JPH0796500B2 - Pyrrolidone-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] A drug delivery system (DDS) has been actively studied for the purpose of more efficiently reaching a 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 in order to solve the above problems, and as a result, have found that a pyrrolidone derivative having a specific substituent has an extremely excellent transdermal absorption promoting action, and have completed the present invention. .

[Means for solving problems]

That is, the present invention has the general formula The present invention relates to a percutaneous absorption enhancer of a drug comprising a pyrrolidone derivative represented by the formula (wherein R ¹ is a lower alkyl group or a lower alkenyl group, and R ² is a hydrocarbon group having 6 or more carbon atoms).

In the formula, the hydrocarbon group having 6 or more carbon atoms represented by R ² is a saturated or unsaturated branched or linear hydrocarbon group, for example, normal- (n-), iso- (i-). Or a 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. , 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 pyrrolidone derivative in the present invention has, for example, the general formula (Wherein R ¹ is the same as the above), in the presence of a base, 1-alkyl-2-pyrrolidone represented by the general formula R ² X-(III) (wherein R ² is the same as the above). And X represents a halogen atom, a tosyloxy group, a mesyloxy group, or a trifluoromethanesulfonyloxy group.), And can be easily produced by reacting an alkylating agent represented by the formula.

Examples of the 1-alkyl-2-pyrrolidone derivative represented by the general formula (II) include 1-methyl-2-pyrrolidone and 1-
Ethyl-2-pyrrolidone, 1-n-propyl-2-pyrrolidone, 1-i-propyl-2-pyrrolidone, 1-n-
Butyl-2-pyrrolidone, 1-s-butyl-2-pyrrolidone, 1-i-butyl-2-pyrrolidone, 1-n-pentyl-2-pyrrolidone, 1-i-pentyl-2-pyrrolidone, 1-n- Examples include hexyl-2-pyrrolidone, 1-i-hexyl-2-pyrrolidone, 1-vinyl-2-pyrrolidone, 1-allyl-2-pyrrolidone and the like. Some of these compounds are commercially available,
Further, it is a compound that can be easily synthesized by alkylation of pyrrolidone.

Examples of the base include n-butyllithium, s-butyllithium, t-butyllithium, phenyllithium, lithium diisopropylamide, lithium bistrimethylsilylamide, potassium hydride, phenylmagnesium bromide and the like, usually 1-alkyl. 2-Equivalent to 1.5 equivalents with respect to pyrrolidone.

As the alkylating agent represented by the general formula (III), chloride, bromide, iodide, tosylate, mesylate, triflate, etc. of the corresponding hydrocarbon (R ² ) can be used. The base is preferably used, and an amount according to the amount of the base is usually used.

The reaction is preferably carried out in a solvent, and any solvent which does not participate in the reaction may be used, and examples thereof include tetrahydrofuran, dimethoxyethane, dioxane, benzene, toluene and the like. The reaction temperature may be -100 ° C to 50 ° C, preferably -80 ° C to 30 ° C.

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, Phenylbutazone, 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 ampicillin, cephalosporins such as cephalothin, 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, tripamide, meticlotiazide, penfluzide, hydrothiazide, spironolactone,
Metrazone, etc .; cardiotonics, digitalis, ubidecarenone, dopamine, etc .; coronary vasodilators, nitroglycerin, isosorbitol-dinitrate, erythritol-tetranitrate, pentaerythritol tetranitrate, dipyridamole, dilazeb, trapidil, trimetazidine, etc. Vasoconstrictors such as dihydroergotamine, dihydroergotoxin; β-blockers or antiarrhythmic agents such as pindol and propranolol hydrochloride; 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 1-3 Sodium hydride (1.4 g) and 2-pyrrolidone (5.0 g) were refluxed overnight in toluene to react. To each solution, the iodide described in Table 1 was added in the amount shown in Table 1,
The boiling point was refluxed again. The insoluble material was filtered, concentrated, and purified by silica gel column chromatography to obtain the corresponding 1-alkyl-2-pyrrolidone as a yellow oil.

