HK1047041A - Glycyrrhizin preparations for transmucosal absorption - Google Patents

Description

Glycyrrhizin preparation for mucosal absorption

Technical Field

The invention relates to a glycyrrhizin preparation which is easy to be absorbed by mucous membranes, in particular to the grain membranes of the digestive tract.

Background

Glycyrrhizin is a main effective component of licorice, has various effects such as antiallergic action, anti-inflammatory action, antiviral action, sterol-like action, and is mainly used as a therapeutic agent for chronic liver diseases. The glycyrrhizin injection has a remarkable therapeutic effect when administered intravenously, but cannot obtain a satisfactory therapeutic effect when administered orally because of low absorption rate in the digestive tract.

In addition, when glycyrrhizin is orally administered, the intestinal bacterial flora present on the surface layer of the digestive tract mucosa is hydrolyzed, and the glycosyl group is removed and absorbed as glycyrrhetinic acid, but the therapeutic effect of glycyrrhetinic acid on hepatitis is much lower than that of glycyrrhizin.

In order to improve bioavailability of glycyrrhizin, rectal administration method of suppository has been studied (Japanese patent application laid-open No. 1-294619, Japanese patent application laid-open No. 3-21122 and Japanese patent application laid-open No. 3-123731).

In order to improve the absorption in the digestive tract, various attempts have been made to prepare enteric-coated oral preparations (Japanese patent application laid-open No. Hei 3-255037, oral preparations containing fat emulsions or complex lipid mixtures (Japanese patent application laid-open No. Hei 6-192107) by blending with fatty acid glycerides.

The administration by injection is not only painful for the patient, but also troublesome for the doctor each time. Thus, administration by injection, particularly to patients with chronic diseases, is a considerable pain both mentally and physically for the patient.

Therefore, the object of the present invention is to develop and provide a glycyrrhizin preparation which can be administered in a form that does not cause pain in humans and animals and does not bother doctors, such as an oral preparation or a suppository, instead of an injection.

Disclosure of the invention

The present inventors have conducted extensive studies to solve the above problems, and as a result, the present invention has been completed. That is, glycyrrhizin is dissolved or dispersed in the water-soluble substance C_6-18Fatty acid glycerides and C_6-18The self-emulsifying base material of the mixture of fatty acid polyglycol ester is administrated to digestive tract or vagina, so that glycyrrhizin with blood concentration incapable of being obtained from oral preparation or suppository can be easily absorbed by mucosa (especially large intestine mucosa) of digestive tract or vaginaAnd obtaining the effective blood concentration for treating the chronic liver disease patients.

The key points of the invention are as follows:

(1) glycyrrhizin preparation for mucosal absorption comprising glycyrrhizin and C_6-18Fatty acid glycerides and C_6-18Fatty acid polyglycol ester mixture.

(2) The mucosal absorption glycyrrhizin preparation described in the above (1), C_6-18The fatty acid is a saturated fatty acid.

(3) The glycyrrhizin preparation for mucosal absorption as described in the above (1) or (2), wherein the average molecular weight of polyethylene glycol is 100 to 800.

(4) The glycyrrhizin preparation for mucosal absorption described in (1), wherein the weight ratio of glycyrrhizin to ester mixture is 1: 0.05-10.

(5) The mucosal absorption glycyrrhizin preparation described in the above (1) or (4), C_6-18Fatty acid glycerides and C_6-18The weight mixing ratio of the fatty acid polyglycol ester is 1: 0.1-10.

(6) The glycyrrhizin preparation for mucosal absorption according to any one of (1) to (5) above, further comprising an organic acid, a chelating agent or a surfactant.

(7) The method for absorption of a glycyrrhizin preparation through the mucous membrane of the digestive tract according to any one of the above (1) to (6), wherein the drug contained in the preparation is an oral preparation to be released in the large intestine.

(8) The mucosal absorption glycyrrhizin preparation according to any one of the above (1) to (6), which is a rectal or vaginal suppository or a rectal or vaginal ointment.

