JPH0827002A - Pharmaceutical preparation for eliminating storage of basic medicine in horny layer - Google Patents

Abstract

PURPOSE:To obtain a useful pharmaceutical preparation capable of eliminating the storage of a basic medicine in a horny layer and enhancing the percutaneous absorbability of the medicine. CONSTITUTION:This pharmaceutical preparation contains (A) a basic medicine combined with (B) an amino acid or its derivative selected from a neutral amino acid alkyl ester, a neutral amino acid alkenyl ester, a neutral amino acid aralkyl ester, a neutral amino acid amide, a basic amino acid, a basic amino acid alkyl ester, a basic amino acid alkenyl ester, a basic amino acid aralkyl ester, a basic amino acid amide and an N-alpha-benzoylbasic amino acid at (1:1) to (1:200), preferably (1:1) to (1:20) weight ratio of the ingredients (A) to (B). A compound of the formula [ring A is an aromatic or a heterocyclic ring which can be substituted with a halogen, an alkyl, an aryl, an acyl, an alkoxy, an alkylthio, NO2, CF3 or OH; R1 to R3 are each H or an alkyl or R1 and R2 are mutually bound to N to form a cyclic amino; Y is two H or O atoms; (m) is 1 or 2; (n) is 0-2; Z is NH which can be substituted with O, S, an alkyl or an aralkyl] is preferred as the basic medicine.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention efficiently supplies basic drugs,
The present invention also relates to a transdermal preparation that is rapidly absorbed.

[0002]

2. Description of the Related Art Formulations for transdermally administering a drug for the purpose of local action have been developed for a long time in various dosage forms such as plasters, tinctures, ointments, poultices and lotions.

On the other hand, oral routes, injections, suppositories, etc. have been generally used as the administration routes for administering drugs for the purpose of systemic action.

However, in recent years, it has been recognized that transdermal administration has various advantages which are difficult to obtain by other administration routes even as a method of administering a drug for the purpose of systemic action. Such advantages include, for example, avoidance of gastrointestinal disorders, avoidance of the first-pass effect, easy maintenance of the drug administration rate at a constant rate, long-term administration is possible with one administration, and only peeling off when administration is desired to be interrupted , Etc. (Sotarou Ogi; PHARM TACH JAPAN, Volume 10, No. 1, 13-2)
Page 4 (1994)).

Various preparations have been studied so far in order to take advantage of such advantages, and patches for the systemic action of drugs such as nitroglycerin, isosorbide dinitrate, scopolamine, clonidine, estradiol, and nicotine have been marketed. There is.

On the other hand, however, there are some problems peculiar to transdermal preparations. That is, it is difficult to absorb a necessary amount of the drug into the body because many drugs have low skin permeability. In addition, there are drawbacks such that the time from the administration of the preparation to the absorption of the drug in the body is often very long.

Originally, the skin, especially the stratum corneum forming the outermost layer thereof, has a physiological function as a defense wall against the permeation of substances into the body, and the above-mentioned problems are derived from the defense function of the stratum corneum. It is thought that. Therefore, in recent years, measures to temporarily reduce the barrier function of the stratum corneum and enhance the transdermal absorbability of drugs have been investigated, and various absorption enhancers ("Pha
rmaceutical Skin Penetration Enhancement "ed by Ke
nneth A. Walters and Jonathan Hadgraft, Marcel Dekk
er, Inc., New York, 1993) and iontophoresis (YWChien, O.Siddiqui, WMShi, P.Lelawongs &
JCLiu, J. Pharm.Sci., 78, 376 (198).
9)), Sonophoresis (DMSkauen and GMZentner,
Int. J. Pharm., 20: 235-245 (198).
4), sealing therapy (H. Oishi, Y. Uno, K. Narahara and M.
Takehara, Chem.Pharm.Bull., 24, 1765-17
It is well known that means such as page 73 (1976) has been found.

On the other hand, the above-mentioned problems are largely due not only to the barrier ability of the stratum corneum but also to the ability of the stratum corneum to bind a certain drug at a high concentration. That is, when such a drug is administered to the skin, it easily migrates to the stratum corneum, but since it is stored in a high concentration there, the amount of the drug that can reach the tissue below the stratum corneum is not enough. The result is that the amount of the drug administered is extremely small compared to the total amount of the drug administered, and the arrival time is significantly delayed.

It has been reported that binding to epidermal tissue containing such a stratum corneum occurs in some drugs (K. Walter and H. Kurt, J. Pharm. Pharmacol.,
40, 689-693 (1988)), and the mechanism and solution to it have not been found so far.

[0010]

DISCLOSURE OF INVENTION Problems to be Solved by the Invention The present inventors have conducted diligent studies to find effective additives for eliminating the retention of drugs in the stratum corneum and increasing the transdermal absorbability of drugs,
The present invention has been completed by finding that a specific substance group specifically eliminates retention of a basic drug in the stratum corneum.

[0011]

The present invention provides a basic drug, a neutral amino acid alkyl ester, a neutral amino acid alkenyl ester, a neutral amino acid aralkyl ester,
Neutral amino acid amide, basic amino acid, basic amino acid alkyl ester, basic amino acid alkenyl ester, basic amino acid aralkyl ester, basic amino acid amide, N-α-benzoyl basic amino acid amide selected from one or more kinds The present invention relates to a preparation for transdermal administration consisting of a selected amino acid or amino acid derivative, or a combination thereof.

The term "consisting of" means the following.

That is, a basic drug, a neutral amino acid alkyl ester, a neutral amino acid alkenyl ester, a neutral amino acid aralkyl ester, a neutral amino acid amide,
Amino acids or amino acids selected from one or more of basic amino acids, basic amino acid alkyl esters, basic amino acid alkenyl esters, basic amino acid aralkyl esters, basic amino acid amides, and N-α-benzoyl basic amino acid amides This is the case when the derivative is contained in the same preparation. On the other hand, "combination" means the following.

That is, a basic drug, a neutral amino acid alkyl ester, a neutral amino acid alkenyl ester, a neutral amino acid aralkyl ester, a neutral amino acid amide,
Amino acids or amino acids selected from one or more of basic amino acids, basic amino acid alkyl esters, basic amino acid alkenyl esters, basic amino acid aralkyl esters, basic amino acid amides, and N-α-benzoyl basic amino acid amides This is the case where each derivative is manufactured as a single preparation.

Then, a basic drug, a neutral amino acid alkyl ester, a neutral amino acid alkenyl ester,
Neutral amino acid aralkyl ester, neutral amino acid amide, basic amino acid, basic amino acid alkyl ester, basic amino acid alkenyl ester, basic amino acid aralkyl ester, basic amino acid amide, N-α
-When an amino acid or an amino acid derivative selected from one or more of benzoyl basic amino acid amides is manufactured as a single preparation, the administration method is amino acid before or after administration of the basic drug. Alternatively, an amino acid derivative may be administered.

Here, the basic drug is preferably a drug having one or more primary, secondary or tertiary amino groups as a dissociative amino group and no other dissociative functional group. Is. Further, as the drug having a plurality of these amino groups, derivatives of piperazine, hydrazine, guanidine, imidazole and isoquinoline are also included in the basic drug having a plurality of primary, secondary or tertiary amino groups of the present invention.

Examples of the basic drug include the following compounds.

(1) Compound having a primary amino group Amantadine hydrochloride, epinephrine, norepinephrine,
Metallaminol tartrate, norphenephrine hydrochloride, octopamine hydrochloride, methoxamine hydrochloride, hexothiocaine hydrochloride, ethifermine hydrochloride, benserazide hydrochloride, dopamine hydrochloride.