Production Examples 1-6 A 15% hexane solution of n-butyllithium was added to a tetrahydrofuran (THF) solution of diisopropylamine at -78 ° C, and the mixture was reacted at the same temperature for 30 minutes. Into this solution, the amounts of 1-methyl-2-pyrrolidone, 1-ethyl-2-pyrrolidone, 1-vinyl-2-pyrrolidone (each commercially available) shown in Table 2 or Reference Examples 1 to 3 were obtained. Then, a THF solution of 1-alkyl-2-pyrrolidone was added and reacted at the same temperature. Furthermore, 1.2 equivalents of a solution of dodecyl bromide in THF was added and after reaction, the reaction mixture was treated by a conventional method and purified by silica gel column chromatography. The corresponding 3-dodecyl-1-alkylpyrrolidone was obtained as a yellow oil.

Production Example 7-8 A 15% hexane solution of n-butyllithium was added to a tetrahydrofuran (THF) solution of diisopropylamine at -78 ° C, and the mixture was reacted at the same temperature for 30 minutes. To this solution, 1.27 g of the 1-n-propyl-2-pyrrolidone THF solution obtained in Reference Example 1 was added and reacted at the same temperature. Further, 1.2 equivalents of a THF solution of bromide shown in Table 3 was added and reacted, and then the reaction mixture was treated by a conventional method and purified by silica gel column chromatography to obtain the corresponding 3-alkyl-1-
n-Propylpyrrolidone was obtained as a yellow oil. The results are shown in Table 3.

Examples 1 to 4 Rabbit abdominal exfoliation skin was sandwiched between two-chamber diffusion cells (effective area 0.95 cm ² ), and the anti-inflammatory agent indomethacin (1%) and the transdermal absorption enhancer of the present invention (2%) were 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 portion 6 hours after stirring 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.

Examples 5 to 9 A rabbit abdominal peeling skin is sandwiched between two-chamber diffusion cells (effective area 0.95 cm ² ), and an anti-inflammatory agent indomethacin (1%) and a transdermal absorption enhancer of the present invention (2%) are placed on the donor part. 2 ml of a 60% aqueous solution of ethyl alcohol was added, 2 ml of phosphate buffer was added to the receptor portion, and the entire cell was immersed in a constant temperature bath at 37 ° C. After stirring both chambers for 6 hours,
After 12 hours, the sample was sampled from the receptor and the amount of permeated indomethacin was quantified by high performance liquid chromatography. The transmission measurement results are shown in Table 5. Comparative Example 3 in which no percutaneous absorption enhancer was added, and Azone (1-dodecylazacycloheptane-2-
The case where "ON" is added is shown as Comparative Example 4.

Example 10 Rabbit abdominal exfoliated skin was sandwiched between two-chamber diffusion cells (effective area 0.95 cm ² ), and an antitumor agent 5-fluorouracil (1%) and a skin absorption enhancer of the present invention (2%) were placed on the donor part.
2 ml of the ethyl alcohol solution of 1 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 portion after stirring for 6 hours and 12 hours, and the permeated 5-fluorouracil was quantified by high performance liquid chromatography. The transmission measurement results are shown in Table 6. Comparative Example 5 shows the case where no transdermal absorption enhancer was added.

Example 11 A rabbit abdominal peeling skin was sandwiched between two-chamber diffusion cells (effective area 0.95 cm ² ), and β-blocker propranolol hydrochloride (1%) and the transdermal absorption enhancer of the present invention (2%) were placed in the donor part. 2 ml of a 60% aqueous solution of ethyl alcohol was placed, 2 ml of a phosphate buffer 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 6 hours after stirring and 12 hours after stirring, and the amount of permeated propranolol hydrochloride was quantified by high performance fluid chromatography. The transmission measurement results are shown in Table 7. Comparative Example 6 shows the case where no transdermal absorption enhancer was added.

Claims (1)

[Claims] 1. A general formula A percutaneous absorption enhancer of a drug comprising a pyrrolidone derivative represented by the formula (wherein R ¹ is a lower alkyl group or a lower alkenyl group, and R ² is a hydrocarbon group having 6 or more carbon atoms).