
In this test, 18-α glycyrrhizic acid magnesium adopts HPLC-UV method to measure, and this analytical method specificity is strong, and sensitive, reliable, and the range of linearity is wide, can meet the analysis requirement of biological sample in research completely.
3, test method:
Beagle dog 6, buys raising back and is divided into 18-α glycyrrhizic acid magnesium enteric-coated pellet capsule 32mg/kg group and the common enteric coated capsule 32mg/kg of 18-α glycyrrhizic acid magnesium after 1 week at random, often organizes 3.Consider that the preparation specification of this institute is 50mg/ grain, the Beagle dog of the nearly 12.5kg of selective body reclosing, the dosage of two groups of single dogs is 400mg, namely distinguishes oral test preparation and each 8 of reference preparation.Dog test day fasting can't help water 12 hours, and venous blood sampling 2 ~ 2.5ml is in anticoagulant heparin pipe.After getting blood, dog is distinguished administered by oral gavage oral test preparation and reference preparation by arranging dosage, and after administration, adopt same procedure to get blood when different time points, by the blood of collection with the centrifugal 10min of 3000r/min, get upper plasma 1ml and put in EP pipe ,-20 DEG C of preservations are to be measured.Take out plasma sample during mensuration, thaw laggard row relax, and detect the concentration of magnesium isoglycyrrhetate in blood plasma.
10 days cleaning after dates, 18-α glycyrrhizic acid magnesium enteric-coated pellet capsule 32mg/kg group and 18-α glycyrrhizic acid magnesium common enteric coated capsule group 32mg/kg treated animal intersect, and the same method administration, get blood, mensuration.
Calculate relevant medicine for parameter, evaluate the Pharmacokinetic Characteristics of 18-α glycyrrhizic acid magnesium enteric-coated pellet capsule, and calculate its relative bioavailability.
4, result of the test:
Both results contrast after Beagle dog distinguishes single oral enteric-coated pellet capsule and common enteric coated capsule show, with the common enteric coated capsule of 18-α glycyrrhizic acid magnesium for reference preparation, the relative bioavailability of Beagle dog oral 18-α glycyrrhizic acid magnesium enteric-coated pellet capsule is 211%.Result of the test is in table 1.
The main pharmacokinetic parameter of table 1 magnesium isoglycyrrhetate in Beagle dog compares and relative bioavailability (Mean ± SD, n=6)
| Parameter | Common enteric coated capsule (32mg/kg) | Enteric-coated pellet capsule (32mg/kg) |
| Tmax(h) | 8.2±4.1 | 7.3±3.0 |
| Cmax(μg/L) | 2346±1217 | 4095±2023 |
| T 1/2z(h) | 11.74±2.18 | 10.82±2.43 |
| AUC 0～T(μg·h/L) | 34652±12047 | 73117±27489 |
Both AUC
0-Tpole significant difference (P < 0.001) is shown through Doubled haploid population with Cmax.
The oral bioavailability of 18-α glycyrrhizic acid magnesium enteric-coated pellet capsule Beagle dog is obviously better than the common enteric coated capsule of 18-α glycyrrhizic acid magnesium, AUC
0-Tbe about 2.11 times of the latter.
Stability test example: 18-α glycyrrhizic acid magnesium enteric-coated pellet capsule (embodiment 1) stability test
By 18-α glycyrrhizic acid magnesium enteric-coated pellet capsule (lot number: 050516,050518,050522) by commercially available back (adopt aluminium foil and PVC stiff sheet packaging) respectively at accelerated test under the condition of temperature 40 DEG C ± 2 DEG C, relative humidity 75% ± 5% 6 months (sampling in 1,2,3,6 month); In temperature 25 DEG C ± 2 DEG C, long term test 18 months (sampling in 0,3,6,9,12,18 month) under relative humidity 60% ± 10% condition.Observe enteric coated micropill character in capsule, measure related substance, release and content, and compare with the analytical data of 0 month sample, indices is showed no significant change.Result of the test is in table 2 and table 3.
Table 2 accelerated test result
Table 3 long-term stable experiment result
Vitro release test example: 18-α glycyrrhizic acid magnesium enteric-coated pellet capsule (embodiment 1) vitro release is tested
Instrument: ZRS-8G intelligence digestion instrument (Tianjin radio factory)
High performance liquid chromatograph (Japanese Shimadzu Corporation)
Method: get this product, according to drug release determination method (China's coastal port two annex X D second methods), adopts Rotating shaker (China's coastal port two annex X C first methods).Release medium in acid: 0.1mol/L hydrochloric acid 750ml; Release medium in buffer: pH6.8 phosphate buffered solution 1000ml.Rotating speed: 75r/min.This product discharges 2 hours respectively in acid, and then discharges 5,10,15,20,30,45 minutes in buffer salt solution, detects release medium drug content, draws Cumulative release amount curve, the results are shown in Table 4 and accompanying drawing 1.
