JPH0796499B2 - Sulfoxide-based transdermal absorption enhancer - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial field of use] The present invention relates to a percutaneous absorption enhancer which promotes permeation and absorption of a drug through the skin.

[Prior art]

Drug delivery systems (DDS) are being actively researched for the purpose of more efficiently reaching the target site and suppressing side effects. Among these, in recent years, a percutaneous absorption system in which the skin is the application site of the drug has attracted attention. The advantages of this system are that it avoids the first-pass effect in the liver, the skin permeation rate of the drug is controlled, the blood concentration can be maintained continuously and constantly, the administration is not affected by food and vomiting, the administration is not regulated. Easy,
The point is that it can be administered near the target site. But,
At present, there are disadvantages such that the dose is limited to a relatively small amount of drug, the drugs that can be used are limited, the deterioration of angular mass and skin allergic reaction may be promoted, and immediate effect cannot be expected. Therefore, in order to improve these points, the combined use of a percutaneous absorption enhancer is being studied.

So far, dimethyl sulfoxide, 1-dodecyl-2
-Pyrrolidone, 1-dotecilazacycloheptane-2-
The use of ON, urea, etc. has been proposed (supervised by Isao Kaetsu, drug delivery system, pages 213-237, CMC).

[Problems to be solved by the invention]

However, these accelerating agents are not always satisfactory in their accelerating effect, and the accelerating effect may be drastically reduced depending on the type of the drug medium. Therefore, a more versatile accelerating agent has been desired.

The present inventors have conducted extensive studies to solve the above-mentioned problems, and as a result, found that a benzyl sulfoxide derivative having a specific substituent exhibits an extremely excellent transdermal absorption promoting action, and completed the present invention. I arrived.

[Means for solving problems]

That is, the present invention has the general formula A percutaneous absorption enhancer of a drug consisting of a benzyl sulfoxide derivative represented by the formula (wherein R is a hydrocarbon group having 6 or more carbon atoms, X is a hydrogen atom, a lower alkyl group, a lower alkenyl group, a halogen atom, or a nitro group). Group, acyl group, amino group,
An acylamino group, a hydroxyl group, a carboxyl group, a lower alkoxycarbonyl group, and a lower alkoxy group. ) Is related to.

In the formula, the hydrocarbon group having 6 or more carbon atoms represented by R is a saturated or unsaturated branched or linear hydrocarbon group, for example, normal- (n-), iso- (i-), Alternatively, secondary (s-) hexyl group, heptyl group, octyl group, nonyl group, decyl group, undecyl group, dodecyl group, tridecyl group, tetradecyl group, pentadecyl group, hexadecyl group, heptadecyl group, octadecyl group, nonadecyl group, Examples thereof include eicosanyl group, oleyl group, geranyl group, farnesyl group and the like. Among these, those having 8 or more carbon atoms, particularly those having 10 or more carbon atoms, are preferable because of their large promoting effect.

The benzyl sulfoxide derivative in the present invention has, for example, a general formula (In the formula, X is the same as above, and Y represents a halogen atom, a tosyloxy group, a mesyloxy group, or a trifluoromethanesulfonyloxy group.) In the presence of a base, a benzene derivative represented by the general formula RSH-(III ) (In the formula, R is the same as the above), a general formula obtained by reacting a thiol compound It can be easily produced by oxidizing the benzyl sulfide derivative represented by

