CN102008492B - Oral medicinal composition of glycyrrhizic acid or glycyrrhetate and preparation method thereof - Google Patents
Oral medicinal composition of glycyrrhizic acid or glycyrrhetate and preparation method thereof Download PDFInfo
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- CN102008492B CN102008492B CN2010105180159A CN201010518015A CN102008492B CN 102008492 B CN102008492 B CN 102008492B CN 2010105180159 A CN2010105180159 A CN 2010105180159A CN 201010518015 A CN201010518015 A CN 201010518015A CN 102008492 B CN102008492 B CN 102008492B
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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
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- 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
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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
- A61K9/50—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
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- 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
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- 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
The invention discloses an oral medicinal composition of glycyrrhizic acid or glycyrrhetate and a preparation method thereof. The composition consists of a plurality of units, wherein each unit consists of an outer layer enteric coating and content; and the content contains glycyrrhizic acid or glycyrrhetate and at least one intestinal absorption accelerator. The composition can be used for treating chronic hepatitis and improving liver dysfunction.
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 medicinal plants commonly used, and its main active is the Radix Glycyrrhizae acid, i.e. the glycyrrhizic acid (being also referred to as Isoglycyrrhiza acid) of the glycyrrhizic acid of 18-beta comfiguration and 18-α configuration.Pharmacology, biochemistry and structure activity relationship analysis and research proof, glycyrrhizic acid or its salt have very strong antiinflammatory, protect hepatocyte and improve the effect (referring to the open CN1381462A of Chinese patent and CN1569005A) of liver function.
At present, all there are 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, in gastrointestinal tract, absorb relatively poorly, and easily form the molecule aggregation body under glycyrrhizic acid or its salt sour environment under one's belt.Therefore need the Radix Glycyrrhizae acids oral formulations that exploitation has high bioavailability badly.
Above-mentioned publication number is the enteric coated preparation that the Chinese patent application of CN1569005A discloses glycyrrhizic acid and salt thereof, and the form of employing enteric coated preparation has solved Radix Glycyrrhizae acids preparation and formed under one's belt polymeric problem.
Publication number is the phosphatide complexes that the Chinese patent application of CN1594332A discloses glycyrrhizic acid and salt thereof, and glycyrrhizic acid and phospholipid is compound to absorb in the body that promotes glycyrrhizic acid.
Above-mentioned two pieces of patent documentations all provide the method for the bioavailability that improves Radix Glycyrrhizae acids oral formulations, but the bioavailability of Radix Glycyrrhizae acids oral formulations does not still get a desired effect.The inventor thinks the above-mentioned improved Radix Glycyrrhizae acids oral formulations performance drug effect that had following 2 cause influences at least:
The first, be difficult to guarantee the enteric solubility of said preparation by the enteric coated preparation of the glycyrrhizic acid preparation of enteric coating or enteric capsule shell, that formed by release unit of single dose or its salt.In a single day enteric coated capsule or enteric coating break under the crunch of gastric peristalsis, and the enteric performance of whole preparation will completely lose.
The second, after the glycyrrhizic acid by enteric capsule shell preparation or the enteric coated preparation of its salt entered intestinal, medicine concentrated on small intestinal and discharges.The phosphatide complexes of glycyrrhizic acid or its salt very easily forms the gel agglomerate under the intestinal juice environment, affect medicine and fully contacting of small bowel and finally affect the absorption of medicine.Simultaneously, may there be saturated phenomenon in the absorption of Radix Glycyrrhizae acid in small intestinal with carrier related, resulting absorbance when resulting absorbance will be far below the medicine Uniform Dispersion when medicine concentrate to discharge.
The inventor finds unexpectedly, and the oral enteric pharmaceutical composition of glycyrrhizic acid of the present invention or its salt has solved existing defects in the Glycyrrhizin by suitable dosage form, and has solved the low problem of bioavailability.
