WO2008083561A1

WO2008083561A1 - Oral pharmaceutical composition of glycyrrhizin or its salts and the preparation method thereof

Info

Publication number: WO2008083561A1
Application number: PCT/CN2007/003950
Authority: WO
Inventors: Ping Dong; Cheng Zuo; Chunguang Xia
Original assignee: Jiangsu Chiatai Tianqing Pharmaceutical Co., Ltd.
Priority date: 2006-12-29
Filing date: 2007-12-29
Publication date: 2008-07-17
Also published as: CN102008492A; CN102008492B; HK1151466A1; CN101600439B; CN101600439A

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

Oral pharmaceutical composition of glycyrrhizic acid or salt thereof and preparation method thereof

Technical field

The present invention relates to an oral pharmaceutical composition of glycyrrhizic acid or a salt thereof and a process for the preparation thereof, specifically, an oral enteric pharmaceutical composition containing glycyrrhizic acid or a salt thereof. Background technique

Glycyrrhiza is a commonly used medicinal plant whose main active ingredient is a glycyrrhizic acid shield, namely glycyrrhizic acid in the 18-β configuration and glycyrrhizic acid (also known as isoglycyrrhizic acid) in the 18-α configuration. . Pharmacological, biochemical and structure-activity relationship analysis studies have shown that glycyrrhizic acid or its salt has a strong anti-inflammatory, protective effect on liver cells and an improvement in liver function (see Chinese Patent Publication No. CN1381462A and CN1569005A).

At present, all oral preparations of glycyrrhizic acid or its salt have the problem of low oral bioavailability, because glycyrrhizic acid or its salt is a highly polar, hydrophilic macromolecular substance, which is poorly absorbed in the gastrointestinal tract, and Glycyrrhizic acid or a salt thereof easily forms a molecular polymer in an acidic environment in the stomach. Therefore, it is urgent to develop a glycyrrhizic oral preparation having high bioavailability.

The Chinese Patent Application Publication No. WO1569005A discloses an enteric preparation of glycyrrhizic acid and a salt thereof, and the use of an enteric preparation forms a problem in which a glycyrrhizic acid preparation forms a polymer in the stomach.

Chinese Patent Application Publication No. CN1594332A discloses a phospholipid complex of glycyrrhizic acid and a salt thereof, which combines glycyrrhizic acid with a phospholipid to promote in vivo absorption of glycyrrhizic acid.

Both of the above patent documents provide a method for improving the bioavailability of glycyrrhizic oral preparations, but the bioavailability of glycyrrhizic oral preparations still does not achieve the desired effects. The inventors believe that at least the following two reasons affect the above-mentioned improved glycyrrhizic acid oral preparations to exert pharmacological effects: First, glycyrrhizic acid consisting of a single-dose one-release unit prepared from an enteric coating or an intestinal sol-shell The enteric preparation of the salt is difficult to ensure the enteric solubility of the preparation. Once the intestinal sol or enteric coating breaks under the strong pressure of gastric peristalsis, the enteric properties of the entire formulation will be completely lost.

Second, after the enteric preparation of glycyrrhizic acid or a salt thereof prepared by the intestinal sol shell enters the intestinal tract, the drug is concentrated in the small intestine. The phospholipid complex of glycyrrhizic acid or its salt can easily form a gel-like mass in the intestinal fluid environment, affecting the full contact of the drug and the small intestinal wall and ultimately affecting the absorption of the drug. At the same time, the absorption of glycyrrhizic acid in the small intestine may be related to the carrier, there is saturation, when the drug is released intensively The resulting absorbance will be much lower than the absorbance obtained when the drug is uniformly dispersed.

The inventors have unexpectedly found that the oral enteric pharmaceutical composition of glycyrrhizic acid or a salt thereof of the present invention solves the above-mentioned defects in the licorice preparation by an appropriate preparation form, and solves the problem of low bioavailability. Summary of the invention

One aspect of the present invention is to provide an oral enteric pharmaceutical composition of glycyrrhizic acid or a salt thereof.

The oral enteric pharmaceutical composition of the glycyrrhizic acid or a salt thereof according to the present invention is a dose-dispersed preparation comprising a plurality of units, each unit comprising a content and an enteric coating composition encapsulating the content, The contents may be in the form of pellets or granules, preferably pellets, and the contents contain glycyrrhizic acid or a salt thereof, which is isolated from the environment by an enteric coating layer.

The orally enteric pharmaceutical composition of glycyrrhizic acid or a salt thereof according to the present invention, wherein the weight ratio of the content to the enteric coating is 1: 0.15 to 0.45, preferably 1:0.2 to 0.4, more preferably 1:0.25 to 0.35.

Oral enteric pharmaceutical composition of glycyrrhizic acid or a salt thereof according to the present invention, wherein the maximum diameter of each unit is not more than 2 mm, preferably 0.5 nm! Between 1.5 mm, more preferably between 0.7 mm and 1.2 mm. A plurality of the units constitute the composition of the present invention, each composition containing 1-500 mg of glycyrrhizic acid or a salt thereof, preferably 25-150 mg of glycyrrhizic acid or a salt thereof, more preferably 40-100 mg of glycyrrhizic acid or a salt thereof .