Examples of the benzene derivative represented by the general formula (II) include benzyl chloride, benzyl bromide, p-fluorobenzyl chloride, p-chlorobenzyl bromide, m-bromobenzyl bromide, o-methylbenzyl chloride and p-.
Ethylbenzyl chloride, p-isopropylbenzyl bromide, m- (n-butyl) benzyl chloride, p-vinylbenzyl chloride, m-allylbenzyl bromide,
p-trifluoromethylbenzyl bromide, p-nitrobenzyl chloride, p-acetylbenzyl chloride, m
-Aminobenzyl chloride, p-acetylaminobenzyl bromide, o-hydroxybenzyl chloride, m-bromomethylbenzoic acid, ethyl p-chloromethylbenzoate, p-methoxybenzyl chloride, m-ethoxybenzyl chloride, benzyl methanesulfonate, trifluoro Examples thereof include p-methylbenzyl methanesulfonate and o-chlorobenzyl p-toluenesulfonate. Some of these compounds are commercially available and can be easily synthesized by chloromethylation of the corresponding substituted benzene or halogenation or esterification of the corresponding benzyl alcohol or toluene derivative.

Examples of the base in sulfide synthesis include alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium t-butoxide, alkali metal hydrides such as sodium hydride and potassium hydride, and n-.
Butyllithium, phenyllithium, lithium diisopropylamide, lithium bistrimethylsilylamide,
Methylmagnesium bromide, phenylmagnesium bromide and the like can be mentioned, and they are usually used in the equivalent amount to 1.2 equivalents relative to the alkanethiol.

The reaction is preferably carried out in a solvent, and any solvent may be used so long as it does not participate in the reaction, and examples thereof include tetrahydrofuran, dimethoxyethane, dioxane, methanol, ethanol, benzene and toluene. The reaction temperature can be -30 ° C to 80 ° C, preferably -10 ° C to 50 ° C.

Examples of the oxidizing agent that can be used in the oxidation of the benzyl sulfide derivative represented by the general formula (IV) include m-chloroperbenzoic acid, hydrogen peroxide, peracetic acid, sodium metaperiodate, N-chlorosuccinimide and the like. Can be illustrated.

The amount of the oxidizing agent used may be an equivalent amount to the benzyl sulfide derivative represented by the general formula (IV), and may be appropriately increased depending on the progress of oxidation.

The reaction is preferably carried out in a solvent, and any solvent may be used as long as it does not participate in the reaction, and examples thereof include chloroform, methylene chloride, water and acetic acid. The reaction temperature may be selected such that the oxidation reaction proceeds and the by-product of sulfone is minimized. Generally, the reaction temperature is -100 ° C to 50 ° C, preferably -80 ° C to 30 ° C. be able to.

The transdermal absorption enhancer of the present invention, together with the drug to be administered,
A tincture dissolved in a solvent such as water or alcohol, or an ointment or cream mixed with an ointment or cream base.
Further, it can be used in any form such as a tape preparation mixed in a polymer film or an adhesive.

Although the content of the absorption enhancer of the present invention varies depending on the form of use, it is generally 0.1% by weight to 50% by weight, preferably 1% to 20% by weight, and when it is small, the absorption enhancing effect becomes small. When the amount is large, side effects such as skin irritation become significant and the drug release may be suppressed rather.