Summary of the invention
One aspect of the present invention is to provide the oral enteric pharmaceutical composition of 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 that the enteric coating of content and this content of parcel forms, described content can be micropill or particle form, preferred micropill, and this content contains glycyrrhizic acid or its salt, by enteric coat layer and external environment isolation.
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, preferred 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 surpass 2mm, preferably between 0.5mm～1.5mm, more preferably between 0.7mm～1.2mm.A plurality of described cell formations compositions of the present invention, each compositions contains 1-500mg glycyrrhizic acid or its salt, preferably contains 25-150mg glycyrrhizic acid or its salt, more preferably contains 40-100mg glycyrrhizic acid or its salt.
Enteric-coating material of the present invention is selected the conventional enteric-coating material that is fit to micropill or granule are 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 a intestinal absorption promoter, and described intestinal absorption promoter refers to strengthen the material of medicine intestinal permeability, promotion drug absorption, raising drug bioavailability.
The intestinal absorption promoter of using among the present invention can be any intestinal absorption promoter that pharmaceutically is fit to oral application, includes but not limited to: phospholipid substance; The bioadhesive high molecular polymers such as chitosan and derivant thereof, polyvinylpyrrolidone, carbomer; Amino acid derivativges; Cholic acid class 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 promoter is phospholipid substance.Preferred embodiment is that content of the present invention contains the glycyrrhizic acid made by glycyrrhizic acid or its salt and phospholipid substance or the phosphatide complexes of its salt.The phosphatide complexes of described glycyrrhizic acid or its salt is to be 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 ammonium salt, magnesium salt, sodium salt, potassium salt, zinc salt, calcium salt, bismuth salt or the silver salt of glycyrrhizic acid, magnesium salt and the ammonium salt of preferred glycyrrhizic acid, 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 a intestinal absorption promoter, also can contain other intestinal absorption promoter and other conventional adjuvant in the 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 specific (special) requirements to selected Blank Pellets ball core, as long as it does not react with active component and other adjuvant, does not affect active component and detects, and the profile rounding easily carries out the medicine-feeding of ball core and gets final product.
Needed adjuvant when described filler (diluent) is preparation pastille micropill or granule, the filler that the present invention selects can be selected from one or more in starch, pregelatinized Starch, dextrin, microcrystalline Cellulose, lactose, sucrose, glucose, mannitol, sorbitol, xylitol, dextran, fructose, calcium sulfate, calcium hydrogen phosphate, calcium phosphate, calcium carbonate, the micropowder silica gel.
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 binding agent of the present invention and be selected from methylcellulose, ethyl cellulose, Polyethylene Glycol, polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, sucrose, maltose, starch slurry, gelatin, the arabic gum one or more.
Described disintegrating agent is to help the easy material of disintegrate and the stripping mixture of this kind material maybe in intestinal of compositions among the present invention, and disintegrating agent is selected from one or more in starch, carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose, crosslinked hydroxypropyl methylcellulose, polyvinylpolypyrrolidone, the low-substituted hydroxypropyl cellulose.
Described lubricant and fluidizer are selected from one or more in 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, the hydrogenated vegetable oil.
In addition, can also use in case of necessity other additives commonly used, such as coloring agent, aromatic, correctives, antioxidant.
Can be the dosage form that is suitable for oral administration with the oral enteric pharmaceutical composition prescription of glycyrrhizic acid of the present invention or its salt, such as capsule, tablet and granule etc.Wherein capsule shells can be selected enteric capsule shell any capsule form in addition; Tablet can coating or coating not, and coatings can be selected any coating form beyond the enteric coating.Every capsules or tablet contain glycyrrhizic acid or its salt 25-150mg, preferred 40-100mg, administration behind the conventional capsule of preferably the oral enteric pharmaceutical composition of glycyrrhizic acid of the present invention or its salt being packed into.