The enteric coating material of the present invention is selected from conventional enteric coating materials suitable for coating pills or granules, such as: cellulose acetate phthalate, shellac, acrylic or hypromellose. As the phthalate ester or the like, an acrylic resin enteric coating material is preferred.

The content of the present invention contains glycyrrhizic acid or a salt thereof and at least one intestinal absorption enhancer, and the intestinal absorption enhancer refers to enhancing intestinal permeability of the drug, promoting drug absorption, and improving bioavailability of the drug. substance.

The intestinal absorption enhancer used in the present invention may be any intestinal absorption enhancer which is pharmaceutically suitable for oral use, including but not limited to: phospholipids; chitosan and its derivatives, polyvinylpyrrolidone, carbomer, etc. Affinity polymer; amino acid derivative; natural bile, deoxycholic acid, sodium deoxycholate, sodium glycocholate, sodium taurocholate and other cholic acid shields and salts thereof; sodium octanoate, strontium Fatty acids and salts thereof such as sodium, sodium laurate and sodium oleate; surfactants such as sodium lauryl sulfate, polyoxyethylene ethers, esters, sorbitan esters and the like. Among them, the preferred intestinal absorption enhancer is Phospholipids. A more preferred embodiment is that the content of the present invention contains a phospholipid complex of glycyrrhizic acid or a salt thereof prepared from glycyrrhizic acid or a salt thereof and an anthraquinone substance. The phospholipid complex of glycyrrhizic acid or a salt thereof is formed by complexing glycyrrhizic acid or a salt thereof and a phospholipid substance, wherein a weight ratio of glycyrrhizic acid or a salt thereof to a phospholipid substance is 1:0.3-2, and a preferred weight ratio It is 1:0.5~1.5.

The glycyrrhizic acid or a salt thereof according to the present invention may be 18-α glycyrrhizic acid or a salt thereof, or may be 18-β glycyrrhizic acid or a salt thereof, preferably 18-α glycyrrhizic acid or a salt thereof.

The glycyrrhizinate of the present invention includes, but is not limited to, an ammonium salt, a magnesium salt, a sodium salt, a potassium salt, a zinc salt, a calcium salt, a barium salt or a silver salt of glycyrrhizic acid, preferably a magnesium salt and an ammonium salt of glycyrrhizic acid. Most preferred is the magnesium salt of glycyrrhizic acid.

The phospholipid substance according to the present invention is a lecithin-based shield, a cephalin-based substance, an inositol phospholipid substance or a phosphatidic acid substance, preferably a lecithin-based substance, more preferably a polyene phosphatidylcholine or a phosphatidylcholine. .

In addition to glycyrrhizic acid or a salt thereof and at least one intestinal absorption enhancer, the contents may further contain other intestinal absorption enhancers and other conventional excipients. The excipient may be a blank pellet core, a filler (diluent), a wetting agent, a binder, a disintegrant, a lubricant, a glidant, and the like.

The blank pellet core is a carrier of the pellets, but the present invention has no special requirement for the selected blank pellet core, as long as it does not react with the active ingredient and other auxiliary materials, does not affect the detection of the active component, and has a round shape and is easy to carry out the pellet. The core medicine can be used.

The filler (diluent) is an auxiliary material required for preparing the drug-containing pellets or granules, and the filler selected in the invention may be selected from the group consisting of starch, pregelatinized starch, dextrin, microcrystalline cellulose, lactose, sucrose, One or more of glucose, mannitol, sorbitol, xylitol, dextran, fructose, calcium sulfate, calcium hydrogen phosphate, calcium phosphate, carbonic acid, and micronized silica gel.

Wetting agents suitable for use in the present invention may be distilled water, absolute ethanol or aqueous solutions of various concentrations. Suitable binders for use in the present invention are selected from the group consisting of mercaptocellulose, ethylcellulose, polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, hydroxypropylcellulose, sucrose, sucrose One or more of starch syrup, gelatin, and gum arabic.

The disintegrant is a substance or a mixture of the substances which facilitates the disintegration and dissolution of the composition in the intestinal tract in the present invention, and the disintegrant is selected from the group consisting of starch, sodium carboxymethyl starch, and croscarmylmethyl. One or more of cellulose sodium, crosslinked hydroxypropyl ketone cellulose, crospovidone, and low-substituted hydroxypropyl cellulose. The lubricant and glidant are selected from the group consisting of talc, magnesium stearate, calcium stearate, zinc stearate, liquid paraffin, polyethylene glycol, magnesium lauryl sulfate, sodium lauryl sulfate. One or more of long-chain fatty acids, stearic acid, micronized silica gel, and hydrogenated vegetable oil.

In addition, other commonly used additives such as coloring agents, fragrances, flavoring agents, and antioxidants may be used as necessary.