The glycyrrhizin, the main component of the invention, is a glycoside contained in roots of a perennial herb of the family Leguminosae, such as licorice, and is also called glycyrrhizic acid due to carboxyl in the molecule. In glycyrrhizin, there are salts such as alkali metal salts, and these salts are also included in the scope of glycyrrhizin of the present invention.

Glycyrrhizin is hydrolyzed by monoglucuronidate to glycyrrhetinic acid and two molecules of glucuronic acid, which are much less effective against viruses than glycyrrhizin. Therefore, in order to obtain a good therapeutic effect, it is preferable that glycyrrhizin be absorbed in vivo as it is.

C_6-18The fatty glyceride is C_6-18At least one of fatty acid mono-, di-and triglycerides, and a mixture thereof is usually used.

C_6-18The fatty acid may be a saturated or unsaturated fatty acid having 6 to 18 carbon atoms, but it is preferable to use a saturated fatty acid, particularly a saturated fatty acid having 6 to 12 carbon atoms, that is, caproic acid, caprylic acid, capric acid and lauric acid.

C_6-18The polyethylene glycol used in the fatty acid polyethylene glycol ester is usually a polyethylene glycol having a molecular weight of 100 to 800, preferably 200 to 600, and any of mono-, di-and mixed esters thereof may be used as the ester. C constituting polyethylene glycol ester_6-18The fatty acid is the same as that for the glyceride.

The weight mixing ratio of the glyceride to the polyethylene glycol ester is usually 1: 0.1-10, preferably 1: 0.2-5.

Mixed esters of glycerides and polyglycol esters are well known as Self-Emulsifying bases (Self Emulsifying agents) and are conveniently used as sold under the trade name LABRASOL by the company Gattefosse s.a. in the european pharmacopoeia under the name caprylocaproyl polyglycol glyceride.

The weight ratio of glycyrrhizin to the ester mixture is usually 1: 0.05-10, preferably 1: 0.1-5.0.

In addition, as the absorption enhancer, organic acids such as citric acid, malic acid, maleic acid, fumaric acid, and tartaric acid which are pharmaceutically acceptable; anionic surfactants such as alkyl sulfates, nonionic surfactants such as polyoxyethylene sorbitan fatty acid esters, polyoxyethylene hardened castor oil, polyoxyethylene alkyl ethers, and polyoxyethylene alkylphenyl ethers; surfactants which can be used in pharmaceutical preparations, such as steroid surfactants including deoxycholic acid and ursodeoxycholic acid, and chelating agents such as EDTA.

The amount of the absorption enhancer used is not particularly limited, but is usually 1 to 200 parts by weight, preferably 5 to 50 parts by weight, based on 100 parts by weight of glycyrrhizin.

The glycyrrhizin preparation of the present invention can be mixed with excipients, binders, lubricants, swelling agents, disintegrating agents, stabilizers, coloring agents, etc. and made into oral preparations such as capsules, tablets, granules and powders, rectal or vaginal suppositories, rectal or vaginal injection ointments, etc. by a well-known method.

The preferable mode of administration of the glycyrrhizin preparation of the present invention is designed in consideration of absorption of the main ingredient from the mucosa of the lower digestive tract, so-called large intestine targeted drug delivery system (large intestine targeted DDS).

The glycyrrhizin is processed into an oral preparation of a large intestine targeted drug delivery system, and the administered glycyrrhizin is released intensively in a high concentration in the large intestine, so that hydrolysis caused by intestinal bacterial flora is saturated, and most of the glycyrrhizin is absorbed in the large intestine as an original active body. And after being absorbed, the glycyrrhizin can avoid the excretion of the first pass effect of the liver into the bile, and obviously improve the bioavailability of the glycyrrhizin serving as an active body.

The following description relates to a large intestine targeting DDS (drug administration system) used in the present invention.

(1) Method for filling rectal suppository-like component containing glycyrrhizin into anionic polymer capsule

The time for solid preparations such as capsules, tablets and the like to pass through the small intestine is consistent, and about 3-4 hours is needed. Which slowly dissolves over time and eventually disintegrates to release the drug in the lower small intestine, these required necessary capsule film thicknesses being readily determinable by in vitro testing.