Another aspect of the present invention is to provide the preparation method of the oral enteric pharmaceutical composition of 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 makes:
At first, with glycyrrhizic acid or its salt and intestinal absorption promoter and or other adjuvant of getting along well be prepared into according to a conventional method micropill or granule; Then with enteric-coating material micropill or the granule of gained carried out enteric coating, obtain the compositions unit; A plurality of described compositionss unit is mixed the described compositions of formation.
In the preferred embodiment of the present invention, at first, glycyrrhizic acid or its salt and phospholipid substance are carried out compound, obtain the phosphatide complexes of glycyrrhizic acid or its salt; Then with 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 micropill or the granule of gained carried out enteric coating subsequently, obtain the compositions unit; At last a plurality of described compositionss unit is mixed and consist of 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, be preferably 1: 0.2-1: 0.4, more preferably 1: 0.25-1: 0.35.
In preferred embodiment of the present invention, glycyrrhizic acid or its salt and phospholipid substance to be carried out compound with weight ratio 1: 0.3～2, preferred weight ratio is 1: 0.5～1.5
The technique of preparation pastille micropill can be selected and extrude round as a ball technique, general ball technique and ball core drug layering.The preferred ball core drug layering that adopts prepares the pastille micropill.
Another aspect of the present invention is to provide the method for the treatment of hepatitis, comprises the oral enteric pharmaceutical composition of glycyrrhizic acid of the present invention or its salt is carried out administration to the individuality of the described treatment of needs.
Another aspect of the present invention is to provide the method for improving individual abnormal liver function, comprises that the oral enteric pharmaceutical composition with glycyrrhizic acid of the present invention or its salt carries out administration to described individuality.
The oral enteric pharmaceutical composition that is on the one hand again to provide glycyrrhizic acid of the present invention or its salt of the present invention is for the preparation of the purposes in the medicine for the treatment of hepatitis.
The oral enteric pharmaceutical composition that is on the one hand again to provide glycyrrhizic acid of the present invention or its salt of the present invention is for the preparation of the purposes in the medicine that improves abnormal liver function.
In the oral enteric pharmaceutical composition of the present invention, with glycyrrhizic acid or its salt and the simultaneously administration of intestinal absorption promoter, improved the bioavailability of medicine, especially glycyrrhizic acid or its salt and phospholipid substance are carried out the compound phosphatide complexes that is prepared into glycyrrhizic acid or its salt, improve simultaneously hydrophilic and the lipotropy of glycyrrhizic acid or its salt, thereby promoted 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 to the quality of this unit, for example the weight ratio of particle diameter, content and enteric coating is controlled, and further improves the bioavailability of medicine.Particle diameter by the control enteric coated micropill enters intestinal with making the medicine Uniform Dispersion, has enlarged the contact area of medicine and intestinal, and medicine Uniform Dispersion ground is fully contacted with small bowel, is difficult for forming the gel agglomerate of adhesion, thereby promotes the absorption of medicine.By the weight ratio of Control the content thing and enteric coating effectively, both can avoid can guaranteeing again that because the enteric coating of enteric coated micropill causes glycyrrhizic acid or its salt to form polymer under gastric acid environment breaking under the crunch of gastric peristalsis the medicine of enteric coated micropill form can discharge rapidly fully in intestinal.In addition, can recently control the rate of release of medicine in intestinal by the weight of Control the content thing and enteric coating.
Glycyrrhizic acid or its salt absorb in intestinal reliably, steadily, effectively, not only improved the bioavailability of glycyrrhizic acid or its salt, reach the purpose that improves glycyrrhizic acid or its salt oral formulations curative effect, and reduced its untoward reaction, guaranteed drug safety and facility.
Description of drawings
The 18-α glycyrrhizic acid magnesium enteric coated micropill vitro release curve chart that Fig. 1: embodiment 1 makes.
The specific embodiment
The following example is intended to further describe for example the present invention, rather than limits by any way the present invention.