(2) Compound having secondary amino group Isopropylaminomethylheptane hydrochloride, improsulfan tosylate, ethambutol hydrochloride, ketamine hydrochloride,
Mecamylamine hydrochloride, demecorcin, salbutamol sulfate, chlorprenaline hydrochloride, orciprenaline sulfate, terbutaline sulfate, hexoprenaline sulfate, protoxylol hydrochloride, isoproterenol hydrochloride, ephedrine hydrochloride,
Phenylephrine hydrochloride, etilefrine hydrochloride, buprenolol hydrochloride, alprenolol hydrochloride, oxprenolol hydrochloride, niridrine hydrochloride, isoxpurine hydrochloride, bamethan sulfate, bitolterol mesylate, metoprolol tartrate, tulobuterol hydrochloride, oxyfedrine hydrochloride, meprilcaine hydrochloride, methamphetamine hydrochloride, Methoxyphenamine Hydrochloride, Pleniryl Lactate, Ambroxol Hydrochloride, Labetalol Hydrochloride, Acebutolol Hydrochloride, Bunitrolol Hydrochloride, Azacyclonol, Piperadol Hydrochloride,
Maprotiline hydrochloride, nortriptyline hydrochloride, bumolol hydrochloride, betahistine mesylate, phenylamidol hydrochloride, pirbuterol hydrochloride, methylphenidate hydrochloride, trimethoquinol hydrochloride, procaterol hydrochloride, clonidine hydrochloride.

(3) Compounds having a tertiary amino group Dimethyl thiambutene hydrochloride, triethanolamine hydrochloride, troll nitrate hydrochloride, carbetapentene citrate, dicyclomine hydrochloride, bencyclane fumarate, aromatic compounds, crobutynol hydrochloride, Methylephedrine hydrochloride, bufetrol hydrochloride, trihexyphenidyl hydrochloride,
Biperidene hydrochloride, procyclidine hydrochloride, carbinoxamine maleate, diphenhydramine, chlorphenoxamine hydrochloride, difeterol hydrochloride, etafenone hydrochloride,
Pipamperone hydrochloride, moperone hydrochloride haloperidol, trifluperidol hydrochloride, spiperone, tolperisone hydrochloride,
Eperisone hydrochloride, procaine hydrochloride, tetracaine hydrochloride,
Chlorprocaine hydrochloride, oxybuprocaine hydrochloride, oxerazine tannate, meclofenoxate hydrochloride, tonzylamine hydrochloride, bromhexine hydrochloride, chlorpheniramine maleate, procainamide hydrochloride, metoclopramide hydrochloride, aloclamide hydrochloride, loperamide hydrochloride, disopyramide, oxacezain, lidocaine, Prilocaine hydrochloride, hominoben hydrochloride, verapamil hydrochloride, isoaminyl citrate, guanethidine sulfate, diphenidol hydrochloride, diphenyl-N-piperidinobutanol hydrochloride, puridinol methanesulfonate, clofedanol hydrochloride, piperidolate hydrochloride, pipetanate hydrochloride, benactidine hydrochloride, bucridine hydrochloride. , Hydroxyzine, cinnarizine, meclizine hydrochloride, cyclidine hydrochloride, homochlorcyclidine hydrochloride, crema fumarate Chin, hydrochloric acid diphenylpyraline,
Cloperastine hydrochloride, tinsedal, tamoxifen citrate, dimethindene maleate, indenolol hydrochloride, propranolol hydrochloride, melitracene hydrochloride, amitriptyline hydrochloride, pyroheptin hydrochloride, cyproheptadine hydrochloride, doxepin hydrochloride, carbochromene hydrochloride, flavoxate hydrochloride, dimephrine hydrochloride, flupentixol hydrochloride, Methixene hydrochloride, chlorprothixene, thiothixene, prolintan hydrochloride, mebuhydroline napadisylate,
Strychnine sulfate, ajmaline, triprolidine hydrochloride, nicametate citrate, nicardipine hydrochloride, pethidine hydrochloride, mepivacaine hydrochloride, bupivacaine hydrochloride, picoperin palmitate, benproperine phosphate, fentanyl citrate, ifenprodil tartrate, dibucaine hydrochloride, dimethamine hydrogen tartrate, imipramine hydrochloride, Clomipramine hydrochloride, clocapramine hydrochloride, trimipramine maleate, desipramine hydrochloride, carpipramine, lofepramine hydrochloride, perrapine, opipramol hydrochloride, pentazocine, morphine hydrochloride, ethylmorphine hydrochloride, codeine phosphate, dihydrocodeine phosphate, oxymorphone hydrochloride, oxycodone hydrochloride, levorfa tartrate. Noor,
Levallorphan tartrate, dextromethorphan hydrobromide, dimemorphan phosphate, oxymethebanol, atropine sulfate, cocaine hydrochloride, benztropine methanesulfonate, mazathicol hydrochloride, scopolamine hydrobromide, benzydamine hydrochloride, clemizole hydrochloride, oxyphencyclyl hydrochloride. Min, flurazepam hydrochloride, divenzepine hydrochloride, mianserin hydrochloride, perisoxacitrate,
Tinolidine hydrochloride, ticlopidine hydrochloride, diltiazem hydrochloride, chlorpromazine hydrochloride, promazine hydrochloride, perazine, levomepromazine maleate, spirocromazine hydrochloride, thioridazine hydrochloride, pericazine, promethazine hydrochloride, ethopropazine hydrochloride, phenetazine hydrochloride, methomilazine tartrate, alfimezine hydrochloride, isofemazine hydrochloride, isofomemazine hydrochloride, oxomedamazine, oxomedamidine. Promazine, mequitazine, vinpocetine, buprenorphine hydrochloride, proxasol citrate, mexazolam, haloxazolam, ketotifen fumarate.

(4) Piperazine Derivatives trimetazidine hydrochloride, eplazinone hydrochloride, cinepazide maleate, prazosin hydrochloride, tiaramide hydrochloride, prochlorperazine maleate, perphenazine, fluphenazine hydrochloride, triproperazine, thioproperazine, fluphenazine enanthate. .

(5) Hydrazine derivative Procarbazine hydrochloride, hydralazine hydrochloride, ecarazine hydrochloride.

(6) Guanidine Derivatives Metformin hydrochloride, buformin hydrochloride, gabexate mesylate, betanidine sulfate.

(7) Imidazole derivative pilocarpine hydrochloride, tolazoline hydrochloride, tramazoline hydrochloride, tetrahydrozoline nitrate, oxymetazoline hydrochloride,
Naphazoline nitrate.

(8) Isoquinoline derivative Papaverine hydrochloride, etaverine hydrochloride.

(9) General formula

[0027]

Embedded image

(In the formula, Ring A is the same or different and is substituted with a halogen atom, a lower alkyl group, an aryl group, an acyl group, a lower alkoxy group, a lower alkylthio group, a nitro group, a trifluoromethyl group or a hydroxyl group. R ₁ and R ₂ are the same or different and each independently represent a hydrogen atom, a lower alkyl group or a cyclic amino group formed by bonding to a nitrogen atom,
₃ represents a hydrogen atom or a lower alkyl group, Y represents two hydrogen atoms or an oxygen atom, m represents 1 or 2, n represents 0, 1 or 2, Z represents an oxygen atom, a sulfur atom or It represents an imino group which may have a lower alkyl group or an aralkyl group as a substituent. And a pharmaceutically acceptable acid addition salt thereof.

In the compound having the above-mentioned general formula (I), ring A preferably has as a substituent a halogen atom such as a fluorine atom or a chlorine atom or an alkyl group having 1 to 2 carbon atoms such as methyl or ethyl. A benzene ring or a thiophene ring having a formula —N (R ₁ ) (R ₂ ) group which is a dimethylamino group, a dialkylamino group having 1 or 2 carbon atoms such as a diethylamino group, a 1-pyrrolidinyl group or a piperidino group. R ₃ is a hydrogen atom, Y is two hydrogen atoms or oxygen atoms, n is 0 or 1, and Z is a sulfur atom.

