JPH0618787B2 - Transdermal absorption enhancer and percutaneous absorption preparation using the same - Google Patents

Description

TECHNICAL FIELD The present invention relates to a percutaneous absorption enhancer of a locally acting drug and a percutaneous absorption type preparation containing the same.

[Prior Art] Conventionally, there are various drugs that are percutaneously absorbed and locally act on the human body. For example, for a preparation for local anesthesia, an injection, and as a surface anesthetic, a liquid, a jelly, a spray. There are agents. However, the latter is known to have a remarkable local effect on the mucous membrane of the esophagus, stomach, oral cavity, etc., but is not effective for local anesthesia of the skin.

[Problems to be Solved by the Invention] In recent years, in the field of anesthesiology, there is a demand for pain relief when inserting a relatively thick needle such as venipuncture, epidural anesthesia and spinal anesthesia in securing blood vessels during surgery. ing. That is, conventionally, local anesthetics such as lidocaine hydrochloride and procaine hydrochloride are administered by injection, but pain during administration is inevitable.

In view of such circumstances, the inventors of the present application pursued the transdermal absorption promoting action of various substances, and attempted to shorten the local anesthesia onset time in order to realize transdermal absorption of lidocaine and the like. As a result, they have found that glycyrrhizin, glycyrrhetinic acid and their derivatives have a remarkable transdermal absorption promoting effect, and completed the present invention.

The compound useful for promoting absorption in the present invention has a general formula; [However, in the formula, R ₁ -H, -OCCH ₂ CH ₂ COOH, or And a compound having a pharmaceutically acceptable salt thereof as an active ingredient, and a general formula: [Wherein, X is 18β-olean-12-ene-3β, 3
0-diol, 18β-olean-9, (11) 12-diene-
It is a residue of 3β, 30-diol or olean-11,13 (18) -diene-3β, 30-diol] and a pharmaceutically acceptable salt thereof.

The compounds contained in the above general formulas (I) and (II) include (1) glycyrrhizin (2) glycyrrhetinic acid (3) glycyrrhetinic acid 3β-monohemisuccinate (4) glycyrrhetinic acid 3β-monohemiphthalate (5) 18β -Olean-12-ene-3β, 30-dihemiphthalate (6) 18β-olean-9, (11) 12-diene-3β, 30-
Diol-dihemiphthalate (7) olean-11,13 (18) -diene-3β, 30-diol-dihemiphthalate.

These compounds (1) to (7) are hereinafter referred to as compounds 1 to 7.

The skeleton of these compounds is an active ingredient contained in licorice and is a known compound, but it has a remarkable dermal absorption-promoting action, but the side effects on the skin are extremely small. Therefore, the compound of the present invention can significantly shorten the skin anesthesia effect manifestation time by the administration of a local anesthetic such as lidocaine. Further, it can be fully expected to promote the absorption of various other drugs which are percutaneously absorbed and act locally.

Of these, the disodium salts of compounds 3 to 7 can be produced by the following method.

(1) In the production of compound 3, succinic anhydride is added to glycyrrhetinic acid, (2) in the production of compound 4, glycyrrhetinic acid, and (3) in the production of compound 5, 18β-olean-12-ene-
In the production of (4) compound 6, 18β-olean-9, (11) 12 was added to 3β, 30-diol.
In the production of (5) Compound 7, -diene-3β, 30-diol was prepared by adding phthalic anhydride to olean-11,13 (18) -diene-3β, 30-diol, and adding a weak solvent in an organic solvent. It can be synthesized using a base catalyst or a strong base catalyst. Here, pyridine, chloroform, methanol, ethanol and the like can be used as the organic solvent, diethylamine, triethylamine and the like can be used as the weak base catalyst, and 4-dimethylaminopyridine and the like can be used as the strong base catalyst.

The compound of the general formula (I) (II), as it is, or in the form of a pharmaceutically acceptable alkali addition salt, as a percutaneous absorption enhancer, according to a conventional method, to be an ointment, a tape, a poultice It is also possible to use a spray or lotion as a liquid.

The production examples are given below.

[Formulation Example] Ointment for local anesthetic Lidocaine 1-30 g Compound 4 1-10 g Propylene glycol 1-20 g Ethyl alcohol 1-40 Water 5-20 Polyacrylic acid 1-5 g Diisopropanolamine 0.5-2 g Total amount 100 g Above The mixture is made into an aqueous gel ointment according to a conventional method. In addition, stabilizers, preservatives and the like can be added if necessary.

Hereinafter, test examples of the absorption promoting action of the compound of the present invention will be listed.

[Test Example 1] (1) Test subject Wistar rat (2) Test drug a. Aqueous gel ointment containing 2% lidocaine b. Aqueous gel ointment containing 10% lidocaine c. Aqueous solution b. Containing 3% of compound 4 Gel ointment d. Aqueous gel ointment containing 3% of compound e. A. Aqueous gel ointment containing 3% of compound f. A. Aqueous gel ointment of 3% containing compound 5 g. Compound 6 of a. % A. Aqueous gel ointment h. A. Aqueous gel ointment containing 3% of Compound 7 was prepared (hereinafter referred to as ointments a, b, c, ..., H).