The orally enteric pharmaceutical composition of the glycyrrhizic acid or a salt thereof according to the present invention may be formulated into a form suitable for oral administration such as capsules, tablets and granules and the like. The capsule may be in the form of any capsule other than the intestinal sol shell; the tablet may or may not be coated, and the coating layer may be in any coating form other than the enteric coating. Each capsule or tablet contains 25-150 mg, preferably 40-100 mg of glycyrrhizic acid or a salt thereof, and the orally enteric pharmaceutical composition of the glycyrrhizic acid of the present invention or a salt thereof is preferably administered after being filled into a common capsule.

Another aspect of the present invention is a method for producing an oral enteric pharmaceutical composition which provides glycyrrhizic acid or a salt thereof.

According to a specific embodiment of the production method of the present invention, the orally enteric pharmaceutical composition of glycyrrhizic acid or a salt thereof is obtained by the following steps:

First, glycyrrhizic acid or a salt thereof and an intestinal absorption enhancer and/or other excipients are prepared into pellets or granules in a conventional manner; and then the obtained pellets or granules are enteric coated with an enteric coating material to obtain Composition unit; a plurality of the composition units are mixed to constitute the composition.

In a preferred embodiment of the present invention, first, glycyrrhizic acid or a salt thereof and a phospholipid substance are compounded to obtain a phospholipid complex of glycyrrhizic acid or a salt thereof; and then the phospholipid complex of glycyrrhizic acid or a salt thereof is combined with or The other excipients are prepared into pellets or granules; the obtained pellets or granules are then enteric coated with an enteric coating material to obtain a composition unit; finally, a plurality of the composition units are mixed to constitute the invention. combination.

In the preparation method of the present invention, the weight ratio of the obtained pellets or granules to the enteric coating material is 1:0.15-1:0.45, preferably 1:0.2-1:0.4, more preferably 1:0.25. -1: 0.35.

In a preferred embodiment of the present invention, glycyrrhizic acid or a salt thereof and a phospholipid substance are compounded at a weight ratio of 1:0.3 to 2, preferably a weight ratio of 1:0.5-1.5.

The process for preparing the drug-containing pellets may employ an extrusion spheronization process, a pan-pill process, and a pellet core process. Preferably, the drug-containing pellets are prepared by a pellet core drug process.

Another aspect of the present invention is to provide a method of treating hepatitis comprising the licorice of the present invention An oral enteric pharmaceutical composition of an acid or a salt thereof is administered to an individual in need of such treatment. Another aspect of the present invention is to provide a method for improving abnormal liver function in an individual comprising administering to the individual an oral enteric pharmaceutical composition of glycyrrhizic acid or a salt thereof according to the present invention.

A further aspect of the invention is the use of an oral enteric drug composition for providing glycyrrhizic acid or a salt thereof according to the invention for the preparation of a medicament for the treatment of hepatitis.

A further aspect of the present invention provides a use of an oral enteric drug composition for providing glycyrrhizic acid or a salt thereof according to the present invention for the preparation of a medicament for improving liver function abnormality.

In the oral enteric pharmaceutical composition of the present invention, the glycyrrhizic acid or a salt thereof is administered simultaneously with the intestinal absorption enhancer, thereby improving the bioavailability of the drug, especially by combining glycyrrhizic acid or a salt thereof with the phospholipid substance. The phospholipid complex prepared as glycyrrhizic acid or a salt thereof improves the hydrophilicity and lipophilicity of glycyrrhizic acid or a salt thereof, thereby promoting the absorption of the active ingredient in the intestinal tract.

In addition, the medicament is made into a dose-dispersible enteric preparation, each preparation consists of a plurality of units, and the quality of the unit, such as the particle size, the weight ratio of the contents and the enteric coating, is controlled to further improve the drug. bioavailability. By controlling the particle size of the enteric pellets, the drug is uniformly dispersed into the intestinal tract, and the contact area between the drug and the intestine is enlarged, so that the drug is uniformly dispersed and fully contacted with the small intestine wall, and it is difficult to form a gel-like mass forming adhesion. , thereby promoting the absorption of drugs. By effectively controlling the weight ratio of the contents to the enteric coating, it is possible to prevent the enteric coating of the enteric pellets from rupturing under the strong pressure of gastric peristalsis, thereby causing the glycyrrhizic acid or its salt to form a polymer in a gastric acid environment. It is also possible to ensure that the drug in the form of enteric pellets is rapidly released completely in the intestinal tract. Alternatively, the rate of drug release in the intestinal tract can be controlled by controlling the weight ratio of the contents to the enteric coating.