Preparation Example
Preparation Example 1:18-α glycyrrhizic acid magnesium (magnesium isoglycyrrhetate) enteric-coated pellet capsule
The micropill prescription:
Component title 1000 capsules consumptions (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:
The per 1000 gram micropill consumptions (g) of component title
Opadry (ACRYC-EZE MP) 300
Water 2000
Production technology:
1, recipe quantity 18-α glycyrrhizic acid magnesium and soybean lecithin are dissolved in (can drip in case of necessity a small amount of water and make dissolving) evaporate to dryness ethanol behind the ethanol, obtain the complex of 18-α glycyrrhizic acid magnesium and soybean lecithin;
2, be scattered in resulting complex in the item 1 in the distilled water and add polyethylene glycol 6000 and the Pulvis Talci of recipe quantity, stir;
3, by recipe quantity medicinal Blank Pellets ball core (cane sugar type) is put into fluid bed, resulting suspension in the item 2 is slowly sprayed into, make the pastille micropill;
4, by recipe quantity Opadry is added in the suitable quantity of water, be mixed with coating solution;
5, in fluid bed, the coating solution that item 4 is prepared slowly sprays into, and makes diameter 0.5mm～1.2mm enteric coated micropill;
6, fill capsule behind the enteric coated micropill mensuration content.
Preparation Example 2:18-α diammonium glycyrrhizinate enteric-coated pellet capsule
The micropill prescription:
Component title 1000 capsules consumptions (g)
Diammonium Glycyrrihizinate 50 (C
42H
68N
2O
16Meter)
Polyene phosphatidylcholine 25
Low-substituted hydroxypropyl cellulose 100
Pulvis Talci 37.5
Appropriate amount of ethanol
15% alcohol-water solution is an amount of
The prescription of enteric coating liquid:
The per 1000 gram micropill consumptions (g) of component title
Opadry (ACRYC-EZE MP) 300
Water 2000
Production technology:
1, recipe quantity Diammonium Glycyrrihizinate and polyene phosphatidylcholine are dissolved in (can drip in case of necessity a small amount of water and make dissolving) evaporate to dryness ethanol behind the ethanol, obtain the complex of Diammonium Glycyrrihizinate and polyene phosphatidylcholine;
2, microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, the Pulvis Talci of resulting complex, recipe quantity in the item 1 are all pulverized rear mistake 80 mesh sieves for subsequent use;
3, with resulting described complex, microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, Pulvis Talci mix homogeneously behind crushing screening in the item 2, with 15% alcohol-water solution soft material processed, extrude and round as a ball one-tenth pastille micropill with the screen cloth of 0.6mm;
4, the pastille micropill is dry in 40 ℃ of fluid beds;
5, by recipe quantity Opadry is added in the suitable quantity of water, be mixed with coating solution;
6, in fluid bed, the coating solution that item 5 is prepared slowly sprays into, and makes diameter 0.5mm～1.2mm enteric coated micropill;
7, fill capsule behind the enteric coated micropill mensuration content;
Preparation Example 3:18-β glycyrrhizic acid dipotassium enteric-coated pellet capsule
The micropill prescription:
Component title 1000 capsules consumptions (g)
18-β glycyrrhizic acid dipotassium 100 (C
42H
60K
2O
16Meter)
Cephalin 30
Lactose 30
Low-substituted hydroxypropyl cellulose 5
Pulvis Talci 10
Appropriate amount of ethanol
30% alcohol-water solution is an amount of
The prescription of enteric coating liquid:
The per 1000 gram micropill consumptions (g) of component title
Strange (EUDRAGIT) (L100-55) 300 especially
Water 2000
Adopt the production technology described in the Preparation Example 2, use the various components of the recipe quantity described in the above-mentioned prescription to prepare diameter and be the enteric coated micropill of 0.5mm～1.5mm, then measure fill capsule behind the medicament contg of enteric coated micropill.