For this purpose, examples of the capsule material include enteric acrylic polymers such as Eudragid S-100 (trade name) (methacrylic acid-methyl methacrylate copolymer) and Eudragid anionic polymer P4135F (methacrylic acid-methyl acrylate-methyl methacrylate copolymer) (trade name).

As mentioned above, it is desirable that the capsule after disintegration releases a high concentration of glycyrrhizin, preferably in the lower part of the digestive tract, especially in the large intestine, so that a formulation with a capsule content resembling a rectal suppository is only suitable for this purpose. The preparation of these formulations is well known to those skilled in the art and involves melting a suitable base such as Witepsol H15(Dynamit Nobel, a higher fatty acid di-or triglyceride), adding glycyrrhizin and the ingredients used in the present invention to the melt, filling the suspension into the capsules and sealing the mouthpiece with the same polymer. Alternatively, a coating having a desired film thickness may be formed on the surface of a suppository-like preparation by a dipping method, or encapsulated.

(2) Method for coating enteric sugar-coated capsule with time-controlled release of enteric sugar-coated capsule corresponding to gastric discharge time to large intestine (passage through small intestine)

Capsules made in this way are marketed under the name CTDC (ColonTargeted Delivery Capsule) (cf. the high bridge, journal of medicine vol., 34, S1, 1998, 238-242).

The CTDC is characterized in that a common gelatin hard capsule is filled with a medicament and an organic acid used as a pH regulator, and then the outer side of the capsule is coated with a gastric-soluble coating layer, a water-soluble coating layer and an enteric-soluble coating layer in sequence in a multilayer way. Also, a lower gastrointestinal tract release type coated capsule disclosed in Japanese patent laid-open No. 9-87169 is included in this capsule.

(3) Using the pulsencap method

This approach was performed in c.g. wilson et al, Drug Delivery, 4: 201-206 (1997). The large intestine delivery system uses capsules in which the trunk is a water-insoluble material such as low density polyethylene and the lid is a conventional gelatin. A coating of ethyl cellulose on a torso made of conventional gelatin may also be used.

The trunk of the water-insoluble capsule is filled with an excipient or the like and the drug of the present invention after leaving a space capable of accommodating the embolism. Then, a plug made of hydrogel which is easy to swell after absorbing water, such as cross-linked polyethylene glycol, is inserted into the opening and then the neck is sealed, then a gelatin cover is embedded, and the interface is sealed by proper coating liquid to obtain the capsule.

After the capsule is taken orally, the cover is dissolved under the action of gastric juice, and the capsule with exposed embolism is discharged from the stomach to the small intestine. The plug made of hydrogel between small intestines gradually absorbs water to swell, and the content of the capsule is released into the digestive tract after the plug is pushed out from the neck at a certain time.

The time at which the plug is pushed out of the trunk lid can be controlled by adjusting the size of the plug.

(4) Method for coating tablet with enteric polymer or filling medicine in capsule made of enteric polymer

It is known that the large intestine intestinal flora secretes an azoreductase which reduces the schizo-azo group. For this reason, the azo group-containing polymer (azo polymer) is specifically decomposed (depolymerized) in the large intestine. By utilizing this phenomenon, a large intestine-targeted Drug Delivery System (DDS) can be designed by coating a tablet with an azo polymer or filling a capsule made of an azo polymer with a drug.

There are various known azo polymers, and a styrene-hydroxyethyl methacrylate-divinylazobenzene copolymer is an example thereof.

In addition to azo polymers, there are other enteric soluble polymers, an example of which is a polyester (CTPT polymer) or chitosan in which cellobiose and poly-1, 4-butanediol are linked to terephthalic acid by esterification, as published by the present inventors in the section PHARM TECH JAPAN Vol.11(11), 37-46 (1995).

(5) Method for preparing controlled release time type large intestine release capsule

This process is described in U.S. Pat. No. 5,637,319 to first. The outline is a system in which a capsule made of ethyl cellulose is filled with a water-swellable substance in addition to a drug, and the capsule is ruptured by swelling pressure after administration for a predetermined period of time to release the drug.