Glycyrrhizic acid or its salt is absorbed reliably, smoothly and effectively in the intestine, which not only improves the bioavailability of glycyrrhizic acid or its salt, but also improves the efficacy of oral preparation of glycyrrhizic acid or its salt, and reduces its adverse reactions. The medication is safe and convenient. DRAWINGS

Fig. 1 is a graph showing the in vitro release rate of 18-α-Glycyrrhizic acid enteric pellets prepared in Example 1. detailed description

The following examples are intended to further illustrate the invention and are not intended to limit the invention in any way. Preparation example

Preparation Example 1 : 18-α magnesium glycyrrhizinate (magnesium isoglycyrrhizinate) enteric pellets capsule

Pill prescription:

Component name 1000 capsules (g)

18-α magnesium glycyrrhizinate 50 (calculated as C ₄₂ H ₆₀ MgO ₁₆ ) medicinal blank pellet core (sucrose type) 100

Soy lecithin 50

Polyethylene glycol 6000 0.16

Talc

Ethanol

Formulation of enteric coating solution:

Production and production craftsmanship::

11. After the prescription amount 1188--αα glycyrrhizic acid magnesium magnesium and the large soybean egg egg phospholipid fat are dissolved in the ethyl alcohol alcohol (the necessary time can be added dropwise Adding a small amount of water to dissolve the solution)) Evaporating dry ethyl alcohol, and obtaining a complex of 1188--αα glycyrrhizic acid magnesium magnesium and large soybean egg egg phospholipid Object;

22. The component obtained by the item 11 is dispersed and dispersed in distilled distilled water and added to the prescription amount of polyethylene polyethylene. Alcohol 66000000 and the slip talc powder powder, stir and mix evenly;

33. According to the prescription of the prescription, put the empty blank white micro-pill pill core ((cane sugar type)) into the inflow fluidized bed, and the item 22 will be The mixed suspension liquid obtained by the middle middle is slowly sprayed into the mixture, and is prepared into a micro-pill containing a drug-containing medicine;

44. According to the prescription, the Ou Baba will be added to the appropriate amount of water, and formulated into a coating liquid;

55. In the fluidized bed, the liquid of the coating and clothing prepared by the item 44 is slowly sprayed into the straight diameter diameter. 00..55mmmm~~..22mmmm intestinal enteric micro-pill pills;;

66, Intestinal dissolution of micro-pill pills to determine the content of the content after the filling and filling of plastic bottles. . Preparation of the preparation example 22:: 1188--αα glycyrrhizic acid diammonium ammonium enteric solution ίί敖敖 pill capsule

Prescription side of the pill::

Group component name 18-α-diammonium glycyrrhizinate 50 (based on C ₄₂ H ₆₈ N ₂ 0 ₁₆ ) polyene phosphatidylcholine 25

Microcrystalline cellulose 100

Low substituted hydroxypropyl cellulose 100

Talc 37.5

Ethanol

15% alcohol solution

Formulation of enteric coating solution:

Component name Per 1000 g of pellets (g) Opadry (ACRYC-EZE MP) 300

Water 2000

Production Process:

1. After dissolving the prescription amount of diammonium glycyrrhizinate and polyene phosphatidylcholine in ethanol (if necessary, a small amount of water may be added to dissolve), the ethanol is evaporated to obtain 18-α-ammonium glycyrrhizinate and polyene phosphate. a complex of choline;

2. The composite obtained in item 1, the prescribed amount of microcrystalline cellulose, low-substituted hydroxypropylcellulose, and talc powder are pulverized and passed through an 80-mesh sieve for use;

3. The pulverized sieved composite obtained in Item 2, microcrystalline cellulose, low-substituted hydroxypropylcellulose, and talc powder are uniformly mixed, and soft material is made of 15% alcohol aqueous solution, and 0.6 mm is used. The screen is extruded and rolled into a drug-containing pellet;

4. The drug-containing pellets are dried in a fluidized bed at 40 ° C;

5. Add Opadry to an appropriate amount of water according to the amount of the prescription, and prepare it as a coating liquid;

6. In the fluidized bed, the coating liquid prepared in item 5 is slowly sprayed into the intestines: pill having a diameter of 0.5 mm to 1.2 mm;

7. The enteric pellets were filled with the capsule after the content was determined; Preparation Example 3: 18-β-di-glycyrrhizinate enteric-coated pellets

Pill prescription:

Component name 1000 capsules (g)

18-β dipotassium glycyrrhizinate 100 (calculated as C ₄₂ H ₆ .K ₂ 0 ₁₆ ) To 30

Lactose 30

Microcrystalline cellulose 100

Low substituted hydroxypropyl cellulose 5

Talc 10

Ethanol

30% alcohol solution

Formulation of enteric coating solution:

Component name Per 1000 g of pellets (g) EUDRAGIT (L 100-55) 300

Water 2000

The enteric pellets having a diameter of 0.5 mm to 1.5 mm were prepared by using the various components described in the above prescription using the production process described in Preparation Example 2, and then the drug content of the enteric pellets was measured and then poured. Packed with plastic bottles. Preparation Example 4: 18-β zinc glycyrrhizinate enteric pellets capsule

Pill prescription:

Component name 1000 capsules (g) 18-β zinc glycyrrhizinate 50 (calculated as C ₄₂ H ₆₍₎ Zn0 ₁₆ ) Pharmaceutical blank pellet core (sucrose type) 110

Phosphatidylcholine 100

Polyethylene glycol 6000 0.22

Talc powder 8

Ethanol

Formulation of enteric coating solution:

Component name Per 1000 g of pellets (g) Opadry (ACRYC-EZE MP) 300

Water 2000 Using the production process described in Preparation Example 1, an enteric pellet having a diameter of 0.5 mm to 1.2 mm was prepared using various components of the prescribed amount described in the above prescription, and then the drug content of the enteric pellet was measured and then filled. Plastic bottles. Preparation Example 5: 18-α glycyrrhizic acid enteric pellets capsule

^: Pill prescription:

Component name 1000 capsules (g)

18- glycyrrhizic acid 50 (calculated as C ₄₂ H ₆₂ 0 ₁₆ )

Polyene phosphatidylcholine 75

Microcrystalline cellulose 100

Low substituted hydroxypropyl cellulose 100

Talc 37.5

Ethanol

15% alcohol solution

Formulation of enteric coating solution:

Component name Per 1000 g of pellets (g) Opadry (ACRYC-EZE MP) 300

Water 2000

Production Process:

1. Microcrystalline cellulose, low-substituted hydroxypropyl cellulose, and talc powder are pulverized and sieved through an 80-mesh sieve;

2. After the prescription amount of 18-α glycyrrhizic acid and polyene phosphatidylcholine is dissolved in ethanol (if necessary, a small amount of water may be added to dissolve), it is steamed to a relatively thin semi-solid;

3. Weigh the sieved microcrystalline cellulose, low-substituted hydroxypropyl cellulose and talc obtained in item 1 of the prescription and mix well;

4. Add the powder obtained in item 3 to the semi-solid obtained in item 2, stir and mix well, make soft material (if necessary, add 15% alcohol aqueous solution to wet), extrude with 0.6mm sieve and Rolling into drug-containing pellets;

5. The drug-containing pellets are dried in a fluidized bed at 40 ° C;

6. Add Opadry to an appropriate amount of water according to the amount of the prescription, and prepare it into a coating liquid; 7. In the fluidized bed, slowly spray the coating liquid prepared in Item 6 to make 0.5mn! ~ 1.2mm enteric pellets;

8. The enteric pellets are filled with capsules after the content is determined. Preparation Example 6: 18-β glycyrrhizic acid according to enteric pellets

Core prescription:

Component name 1000 tablets (g)

18-β-diammonium glycyrrhizinate 50 (with C ₄₂ H ₆₈ N ₂ 0 ₁₆

Phosphatidic acid 25

Lactose 15

Microcrystalline cellulose (within) 60

Low substituted hydroxypropyl cellulose 15

N-butanol

25% alcohol solution

Microcrystalline cellulose (plus) 120

Magnesium stearate 3

Formulation of enteric coating solution:

Component name Per 1000 g of pellets (g) Opadry (ACRYC-EZE MP) 300

Water 2000

Production Process:

1. After the prescription amount of 18-β diammonium glycyrrhizinate and phosphatidic acid are dissolved in n-butanol (a small amount of water may be added to dissolve if necessary), n-butanol is completely evaporated to obtain 18-β diammonium glycyrrhizinate and phosphatidic acid. Complex

2. The compound obtained in item 1, the prescription amount of lactose, microcrystalline cellulose (additional), and low-substituted hydroxypropyl cellulose are pulverized and passed through an 80 mesh sieve for use;

3. The pulverized sieved composite obtained in Item 2, lactose, microcrystalline cellulose (additional), and low-substituted hydroxypropylcellulose are uniformly mixed, and a soft material is prepared using a 25% alcohol aqueous solution. Extrusion and rounding into a drug-containing pellet with a 0.6 mm sieve;

4. Dry the pellets in a fluidized bed at 40 °C;

5. Add Opadry to an appropriate amount of water according to the amount of the prescription, and prepare it as a coating liquid; 6. In the fluidized bed, slowly spray the coating liquid prepared in item 5 into the diameter.

0.5mm~l .5mm enteric solution ^ [effect pills;

7. The enteric pellets are mixed with the prescribed amount of microcrystalline cellulose (plus) and magnesium stearate to determine the content, which is obtained by tableting. Preparation Example 7: 18-α-Glycyrrhizic Acid Enteric Pellets

Pill prescription:

Component name 1000 capsules (g)

18-α calcium glycyrrhizinate 50 (calculated as C ₄₂ H ₆₍₎ Ca0 ₁₆ ) medicinal blank pellet core 100

Inositol phospholipid 50

Polyethylene glycol 6000 0.16

Talc

N-butanol

Formulation of enteric coating solution:

Component name per 1000g pellets (g) Eudragit (L30D_ ⁵⁵ ) 1000

Water 1000

Using the production process described in Preparation Example 1, an enteric pellet having a diameter of 0.5 mm to 1.2 mm was prepared using various components of the prescribed amount described in the above prescription, and then the drug content of the enteric pellet was measured and then filled. Plastic bottles. Preparation Example 8: 18-o magnesium glycinate powder enteric pellets

Pill prescription:

Component name 1000 capsules (g)

18- Magnesium glycyrrhizinate 50 (calculated as C ₄₂ H ₆ .Mg0 ₁₆ ) Medicinal blank pellet core (sucrose type) 100

