JPH0242027A - Transmucosal absorbefacient and pernasal administration agent using said absorbefacient - Google Patents

Abstract

PURPOSE:To obtain a transmucosal absorbefacient which is a hardly absorbable substance containing glycyrrhizin and a salt thereof as an active ingredient. CONSTITUTION:A transmucosal absorbefacient containing glycyrrhizin expressed by the formula which is an ingredient of licorice, having surface activity, used as a drug for internal use and further external use of eye drops or ointment and as a cosmetic or sweetener added to foods and a pharmaceutically acceptable salt thereof as an active ingredient. Sufficient absorbability is obtained with the above-mentioned compound even by transmucosal administration with conventional hardly any pharmacological effect, e.g., pernasal administration, in administering a high-molecular weight hardly absorbable substance, such as peptide hormone or interferon, in the same manner as that in the case of injection. Prescribed treating effects can be expected by a method other than the injection. As for especially insulin, the absorbefacient is greatly expected to provide a pharmaceutical extremely useful in treating diabetes.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention relates to a transmucosal absorption enhancer for poorly absorbed substances containing glycyrrhizin and its pharmaceutically acceptable salt as active ingredients, and a nasal transmucosal absorption enhancer containing the same. Concerning administration agents.

[Prior Art and Problems] Among conventionally used pharmaceuticals, poorly absorbed drugs such as peptide hormones, such as insulin, were administered only by injection to diabetic patients.

However, the injection method for insulin, which is a poorly absorbed substance, has the drawback that it causes pain during injection, and continuous administration over a long period of time causes tissue thickening at the injection site in the body.

On the other hand, recently, research has been conducted on the production of nasal sprays and cloth, etc., as preparations that can avoid these situations and enable home administration.
It has a molecular weight of 0, and because of its large molecular weight, it is extremely difficult to be absorbed through the nasal mucosa or rectal mucosa, which is a major obstacle in its development.

Therefore, in recent years, studies have been conducted on substances that can promote the absorption of insulin, etc., and as a result, it has been found that substances with surfactant effects such as bile acids, medium-chain fatty acids, nonionic or ionic synthetic surfactants, and saponins have an effect on absorption. It is now known that it has a promoting effect.

The inventors of the present application searched for various practical substances under these circumstances, and found that they have surfactant properties and are used not only as internal medicines but also as external medicines such as eye drops and ointments, and are also used in cosmetics and foods as sweeteners. The present invention was completed by discovering that glycyrrhizin and its salts, which are added active ingredients in licorice, have a remarkable effect on promoting the transmucosal absorption of high-molecular weight peptide hormones, including insulin and glucagon. This is what I did.

Compounds useful for promoting absorption in the present invention are glycyrrhizin (glycyrrhizic acid) represented by the formula: and its pharmaceutically acceptable salts.

Here, salts include, for example, ammonium glycyrrhizinate, alkali salt of glycyrrhizinate (-, disodium, -
, dipotassium salt, etc.).

While these compounds have a remarkable absorption promoting effect,
The side effects on biological mucous membranes are extremely small. Therefore,
The compound of the present application can be used to administer high-molecular weight absorption substances such as peptide hormones and interferons by transmucosal administration, such as nasal administration, which previously had no pharmacological effects, as well as by conventional injections. Provides absorbency. As a result, the desired therapeutic effect can be expected by methods other than injection. In particular, there are great expectations regarding insulin as it will provide a preparation that is extremely useful for the treatment of diabetes.

When the compound of the present application is used as an absorption enhancer, it can be administered as a dissolved aqueous solution together with an applied amount of a poorly absorbed substance, and as a result of promoting transmucosal absorption, the drug layer is , a spray, etc.

The compound of the present invention can also be added to an applied amount of a poorly absorbable substance and applied topically as a cloth or plaster by a conventional method.

In these cases, a sufficient transmucosal absorption promoting effect can be expected by using the compound of the present application in a content in the range of 0.01 to 10%.

Formulation Examples and Pharmacological Test Examples are listed below, but it goes without saying that the present invention is not limited to these Examples and Test Examples.

[Example of Formulation M Production of nasal spray Add 0.01% to 10% aqueous solution of glycyrrhizin dipotassium salt or glycyrrhizin ammonium salt to the administration solution.
Prepare by dissolving bovine insulin in dosage units per ml.

Current insulin injection preparations come in two specifications: 40U and 100U, and when administering the same dose as the injection, the amount of solution administered through the nose is 0.4 to 1ml, which is sufficient for use as a nasal spray for humans. It is quantity.

In addition, tonicity agents, stabilizers, preservatives, etc., which are acceptable for formulation, are added as necessary.

Preparation of spray The solution for spray is prepared in the same manner as the nasal spray described above, and the container is filled with air or preon.

In this case, a container is used that can be administered in the form of a mist by manually pressing the container or compression device. The amount of spray is
Each dose is 0.1-0.2 ml, and 2-5 sprays are enough to administer a therapeutic amount of insulin.

[Pharmacological test example] Absorption promoting effect (1) Preparation of insulin administration solution Maggot insulin was prepared as follows: ■ pH 7.4 0. OIM phosphate buffer ■Ioo U/ml of each insulin solution was prepared by dissolving it in the same buffer containing 1% glycyrrhizin dipotassium or glycyrrhizin ammonium.

(2) Test animals: 3 to 7 Wistar rats (weighing around 250 g) per group.
The animals were placed in a dorsal position under bendoparbital anesthesia, and a cannula was inserted into the trachea to ensure breathing. A cannula was also inserted into the esophagus to prevent leakage of the administered solution.