Preparation Example 4:18-β zinc glycyrrhetate enteric-coated pellet capsule
The micropill prescription:
Component title 1000 capsules consumptions (g)
18-β zinc glycyrrhetate 50 is (with C
42H
60ZnO
16Meter)
Medicinal Blank Pellets ball core (cane sugar type) 110
Polyethylene glycol 6000 0.22
Pulvis Talci 8
Appropriate amount of ethanol
The prescription of enteric coating liquid:
The per 1000 gram micropill consumptions (g) of component title
Opadry (ACRYC-EZE MP) 300
Water 2000
Adopt the production technology described in the Preparation Example 1, use the various components of the recipe quantity described in the above-mentioned prescription to prepare diameter 0.5mm～1.2mm enteric coated micropill, then measure fill capsule behind the medicament contg of enteric coated micropill.
Preparation Example 5:18-α glycyrrhizic acid enteric-coated pellet capsule
The micropill prescription:
Component title 1000 capsules consumptions (g)
18-α glycyrrhizic acid 50 is (with C
42H
62O
16Meter)
Polyene phosphatidylcholine 75
Low-substituted hydroxypropyl cellulose 100
Pulvis Talci 37.5
Appropriate amount of ethanol
15% alcohol-water solution is an amount of
The prescription of enteric coating liquid:
The per 1000 gram micropill consumptions (g) of component title
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 sieves for subsequent use;
2, recipe quantity 18-α glycyrrhizic acid and polyene phosphatidylcholine are dissolved in ethanol after (can drip in case of necessity a small amount of water and make dissolving) steam to rarer semisolid;
3, take by weighing resulting microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, Pulvis Talci behind crushing screening in the item 1 of recipe quantity, and mix homogeneously;
4, the powder that obtains in the item 3 is joined in the semisolid that obtains in the item 2, mix, make soft material (can add in case of necessity 15% alcohol-water solution moistening), extrude and round as a ball one-tenth pastille micropill with the screen cloth of 0.6mm;
5, the pastille micropill is dry in 40 ℃ of fluid beds;
6, by recipe quantity Opadry is added in the suitable quantity of water, be mixed with coating solution;
7, in fluid bed, the coating solution that item 6 is prepared slowly sprays into, and makes 0.5mm～1.2mm enteric coated micropill;
8, fill capsule behind the enteric coated micropill mensuration content.
Preparation Example 6:18-β diammonium glycyrrhizinate enteric coated micropill sheet
Core formulation:
1000 consumptions of component title (g)
18-β diammonium glycyrrhizinate 50 is (with C
42H
68N
2O
16Meter)
Phosphatidic acid 25
Lactose 15
Microcrystalline Cellulose (in add) 60
Low-substituted hydroxypropyl cellulose 15
N-butyl alcohol is an amount of
25% alcohol-water solution is an amount of
Microcrystalline Cellulose (adding) 120
Magnesium stearate 3
The prescription of enteric coating liquid:
The per 1000 gram granule consumptions (g) of component title
Opadry (ACRYC-EZE MP) 300
Water 2000
Production technology:
1, recipe quantity 18-β diammonium glycyrrhizinate and phosphatidic acid are dissolved in behind the n-butyl alcohol (can drip in case of necessity a small amount of water and make dissolving) thoroughly evaporate to dryness n-butyl alcohol, obtain the complex of 18-β diammonium glycyrrhizinate and phosphatidic acid;
2, with the lactose of resulting complex, recipe quantity in the item 1, microcrystalline Cellulose (in add), that low-substituted hydroxypropyl cellulose is all pulverized rear mistake 80 mesh sieves is for subsequent use;
3, with resulting described complex, lactose, microcrystalline Cellulose (in add), low-substituted hydroxypropyl cellulose mix homogeneously behind crushing screening in the item 2, with 25% alcohol-water solution soft material processed, extrude and round as a ball one-tenth pastille micropill with the 0.6mm screen cloth;
4, micropill is dry in 40 ℃ of fluid beds;
5, by recipe quantity Opadry is added in the suitable quantity of water, be mixed with coating solution;
6, in fluid bed, the coating solution that item 5 is prepared slowly sprays into, and makes diameter 0.5mm～1.5mm enteric coated micropill;
7, enteric coated micropill is measured content after with the microcrystalline Cellulose (adding) of recipe quantity and magnesium stearate mix homogeneously, tabletting and get final product.