Polyvinylpyrrolidone 50

Polyethylene glycol 6000 0.50

Talc 9 03950 Anhydrous ethanol

Formulation of enteric coating solution:

Component name Per 1000 g of pellets (g) EUDRAGIT (L30D-55) 1000

Water 1000

In addition to the use of polyvinylpyrrolidone instead of soy lecithin as an intestinal absorption enhancer, the production process described in Preparation Example 1 was used to prepare a diameter of 0.5 nm using various components of the prescribed amounts described in the above prescription! ~ 1.2mm enteric pellets, then the drug content of the enteric pellets is determined and then filled with capsules. Preparation Example 9: 18-α-diammonium glycyrrhizinate enteric-coated pellets

Particle prescription:

Component name 1000 capsules (g)

18- Diammonium glycyrrhizinate 50 (calculated as C ₄₂ H ₆₈ N ₂ 0 ₁₆ ) sodium dodecyl citrate 3

Lactose 65

Microcrystalline cellulose 80

Low substituted hydroxypropyl cellulose

3% HPMC aqueous solution

Formulation of enteric coating solution:

Component name Per 1000 g of pellets (g) Opadry (ACRYC-EZE MP) 300

Water 2000

Production Process:

1. Mix the prescription amount of 18-α-diammonium glycyrrhizinate and sodium lauryl sulfate, and then mix with other components mentioned in the prescription of the prescription. The soft material was made of 3% HPMC aqueous solution, and sieved by 18 mesh sieve.

2. The granules are dried in a fluidized bed at 50 ° C, sieved with a 20 mesh sieve, and passed through a 40 mesh sieve to remove fine particles and placed in a fluidized bed;

3. Add Opadry to an appropriate amount of water according to the amount of the prescription, and prepare it into a coating liquid; 7 003950

4. In the fluidized bed, the coating liquid prepared in item 3 is slowly sprayed into an enteric granule having a diameter of 0.5 mm to 2.0 mm;

7. The enteric granules are filled into ordinary capsules, which is obtained. Preparation Example 10: 18-α glycyrrhizic acid enteric granule

Particle prescription:

Component name 1000 capsules (g)

18- glycyrrhizic acid 50 (calculated as C ₄₂ H ₆₂ 0 ₁₆ ) Carbomer 4

Lactose 95

Microcrystalline cellulose 65

Ethanol

Formulation of enteric coating solution:

Component name Per 1000 g of pellets (g) Opadry (ACRYC-EZE MP) 300

Water 2000

In addition to the use of carbomer instead of sodium lauryl sulfate as an intestinal absorption enhancer, the production process described in Preparation Example 12 was used, and the diameter of 0.5 mn was prepared using the various components of the prescription described in the above prescription! ~ 2.0mm enteric granules, then the enteric granules are filled into common capsules. Preparation Example 11: 18-α-Glycyrrhizic acid disodium enteric^: pill

Pill prescription:

Ingredient name 1000 capsules (g) 18- Disodium glycyrrhizinate 50 (as C ₄₂ H ₆ .Na ₂ 0 ₁₆ ) Pharmaceutical blank pellet core (sucrose type) 100

Deoxycholic acid 10

Polyethylene glycol 6000 0.2

Talc powder 3

3% HPMC aqueous solution ·

Formulation of enteric coating solution: Component name per 1000g pellets (g) Eudragit (L30D-55) 1000

Water 1000

In addition to the use of deoxycholic acid instead of soy lecithin as an intestinal absorption enhancer, the production process described in Preparation Example 1 was used to prepare a diameter of 0.5 mm to 1.2 using the various components of the prescribed amount described in the above prescription. Mm enteric pellets, then enter the enteric ^: pill into the capsule. Animal Experimental Example: Oral relative bioavailability of 18-alpha magnesium glycyrrhizinate enteric pellets in Beagle dogs

The enteric drug composition of glycyrrhizic acid or a salt thereof according to the present invention is exemplified by an animal experiment as a pharmaceutical preparation for treating chronic viral hepatitis with a low toxic side effect and improving liver function abnormality.

Further, the enteric pharmaceutical composition of glycyrrhizic acid or a salt thereof of the present invention has a markedly improved bioavailability as compared with the conventional intestinal sol of glycyrrhizic acid or a salt thereof.

This study was based on the HPLC-UV method for the determination of 18-a magnesium glycyrrhizinate in Beagle dog plasma. The 18-α-Glycyrrhizic acid enteric pellets developed by Beagle Dog Oral Jiangsu Zhengda Tianqing Pharmaceutical Co., Ltd. were observed. The blood drug concentration of sputum was calculated over time, and the corresponding pharmacokinetic parameters were calculated. The relative bioavailability was calculated by using common intestinal sol was used as a reference preparation.