Specific examples of the compound having the above general formula (I) include the following compounds and salts thereof. 1) 3- (1-pyrrolidinyl) methyl-4- (1-indanecarbonyl) thiomorpholine 2) 3- (1-pyrrolidinyl) methyl-4- (3-oxo-1-indanecarbonyl) thiomorpholine 3) 3- (1-Pyrrolidinyl) methyl-4- (3-oxo-5-chloro-1-indancarbonyl) thiomorpholine 4) 3- (1-pyrrolidinyl) methyl-4- (5-chloro-1-indancarbonyl) thiomorpholine 5) 3- (1-pyrrolidinyl) methyl-4- (3-oxo-5-methyl-1-indanecarbonyl) thiomorpholine 6) 3- (1-pyrrolidinyl) methyl-4- (5-methyl-1-indane Carbonyl) thiomorpholine 7) 3- (1-pyrrolidinyl) methyl-4- (3-oxo-5-methoxy-1-indanecarbonyl) thiomo Folin 8) 3- (1-pyrrolidinyl) methyl-4- (5-methoxy-1-indanecarbonyl) thiomorpholine 9) 3- (1-pyrrolidinyl) methyl-4- (3-oxo-5-isopropyl-1- Indancarbonyl) thiomorpholine 10) 3- (1-pyrrolidinyl) methyl-4- (5-isopropyl-1-indancarbonyl) thiomorpholine 11) 3- (1-pyrrolidinyl) methyl-4- (3-oxo-6- Chloro-1-indancarbonyl) thiomorpholine 12) 3- (1-pyrrolidinyl) methyl-4- (6-chloro-1-indancarbonyl) thiomorpholine 13) 3- (1-pyrrolidinyl) methyl-4- (3- Oxo-6-methyl-1-indancarbonyl) thiomorpholine 14) 3- (1-pyrrolidinyl) methyl-4- ( -Methyl-1-indancarbonyl) thiomorpholine 15) 3- (1-pyrrolidinyl) methyl-4- (3-oxo-6-methoxy-1-indanecarbonyl) thiomorpholine 16) 3- (1-pyrrolidinyl) methyl- 4- (6-Methoxy-1-indanecarbonyl) thiomorpholine 17) 3- (1-pyrrolidinyl) methyl-4- (3-oxo-6-isopropyl-1-indanecarbonyl) thiomorpholine 18) 3- (1- Pyrrolidinyl) methyl-4- (6-isopropyl-1-indanecarbonyl) thiomorpholine 19) 3- (1-pyrrolidinyl) methyl-4- (3-oxo-5,6-dichloro-1-indanecarbonyl) thiomorpholine 20 ) 3- (1-Pyrrolidinyl) methyl-4- (5,6
-Dichloro-1-indancarbonyl) thiomorpholine 21) 3- (1-pyrrolidinyl) methyl-4- (3-oxo-5,6-difluoro-1-indanecarbonyl)
Thiomorpholine 22) 3- (1-pyrrolidinyl) methyl-4- (5,6
-Difluoro-1-indancarbonyl) thiomorpholine 23) 3- (1-pyrrolidinyl) methyl-4- (3-oxo-5,6-dimethyl-1-indanecarbonyl) thiomorpholine 24) 3- (1-pyrrolidinyl) Methyl-4- (5,6
-Dimethyl-1-indanecarbonyl) thiomorpholine 25) 3-piperidinomethyl-4- (3-oxo-1-)
Indancarbonyl) thiomorpholine 26) 3-piperidinomethyl-4- (1-indancarbonyl) thiomorpholine 27) 3-piperidinomethyl-4- (3-oxo-5-)
Chlor-1-indancarbonyl) thiomorpholine 28) 3-piperidinomethyl-4- (5-chloro-1-)
Indancarbonyl) thiomorpholine 29) 3-piperidinomethyl-4- (3-oxo-5-
Methyl-1-indancarbonyl) thiomorpholine 30) 3-piperidinomethyl-4- (5-methyl-1-)
Indancarbonyl) thiomorpholine 31) 3-piperidinomethyl-4- (3-oxo-5-
Isopropyl-1-indancarbonyl) thiomorpholine 32) 3-piperidinomethyl-4- (5-isopropyl-1-indancarbonyl) thiomorpholine 33) 3-piperidinomethyl-4- (3-oxo-6-
Chlor-1-indancarbonyl) thiomorpholine 34) 3-piperidinomethyl-4- (6-chloro-1-)
Indanecarbonyl) thiomorpholine 35) 3-piperidinomethyl-4- (3-oxo-6-
Methyl-1-indancarbonyl) thiomorpholine 36) 3-piperidinomethyl-4- (6-methyl-1-)
Indancarbonyl) thiomorpholine 37) 3-piperidinomethyl-4- (3-oxo-6-
Isopropyl-1-indancarbonyl) thiomorpholine 38) 3-piperidinomethyl-4- (6-isopropyl-1-indancarbonyl) thiomorpholine 39) 3-piperidinomethyl-4- (3-oxo-5,
6-dichloro-1-indancarbonyl) thiomorpholine 40) 3-piperidinomethyl-4- (5,6-dichloro-1-indancarbonyl) thiomorpholine 41) 3-piperidinomethyl-4- (3-oxo-5,
6-difluoro-1-indancarbonyl) thiomorpholine 42) 3-piperidinomethyl-4- (5,6-difluoro-1-indancarbonyl) thiomorpholine 43) 3-piperidinomethyl-4- (3-oxo-5,
6-dimethyl-1-indancarbonyl) thiomorpholine 44) 3-piperidinomethyl-4- (5,6-dimethyl-1-indancarbonyl) thiomorpholine 45) 3-morpholinomethyl-4- (3-oxo-5,
6-dichloro-1-indancarbonyl) thiomorpholine 46) 3-morpholinomethyl-4- (5,6-dichloro-1-indancarbonyl) thiomorpholine 47) 3- [1- (4-methyl) piperazinyl] methyl- 4- (3-oxo-5,6-dichloro-1-indancarbonyl) thiomorpholine 48) 3- [1- (4-methyl) piperazinyl] methyl-4- (5,6-dichloro-1-indancarbonyl)
Thiomorpholine 49) 3- (1-pyrrolidinyl) methyl-4- [4 (3
H) -oxo-1,2-dihydro-1-naphthoyl] thiomorpholine 50) 3- (1-pyrrolidinyl) methyl-4- [1,
2,3,4-Tetrahydro-1-naphthoyl] thiomorpholine 51) 3- (1-pyrrolidinyl) methyl-4- [6-chloro-4 (3H) -oxo-1,2-dihydro-1-naphthoyl] thio Morpholine 52) 3- (1-pyrrolidinyl) methyl-4- [6-chloro-1,2,3,4-tetrahydro-1-naphthoyl] thiomorpholine 53) 3- (1-pyrrolidinyl) methyl-4- [6 -Methyl-4 (3H) -oxo-1,2-dihydro-1-naphthoyl] thiomorpholine 54) 3- (1-pyrrolidinyl) methyl-4- [6-methyl-1,2,3,4-tetrahydro- 1-naphthoyl] thiomorpholine 55) 3- (1-pyrrolidinyl) methyl-4- [6-isopropyl-4 (3H) -oxo-1,2-dihydro-
1-naphthoyl] thiomorpholine 56) 3- (1-pyrrolidinyl) methyl-4- [6-isopropyl-1,2,3,4-tetrahydro-1-naphthoyl] thiomorpholine 57) 3- (1-pyrrolidinyl) methyl -4- [7-Chloro-4 (3H) -oxo-1,2-dihydro-1-naphthoyl] thiomorpholine 58) 3- (1-pyrrolidinyl) methyl-4- [7-chloro-1,2,3 , 4-Tetrahydro-1-naphthoyl] thiomorpholine 59) 3- (1-pyrrolidinyl) methyl-4- [7-methyl-4 (3H) -oxo-1,2-dihydro-1-naphthoyl] thiomorpholine 60) 3- (1-pyrrolidinyl) methyl-4- [7-methyl-1,2,3,4-tetrahydro-1-naphthoyl] thiomorpholine 61) 3- (1-pyrrolidinyl) Chill-4- [7- isopropyl -4 (3H) - oxo-1,2-dihydro -