(3) Experimental Method First, Wistar rats (body weight: around 300 g) were fixed in a dorsal position under urethane anesthesia, and an ointment was applied to the rat abdomen after hair removal, and the rats were separated into the following groups.

Group of ointment a application Group of ointment e application Group of ointment b application Group of ointment c application 3% Azone (trade name) -10% lidocaine aqueous gel ointment application group These (hereinafter, group) 1 g / 20 cm ² was applied, and each group consisted of 3 to 5 animals.

In these groups, the application site was covered with a polyethylene sheet for food packaging and further sealed with a transparent tape.

After that, blood was collected from a cannula inserted into the jugular vein, heparin-pretreated blood was centrifuged (3,000 rpm, 10 minutes) to obtain plasma, and the concentration of lidocaine in the blood was measured using fluorescence polarization immunoassay. Was measured. The drawings show the results of animal experiments. This represents the change in blood concentration up to 5 hours after application.

In the group, no significant difference in blood concentration was observed at any time regardless of the presence or absence of the compound 4. However, in the groups with the lidocaine concentration of 10%, the absorption promoting effect of compound 4 was observed. Further, in the group to which 3% of Azone, which is known as a transdermal absorption enhancer, was added, no particular absorption enhancing effect was observed.

[Test Example 2] (1) Subject of experiment Healthy adult (2) Test drug The same as in Test Example 1.

(3) Experimental method a. Preliminary test First, as a preliminary test, various lidocaine aqueous gel ointments.
The skin anesthesia effect of 3 g / 4 cm ² was examined.

Ointments d to h, and xylocaine jelly (trade name, containing 2% lidocaine hydrochloride manufactured by Fujisawa Pharmaceutical Co., Ltd.), Azone which is a known transdermal absorption enhancer, sodium caprate (hereinafter, referred to as Cap N
a), isopropyl myristate (hereinafter IPM), 3 each
%, Lidocaine aqueous gel ointment was used to compare them by ping prick test.

(Evaluation Criteria) After application of various ointments, at 1, 1.5, 2, 3, and 4 hours, 2
A 6-gauge intradermal needle was pierced at the application site several times, and the degree of pain was evaluated according to the following criteria.

++ There is no pain in the applied part + There is a painful part in the applied part-Table 1 shows the results of feeling pain in the applied part.

With Compound 3, Compound 4, and Compound 7, skin anesthesia developed 1.5 hours after application, and complete skin anesthesia occurred 2 hours after application. In addition, since Compound 5 and Compound 6 have almost the same skin anesthetic effect as Azone, it was shown that the glycyrrhetinic acid derivative has a transdermal absorption promoting action. In addition, xylocaine jelly was not effective in skin anesthesia even 4 hours after application.

B. Skin anesthesia effect Next, 0.3 g of ointment e was absorbed in a sponge with a diameter of 25 mm and a thickness of 1 mm, applied on the human forearm inner skin, and then sealed with a transparent tape, and the skin anesthesia effect was evaluated by the pinprick method. did. In addition, local skin reactions such as redness, edema, and blisters were examined.

(Evaluation Criteria) 5 points of application were pierced with a 26-gauge intradermal needle, and there was no pain 0 points, a little pain was felt 0.5 points, no effect at all, 1 point was displayed as a pain score. .

In case of 0 points, select one point and cut the needle to 1.0m.
It was inserted to a depth of about m, and it was confirmed whether there was deeper pain. In this case, when there is no pain, it is indicated as ○, and when there is pain, it is indicated as △.

Stance is used to test the significant difference between the pain score 5.0 before applying the sponge and the pain score (mean ± standard deviation) at each time after applying the sponge
The udent paired t-test was used.

The results are shown in Table 2.

Average pain score is 4.0 ± 1.0 for 30 minutes and 2.2 ± for 1 hour
1.6 ± 1.5 hours 1.3 ± 1.0, 2 hours 0.8 ± 0.8 3 hours
It decreased significantly with the application time, such as 0.1 ± 0.3. 3 hours after application, 8 out of 12 (67%)
However, I could not feel any pain even if I inserted a 26-gauge intradermal needle into the skin about 1 mm vertically. After 30 minutes of wiping the applied aqueous gel ointment, pain started to appear, although it was not significant with a pain score of 0.5 ± 0.8. As a local reaction of skin on the application site, mild redness was observed in 3 subjects (25%), but no pallor, edema, blistering, etc. were observed, and there was no complaint of abnormal perception. The redness of the skin disappeared within 1 hour of wiping the ointment.

[Test Example 3] (1) Subject of experiment Patient scheduled for surgery (2) Test drug The same as in Test Example 1.

(3) Experimental method Ointment c to which compound 4 was added and ointment b to which compound 4 was not added as a control were absorbed by 0.3 g each into a sponge having a diameter of 25 mm and a thickness of 1 mm, and venipuncture was performed by a double blind method. It was attached to a predetermined site, sealed with a transparent tape, and after about 1 hour (time until surgery), local skin reaction and analgesic effect were compared.