Table 4: Cumulative release amount result
Coating weight gain experimental example
Method: based on the preparation method preparing embodiment 1, by changing the weight ratio of content and coating, obtain the sample of different coating weight gain, measure disintegration (use Chinese Pharmacopoeia 2005 editions annex XA the 3rd subtraction unit) and release (Chinese Pharmacopoeia 2005 editions annex XD second method methods 1) again and compare, result of the test is in table 5:
Table 5. coating weight gain result of the test
As can be known from Table 5, coating weight gain is controlled rationally and effectively, not only can ensure that enteric coated micropill discharges hardly in gastric juice, and can ensure this enteric coated micropill in intestinal can fater disintegration and release completely, improve the bioavailability of medicine, meet the requirement of pharmaceutical composition of the present invention.
Claims (1)
- The preparation method of 1.18-α glycyrrhizic acid magnesium enteric-coated pellet capsule,Wherein said micropill prescription is as follows:Wherein the prescription of enteric coating liquid is as follows:The every 1000 grams of micropill consumption/g of ingredient namesOpadry 300Water 2000;Wherein said preparation method:(1), by recipe quantity 18-α glycyrrhizic acid magnesium and soybean lecithin be dissolved in evaporate to dryness ethanol after ethanol, obtain the complex of 18-α glycyrrhizic acid magnesium and soybean lecithin;(2), by the complex obtained in item (1) to be scattered in distilled water and to add polyethylene glycol 6000 and the Pulvis Talci of recipe quantity, stirring;(3), by recipe quantity medicinal Blank Pellets ball core is put into fluid bed, the suspension obtained slowly is sprayed into, make pastille micropill in item (2);(4), by recipe quantity, Opadry is added in suitable quantity of water, be mixed with coating solution;(5), in fluid bed, the coating solution that item (4) is prepared slowly is sprayed into, make diameter 0.5mm ~ 1.2mm enteric coated micropill;(6), fill capsule after enteric coated micropill mensuration content.
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| PCT/CN2007/003950 WO2008083561A1 (en) | 2006-12-29 | 2007-12-29 | Oral pharmaceutical composition of glycyrrhizin or its salts and the preparation method thereof |
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| 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 |
| CN102525943B (en) * | 2012-01-05 | 2014-07-16 | 金陵药业股份有限公司 | Micro-pill and preparation method thereof |
| CN103242391B (en) * | 2012-02-13 | 2016-04-13 | 南京华狮化工有限公司 | A kind of prepare method of strontium glycyrrhetate compound and products thereof and application |
| CN103301074B (en) * | 2013-06-20 | 2015-04-22 | 成都华神集团股份有限公司 | Diammonium glycyrrhizinate enteric-coated pellet as well as preparation method and preparation thereof |
| CN104288108B (en) * | 2014-10-18 | 2017-01-25 | 山东世博金都药业有限公司 | Diammonium glycyrrhizinate enteric-coated sustained-release pellet and preparation method thereof |
| CN111067877A (en) * | 2020-01-19 | 2020-04-28 | 安徽省先锋制药有限公司 | Diammonium glycyrrhizinate enteric-coated tablet and preparation method thereof |
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| CN1569005A (en) * | 2003-07-18 | 2005-01-26 | 江苏正大天晴药业股份有限公司 | Enteric-coated formulation of glycyrrhizic acid and its salt and its preparing method |
| CN1594332A (en) * | 2004-06-23 | 2005-03-16 | 江苏正大天晴药业股份有限公司 | Glycyrrhetic acid and phospholipid composites of glycyrrhetate and process for preparing same |
| CN1686151A (en) * | 2005-04-04 | 2005-10-26 | 张红军 | Enteric dissolving preparation of compound glycyrrbizic acid and its salt and its preparation method |
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| CN1586490A (en) * | 2004-07-14 | 2005-03-02 | 李�杰 | Compound glycyrrhizunate tablet and its preparing method |
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| CN1569005A (en) * | 2003-07-18 | 2005-01-26 | 江苏正大天晴药业股份有限公司 | Enteric-coated formulation of glycyrrhizic acid and its salt and its preparing method |
| CN1594332A (en) * | 2004-06-23 | 2005-03-16 | 江苏正大天晴药业股份有限公司 | Glycyrrhetic acid and phospholipid composites of glycyrrhetate and process for preparing same |
| CN1686151A (en) * | 2005-04-04 | 2005-10-26 | 张红军 | Enteric dissolving preparation of compound glycyrrbizic acid and its salt and its preparation method |
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| CN102008492B (en) | 2013-10-23 |
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