(3) Measurement of blood concentration In this experimental example, the amount of insulin was 10 U10.1 ml.
Blood was collected from a cannula inserted into the femoral vein, and the heparin-pretreated blood was centrifuged (3,00 rpm, 10 minutes) to obtain plasma. Insulin was administered by enzyme immunotherapy (insulin B-test Wako,
(manufactured by Wako Tsumugi Pharmaceutical Co., Ltd.). Blood sugar levels were measured using the mutarotase-glucose oxidase method (Glucose C-Test Fuco, manufactured by Wako Tsumugi Pharmaceutical Co., Ltd.).

(4) Minota method In addition, the absorption rate of insulin and the rate of decrease in blood sugar level were calculated using the following formula.

■Relative absorption rate of insulin (%) Nasal: 0 of insulin during nasal administration of insulin
Area under the blood concentration time curve up to 4 hours (h・μU/ml) Control: Insulin O when no insulin was administered
Area under the blood concentration time curve up to the 4th hour (h・μU/ml) Intravenous injection: Area under the blood concentration time curve of insulin from 0 to the 4th hour during intravenous injection of insulin (h・μU/ml ) ■Decrease rate of blood sugar level (DX) Nasal: 0 to 4 of blood sugar level during nasal administration of insulin
Area under the blood concentration time curve (h - mg/dl) Control: Area under the blood concentration time curve from 0 to 4 hours of blood glucose level without insulin administration (h - mg/di) Intravenous injection 2 Blood sugar level during intravenous insulin injection: 0-4
Area under the blood concentration time curve (h - mg/di) (5) Results Figure 1 shows the results for non-insulin administration (control), insulin administration alone (alone, 10 u/kg), and 1% glycyrrhizin. The blood concentration time curves of each insulin after administration (IOU/kg) of an insulin solution containing dipotassium (hereinafter referred to as GL/2K) are shown.

Even when insulin was administered alone, the plasma insulin concentration increased significantly (p<0.01) 15 minutes after administration compared to the control, and the time to reach the maximum blood concentration (t max) was 1 hour. Furthermore, the area under the blood concentration time curve (AUCo-4>) up to 4 hours after administration was about 6 times that of the control, but it did not lead to a decrease in blood sugar level.

When 10 U/kg of insulin contained in 1% GL.2 was administered, the change in blood insulin concentration reached a maximum of about 190 μU/ml at 15°C 2 hours after administration.

FIG. 2 shows the time course of the blood sugar level at this time. No significant difference was observed between the control and single administration, but in the 1% GL-2 addition group, the amount decreased by about 20% compared to the control 15 minutes after administration. This reduction in blood sugar level continued even 4 hours after administration, and the blood sugar reduction rate at that time was 65%.

In addition, Table 1 below shows GL・2K and glycyrrhizin・
The nasal absorption of ammonium (hereinafter referred to as GL-NH4) is compared with intravenous injection and subcutaneous injection.

Table 1 Effect of glycyrrhizin on the nasal absorption rate and blood glucose reduction rate of insulin after intranasal administration of insulin in rats Insulin AUC, -.

h・μ [J/ml Control 28.7±5.1 diameter nose alone 172±14.2 GL・2K 544±59.4GL-NH,2
68±54,2 Intravenous injection 3576±507 Subcutaneous 1456±260 Reduction rate by area % Relative absorption rate % 3.9±11.0 2.02 51.7±2.3 7.26 53.1±8. 2 3.37 81.8±1.0 100 76.2+:4.4 40.2 The nasal dose of insulin is 1001 kg, and the intravenous and subcutaneous dose is 501 kg.

6 Values are the standard error above the mean of 3 to 7 rats.

In the case of no insulin administration, the AUG of insulin up to the 4th hour was 28.7b-71U/ml, but when insulin was administered alone, it was 172h·μU/ml.

On the other hand, in the group added to 1% GL・2, the insulin 80C0-4 was 554 h・μU/ml, which was about 19 times the control value, which decreased the absorption rate of intravenous injection to 100%.
In this case, it corresponds to 7.26%, and the blood sugar reduction rate at this time was 52%. Furthermore, in the 1% GL-NH4 addition group, although the absorption rate was as low as 3.37%, the blood sugar reduction rate was 53%.

If the intranasal dose of insulin in this test example were compared to humans, it would be 10 times the dose, but judging from the blood sugar-reducing effect described above, sufficient effects are expected even with lower doses than these.

[Brief explanation of the drawing]

Figure 1 shows an insulin solution (10 U) containing 1% GL.2.
Figure 2 shows the non-administration time curve of plasma insulin after intranasal administration of 3) in rats.
FIG. 2 is a diagram showing (1) changes in blood glucose level after intranasal administration of 1' insulin solution (1001 kg) to rats. 0.5 0.5 Word spacing

Claims (4)

[Claims] (1) Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ A transmucosal absorption enhancer for poorly absorbed substances containing glycyrrhizin and its pharmaceutically acceptable salts as active ingredients. (2) Formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ A peptide hormone transmucosal absorption enhancer containing glycyrrhizin and its pharmaceutically acceptable salt as active ingredients. (3) A nasal administration agent characterized by adding glycyrrhizin represented by the formula: ▲Mathematical formula, chemical formula, table, etc.▼ and a pharmaceutically acceptable salt thereof to a poorly absorbed substance. (4) The nasal preparation according to claim 3, wherein the poorly absorbed substance is a peptide hormone.