As the swelling substance, low-substitution hydroxypropylcellulose (L-HPC), sodium carboxymethylcellulose, calcium carboxymethylcellulose, or the like is used. The swelling substance is shaped into a block like a tablet, and filled in a proper position, and the drug glycyrrhizin is mixed with an excipient or a carrier in the remaining space and then filled. The capsule is sealed except that fine holes are provided at appropriate places on the capsule wall in contact with the swelling substance in order to facilitate permeation of water.

When the capsule is orally taken, the water permeating from the pores gradually swells, and after some time, the swelling pressure makes the capsule break to release the medicine. The number and diameter of pores, the thickness of the capsule membrane, the type and size of the swelling substance are appropriately selected to control the time required for the capsule to rupture, i.e., the time required for the release from the large intestine.

(6) Method for preparing enteric-coated capsule

This method is described in U.S. Pat. No. 5,637,319, and also in "preparations and machines", in the 10 years, 1 month, 15 days.

Such capsules disintegrate in the large intestine on the principle described below. The ingested food has a good fluidity because of the abundance of water such as digestive juice in the stomach and small intestine, but the viscosity of the contents increases significantly in the large intestine due to the reabsorption of water and the formation of feces. The capsule in this high density environment is ruptured by the internal pressure of the large intestine lumen derived from the peristaltic movement of the large intestine, releasing the contents of the drug.

These capsules are made of a high molecular polymer such as ethyl cellulose which does not decompose or dissolve in the digestive tract, or are formed by lining a gelatin capsule with the polymer.

The content of the capsule is preferably liquid when the capsule is crushed, and for this reason, the glycyrrhizin preparation is preferably dissolved or dispersed with oil and fat liquefied at body temperature such as propylene glycol, polyethylene glycol, vegetable oil, etc. as a base material, and then filled into the capsule. The disintegration time of the capsule in the large intestine is controlled by changing the film thickness of the ethyl cellulose capsule.

The glycyrrhizin preparation of the present invention is useful as a preventive and therapeutic agent for viral diseases including allergic diseases, liver dysfunction caused by chronic liver diseases, various eczemas, drug eruptions, stomatitis, infantile tooth eruptions, blisters, alopecia areata, etc., and aids.

The dose of the glycyrrhizin preparation of the present invention is determined by considering factors such as age, body weight, disease type and condition, sex, administration form and administration channel of the patient. However, for the treatment of liver diseases, the glycyrrhizin is administered to adults (in terms of body weight of 60 kg) in an amount of 10 to 1,000mg, preferably about 100 to 800mg, per day, and this amount is administered orally or rectally or vaginally at one or several times.

Best mode for carrying out the invention

The present invention will be described in further detail below with reference to examples and test examples.

Example 1

Each capsule was prepared by filling a homogeneous mixture of 100mg of glycyrrhizin disodium, water and 1.0ml of a mixed liquid of LABRASOL (trade name) in a weight ratio of 1: 1 in an ethyl cellulose-lined gelatin capsule, i.e., a large intestine internal pressure disintegrating type large intestine administration capsule.

Examples 2 to 4 and comparative example 1

Capsules for oral use were prepared in the same manner as in example 1, each containing the respective ingredients in the proportions shown in [ table 1 ].

[ Table 1]

Composition (I)	Example 1	Example 2	Example 3	Example 4	Comparative example 1
						Glycyrrhizin-2 Na (mg)	100	100	100	100	100
water/LABRASOL 1/1☆1	1.0	1.0	1.0	1.0
						TO-10M☆2(ml)		0.05
Deoxycholic acid (mg)			25
						MYS-40☆3				25
EDTA-Na(mg)					10.5

1: product of Gattefosse s.a., caprylocaproyl macrogolglycerides 2: nikko chemicals, polyoxyethylene (20) sorbitan monooleate 3: nikko chemical Co., product of polyoxyethylene (40) ethylene glycol monostearate

Test example 1

Four male beagle dogs (10 to 12kg in body weight) fasted for 12 hours from the night before were selected and orally administered each time the glycyrrhizin capsules prepared by the methods of examples 1 to 4 and comparative example 1, with a net glycyrrhizin amount of 200 mg. Blood was then periodically collected from the jugular vein, and the time-dependent change in the glycyrrhizin concentration in the plasma was measured by High Performance Liquid Chromatography (HPLC). The results are shown in Table 2 (values are the average of four).