1-naphthoyl] thiomorpholine 62) 3- (1-pyrrolidinyl) methyl-4- [7-isopropyl-1,2,3,4-tetrahydro-1-naphthoyl] thiomorpholine 63) 3- (1-pyrrolidinyl) methyl -4- [6, 7
-Dichloro-4 (3H) -oxo-1,2-dihydro-
1-naphthoyl] thiomorpholine 64) 3- (1-pyrrolidinyl) methyl-4- [6,7
-Dichloro-1,2,3,4-tetrahydro-1-naphthoyl] thiomorpholine 65) 3- (1-pyrrolidinyl) methyl-4- [6,7
-Difluoro-4 (3H) -oxo-1,2-dihydro-1-naphthoyl] thiomorpholine 66) 3- (1-pyrrolidinyl) methyl-4- [6,7
-Difluoro-1,2,3,4-tetrahydro-1-naphthoyl] thiomorpholine 67) 3-piperidinomethyl-4- [4 (3H) -oxo-1,2-dihydro-1-naphthoyl] thiomorpholine 68) 3 -Piperidinomethyl-4- [1,2,3,4-
Tetrahydro-1-naphthoyl] thiomorpholine 69) 3-piperidinomethyl-4- [6-chloro-4
(3H) -oxo-1,2-dihydro-1-naphthoyl] thiomorpholine 70) 3-piperidinomethyl-4- [6-chloro-1,
2,3,4-Tetrahydro-1-naphthoyl] thiomorpholine 71) 3-piperidinomethyl-4- [6-methyl-4
(3H) -oxo-1,2-dihydro-1-naphthoyl] thiomorpholine 72) 3-piperidinomethyl-4- [6-methyl-1,
2,3,4-Tetrahydro-1-naphthoyl] thiomorpholine 73) 3-piperidinomethyl-4- [7-chloro-4
(3H) -oxo-1,2-dihydro-1-naphthoyl] thiomorpholine 74) 3-piperidinomethyl-4- [7-chloro-1,
2,3,4-Tetrahydro-1-naphthoyl] thiomorpholine 75) 3-piperidinomethyl-4- [7-methyl-4]
(3H) -oxo-1,2-dihydro-1-naphthoyl] thiomorpholine 76) 3-piperidinomethyl-4- [7-methyl-1,
2,3,4-Tetrahydro-1-naphthoyl] thiomorpholine 77) 3-Piperidinomethyl-4- [6,7-dichloro-4 (3H) -oxo-1,2-dihydro-1-naphthoyl] thiomorpholine 78) 3-Piperidinomethyl-4- [6,7-dichloro-1,2,3,4-tetrahydro-1-naphthoyl] thiomorpholine 79) 3-morpholinomethyl-4- [4 (3H) -oxo-1,2- Dihydro-1-naphthoyl] thiomorpholine 80) 3-morpholinomethyl-4- [1,2,3,4-
Tetrahydro-1-naphthoyl] thiomorpholine 81) 3-morpholinomethyl-4- [6,7-dichloro-4 (3H) -oxo-1,2-dihydro-1-naphthoyl] thiomorpholine 82) 3-morpholinomethyl- 4- [6,7-Dichloro-1,2,3,4-tetrahydro-1-naphthoyl] thiomorpholine 83) 3- (1-pyrrolidinyl) methyl-4- [3-oxo-1-indanecarbonyl] morpholine 84 ) 3- (1-Pyrrolidinyl) methyl-4- [3-oxo-5-chloro-1-indancarbonyl] morpholine 85) 3- (1-pyrrolidinyl) methyl-4- [3-oxo-5,6-dichloro -1-Indancarbonyl] morpholine 86) 3-morpholinomethyl-4- [3-oxo-5,
6-dichloro-1-indancarbonyl] morpholine 87) 3- (1-pyrrolidinyl) methyl-4- [4 (3
H) -oxo-1,2-dihydro-1-naphthoyl] morpholine 88) 3- (1-pyrrolidinyl) methyl-4- [1,
2,3,4-Tetrahydro-1-naphthoyl] morpholine 89) 3- (1-pyrrolidinyl) methyl-4- [6,7
-Dichloro-4 (3H) -oxo-1,2-dihydro-
1-naphthoyl] morpholine 90) 3- (1-pyrrolidinyl) methyl-4- [6,7
-Dichloro-1,2,3,4-tetrahydro-1-naphthoyl] morpholine 91) 3-dimethylaminomethyl-4- [3-oxo-
5-chloro-1-indancarbonyl] morpholine 92) 1- (3-oxo-1-indanecarbonyl)-
2- (1-Pyrrolidinyl) methyl-4-methylpiperazine 93) 1- (1-Indancarbonyl) -2- (1-pyrrolidinyl) methyl-4-methylpiperazine 94) 1- (3-oxo-5-chloro- 1-Indancarbonyl) -2- (1-pyrrolidinyl) methyl-4-methylpiperazine 95) 1- (5-chloro-1-indancarbonyl)-
2- (1-pyrrolidinyl) methyl-4-methylpiperazine 96) 1- (3-oxo-5-methyl-1-indanecarbonyl) -2- (1-pyrrolidinyl) methyl-4-methylpiperazine 97) 1- ( 5-methyl-1-indanecarbonyl)-
2- (1-Pyrrolidinyl) methyl-4-methylpiperazine 98) 1- (3-oxo-5,6-dichloro-1-indanecarbonyl) -2- (1-pyrrolidinyl) methyl-
4-Methylpiperazine 99) 1- (5,6-dichloro-1-indancarbonyl) -2- (1-pyrrolidinyl) methyl-4-methylpiperazine 100) 1- [4 (3H) -oxo-1,2- Dihydro-1-naphthoyl] -2- (1-pyrrolidinyl) methyl-4-methylpiperazine 101) 1- [1,2,3,4-tetrahydro-1-naphthoyl] -2- (1-pyrrolidinyl) methyl-4 -Methylpiperazine 102) 1- [6-chloro-4 (3H) -oxo-1,
2-Dihydro-1-naphthoyl] -2- (1-pyrrolidinyl) methyl-4-methylpiperazine 103) 1- [6-chloro-1,2,3,4-tetrahydro-1-naphthoyl] -2- (1 -Pyrrolidinyl) methyl-4-methylpiperazine 104) 1- [6,7-dichloro-4 (3H) -oxo-1,2-dihydro-1-naphthoyl] -2- (1-pyrrolidinyl) methyl-4-methyl Piperazine 105) 1- [6,7-dichloro-1,2,3,4-tetrahydro-1-naphthoyl] -2- (1-pyrrolidinyl) methyl-4-methylpiperazine 106) 1- (3-oxo-5 , 6-Dichloro-1-indancarbonyl) -2-piperidinomethyl-4-methylpiperazine 107) 1- (5,6-dichloro-1-indancarbonyl) -2-piperi Nomechiru methylpiperazine 108) 3- (1-pyrrolidinyl) methyl-4- (5,
6-Dichloro-1-indancarbonyl] morpholine 109) 4,5-dihydro-4- [3- (1-pyrrolidinyl) methylthiomorpholine-4-carbonyl] -6-
Oxo-6H-cyclopenta [b] thiophene 110) 4,5-dihydro-4- [3- (1-pyrrolidinyl) methylthiomorpholine-4-carbonyl] -6H
-Cyclopenta [b] thiophene 111) 4,5-Dihydro-4- [3- (1-pyrrolidinyl) methylthiomorpholine-4-carbonyl] -6-
Oxo-6H-cyclopenta [b] furan 112) 4,5-dihydro-4- [3- (1-pyrrolidinyl) methylthiomorpholine-4-carbonyl] -7
(6H) -oxo-benzo [b] thiophene 113) 3- (1-pyrrolidinyl) methyl-4- (2,
2-dimethyl-3-oxo-1-indanecarbonyl)
Thiomorpholine 114) 3- (1-pyrrolidinyl) methyl-4- (3-
Oxo-5-methylthio-1-indanecarbonyl) thiomorpholine and their diastereoisomers and optically active isomers.