(4) Evaluation Criteria The score was 0 if there was no pain at all 5 points, 2 points if there was pain at only 2 points, 3.5 points if there was pain at 3 points and slight pain at another point.

When it reached 0 point, a needle was further inserted into the skin to a depth of about 1.0 mm to examine whether or not the pain at that time was felt.

The results are shown in Table 3.

The ointment c group to which the compound 4 was added was 1.3 ± 1.5, and the ointment b group to which the compound 4 was not added was 2.5 ± 1.7, indicating that the compound 4 had a significant analgesic effect (p <0.05). The number of pain scores reaching 0 was 4 in the ointment c group and 1 in the ointment b group. For these 5 people, about 1 26-gauge intradermal needle
3 out of 4 in the ointment c group, even if it penetrates the skin to a depth of mm,
One in the ointment group b did not complain of pain. Ointment c group 8 people, pain ointment b with pain score of 1 point or less by Pinprick method
This group consisted of 4 patients, and 12 patients were directly inserted with an intravenous indwelling needle. In this case, the usual intradermal injection of 0.5% procaine hydrochloride into the venipuncture site was performed, and the diameter of 20-18
Intravenous injection with a gauge indwelling needle was performed, and pain due to puncture in the skin and vein was evaluated by a pain score divided into 5 stages. The evaluation was as follows: 0 was no pain, 1 was touching, no pain, 2 was a little pain, 3 was painful, 4 was very painful. Significance test is performed by Wilcoxon rank sum test,
Others were performed by Student t-test.

In all cases, the risk rate of 5% or less was considered to be significant.

The results are shown in Table 4.

The pain scores at the time of skin puncture were 2.0 ± 1.1 in the ointment c group and 1.8 ± 1.0 in the ointment b group, showing no significant difference between the two groups.
The pain score during venipuncture was 1.9 ± 1.1 in the ointment c group and 3.3 ± 1.0 in the ointment b group, and the pain score was significantly lower in the ointment c group (p <0.05).

In the above test example, percutaneous absorption of lidocaine was promoted by the glycyrrhetinic acid derivative, and it was effective in removing pain during skin anesthesia and venipuncture, ensuring that veins in the anesthesiology area, epidural anesthesia, spinal anesthesia, etc. It is effective not only for children but also for children who fear injection.

Further, also in the dermatological field, when applying skin treatment in a non-anesthetic state, by applying this in advance, the patient can concentrate on the treatment without pain. As described above, the present invention is expected to have a wide range of clinical applications.

The acute toxicity test (LD ₅₀ ) of the compound of the present invention by oral administration in mice is as follows.

Compound 3: 520mg / kg 〃 4: 1,320mg / kg 〃 5: 1,257-1,520mg / kg 〃 6: 1,283-1,499mg / kg 〃 7: 628- 793mg / kg

[Brief description of drawings]

 The drawings show the results of animal experiments.

Continuation of the front page (51) Int.Cl. ⁵ Identification code Reference number within the agency FI Technical display area C07C 233/88 7106-4H C07H 15/256 C07J 63/00 9051-4C

Claims (7)

[Claims] 1. A general formula: [However, in the formula, R ₁ is -H, -OCCH ₂ CH ₂ COOH, or And a pharmaceutically acceptable salt thereof as an active ingredient. 2. A general formula: [Wherein X is 18β-olean-12-ene-3β, 30-diol, 18β-olean-9 (11), 12-diene-3β, 3
0-diol, or olean-11,13 (18) -diene-3
A residue of β, 30-diol], which is a residue of a glycyrrhetinic acid derivative, and a percutaneous absorption enhancer of a locally acting drug containing a pharmaceutically acceptable salt thereof as an active ingredient. 3. A general formula: [However, in the formula, R ₁ is -H, -OCCH ₂ CH ₂ COOH, or And a anesthetic for a local anesthetic containing a pharmaceutically acceptable salt thereof as an active ingredient. 4. A general formula: [Wherein X is olean-11,13 (18) -diene-3β, 30-
Diol, 18β-olean-12-ene-3β, 30-diol, or 18β-olean-9 (11), 12-diene-3
Glycyrrhetinic acid derivative represented by β, 30-diol residue] and a pharmaceutically acceptable salt of these local anesthetics as a percutaneous absorption enhancer. 5. A drug having the general formula: [However, in the formula, R ₁ is -H, -OCCH ₂ CH ₂ COOH, or And a pharmaceutically acceptable salt thereof. 6. A drug of the general formula: [Wherein X is olean-11,13 (18) -diene-3β, 30-
Diol, 18β-olean-12-ene-3β, 30-diol, or 18β-olean-9 (11), 12-diene-3
which is a residue of β, 30-diol] and a glycyrrhetinic acid derivative and a pharmaceutically acceptable salt thereof. 7. The transdermal preparation according to claim 5, wherein the topical agent is lidocaine or bupivacaine.