1. Test materials:

Test drug: 18-α magnesium glycyrrhizinate (referred to as magnesium isoglycyrrhizinate) enteric pellets capsule, each capsule contains 50 mg of magnesium isoglycyrrhizinate, and prepared according to the method in Example 1 of the present application; 18-α magnesium glycyrrhizinate common intestinal sol (in which 18-α-glycyrrhizinate and phosphatidylcholine are prepared into a complex at a weight ratio of 1:1, microcrystalline cellulose and talc are added as an auxiliary material, and the intestinal sol is used to prepare a common intestine according to a conventional method. Sol 嚢) contains 50 mg of magnesium isoglycyrrhizinate per capsule.

Test animals: Beagle dogs, 11.7 ± 1.2 kg, $ half, a total of 6. Provided by Nanjing Yadong Experimental Animal Research Center.

2, detection method:

In this test, 18-α-glycyrrhizinate was determined by HPLC-UV method. The analytical method is specific, sensitive, reliable, and has a wide linear range, which can fully meet the analytical requirements of biological samples in the study.

3. Test method: N2007/003950

Six Beagle dogs were randomly divided into 18-α-Glycyrrhizic acid enteric-coated pellets 32 mg/kg group and 18-α-glycyrrhizinate common intestinal sol-gel 32 mg/kg, 3 in each group. Considering the formulation used in this study is 50mg/particle, Beagle dogs with a body weight close to 12.5kg are selected. The doses of the two dogs in each group are 400mg, that is, 8 tablets of oral test preparation and reference preparation respectively. Dog test Day fasting can not help but water for 12 hours, intravenous blood 2 ~ 2.5ml in the heparin anticoagulation tube. After taking the blood, the dog was orally administered with the oral test preparation and the reference preparation according to the set dose, and the blood was taken by the same method at different time points after the administration, and the collected blood was centrifuged at 3000 r/min for 10 min. 1 ml of the upper plasma was placed in an EP tube and stored at -20 ° C for testing. Plasma samples were taken at the time of the measurement, thawed, and the concentration of magnesium isoglycyrrhizinate in the plasma was measured.

After the 10-day wash period, the 18-α-Glycyrrhizinate enteric-coated pellets 32 mg/kg group and the 18-α-glycyrrhizinate common intestinal sol-gel group 32 mg/kg group were crossed, and the same method was used to take blood. , measurement.

Calculate the relevant pharmacokinetic parameters, evaluate the pharmacokinetic characteristics of 18-alpha magnesium glycyrrhizinate enteric-coated pellets, and calculate their relative bioavailability.

4. Test results:

Comparison of the results of a single oral administration of enteric pellets and normal intestinal sol after Beagle dogs showed that 18-α magnesium glycyrrhizinate common intestinal sol was used as a reference preparation, and Beagle dog was orally administered with 18-α glycyrrhizinate. The relative bioavailability of enteric pellets was 211%. The test results are shown in Table 1.

Table 1 Comparison of main pharmacokinetic parameters and relative organisms of magnesium isoglycyrrhizinate in Beagle dogs

Utilization (Mean soil SD, n = 6)

Both AUC. _ _T and Cmax showed a very significant difference (P < 0.001) by double one-sided t-test.

The bioavailability of 18-α-magnesium glycyrrhizinate enteric-coated pellets in Beagle dogs was significantly better than that of 18-α-glycyrrhizinate common intestinal sputum, AUC. _ _T is about 2.11 times the latter. Stability test example: 18-α magnesium glycyrrhizinate enteric pellets capsule (Example 1) stability test 03950 18-o glycyrrhizic acid enteric pellets (batch number: 050516, 050518, 050522) according to the commercial packaging (using aluminum foil and PVC hard sheet packaging) at 40 ° C ± 2 ° C, relative humidity of 75 Accelerated test for 6 months (1, 2, 3, 6 months) under conditions of 5% soil %; long-term test for 18 months at 25 °C ± 2 °C, relative humidity 60% ± 10% ( 0, 3, 6, 9, 12, 18 months sampling). The characteristics of enteric-coated pellets in the capsules were measured, and the related substances, release and content were determined, and compared with the analysis data of the samples from 0 months, no significant changes were observed in the indexes. The test results are shown in Tables 2 and 3.

Accelerate face test results

Long-term stability test-risk results

Lot Number Item 0 Month June June September December 18 Month Light yellow Light yellow Light yellow Light yellow Light yellow

050516 gum intestines, drum traits

Xiaomao pellets pellets pellets pellets release 0.1mol L it acid 0.7 1.4 1.3 1.0 · 0.3 0.3 (%) pH 6.8 buffer

101.4 98.8 97.5 97.3 97.8 94.4 liquid

Related substances 18 (3-glycyrrhizic acid 0.90 0.89 0.88 0.84 0.89 1.10 quality (%) Total amount of impurities 2.86 2.87 3.11 2.94 3.10 2.76 Labeled content (%) 101.7 101.3 101.5 101.2 100.9 100.7 Light yellow yellowish yellowish yellowish yellowish yellowish yellow Capsule intestines ^ 鼓丸丸丸