The carboxylic acid amide compound having the general formula (I) or a pharmacologically acceptable acid addition salt thereof is a known compound, for example, its production method and use are described in JP-A-3-163068. Has been done.

Neutral amino acid alkyl ester, neutral amino acid alkenyl ester, neutral amino acid aralkyl ester, neutral amino acid amide, used in the present invention,
Basic amino acids, basic amino acid alkyl esters, basic amino acid alkenyl esters, basic amino acid aralkyl esters, basic amino acid amides, N-α-benzoyl basic amino acid amides, for example, glycine, alanine, valine, Leucine,
Isoleucine, phenylalanine, tyrosine, proline, serine, threonine, cystine, methionine, neutral amino acids such as tryptophan, basic amino acids such as lysine, arginine, histidine, preferably glycine, alanine, lysine, arginine. Yes,
Most preferably, lysine and arginine.

Examples of the alkyl group in the neutral amino acid alkyl ester or basic amino acid alkyl ester used in the present invention include carbon such as methyl, ethyl, propyl, butyl, isopropyl, t-butyl, pentyl, hexyl, heptyl and octyl. Number 1 to 8
A linear or branched alkyl group having a number of
Preferred is a linear or branched alkyl group having 1 to 4 carbon atoms such as methyl, ethyl, propyl and t-butyl, and most preferred is methyl or ethyl. The alkenyl group in the neutral amino acid alkenyl ester or basic amino acid alkenyl ester used in the present invention has 2 to 5 carbon atoms such as vinyl, allyl, 1-propenyl, isopropenyl, 2-butenyl and 2-pentenyl. A straight chain or branched chain alkenyl group having, preferably a straight chain or branched chain alkyl group having 2 to 3 carbon atoms such as vinyl, allyl, 1-propenyl and isopropenyl. Yes, optimally allyl.

The aralkyl group in the neutral amino acid aralkyl ester or the basic amino acid aralkyl ester used in the present invention is benzyl, phenethyl, α-methylbenzyl, 3-phenylpropyl, 4-
It is an aralkyl group consisting of phenyl such as phenylbutyl and 5-phenylpentyl and a linear or branched alkyl group having 1 to 5 carbon atoms, preferably benzyl, phenethyl, α-methylbenzyl, 3 An aralkyl group consisting of phenyl, such as phenylpropyl, and straight-chain or branched alkyl having 1 to 3 carbon atoms, most preferably benzyl.

Neutral amino acid alkyl ester, neutral amino acid alkenyl ester, neutral amino acid aralkyl ester, neutral amino acid amide used in the present invention,
Specific examples of the basic amino acid, basic amino acid alkyl ester, basic amino acid alkenyl ester, basic amino acid aralkyl ester, basic amino acid amide, and N-α-benzoyl basic amino acid amide include (1) glycine methyl and glycine Ethyl, glycinepropyl, glycine-t-butyl, glycinebutyl, glycinebutyl, glycineisopropyl, glycinepentyl, glycinehexyl, glycineheptyl, glycineoctyl, alaninemethyl, alanineethyl, alaninepropyl, alaninebutyl, alanineisopropyl, alanine-t -Butyl, alanine pentyl, alanine hexyl,
Alanine heptyl, alanine octyl, valine methyl,
Valine ethyl, valine propyl, valine butyl, valine isopropyl, valine-t-butyl, valine pentyl,
Valine hexyl, valine heptyl, valine octyl, leucine methyl, leucine ethyl, leucine propyl, leucine butyl, leucine isopropyl, leucine-t-
Butyl, leucine pentyl, leucine hexyl, leucine heptyl, leucine octyl, isoleucine methyl,
Isoleucine ethyl, isoleucine propyl, isoleucine butyl, isoleucine isopropyl, isoleucine-t-butyl, isoleucine pentyl, isoleucine hexyl, isoleucine heptyl, isoleucine octyl, phenylalanine methyl, phenylalanine ethyl, phenylalanine propyl, phenylalanine butyl, phenylalanine isopropyl, phenylalanine-t-butyl. , Phenylalanine pentyl, phenylalanine hexyl, phenylalanine heptyl, phenylalanine octyl, tyrosine methyl, tyrosine ethyl,
Tyrosine propyl, tyrosine butyl, tyrosine isopropyl, tyrosine-t-butyl, tyrosine pentyl, tyrosine hexyl, tyrosine heptyl, tyrosine octyl,
Proline methyl, proline ethyl, proline propyl,
Proline butyl, proline isopropyl, proline-t
-Butyl, proline pentyl, proline hexyl, proline heptyl, proline octyl, serine methyl, serine ethyl, serine propyl, serine butyl, serine isopropyl, serine-t-butyl, serine pentyl, serine hexyl, serine heptyl, serine octyl, threonine methyl, threonine ethyl , Threonine propyl,
Threonine butyl, threonine isopropyl, threonine-t-butyl, threonine pentyl, threonine hexyl, threonine heptyl, threonine octyl, cystine methyl, cystine ethyl, cystine propyl, cystine butyl, cystine isopropyl, cystine-t-butyl, cystine pentyl, cystine hexyl , Cystine heptyl, cystine octyl,
Methionine methyl, methionine ethyl, methionine propyl, methionine butyl, methionine isopropyl, methionine-t-butyl, methionine pentyl, methionine hexyl, methionine heptyl, methionine octyl, tryptophan methyl, tryptophan ethyl, tryptophan propyl, tryptophan butyl, tryptophan isopropyl, tryptophan- t-butyl,
Neutral amino acid alkyl esters such as tryptophan pentyl, tryptophan hexyl, tryptophan heptyl, tryptophan octyl; (2) glycine allyl, alanine allyl, valine allyl, leucine allyl, isoleucine allyl, phenylalanine allyl, tyrosine allyl, proline allyl, serine allyl, threonine allyl. Neutral amino acid alkenyl esters such as cystine allyl, methionine allyl, and tryptophan allyl; (3) Glycine benzyl, alanine benzyl, valine benzyl, leucine benzyl, isoleucine benzyl, phenylalanine benzyl, tyrosine benzyl, proline benzyl, serine benzyl, threonine benzyl. , Cystine benzyl, methionine benzyl, tryptophan benzyl Neutral amino acid aralkyl ester; (4) Medium such as glycine amide, alanine amide, valine amide, leucine amide, isoleucine amide, phenylalanine amide, tyrosine amide, proline amide, serine amide, threonine amide, cystine amide, methionine amide, tryptophan amide (5) basic amino acids such as lysine, arginine, and histidine; (6) lysine methyl, lysine ethyl, lysine propyl;
Lysine butyl, lysine isopropyl, lysine-t-butyl, lysine pentyl, lysine hexyl, lysine heptyl, lysine octyl, arginine methyl, arginine ethyl, arginine propyl, arginine butyl, arginine isopropyl, arginine-t-butyl, arginine pentyl, arginine hexyl, (7) Basic amino acid alkyl ester such as arginine heptyl, arginine octyl, histidine methyl, histidine ethyl, histidine propyl, histidine butyl, histidine isopropyl, histidine-t-butyl, histidine pentyl, histidine hexyl, histidine heptyl, histidine octyl; Basic amino acid alkenyl ester such as lysine allyl, arginine allyl, histidine allyl; Basic amino acid aralkyl esters such as benzyl, arginine benzyl and histidine benzyl; (9) basic amino acid amides such as lysine amide, arginine amide and histidine amide; (10) N-α-benzoyl lysine amide, N-α-benzoyl Argininamide, N-α-benzoyl basic amino acid amide such as N-α-benzoylhistidine amide;