Preparation Example 7:18-α glycyrrhizic acid calcium enteric-coated pellet capsule
The micropill prescription:
Component title 1000 capsules consumptions (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 an amount of
The prescription of enteric coating liquid:
The per 1000 gram micropill consumptions (g) of component title
Strange (EUDRAGIT) (L30D-55) 1000 especially
Water 1000
Adopt the production technology described in the Preparation Example 1, use the various components of the recipe quantity described in the above-mentioned prescription to prepare diameter 0.5mm～1.2mm enteric coated micropill, then measure fill capsule behind the medicament contg of enteric coated micropill.
Preparation Example 8:18-α glycyrrhizic acid magnesium enteric coated micropill
The micropill prescription:
Component title 1000 capsules consumptions (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 an amount of
The prescription of enteric coating liquid:
The per 1000 gram micropill consumptions (g) of component title
Strange (EUDRAGIT) (L30D-55) 1000 especially
Water 1000
Except using polyvinylpyrrolidone to replace soybean lecithin as the intestinal absorption promoter, adopt the production technology described in the Preparation Example 1, use the various components of the recipe quantity described in the above-mentioned prescription to prepare the enteric coated micropill of diameter 0.5mm～1.2mm, then measure fill capsule behind the medicament contg of enteric coated micropill
Preparation Example 9:18-α diammonium glycyrrhizinate enteric coated particles
The granule prescription:
Component title 1000 capsules consumptions (g)
Diammonium Glycyrrihizinate 50 is (with C
42H
68N
2O
16Meter)
Sodium lauryl sulphate 3
Lactose 65
Low-substituted hydroxypropyl cellulose 5
The 3%HPMC aqueous solution is an amount of
The prescription of enteric coating liquid:
The per 1000 gram granule consumptions (g) of component title
Opadry (ACRYC-EZE MP) 300
Water 2000
Production technology:
1, with behind recipe quantity Diammonium Glycyrrihizinate and the sodium lauryl sulphate mix homogeneously again with other component mix homogeneously described in the granule of the recipe quantity prescription.With 3%HPMC aqueous solution soft material processed, 18 mesh sieves are granulated.
2, granule is dry in 50 ℃ of fluid beds, after removing fine grained, 40 mesh sieves put into fluid bed with crossing behind the 20 mesh sieve granulate;
3, by recipe quantity Opadry is added in the suitable quantity of water, be mixed with coating solution;
4, in fluid bed, the coating solution that item 3 is prepared slowly sprays into, and makes the enteric coated particles of diameter 0.5mm～2.0mm;
7, the enteric coated particles conventional capsule of packing into, and get final product.
Preparation Example 10:18-α glycyrrhizic acid enteric coated particles
The granule prescription:
Component title 1000 capsules consumptions (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 per 1000 gram granule consumptions (g) of component title
Opadry (ACRYC-EZE MP) 300
Water 2000
Except using carbomer to replace sodium lauryl sulphate as the intestinal absorption promoter, adopt the production technology described in the Preparation Example 12, use the various components of the recipe quantity described in the above-mentioned prescription to prepare diameter 0.5mm～2.0mm enteric coated particles, the conventional capsule of then enteric coated particles being packed into.
Preparation Example 11:18-α disodium glycyrrhizinate enteric coated micropill
The micropill prescription:
Component title 1000 capsules consumptions (g)
18-α disodium glycyrrhizinate 50 (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
The 3%HPMC aqueous solution is an amount of
The prescription of enteric coating liquid:
The per 1000 gram micropill consumptions (g) of component title
Strange (EUDRAGIT) (L30D-55) 1000 especially
Water 1000
Except using deoxycholic acid to replace soybean lecithin as the intestinal absorption promoter, adopt the production technology described in the Preparation Example 1, use the various components of the recipe quantity described in the above-mentioned prescription to prepare diameter 0.5mm～1.2mm enteric coated micropill, then enteric coated micropill is incapsulated and get final product.