The drug used in the present invention may be any drug for humans or animals. For example, as an anti-inflammatory analgesic, acetaminophenone, aspirin, methyl salicylate, choline salicylate, glycol salicylate, l
-Menthol, camphor, mefenamic acid, flufenamic acid, indomethacin, diclofenac, alclofenac, ibuprofen, ketoprofen, naproxen, pranoprofen, fenoprofen, fempfen, flurbiprofen, indoprofen, fentiazac, tolmetin, Suprofen, penzadac, bufexamac, piroxicam, phenylptazone, oxyphenbutazone, clofezone, pentazocine, mepyrizole, etc .; as steroidal anti-inflammatory agents,
Hydrocortisone, prednisolone, dexamethasone,
Triamcinolone acetonide, fluocinolone acetonide, fludrocortisone acetate, etc .; chlorpheniramine as an antihistamine or antiallergic agent,
Glycyrrhizic acid, diphenhydramine, periactin, etc .; local anesthetics include benzocaine, procaine,
Dibucaine, lidocaine, etc .; Antibacterial agents, etc., include tetracyclines such as chlortetracycline, penicillins such as ambicillin, cephalosporins such as cephalotin, aminoglycosides such as kanamycin, macrolides such as erythromycin, chloramphenicol, Iodo compounds, nitrofurantoin, nystatin, amphotericin, fradiomycin, sulfonamides, pyrrolenitrin, clotrimazole,
Nitrofurazone etc .; Clonidine as an antihypertensive agent,
α-methyldova, reserpine, syrosingopine, resinamine, cinnarizine, hydrazine, brazosin, etc .;
Antihypertensive diuretics include theophylline, trichloromethiazide, furosemide, tribamide, meticlotiazide, penfluzide, hydrothiazide, spironolactone,
Metrazone, etc .; cardiotonics, digitalis, ubidecarenone, dovamine, etc .; coronary vasodilators, nitroglycerin, isosorbitol-dinitrate, erythritol-tetranitrate, pentaerythritol tetranitrate, dipyridamole, dilazeb, trapidil, trimetazidine, etc. Vasoconstrictors such as dihydroergotamine, dihydroergotoxin, etc .; β-blockers or antiarrhythmic agents such as vindol, propranolol hydrochloride, etc .; calcium antagonists such as diltiazem, nifedipine, nicardipine, verapamil, bencyclane, dilazeb; antiepileptic agents. As nitrazepam, meprobamate, phenytoin, etc .;
Anti-vertigo agents such as isoprenaline, betahistine, scopolamine; tranquilizers such as diazepam, lorazepam, flunitrazepam, fluphenazine, etc .; hypnotics such as phenobarbital, amobarbital, cyclobarbital; and muscle relaxants triperizone, baclofen. , Tantrolene sodium, cyclobenzaprine, etc .; atropine, levodova, etc. as agents for autonomic nerves; codeine, ephedrine, isoproterenol, dextromethorphan, orciprenaline, ipratropium bromide, as agents for respiratory organs
Cromoglycic acid etc .; Hormonal agents or antihormonal agents include corticotropin, oxytocin, vasopressin, testosterone, progesterone, estradiol, salivary gland hormone, thyroid hormone, adrenal hormone,
Kallikrein, insulin, oxendron, etc .; vitamins A, B, C, D, E, K and their derivatives, calcium cheferols, mecobalamin, etc .; antitumor agents 5-fluorouracil (5-FU) and Derivatives thereof, adriamycin, krestin, picibanil, ancitabine, cytarabine, etc .; Enzymes such as urokinase; Chinese herbs or herbal extracts
Licorice, aloe, purple root and the like; antiulcer agents include allantoin, aldioxa, alcloxa and the like; other prostaglandins, antidiabetic agents and the like.

If necessary, two or more of these drugs may be used in combination.

The drug preparation containing the transdermal absorption enhancer of the present invention can be applied by applying a necessary amount to the skin and mucous membranes (oral cavity, nasal cavity, rectum, vagina) of various parts of the human body according to the purpose. For example,
For local treatment of trauma, skin ulcer, myalgia, arthritis, etc., the site where the drug is easily absorbed is directly applied to or near the affected area or for systemic treatment of internal organs (eg: It is preferably applied to a non-developed area of keratin. When used as a cosmetic, the above-mentioned preparations as they are or those containing known cosmetic ingredients selected from the above-mentioned drugs are used for the purpose of cleaning the skin, packing, measures against sunburn and rough skin, and moisturizing. Can be used.

Hereinafter, the present invention will be described in more detail with reference to Reference Examples, Production Examples, Examples, and Comparative Examples.

Reference examples 1-7 The amounts of sodium hydride and thiol compound shown in Table 1 were reacted in tetrahydrofuran at 0 ° C. or room temperature. The benzene derivatives shown in Table 1 were added to this solution in the amounts shown in Table 1, and the mixture was reacted again at 0 ° C. or room temperature overnight. The insoluble material in the reaction mixture was filtered, concentrated, and purified by silica gel column chromatography to obtain the corresponding benzyl sulfide derivative.