Of these, (1) glycine methyl, glycine ethyl, glycine propyl, glycine-t-butyl, glycine butyl, glycine isopropyl, alanine methyl, alanine ethyl, alanine propyl, alanine butyl, alanine isopropyl, Alanine-t-butyl, valine methyl, valine ethyl, valine propyl, valine butyl, valine isopropyl, valine tert-butyl, leucine methyl, leucine ethyl, leucine propyl, leucine butyl, leucine isopropyl, leucine tert-butyl, isoleucine methyl, Isoleucine ethyl, isoleucine propyl,
Isoleucine butyl, isoleucine isopropyl, isoleucine-t-tyl, phenylalanine methyl, phenylalanine ethyl, phenylalanine propyl, phenylalanine butyl, phenylalanine isopropyl,
Phenylalanine-t-butyl, tyrosinemethyl, tyrosineethyl, tyrosinepropyl, tyrosinebutyl, tyrosineisopropyl, tyrosine-t-butyl, prolinemethyl, prolineethyl, prolinepropyl, prolinebutyl, prolineisopropyl, proline-t-butyl,
Serine methyl, serine ethyl, serine propyl, serine butyl, serine isopropyl, serine-t-butyl, threonine methyl, threonine ethyl, threonine propyl, threonine butyl, threonine isopropyl, threonine t-butyl, cystine methyl, cystine ethyl, cystine propyl, cystine butyl , Cystine isopropyl, cystine-t-butyl, methionine methyl, methionine ethyl, methionine propyl, methionine butyl, methionine isopropyl, methionine-t-butyl, tryptophan methyl, tryptophan ethyl, tryptophan propyl, tryptophan butyl, tryptophan isopropyl, tryptophan-t.
(2) Glycine allyl, alanine allyl, valine allyl, leucine allyl, isoleucine allyl, phenylalanine allyl, tyrosine allyl, proline allyl, serine allyl, threonine allyl, cystine allyl, methionine allyl, tryptophan. (3) Glycine benzyl, alanine benzyl, valine benzyl, leucine benzyl, isoleucine benzyl, phenylalanine benzyl, tyrosine benzyl, proline benzyl, serine benzyl, threonine benzyl, cystine benzyl, methionine benzyl, tryptophan. Neutral amino acid aralkyl ester such as benzyl; (4) Lysine methyl, lysine ethyl, lysine propyl ,
Lysine butyl, lysine isopropyl, lysine-t-butyl, arginine methyl, arginine ethyl, arginine propyl, arginine butyl, arginine isopropyl, arginine-t-butyl, histidine methyl, histidine ethyl, histidine propyl, histidine butyl, histidine isopropyl, histidine-t. A basic amino acid alkyl ester such as butyl; (5) a neutral amino acid amide such as glycine amide, alanine amide, valine amide, leucine amide, isoleucine amide, proline amide, serine amide, threonine amide; (6) lysine allyl, arginine allyl , Basic amino acid alkenyl ester such as histidine allyl; (7) Salts such as lysine benzyl, arginine benzyl and histidine benzyl Amino acid aralkyl ester; (8) Basic amino acid amide such as lysine amide and arginine amide; (9) N such as N-α-benzoyl lysine amide, N-α-benzoyl arginine amide and N-α-benzoyl histidine amide -Α-benzoyl basic amino acid amide;

More preferably, (1) glycine methyl, glycine ethyl, glycine propyl, glycine-t-butyl, glycine butyl, glycine isopropyl, alanine methyl, alanine ethyl, alanine propyl, alanine butyl, alanine isopropyl, alanine-t. -Butyl, valine methyl, valine ethyl, valine propyl, valine butyl, valine isopropyl, valine-t-butyl, leucine methyl, leucine ethyl, leucine propyl, leucine butyl, leucine isopropyl, leucine-t-tyl, isoleucine methyl, isoleucine ethyl , Isoleucine propyl,
Isoleucine butyl, isoleucine isopropyl, isoleucine-t-butyl, serine methyl, serine ethyl,
Serine propyl, serine butyl, serine isopropyl,
Neutral amino acid alkyl esters such as serine-t-butyl, threonine methyl, threonine ethyl, threonine propyl, threonine butyl, threonine isopropyl, threonine t-butyl; (2) glycine allyl, alanine allyl, valine allyl, leucine allyl, Neutral amino acid alkenyl esters such as isoleucine allyl, phenylalanine allyl, tyrosine allyl, proline allyl, serine allyl, threonine allyl; (3) Glycine benzyl, alanine benzyl, valine benzyl, leucine benzyl, isoleucine benzyl, phenylalanine benzyl, tyrosine benzyl, proline Neutral amino acid aralkyl esters such as benzyl, serine benzyl, threonine benzyl; (4) lysine methyl, lysine ethyl, lysine Npuropiru,
Basic amino acid alkyl ester such as lysine butyl, lysine isopropyl, lysine-t-butyl, arginine methyl, arginine ethyl, arginine propyl, arginine butyl, arginine isopropyl, arginine-t-butyl; (5) glycine amide, alanine amide, valinamide Neutral amino acid amides such as, leucine amide, isoleucine amide and proline amide; (6) basic amino acid amides such as lysine amide and arginine amide; (7) N-α-benzoyl lysine amide and N-α-benzoyl Argininamide, N-α-benzoyl basic amino acid amide such as N-α-benzoylhistidine amide;

More preferably, (1) glycine methyl, glycine ethyl, alanine methyl, alanine ethyl, valine methyl, valine ethyl, leucine methyl, leucine ethyl, isoleucine methyl,
Neutral amino acid alkyl ester such as isoleucine ethyl; (2) Neutral amino acid alkenyl ester such as glycine allyl, alanine allyl, valine allyl, leucine allyl, isoleucine allyl; (3) glycine benzyl, alanine benzyl, valine benzyl, leucine Neutral amino acid aralkyl ester such as benzyl and isoleucine benzyl; (4) Basic amino acid alkyl ester such as lysine methyl, lysine ethyl, arginine methyl and arginine ethyl; (5) Glycine amide, alanine amide, valine amide, leucine amide Neutral amino acid amide; (6) Basic amino acid amide such as lysine amide and arginine amide; (7) N-α-benzoyl lysine amide and N-α-benzoyl arginine amide Such as N-α-benzoyl basic amino acid amide;

Optimally, (1) basic amino acid alkyl ester such as lysine methyl, lysine ethyl, arginine methyl and arginine ethyl; (2) basic amino acid amide such as lysine amide and arginine amide; (3) N-α- Benzoyl lysine amide, N-alpha-benzoyl basic amino acid amide such as N-alpha-benzoyl argininamide.

In the preparation of the present invention, 1) preferably, a base having one or more primary, secondary or tertiary amino groups as the dissociative amino group and no other dissociative functional group. Neutral drug, neutral amino acid alkyl ester, neutral amino acid alkenyl ester, neutral amino acid aralkyl ester, neutral amino acid amide, basic amino acid, basic amino acid alkyl ester, basic amino acid alkenyl ester, basic amino acid aralkyl ester, base Or a combination of amino acid amides or amino acid derivatives selected from one or more of N-α-benzoyl basic amino acid amides, or a combination thereof.

2) More preferably, a basic drug having one or more primary, secondary or tertiary amino groups as a dissociative amino group and no other dissociative functional group, Basic amino acid amide, basic amino acid, basic amino acid alkyl ester, basic amino acid alkenyl ester, basic amino acid aralkyl ester, basic amino acid amide, or N-α-benzoyl basic amino acid amide selected from one or more kinds. A percutaneous preparation comprising an amino acid derivative or a combination thereof.

3) Optimally, as a dissociative amino group,
A basic drug having one or more primary, secondary or tertiary amino groups and no other dissociative functional group, and a basic amino acid alkyl ester, basic amino acid amide or N-α-benzoyl basic A transdermal preparation comprising an amino acid derivative selected from one or more amino acid amides, or a combination thereof.

The basic drug and neutral amino acid alkyl ester, neutral amino acid alkenyl ester of the present invention,
Neutral amino acid aralkyl ester, neutral amino acid amide, basic amino acid, basic amino acid alkyl ester, basic amino acid alkenyl ester, basic amino acid aralkyl ester, basic amino acid amide and /
Alternatively, the ratio (weight ratio) with the N-α-benzoyl basic amino acid amide is preferably 1: 1 to 1: 200, and more preferably 1: 1 to 1:20.

The transdermal preparation of the present invention contains many external preparations, such as liquid sprays, lotions, which are expected to have a pharmacological effect by absorbing the drug when applied to the skin.
It can be used for ointments, creams, gels, sols, aerosols, poultices, plasters, tape preparations and the like.