Zoopery example: the oral relative bioavailability of 18-α glycyrrhizic acid magnesium enteric-coated pellet capsule in the Beagle dog
Illustrate that below by zoopery 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, treatment chronic viral hepatitis evident in efficacy, and improve the pharmaceutical preparation of abnormal liver function.
Illustrate that simultaneously glycyrrhizic acid among the present invention or the enteric-coated medicament combination of its salt compare with the common enteric coated capsule of glycyrrhizic acid or its salt, bioavailability is significantly improved.
This research is based upon on the basis of 18-α glycyrrhizic acid magnesium in the HPLC-UV method detection Beagle dog plasma, observe the development of the oral Jiangsu Zhengda Tianqing Drug Industry Co., Ltd of Beagle dog 18-α glycyrrhizic acid magnesium enteric-coated pellet capsule blood drug level through the time process, calculate corresponding pharmacokinetic parameter, and take common enteric coated capsule as 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 contains magnesium isoglycyrrhetate 50mg, and prepares 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 were prepared into complex by weight 1: 1, add microcrystalline Cellulose and Pulvis Talci as adjuvant, use enteric capsule shell, be prepared into according to a conventional method common enteric coated capsule) every contain magnesium isoglycyrrhetate 50mg.
Experimental animal: Beagle dog, 11.7 ± 1.2kg, ♀
Half and half, totally 6.Provided by Animal Experimental Study center, Yadong, Nanjing.
2, detection method:
18-α glycyrrhizic acid magnesium adopts the HPLC-UV method to measure in this test, and this analytical method specificity is strong, and sensitive, reliable, and the range of linearity is wide, can satisfy the analysis requirement of biological sample in the research fully.
3, test method:
6 of Beagle dogs are bought back and are divided at random 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, 3 every group after raising for 1 week.Consider that the preparation specification that this institute is used is the 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 each 8 of oral test preparation and reference preparations.A dog test day fasting be can't help water 12 hours, and venous blood sampling 2～2.5ml is in the anticoagulant heparin pipe.Get behind the blood with dog by arrange dosage respectively per os gavage oral test preparation and reference preparation, and in adopting during in different time points same procedure to get blood after the administration, the blood that gathers with the centrifugal 10min of 3000r/min, is got upper plasma 1ml and put in the EP pipe, and-20 ℃ of preservations are to be measured.Take out plasma sample during mensuration, process after thawing, and detect the concentration of magnesium isoglycyrrhetate in the blood plasma.
Cleaned after date in 10 days, 18-α glycyrrhizic acid magnesium enteric-coated pellet capsule 32mg/kg group and the common enteric coated capsule group of 18-α glycyrrhizic acid magnesium 32mg/kg treated animal intersect, and ditto method administration, get blood, mensuration.
Calculate relevant medicine for parameter, estimate the Pharmacokinetic Characteristics of 18-α glycyrrhizic acid magnesium enteric-coated pellet capsule, and calculate its relative bioavailability.
4, result of the test:
Beagle dog respectively both results behind single oral enteric-coated pellet capsule and the common enteric coated capsule relatively shows, take the common enteric coated capsule of 18-α glycyrrhizic acid magnesium as reference preparation, the relative bioavailability of the oral 18-α of Beagle dog glycyrrhizic acid magnesium enteric-coated pellet capsule is 211%.Result of the test sees Table 1.
The main pharmacokinetic parameter of table 1 magnesium isoglycyrrhetate in the Beagle dog relatively reaches relative bioavailability (Mean ± SD, n=6)
Both AUC
0-TShow utmost point significant difference (P＜0.001) with Cmax through two one-side t checks.