Production Examples 1 to 4 The benzyl sulfide derivatives obtained in Reference Examples 1 to 3 and 5 in the amounts shown in Table 2 were dissolved in chloroform, and the solution was added with the chloroform solution of m-chloroperbenzoic acid in the amount shown in Table 2 at -30 ° C. Was slowly added dropwise. The mixture was stirred overnight at room temperature to carry out an oxidation reaction, and then treated by a conventional method. The product was recrystallized from ethanol and purified to obtain the desired benzyl sulfoxide derivative as white crystals.

Production Example 5-7 The benzyl sulfide derivatives obtained in Reference Examples 4, 6 and 7 in the amounts shown in Table 3 were dissolved in acetic acid, and the 30% aqueous hydrogen peroxide solution in the amount shown in Table 3 was added thereto, followed by 30 minutes at room temperature. It was made to react. After treating by a conventional method, the product was purified by silica gel column chromatography to obtain the desired benzyl sulfoxide derivative as white crystals.

Examples 1 to 5 Rabbit abdominal peeling skin is sandwiched between two-chamber diffusion cells (effective area 0.95 cm ² ), and anti-inflammatory drug indomethacin (1%) and transdermal absorption enhancer of the present invention (2%) are placed on the donor part. 2 ml of the ethyl alcohol solution described above was added, 2 ml of the phosphate buffer was added to the receptor portion, and the entire cell was immersed in a constant temperature bath at 37 ° C. Both chambers were sampled from the receptor part after stirring for 6 hours and 12 hours after stirring, and the permeated indomethacin was quantified by high performance fluid chromatography. The transmission measurement results are shown in Table 4. Comparative Example 1 in which no percutaneous absorption enhancer was added, and Azone was used as the percutaneous absorption enhancer.
The case where (1-dodecylazacycloheptan-2-one) is added is shown as Comparative Example 2.

Example 6 Rabbit abdominal exfoliated skin was sandwiched between two-chamber diffusion cells (effective area 0.95 cm ² ), and an antitumor agent 5-fluorouracil (1%) was used as a donor site, and the transdermal absorption enhancer of the present invention (2
%) Ethyl alcohol solution (2 ml), a phosphate buffer solution (2 ml) was placed in the receptor portion, and the entire cell was immersed in a constant temperature bath at 37 ° C. Both chambers were sampled from the receptor portion after stirring for 6 hours and 12 hours, and the amount of permeated 5-fluorouracil was quantified by high performance liquid chromatography. The transmission measurement results are shown in Table 5. Comparative Example 3 shows the case where no transdermal absorption enhancer was added.

Example 7 Rabbit abdominal peeling skin is sandwiched between two-chamber diffusion cells (effective area 0.95 cm ² ) and β-blocker is placed at the donor part.
2 ml of an ethyl alcohol solution of propranolol hydrochloride (1%), the present invention and a percutaneous absorption enhancer (2%) was placed, 2 ml of a phosphate buffer solution was placed in the receptor part, and the entire cell was immersed in a constant temperature bath at 37 ° C. Both chambers were sampled from the receptor portion after stirring for 6 hours and 12 hours under stirring, and the amount of permeated propranolol hydrochloride was quantified by high performance liquid chromatography. The transmission measurement results are shown in Table 6. Comparative Example 4 shows the case where no transdermal absorption enhancer was added.

Claims (1)

[Claims] 1. A general formula A percutaneous absorption enhancer of a drug consisting of a benzyl sulfoxide derivative represented by the formula (wherein R is a hydrocarbon group having 6 or more carbon atoms, X is a hydrogen atom, a lower alkyl group, a lower alkenyl group, a halogen atom, or a nitro group). Group, acyl group, amino group,
An acylamino group, a hydroxyl group, a carboxyl group, a lower alkoxycarbonyl group, and a lower alkoxy group. ).