The base used for producing the transdermal preparation of the present invention includes an oily base used in a usual external preparation, a water-soluble base, an adhesive used in a tape preparation, a support film, etc. Is mentioned. Examples of the oily base include cottonseed oil, sesame oil, vegetable oils such as olive oil, carnauba wax, waxes such as beeswax, white petrolatum, liquid paraffin, higher hydrocarbons such as plastibase, fatty acids such as stearic acid and palmitic acid, and Examples thereof include higher esters such as cetanol, higher alcohols such as cetanol, silicon fluids, and silicones such as silicone rubber. As the water-soluble base, for example, a solution or polymer hydrogel of polyvinyl alcohol, carboxyvinyl polymer, cellulose derivative, polyethylene glycol (macrogol macrophage), polyethylene glycol-polypropylene glycol copolymer, propylene glycol, 1, 3, -Butylene glycol, ethanol, glycerin and the like. Further, a surfactant may be added to the oily base and the water-soluble base to use as an emulsion base.
Examples of the adhesive include a methacrylic acid ester copolymer, a natural rubber-based adhesive, a synthetic rubber-based adhesive such as synthetic isoprene, and a silicone polymer-based adhesive. Examples of the material for the support film include polyethylene, polypropylene, polyethylene-vinyl acetate copolymer, PET, and aluminum laminate.

The formulation of the present invention comprises a surfactant (eg, polyoxyethylene sorbitan oleate), a thickener (eg, polyacrylic acid), a stabilizer (eg, ascorbine), which is usually used, if necessary. Acid, sodium pyrosulfite, EDTA), pH adjuster (eg, phosphate buffer, sodium hydroxide), preservative (eg, parabens) absorption enhancer (eg, oleic acid, isopropyl myristate, and other fatty acids and the like) Esters, phospholipids such as phosphatidylcholine, terpenes such as d-limonene, Azone (trade name, manufactured by Nelson Research)
And other azacycloalkanes).

The preparation of the present invention is prepared by a conventional method using the above-mentioned base, pressure-sensitive adhesive, supporting film and other additives added as necessary.

For example, liquid sprays, lotions,
In the case of sol and aerosol, it is obtained by simply dissolving or dispersing the above basic drug, the above amino acid derivative, and other additives in a solvent such as water, propylene glycol, 1,3-butylene glycol, ethanol or glycerin. To be

For example, in the case of ointments and creams,
It is obtained by mixing the basic drug and the amino acid derivative with the hydrophilic base, the oily base and a suitable solvent, and subjecting the mixture to emulsification with a surfactant if necessary.

For example, in the case of a poultice, plaster or tape preparation, a solution containing the above-mentioned basic drug, the above-mentioned amino acid derivative and an adhesive is coated on a supporting film and, if necessary, a crosslinking treatment or a drying operation is carried out. Is obtained by

[0051]

EXAMPLES Next, examples and test examples will be given, but the present invention is not limited thereto.

Example 1. 3.75 g of the free base of lysine methyl ester was dissolved in 5 ml of methylene chloride, and this was added dropwise to 150 g of a hexane solution containing 50% by weight of silicon adhesive in a dissolved state while stirring little by little to give a dispersion of lysine methyl ester. Prepared. Next, 2 g of fine crystals of the free base of the main ingredient ketotifen were added to hexane.
57 g were evenly dispersed, and this was added dropwise to the previously prepared lysine methyl ester dispersion while stirring. After applying this solution on an aluminum laminate film to a uniform thickness of 200 μm, gently blow hot air heated to 60 ° C to evaporate and remove the solvent methylene chloride and hexane from the application surface, Layers were formed. next,
Stick a release paper for silicone adhesive to this adhesive surface,
A film consisting of three layers of an aluminum laminate film, an adhesive layer and a release paper was obtained. Finally, this film is
It was cut into a circle of cm and used.

Comparative Example 1. 2 g of fine crystals of the free base of ketotifen, which is the main drug, were uniformly dispersed in 57 g of hexane, and this was added dropwise to 150 g of a hexane solution containing 50% by weight of a silicon adhesive in a dissolved state while stirring.
After applying this solution on an aluminum laminate film to a uniform thickness of 200 μm, gently blow off warm air heated to 60 ° C to evaporate and remove the solvent methylene chloride and hexane from the application surface, Layers were formed. Next, a release paper for a silicone adhesive was attached to this adhesive surface to obtain a film composed of three layers of an aluminum laminate film, an adhesive layer and a release paper. Finally, the film was cut into a circle having a diameter of 2 cm and used.

Example 1 thus obtained And Comparative Example 1. The formulation obtained in 1. was used to test hairless mice and humans.

Test Example 1. An in vivo test using hairless mice was carried out to evaluate the inhibitory effect of the test substance on the retention of the drug in the stratum corneum. That is,
The back of a 7-8 week-old hairless mouse was lightly washed with physiological saline and dried, and then Example 1. And Comparative Example 1. 2. A diameter made by using a flexible ethylene-vinyl acetate copolymer film for the purpose of attaching the circularly cut preparation having a diameter of 2 cm obtained in step 2 and preventing the preparation from peeling off.
A 6 cm round tape was further applied over the formulation.
After sticking, the preparation was peeled off at a predetermined time, and the remaining amount of the main drug in the preparation was measured. Then, the hairless mouse is slaughtered, and the pasted portion is immediately stripped 10 times with cellophane tape,
The content of the main drug in the stratum corneum attached to the cellophane tape was measured. After that, the skin on the applied part was peeled off, and the amount of the main drug stored in the skin was measured. On the other hand, the content of the main drug in the preparation before application is measured in advance, and the amount of the active ingredient in the preparation after application is subtracted from the value to determine the amount of disappearance from the preparation. Subcutaneous absorption of the main drug was calculated by subtracting the stored amount of the main drug.

The results are shown in Table 1.

[0057]

[Table 1] Unit: μg / cm ² Numerical values represent mean ± standard deviation.

From Table 1, Example 1. The formulation obtained in
Comparative Example 1. Compared with the preparation obtained in 1., it was absorbed faster through the skin and penetrated the skin without being stored in the corneum.

Test Example 2. The following experiment was conducted to evaluate the inhibitory effect of the test substance on the retention of the drug in the stratum corneum in humans. Two adult males were lightly washed with physiological saline on the inside of the upper arm, dried, and then cut into a circular shape with a diameter of 2 cm. Example 1. And Comparative Example 1. The above formulation was applied.
After sticking, the preparation was peeled off at a predetermined time, and the remaining amount of the main drug in the preparation was measured. Then, the attached portion was stripped 10 times with cellophane tape, and the amount of the main drug stored in the stratum corneum attached to the cellophane tape was measured. On the other hand, the content of the active ingredient in the drug product before application is measured in advance, and the amount of the active drug remaining in the drug product after application is subtracted from this value to obtain the amount lost from the drug product, and the amount of the active drug stored in the stratum corneum is stored from the amount lost. The amount of keratin penetration of the main drug was calculated by subtracting the amount.

The results are shown in Tables 2-1 and 2-2.

[0061]

[Table 2-1]

[0062]

[Table 2-2] From Table 2-1 and Table 2-2, Example 1. The preparation obtained in 1. Compared with the preparation obtained in 1., it was absorbed faster through the skin and penetrated the skin without being stored in the corneum.

[Test Example 1. And test example 2. Effect] As shown in the results of Table 1, Table 2-1, and Table 2-2, the preparation of the present invention remarkably suppressed retention of the basic drug, which is the main drug, in the stratum corneum. On the other hand, the skin permeation amount or the stratum corneum permeation amount is slightly increased by the formulation of the present invention, and as a result, of the drug amount released from the formulation, the ratio of the drug amount permeated through the skin and absorbed into the body is significantly increased. And a significant increase in bioavailability was achieved.