The oral bioavailability of 18-α glycyrrhizic acid magnesium enteric-coated pellet capsule Beagle dog obviously is 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
With 18-α glycyrrhizic acid magnesium enteric-coated pellet capsule (lot number: 050516,050518,050522) press commercially available back (adopting the hard sheet packing of aluminium foil and PVC) respectively at accelerated test under the condition of 40 ℃ ± 2 ℃ of temperature, relative humidity 75% ± 5% 6 months (sampling in 1,2,3,6 month); In 25 ℃ ± 2 ℃ of temperature, 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 the capsule, measure related substance, release and content, and with the analytical data of 0 month sample relatively, indices is showed no significant change.Result of the test sees 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 test
Instrument: ZRS-8G intelligence digestion instrument (Tianjin radio factory)
High performance liquid chromatograph (Japanese Shimadzu company)
Method: get this product, according to drug release determination method (two appendix XD the second methods of Chinese Pharmacopoeia version in 2005), adopt the basket method (two appendix X of Chinese Pharmacopoeia version in 2005 C first method) that turns.Release medium in the acid: 0.1mol/L hydrochloric acid 750ml; Release medium in the 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 Chinese medicine content, draws the Cumulative release amount curve, the results are shown in Table 4 and accompanying drawing 1.
Table 4: Cumulative release amount result
Coating weightening finish experimental example
Method: take the preparation method of Preparation Example 1 as the basis, by changing the weight ratio of content and coating, obtain the sample of different coating weightening finishes, measure disintegration (use Chinese Pharmacopoeia 2005 editions appendix X A the 3rd subtraction unit) and release (2005 editions appendix XD of Chinese Pharmacopoeia the second method method 1) again and compare, result of the test sees Table 5:
Table 5. coating weight increment test result
As can be known from Table 5, weightening finish is controlled rationally and effectively to coating, can guarantee that not only enteric coated micropill discharges hardly in gastric juice, and can guarantee the fast disintegrate and discharging fully in intestinal of this enteric coated micropill, improve the bioavailability of medicine, satisfy the requirement of pharmaceutical composition of the present invention.
Claims (5)
1. pharmaceutical composition, it is characterized in that: compositions is composed of multiple units, each unit comprises the enteric coating of content and the described content of parcel, and wherein said content contains glycyrrhizic acid magnesium salt, intestinal absorption promoter, ethanol, polyethylene glycol 6000, Pulvis Talci; Described enteric coating is made by Opadry and water;
Wherein said intestinal absorption promoter is soybean lecithin, and the phosphatide complexes of glycyrrhizic acid magnesium salt and soybean lecithin formation;
Wherein the glycyrrhizic acid magnesium salt is 18-α glycyrrhizic acid magnesium salt;
Contain glycyrrhizic acid magnesium salt 50mg, soybean lecithin 50mg, polyethylene glycol 6000 0.16mg, Pulvis Talci 5mg, Opadry 300mg in the described pharmaceutical composition.
2. compositions claimed in claim 1, wherein the diameter of each unit is between 0.5mm～1.5mm.
3. compositions claimed in claim 2, wherein the diameter of each unit is between 0.7mm～1.2mm.
4. compositions claimed in claim 1, wherein said compositions prescription is for being suitable for oral administered dosage form.
5. compositions claimed in claim 4, wherein said oral administration type is capsule or tablet.
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| 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 |
| 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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| 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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| CN1284786C (en) * | 2004-06-23 | 2006-11-15 | 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 |
| CN1586490A (en) * | 2004-07-14 | 2005-03-02 | 李�杰 | Compound glycyrrhizunate tablet and its preparing method |
| CN1586489A (en) * | 2004-07-14 | 2005-03-02 | 李�杰 | Compound glycyrrhizunate capsule and particles and the preparing method |
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| Title |
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| 王佩等.异甘草酸镁对大鼠四氯化碳慢性肝损伤的治疗作用.《中国新药与临床杂志》.2004,第23卷(第12期),833页. * |
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| CN102008492A (en) | 2011-04-13 |
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