[ Table 2]

Glycyrrhiza glycyrrhizin concentration in plasma (μ g/ml)

Test results

The preparation of example 1 containing LABRASOL started to increase the plasma concentration of glycyrrhizin three hours after administration, and reached a peak value (10 μ g/ml) 5 to 6 hours after administration, and reached a therapeutically effective concentration.

In addition, the preparations of examples 2 to 4, in which the absorption enhancer was added in addition to LABRASOL, all gave higher plasma concentrations than LABRASOL alone. On the other hand, the preparation of comparative example 1, which did not contain LABRASOL, showed almost no increase in the plasma concentration of glycyrrhizin.

Example 5

Each suppository contains glycyrrhizin 200mg, LABRASOL 0.3ml, propylene glycol 0.8ml, and TRANSCUTOL (product of Gattefosse s.a., diethylene glycol monoethyl ether) 0.1ml, and the mixture is filled into a disposable tube for ointment injection having a volume of 2ml to prepare an injection ointment.

The obtained injectable ointment is injected into rectum of healthy male subject with body weight of about 60kg, and blood is collected at regular time, and time-varying concentration of glycyrrhizin in blood plasma is measured by high performance liquid chromatograph. The results are shown in Table 3.

[ Table 3]]

Time (hr)	1	2	4	6
					Plasma concentration (μ g/ml)	2.9	1.8	0.7	0.1

It is clear from the above table that rectal administration also gives a therapeutically effective plasma concentration of 1.0. mu.g/ml.

Example 6

In each capsule, a homogeneous mixture of 100mg of glycyrrhizin, 0.4ml of polyethylene glycol, 0.15ml of LABRASOL and 0.05ml of TRANSCUTOL was filled in the same capsule as in example 1, and formulated into a large intestine internal pressure disintegrating type large intestine administration capsule.

The obtained capsules were orally administered 200mg of glycyrrhizin to the same animals as those used in test example 1, blood was collected at regular intervals, and the aged concentration of glycyrrhizin in plasma was measured by high performance liquid chromatography. The results are shown in Table 4 (values are averages of four).

[ Table 4]]

Time (hr)	1	2	3	4	5	6	7	8	10	12	24
												Plasma concentration (μ g/ml)	6.5	15	17	14.5	15	15	14	12	13	12	9

Possibility of industrial utilization

According to the invention, the glycyrrhizin with the plasma concentration which is difficult to obtain with treatment by the traditional digestive tract administration is realized, the plasma concentration which is also obtained with treatment by oral administration, rectal administration or vaginal administration is realized, and particularly, the preparation is prepared into a large intestine targeted drug release system to obtain higher bioavailability.

Claims (8)

1. A glycyrrhizin preparation for mucosal absorption, characterized by comprising glycyrrhizin and C_6-18Fatty acid glycerides and C_6-18Ester mixtures of fatty acid polyglycol esters.

2. The mucosally absorbable glycyrrhizin preparation of claim 1, C_6-18The fatty acid is a saturated fatty acid.

3. The glycyrrhizin preparation for mucosal absorption according to claim 1 or 2, wherein the polyethylene glycol has an average molecular weight of 100 to 800.

4. The preparation of claim 1, wherein the weight ratio of glycyrrhizin to ester mixture is 1: 0.05-10.

5. The mucosally absorbable glycyrrhizin preparation according to claim 1 or 4, C_6-18Fatty acid glycerides and C_6-18The weight mixing ratio of the fatty acid polyethylene glycol ester is 1: 0.1-10.

6. The mucosally absorbable glycyrrhizin preparation of any one of claims 1 to 5, further comprising an organic acid, a chelating agent or a surfactant.

7. The glycyrrhizin preparation for mucosal absorption through the digestive tract of any one of claims 1 to 6, which is an oral preparation for releasing the drug into the large intestine.

8. The transmucosal glycyrrhizin preparation according to any one of claims 1 to 6, in the form of a rectal or vaginal suppository or a rectal or vaginal ointment.