Test Example 3. For some amino acids, amino acid alkyl esters and amino acid amides, the effect of basic drugs to eliminate keratin accumulation in vitro.
It was evaluated in the test. As the stratum corneum, the horny stratum corneum (the back of the viper shell of the pit viper), which is said to be most suitable as a model of the human stratum corneum, is used because its structure and composition are very similar to those of the human stratum corneum. In addition, ketotifen and 3- (1-pyrrolidinyl) methyl-4- (5,6-dichloro-1-indancarbonyl) thiomorpholine were used as basic drugs, and neutral drugs such as isosorbide dinitrate and acidic drugs were used as target drugs. The effects were examined using loxoprofen and the zwitterionic drug tryptophan. About 10, 20, 40 μg / ml of drug,
And one kind of amino acid, amino acid alkyl ester or amino acid amide dissolved at a concentration of 0, 0.5, 1 or 2% 0.02M phosphate buffer of pH 7.2 20
About 50 mg of the back of the husk of the pit viper that had been cut into a size of about 1 cm × 2 cm was added to ml and incubated at 37 ° C. overnight. Thereafter, the drug concentration in the buffer solution was measured and compared with the concentration of the liquid in which the snake stratum corneum was not added, and the distribution amount of the drug to the snake stratum corneum was calculated from the difference. The amount of the drug distributed to the horny layer of the snake (per unit weight of the horny layer) is proportional to the concentration of the drug in the buffer solution after incubation, and the law of partition is established. Therefore, the partition coefficient was calculated from the following formula and compared with the concentration of the test substance added.

P (partition coefficient) = partition amount to stratum corneum / drug concentration in buffer solution. Tables 3 to 7 show the results.

[0066]

[Table 3] Storage elimination effect on ketotifen

[0067]

Table 4 3- (1-Pyrrolidinyl) methyl-4- (5,
6-Dichloro-1-indancarbonyl) thiomorpholine retention elimination effect From Tables 3 and 4, the test substance suppressed the retention of the basic drug in the stratum corneum depending on the concentration added.

[0068]

[Table 5] Storage elimination effect on isosorbide dinitrate

[0069]

[Table 6] Elimination effect of storage on loxoprofen

[0070]

[Table 7] Storage elimination effect on tryptophan From Tables 5 to 7, the test substance did not suppress the retention of the neutral drug, the acidic drug and the zwitterionic drug in the stratum corneum, regardless of the concentration added.

[Test Example 3. Effect] As shown in the results of Tables 3 and 4, it was revealed that the test substances markedly suppressed the distribution of the basic drug to the stratum corneum. On the other hand, as shown in the results of Tables 5 to 7, neutral drugs, acidic drugs, and zwitterionic drugs have very low distributivity to the stratum corneum as compared with basic drugs, and the test substance is It was clarified that it did not affect the distributive property of corn to the stratum corneum.

[0072]

INDUSTRIAL APPLICABILITY The preparation of the present invention is a useful preparation that eliminates the retention of a basic drug in the stratum corneum and enhances the transdermal absorbability of the drug.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location A61K 9/70 364 31/495 31/535 47/16 E C07D 241/04 265/30 279/12 413/06 207 417/06 207 307 333 (72) Inventor Kengo Ogawa 1-258 Hiromachi, Shinagawa-ku, Tokyo Sankyo Stock Company

Claims (10)

[Claims] 1. A basic drug and 2) a neutral amino acid alkyl ester, a neutral amino acid alkenyl ester, a neutral amino acid aralkyl ester, a neutral amino acid amide, a basic amino acid, a basic amino acid alkyl ester, a basic amino acid. Transdermal comprising an alkenyl ester, basic amino acid aralkyl ester, basic amino acid amide, amino acid or amino acid derivative selected from one or more of N-α-benzoyl basic amino acid amide, or a combination thereof. Dosage formulation 2. The method according to claim 1, wherein the basic drug has one or more primary, secondary or tertiary amino groups as a dissociative amino group, and no other dissociative functional group. Transdermal preparations that are basic drugs. 3. In [claim 1] or [claim 2], 1) having one or more primary, secondary or tertiary amino groups as a dissociative amino group, and other dissociative functional groups. 2) neutral amino acid alkyl ester, neutral amino acid alkenyl ester, neutral amino acid aralkyl ester, neutral amino acid amide, basic amino acid, basic amino acid alkyl ester, basic amino acid alkenyl ester, A transdermal preparation comprising an amino acid or an amino acid derivative selected from one or more of basic amino acid aralkyl ester, basic amino acid amide or N-α-benzoyl basic amino acid amide, or a combination thereof. 4. In [claim 1], [claim 2] or [claim 3], 1) as a dissociative amino group, a primary,
A basic drug having one or more secondary or tertiary amino groups and no other dissociative functional group, and 2) neutral amino acid amide, basic amino acid, basic amino acid alkyl ester, basic amino acid A transdermal preparation comprising an alkenyl ester, a basic amino acid aralkyl ester, a basic amino acid amide or an amino acid derivative selected from one or more kinds of N-α-benzoyl basic amino acid amides, or a combination thereof. . 5. In [Claim 1], [Claim 2], [Claim 3] or [Claim 4], 1) a primary, secondary or tertiary amino group is used as the dissociative amino group. One or more basic drugs having one or a plurality thereof and no other dissociative functional group, and 2) basic amino acid alkyl ester, basic amino acid amide or N-α-benzoyl basic amino acid amide A transdermal preparation comprising an amino acid derivative selected from, or a combination thereof. 6. In [Claim 1], [Claim 2], [Claim 3], [Claim 4] or [Claim 5], 1).
A transdermal preparation in which the ratio (weight ratio) of the basic drug to the 2) amino acid or amino acid derivative is 1: 1 to 1: 200. 7. [Claim 1], [Claim 2], [Claim 3], [Claim 4], [Claim 5] or [Claim 6].
In 1), the ratio (weight ratio) of 1) the basic drug and 2) the amino acid or the amino acid derivative is 1: 1 to 1:
A preparation for transdermal administration which is 20. 8. [Claim 1], [Claim 2], [Claim 3], [Claim 4], [Claim 5], [Claim 6] or [Claim 7] is basic. The drug has the general formula: (In the formula, the ring A may be the same or different and may be substituted with a halogen atom, a lower alkyl group, an aryl group, an acyl group, a lower alkoxy group, a lower alkylthio group, a nitro group, a trifluoromethyl group or a hydroxyl group. Represents an aromatic ring or a heterocycle, R ₁ and R ₂ are the same or different and each represent a hydrogen atom, a lower alkyl group or a cyclic amino group formed by bonding with a nitrogen atom, and R ₃ represents a hydrogen atom or a lower alkyl group. Represents, Y represents two hydrogen atoms or oxygen atoms, m represents 1 or 2, n represents 0, 1
Or 2 and Z represents an oxygen atom, a sulfur atom, or an imino group optionally having a lower alkyl group or an aralkyl group as a substituent. ) A percutaneous preparation which is a carboxylic acid amide compound or a pharmaceutically acceptable acid addition salt thereof. 9. [Claim 1], [Claim 2], [Claim 3], [Claim 4], [Claim 5], [Claim 6],
In [Claim 7] or [Claim 8], the basic drug is represented by the general formula: (In the formula, ring A is a benzene ring or a thiophene ring having a halogen atom or an alkyl group having 1 to 2 carbon atoms as a substituent, and the formula -N (R ₁ ) (R ₂ ) group has 1 carbon atoms.
To 2 dialkylamino groups, 1-pyrrolidinyl group or piperidino group, R ₃ is a hydrogen atom, Y is 2 hydrogen atoms or oxygen atoms, and n is 0 or 1
And Z represents a sulfur atom. ) A percutaneous preparation which is a carboxylic acid amide compound or a pharmaceutically acceptable acid addition salt thereof. 10. [Claim 1], [Claim 2], [Claim 3], [Claim 4], [Claim 5], [Claim 6],
In [Claim 7], [Claim 8] or [Claim 9], the basic drug is ketotifen or 3- (1-pyrrolidinyl) methyl-4- (5,6-dichloro-1-indancarbonyl) thiomorpholine. A transdermal formulation.