Small pill, small pill, small pill, small pill, small pill, small pill

0.1mol/L salt

0.7 1.1 1.3 0.9 0.8 0.3 release acid

050518 (%) pH 6.8 buffer

102.0 97.1 97.0 96.4 96.6 96.7 liquid

Related substances 18/3-glycyrrhizic acid 0.90 0.83 0.86 0.89 0.83 0.97 Quality (%) Total amount of impurities 2.93 2.75 3.08 2.93 2.75 2.38 Labeled content (%) 102.6 102.3 102.7 101.9 101.7 101.0 Light yellowish yellowish yellowish yellowish yellow gum intestine^ f 敫 pill trait

Small pill, small pill, small pill, small pill, small pill, small pill

O.lmol/L salt

0.6 1.2 1.1 1.0 1.3 0.3 release acid

050522 (%) pH 6.8 buffer

100.5 98.7 99.2 99.5 94.8 98.6 liquid

Related substances 18/3-glycyrrhizic acid 0.91 0.68 0.86 0.88 0.90 0.95 Quality (%) Total amount of impurities 3.12 2.19 2.97 3.51 2.86 2.33 Labeled content (%) 102.1 102.0 102.6 101.7 101.9 101.6

In vitro release test example: 18-α magnesium glycyrrhizinate enteric pellets capsule (Example 1) in vitro release test Apparatus: ZRS-8G intelligent dissolution apparatus (Tianjin Radio Factory)

High Performance Liquid Chromatograph (Shimadzu Corporation, Japan)

Method: Take this product, according to the release method (Chinese Pharmacopoeia 2005 edition two appendix X D second method), using the basket method (Chinese Pharmacopoeia 2005 edition two appendix X C first law). Acid release medium: O.lmol/L hydrochloric acid 750ml; buffer medium: pH6.8 phosphate buffer solution 1000ml. Speed: 75r/min. The product was released in acid for 2 hours, then released in buffered saline for 5, 10, 15, 20, 30, 45 minutes. The drug content in the release medium was measured and the cumulative dry weight curve was plotted. The results are shown in Table 4 and attached. figure 1.

Table 4: Cumulative release results

Cumulative release (%)

O.lmol/L hydrochloric acid pH6.8 carboxylate buffer

2 hours 5 minutes 10 minutes 15 minutes 20 minutes 30 minutes 45 minutes T/CN2007/003950

Coating weight gain experiment

Method: Based on the preparation method of Preparation Example 1, by changing the weight ratio of the contents and the coating, samples with different coating weight gains were obtained, and the disintegration time limit was determined (using the Chinese Pharmacopoeia 2005 version Appendix XA third method device) And the degree of release (Chinese Pharmacopoeia 2005 edition Appendix XD second method method 1) and compare, the test results are shown in Table 5:

Table 5. Coating weight gain test results

It can be seen from Table 5 that reasonable and effective control of the weight gain of the coating not only ensures that the enteric pellets are hardly released in the gastric juice, but also ensures that the enteric pellets can rapidly disintegrate and release completely in the intestinal tract. The bioavailability of the drug is increased to meet the requirements of the pharmaceutical composition of the present invention.

Claims

Claim

A pharmaceutical composition, characterized in that: the composition consists of a plurality of units, each unit comprising a content and an enteric coating encasing said contents, and the weight ratio of the contents to the enteric coating is 1: 0.15-1: 0.45, wherein the content contains glycyrrhizic acid or a salt thereof and at least one intestinal absorption enhancer.

2. The composition of claim 1 wherein the weight ratio of the contents to the enteric coating is from 1: 0.2 to 1: 0.4.

3. The composition of claim 2 wherein the weight ratio of said contents to the enteric coating is from 1:0.25 to 1:0.35.

4. The composition of claims 1-3 wherein each unit has a diameter between 0.7 mm and 1.2 mm.

The composition according to any one of claims 1 to 4, wherein the intestinal absorption enhancer is a phospholipid substance.

6. The composition according to any one of claims 1 to 5, wherein the content contains a phospholipid complex formed from glycyrrhizic acid or a salt thereof and a phospholipid substance, and the weight ratio of glycyrrhizic acid or a salt thereof to the phospholipid substance is 1. :0.5~1 ·5.

The composition according to any one of claims 1 to 5, wherein the glycyrrhizic acid or a salt thereof is 18-α glycyrrhizic acid or a salt thereof.

8. The composition of claim 7 wherein the glycyrrhizinate is a magnesium salt and a salt of 18-alpha glycyrrhizic acid.

9. A method of preparing the composition of claims 1-8, comprising: mixing glycyrrhizic acid or a salt thereof and an intestinal absorption enhancer; and subjecting the resulting mixture to enteric coating.

10. Use of a composition according to claims 1-8 for the manufacture of a medicament for the treatment of hepatitis.

11. Use of the composition of claims 1-8 for the manufacture of a medicament for ameliorating liver dysfunction.

12. A method of treating hepatitis in an individual comprising administering to said individual a therapeutically effective amount of a composition according to any of claims 1-8.

13. A method of improving abnormal liver function in an individual comprising administering to said individual a therapeutically effective amount of a composition according to any of claims 1-8.